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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Barth Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/07/09" /><meta name="citation_author" content="Carlos Ferreira" /><meta name="citation_author" content="Germaine Pierre" /><meta name="citation_author" content="Reid Thompson" /><meta name="citation_author" content="Hilary Vernon" /><meta name="citation_pmid" content="25299040" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK247162/" /><meta name="citation_keywords" content="Tafazzin" /><meta name="citation_keywords" content="TAFAZZIN" /><meta name="citation_keywords" content="Barth Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Barth Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Carlos Ferreira" /><meta name="DC.Contributor" content="Germaine Pierre" /><meta name="DC.Contributor" content="Reid Thompson" /><meta name="DC.Contributor" content="Hilary Vernon" /><meta name="DC.Date" content="2020/07/09" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK247162/" /><meta name="description" content="Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies." /><meta name="og:title" content="Barth Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK247162_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK247162_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/bbs/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/bws/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK247162_"><span class="title" itemprop="name">Barth Syndrome</span></h1><p class="contrib-group"><span itemprop="author">Carlos Ferreira</span>, MD, <span itemprop="author">Germaine Pierre</span>, MBBS, MRCPCH, MSc, <span itemprop="author">Reid Thompson</span>, MD, and <span itemprop="author">Hilary Vernon</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK247162_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK247162_ai__"><div class="contrib half_rhythm"><span itemprop="author">Carlos Ferreira</span>, MD<div class="affiliation small">Head, Skeletal Genomics Unit<br />Medical Genomics and Metabolic Genetics Branch<br />National Human Genome Research Institute<br />National Institutes of Health<br />Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.liam@rcarierref" class="oemail">vog.hin.liam@rcarierref</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Germaine Pierre</span>, MBBS, MRCPCH, MSc<div class="affiliation small">Pediatric Metabolic Consultant<br />Bristol Royal Hospital for Children<br />Bristol, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.shn.lotsirbhu@erreip.eniamreg" class="oemail">ku.shn.lotsirbhu@erreip.eniamreg</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Reid Thompson</span>, MD<div class="affiliation small">Associate Professor, Pediatric Cardiology<br />Johns Hopkins University<br />Baltimore, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.imhj@nospmoht" class="oemail">ude.imhj@nospmoht</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Hilary Vernon</span>, MD, PhD<div class="affiliation small">Associate Professor<br />Department of Genetic Medicine<br />Johns Hopkins University<br />Baltimore, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.imhj@1nonrevh" class="oemail">ude.imhj@1nonrevh</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">October 9, 2014</span>; Last Update: <span itemprop="dateModified">July 9, 2020</span>.</p><p><em>Estimated reading time: 43 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="barth.Abstract" itemprop="description"><h2 id="_barth_Abstract_">Abstract</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal <a class="def" href="/books/n/gene/glossary/def-item/karyotype/">karyotype</a> are asymptomatic and have normal biochemical studies.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Barth syndrome is established in a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with either an increased monolysocardiolipin:cardiolipin ratio (if available) or a <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>TAFAZZIN</i> (formerly <i>TAZ</i>) identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>. The diagnosis of Barth syndrome is usually established in a female proband with suggestive clinical findings and a <i>TAFAZZIN</i> pathogenic variant identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Standard treatment of heart failure including careful fluid and volume management and avoidance of overdiuresis and dehydration, standard heart failure medications to improve symptoms, and cardiac transplantation when heart failure is severe and intractable; consideration of antiarrhythmic medications or implantable cardiac defibrillator for cardiac arrhythmia; granulocyte colony-stimulating factor for neutropenia; physical therapy for skeletal muscle weakness; standard treatment for talipes equinovarus and/or scoliosis; feeding therapy and consideration of gastrostomy tube for persistent feeding issues; uncooked cornstarch prior to bedtime for hypoglycemia; standard treatment for developmental delay / intellectual disability.</p><p><i>Prevention of secondary complications:</i> Aspirin therapy for prevention of clot formation in those with severe cardiac dysfunction and/or marked left ventricular noncompaction; antibiotic prophylaxis to prevent recurrent infections; limiting fasting or providing intravenous glucose infusion prior to planned procedures; regular monitoring of potassium levels during administration of IV fluids that contain potassium and during episodes of diarrhea; consultation with a nutritionist and/or gastroenterologist to determine optimal caloric delivery.</p><p><i>Surveillance:</i> At least annual electrocardiography with Holter monitor and echocardiography; electrophysiologic study to assess for potentially serious arrhythmia as needed; complete blood count with differential with all febrile episodes and at least semiannually; measurement of height and weight, clinical assessment of strength and for scoliosis, and assessment of developmental progress and educational needs at each visit; formal developmental assessments every three to five years during childhood.</p><p><i>Agents/circumstances to avoid:</i> Prolonged fasting, use of rectal thermometers in those with neutropenia, and use of succinylcholine. Growth hormone is typically discouraged unless growth hormone deficiency is conclusively established, as the majority of affected males will attain normal stature by adulthood. The muscular involvement in Barth syndrome may increase the risk for malignant hyperthermia compared to the general population.</p><p><i>Evaluations of relatives at risk:</i> It is appropriate to evaluate the older and younger brothers of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.</p><p><i>Pregnancy management:</i> Pregnancies of male fetuses known to have Barth syndrome should be managed by a high-risk maternal fetal obstetrician; there are no specific recommendations regarding mode, timing, or location of delivery.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Barth syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> manner. If a mother has a <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the chance of transmitting it in each pregnancy is 50%. Males who inherit the <i>TAFAZZIN</i> pathogenic variant will be affected; females who inherit the <i>TAFAZZIN</i> pathogenic variant are typically not affected. Affected males pass the <i>TAFAZZIN</i> pathogenic variant to all of their daughters and none of their sons. Testing for at-risk female relatives and <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk are possible if the <i>TAFAZZIN</i> pathogenic variant has been identified in an affected family member.</p></div></div><div id="barth.Diagnosis"><h2 id="_barth_Diagnosis_">Diagnosis</h2><p>Formal clinical diagnostic criteria for Barth syndrome have not been established.</p><div id="barth.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Barth syndrome is an <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> condition in which <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> females typically do not express clinical or biochemical features, although rare instances of affected females have been reported.</p><p>Barth syndrome <b>should be suspected</b> in an individual (typically a male) with the following clinical features, supportive laboratory findings, and family history.</p><p>
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<b>Clinical features</b>
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</p><ul><li class="half_rhythm"><div>At least one of the following cardiac findings:</div><ul><li class="half_rhythm"><div>Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium</div></li><li class="half_rhythm"><div>Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity</div></li><li class="half_rhythm"><div>Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness</div></li></ul></li><li class="half_rhythm"><div>Skeletal myopathy or hypotonia</div></li><li class="half_rhythm"><div>Prepubertal growth delay</div></li><li class="half_rhythm"><div>Typical <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> findings in infants and toddlers including round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes</div></li></ul><p>
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<b>Supportive laboratory findings</b>
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</p><ul><li class="half_rhythm"><div>Lactic acidosis (normal: 0.5-2.2 mmol/L)</div></li><li class="half_rhythm"><div>Hypocholesterolemia (total cholesterol <110 mg/dL)</div></li><li class="half_rhythm"><div>Neutropenia (absolute neutrophil count <1,500 cells/µL)</div></li><li class="half_rhythm"><div>Elevated 3-methylglutaric acid, 3-methylglutaconic acid (3-MGC), and 2-ethylhydracrylic acid on <b>urine organic acids</b> analysis</div><ul><li class="half_rhythm"><div>3-MGC is typically increased five- to 20-fold [<a class="bk_pop" href="#barth.REF.clarke.2013.23">Clarke et al 2013</a>] with an average value of 44.6±25 SD µg/mg Cr (see <a href="/books/NBK247162/table/barth.T.urine_and_plasma_organic_acid_le/?report=objectonly" target="object" rid-ob="figobbarthTurineandplasmaorganicacidle">Table 1</a>).</div></li><li class="half_rhythm"><div>Note: Urinary 3-MGC levels can be normal on single sample testing [<a class="bk_pop" href="#barth.REF.takeda.2011.1481">Takeda et al 2011</a>], and may be normal for the first six to 18 months of life [<a class="bk_pop" href="#barth.REF.baban.2020.64">Baban et al 2020</a>].</div></li></ul></li><li class="half_rhythm"><div>Increased <b>monolysocardiolipin:cardiolipin ratio is a pathognomonic biochemical finding.</b> Since the protein that is deficient in Barth syndrome is responsible for cardiolipin remodeling within the inner mitochondrial membrane, affected individuals have (in a variety of tissues):</div><ul><li class="half_rhythm"><div>Increased monolysocardiolipins;</div></li><li class="half_rhythm"><div>Decreased cardiolipin (specifically tetralinoleylcardiolipin).</div></li></ul></li></ul><div id="barth.T.urine_and_plasma_organic_acid_le" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Urine and Plasma Organic Acid Levels in Barth Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.urine_and_plasma_organic_acid_le/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.urine_and_plasma_organic_acid_le_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_1" style="text-align:left;vertical-align:middle;">Organic Acid</th><th id="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">In Urine (μg/mg Cr)</th><th id="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">In Plasma (nmol/L)</th></tr><tr><th headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2" id="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Barth Syndrome</th><th headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2" id="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Control</th><th headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3" id="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Barth Syndrome</th><th headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3" id="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Control</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3-methylglutaconic acid</td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Avg: 44.6±25 (SD) <sup>1</sup><br />↑ 5- to 20-fold <sup>2</sup></td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-2 yrs: 6.6±2.4<br />2-12 yrs: 5.3±2.4<br />Adult: 3.7±1.8</td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1,088±435<br />(range: 393-2326) <sup>1</sup></td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">162±68</td></tr><tr><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3-methylglutaric acid</td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderately ↑ <sup>3</sup></td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2-ethylhydracrylic acid</td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderately ↑ <sup>3</sup><br />14.4±10 <sup>1</sup></td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_2 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Trace</td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_1_3 hd_h_barth.T.urine_and_plasma_organic_acid_le_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="barth.TF.1.1"><p class="no_margin">
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<a class="bk_pop" href="#barth.REF.vernon.2013">Vernon et al [2013]</a>
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</p></div></dd><dt>2. </dt><dd><div id="barth.TF.1.2"><p class="no_margin">
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<a class="bk_pop" href="#barth.REF.clarke.2013.23">Clarke et al [2013]</a>
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</p></div></dd><dt>3. </dt><dd><div id="barth.TF.1.3"><p class="no_margin">
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<a class="bk_pop" href="#barth.REF.kelley.1991.738">Kelley et al [1991]</a>
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</p></div></dd></dl></div></div></div><p><b>Family history</b> is consistent with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> inheritance including recurrent pregnancy loss involving male fetuses [<a class="bk_pop" href="#barth.REF.steward.2010.970">Steward et al 2010</a>]. Note: Absence of a known family history of Barth syndrome or recurrent pregnancy loss involving male fetuses does not preclude the diagnosis.</p></div><div id="barth.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p><b>Male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The diagnosis of Barth syndrome <b>is established</b> in a male proband with either an increased monolysocardiolipin:cardiolipin ratio (if available) or a <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>TAFAZZIN</i> (formerly <i>TAZ</i>) identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK247162/table/barth.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobbarthTmoleculargenetictestingusedi">Table 2</a>).</p><p><b>Female <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The diagnosis of Barth syndrome <b>is usually established</b> in a female proband with suggestive clinical findings and a <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK247162/table/barth.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobbarthTmoleculargenetictestingusedi">Table 2</a>).</p><p>Note: (1) Females with a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>TAFAZZIN</i> typically do not express clinical or biochemical features of Barth syndrome (see Clinical Description, <a href="#barth.Female_Heterozygotes">Female Heterozygotes</a>). (2) In the rare cases where a female has presented with clinical features of Barth syndrome there has been an additional scientific explanation (i.e., ring X <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a>) or unfavorably skewed X inactivation. Theoretically, a female with 45,X or another structural X-chromosome anomaly may also be symptomatic.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of Barth syndrome is broad, individuals with the distinctive findings described in <a href="#barth.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#barth.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with cardiomyopathy and/or hypotonia are more likely to be diagnosed using genomic testing (see <a href="#barth.Option_2">Option 2</a>).</p><div id="barth.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of Barth syndrome, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>TAFAZZIN</i> is performed first to detect small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-gene deletions/duplications may not be detected, particularly in females. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect exon and whole-gene deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A cardiomyopathy</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>TAFAZZIN</i> and other genes of interest (see <a href="#barth.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see <a href="/books/NBK247162/table/barth.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobbarthTmoleculargenetictestingusedi">Table 2</a>).</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="barth.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from many other inherited disorders characterized by cardiomyopathy and/or hypotonia, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>If <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> is not diagnostic, <b><a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a></b> (when clinically available) may be considered to detect (multi)<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications that cannot be detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="barth.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Barth Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;"><i>TAFAZZIN</i> (formerly <i>TAZ</i>)</td><td headers="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~92%-93% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:top;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>6</sup></td><td headers="hd_h_barth.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~7%-8% <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="barth.TF.2.1"><p class="no_margin">See <a href="/books/NBK247162/#barth.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="barth.TF.2.2"><p class="no_margin">See <a href="#barth.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="barth.TF.2.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="barth.TF.2.4"><p class="no_margin">Based on <a class="bk_pop" href="#barth.REF.stenson.2020.1197">Stenson et al [2020]</a> and <a href="https://www.barthsyndrome.org/research/taffazindatabase.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Human Tafazzin Gene Mutation & Variation Database</a> (accessed 10-25-22)</p></div></dd><dt>5. </dt><dd><div id="barth.TF.2.5"><p class="no_margin">A synonymous variant in <i>TAFAZZIN</i>, <a href="/books/NBK247162/table/barth.T.notable_tafazzin_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobbarthTnotabletafazzinpathogenicvari">c.348C>T (p.Gly116=)</a>, was shown to cause <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> skipping and determined to be causative for Barth syndrome in one person [<a class="bk_pop" href="#barth.REF.ferri.2016.461">Ferri et al 2016</a>].</p></div></dd><dt>6. </dt><dd><div id="barth.TF.2.6"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd></dl></div></div></div></div></div></div><div id="barth.Clinical_Characteristics"><h2 id="_barth_Clinical_Characteristics_">Clinical Characteristics</h2><div id="barth.Clinical_Description"><h3>Clinical Description</h3><div id="barth.Affected_Males"><h4>Affected Males</h4><p>To date, more than 200 individuals with Barth syndrome have been identified [<a class="bk_pop" href="#barth.REF.miller.2020.139">Miller et al 2020</a>]. The vast majority of affected individuals are male (see <a href="#barth.Female_Heterozygotes">Female Heterozygotes</a>). The following description of the phenotypic features associated with this condition is based on these reports.</p><div id="barth.T.select_features_of_barth_syndrom" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Select Features of Barth Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.select_features_of_barth_syndrom/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.select_features_of_barth_syndrom_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature <sup>1</sup></th><th id="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skeletal myopathy</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">97%</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6MWT is abnormal in almost all individuals.</td></tr><tr><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy <sup>2</sup></td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">73%</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dilated cardiomyopathy is most common. <sup>2</sup></td></tr><tr><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neutropenia</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70%-85%</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prepubertal growth delay</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">58% <sup>3</sup></td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prolonged QTc</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25%-43%</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Arrhythmia</td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-20% <sup>4</sup></td><td headers="hd_h_barth.T.select_features_of_barth_syndrom_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">6MWT = distance walked on six-minute walk test</p></div></dd><dt>1. </dt><dd><div id="barth.TF.3.1"><p class="no_margin">The vast majority of affected individuals are male.</p></div></dd><dt>2. </dt><dd><div id="barth.TF.3.2"><p class="no_margin">At presentation</p></div></dd><dt>3. </dt><dd><div id="barth.TF.3.3"><p class="no_margin">
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<a class="bk_pop" href="#barth.REF.spencer.2006.e337">Spencer et al [2006]</a>
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</p></div></dd><dt>4. </dt><dd><div id="barth.TF.3.4"><p class="no_margin">Based on the study by <a class="bk_pop" href="#barth.REF.kang.2016.167">Kang et al [2016]</a> and <a class="bk_pop" href="#barth.REF.spencer.2006.e337">Spencer et al [2006]</a></p></div></dd></dl></div></div></div><p>Most affected individuals with Barth syndrome are male and present in infancy with cardiac issues, specifically dilated cardiomyopathy. In a French study of 22 males with Barth syndrome from 16 families, the median age at which medical care was first sought was 3.1 weeks (range: 0-1.4 years) [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</p><p>In another study of 73 males enrolled in the Barth Syndrome Registry, the age of onset was 0.76±1.6 years and the mean age at diagnosis was 4.04±5.45 years [<a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al 2012</a>]. Therefore, there is on average a three-year delay between presentation and diagnosis of Barth syndrome. Cardiomyopathy was the presenting manifestation in 73% and infection was the presenting manifestation in 18%.</p><p><b>Cardiomyopathy</b> in Barth syndrome is usually dilated but can also have features of combined dilated and hypertrophic cardiomyopathy, or <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> hypertrophic cardiomyopathy. Left ventricular noncompaction is also seen in many affected males.</p><p>The cardiomyopathy characteristically follows an undulating course in which the cardiac tissue can undergo remodeling, including a transition between hypertrophic and dilated appearances.</p><p>Cardiomyopathy almost always presents before age five years [<a class="bk_pop" href="#barth.REF.clarke.2013.23">Clarke et al 2013</a>]. In many affected individuals the cardiomyopathy improves and in some it stabilizes after the toddler years. In the study by <a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al [2013]</a>, left ventricular size and mass increased during the first six months of life, then decreased until age two years, and then appeared to stabilize. However, data in this study were insufficient to characterize these parameters in older children.</p><p>In a study by <a class="bk_pop" href="#barth.REF.kang.2016.167">Kang et al [2016]</a> of 27 individuals with Barth syndrome followed in the United Kingdom, those with normal left ventricular size and function had abnormalities of longitudinal and circumferential strain and reduced apical rotation. This finding led to the suggestion that cardiac medications be continued as long as functional or mechanical abnormalities persist.</p><p><b>Heart failure</b> is a significant cause of morbidity and mortality; however, overall cardiac function varies greatly in individuals with Barth syndrome. <a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al [2012]</a> noted that there may be a trend toward decline in cardiac function over time, as data from the Barth Syndrome Registry showed that for each five-year increase in age, ejection fraction z-score decreases on average by 0.6.</p><p>In the study by <a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al [2013]</a>, out of 54 total hospitalizations for heart failure, 11 were due to worsening of heart failure attributed to infections. In this cohort, nine died from heart failure and two from sepsis. Median age of death was 5.1 months (range: 1.2-30.7 months). In the study by <a class="bk_pop" href="#barth.REF.kang.2016.167">Kang et al [2016]</a> of 27 people with Barth syndrome followed in the United Kingdom, seven underwent cardiac transplantation at a median age of two years, and five died at a median age of 1.8 years. All deaths were reported to be due to cardiomyopathy or the side effects of its management.</p><p>The response to medical therapy for cardiac failure is generally good. <a class="bk_pop" href="#barth.REF.spencer.2006.e337">Spencer et al [2006]</a> observed that with standard cardiac medications for dilated cardiomyopathy more than 16/30 affected males had normal ejection fraction and left ventricular diastolic volume. However, some responded to therapy initially but deteriorated after a period of stability, requiring cardiac transplantation [<a class="bk_pop" href="#barth.REF.adwani.1997.143">Adwani et al 1997</a>, <a class="bk_pop" href="#barth.REF.mangat.2007.327">Mangat et al 2007</a>].</p><p><b>Arrhythmia.</b> The risk for arrhythmia (including supraventricular and ventricular tachycardia) and sudden death is increased. While arrhythmia has been most often reported in adolescents and young adults, it can occur in children of all ages. EKG abnormalities can include repolarization abnormalities and prolonged QTc intervals.</p><p>All 20 affected males with EKGs in the French cohort had a normal sinus rhythm. Repolarization abnormalities (including ST flattening and T-wave inversion) were seen in 17. Five had QTc values within the normal range (QTc <420 ms), and five had QTc greater than 460 ms. The median QTc was 440 ms (range: 360-530 ms). In the study by <a class="bk_pop" href="#barth.REF.kang.2016.167">Kang et al [2016]</a>, nine of 21 affected individuals had prolonged QTc of greater than 460 ms and three had borderline QTc prolongation between 450 and 460 ms.</p><p>In five instances of ventricular arrhythmia leading to cardiac arrest or placement of an internal defibrillator [<a class="bk_pop" href="#barth.REF.spencer.2005.632">Spencer et al 2005</a>]:</p><ul><li class="half_rhythm"><div>All five individuals had normal QTc intervals;</div></li><li class="half_rhythm"><div>All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability;</div></li><li class="half_rhythm"><div>Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest;</div></li><li class="half_rhythm"><div>Three showed inducible ventricular arrhythmias on electrophysiologic testing;</div></li><li class="half_rhythm"><div>Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> predicted increased risk for arrhythmia;</div></li><li class="half_rhythm"><div>One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates;</div></li><li class="half_rhythm"><div>One had both ventricular and supraventricular tachycardia.</div></li></ul><p>In the study by <a class="bk_pop" href="#barth.REF.kang.2016.167">Kang et al [2016]</a>, 42 Holter recordings were performed in 16 affected individuals, and none had sustained tachyarrhythmia. Two had loop recorder implantation and brief atrial tachycardia was identified in one. One affected individual was noted to have broad complex tachycardia lasting five beats during an echocardiogram, correlating with symptoms.</p><p><b>Neutropenia and infections.</b> In the Barth Syndrome Registry study, self-reported data revealed that neutropenia * was present in 69.1% at some point, a number similar to that from the French study, in which 16 of 22 males had a median absolute neutrophil count (ANC) of fewer than 500 cells/µL at least once.</p><ul><li class="half_rhythm"><div>In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [<a class="bk_pop" href="#barth.REF.dale.2013">Dale et al 2013</a>].</div></li><li class="half_rhythm"><div>These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>]. In both studies, the ANC fluctuated, but without detectable periodicity.</div></li><li class="half_rhythm"><div>In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [<a class="bk_pop" href="#barth.REF.steward.2019.6">Steward et al 2019</a>].</div></li></ul><p>* Defined as follows:</p><ul><li class="half_rhythm"><div>Mild neutropenia: ANC between 1,000 and 1,500 cells/µL</div></li><li class="half_rhythm"><div>Moderate neutropenia: ANC between 500 and 1,000 cells/µL</div></li><li class="half_rhythm"><div>Severe neutropenia: ANC below 500 cells/µL</div></li></ul><p>In the original description of the syndrome by <a class="bk_pop" href="#barth.REF.barth.1983.327">Barth et al [1983]</a> three of seven males with a known cause of death died from infection; however, such high mortality from infection was not observed in subsequent publications. In fact, the effects of neutropenia are more often limited to mild involvement, such as persistent oral infections [<a class="bk_pop" href="#barth.REF.barth.1999.273">Barth et al 1999</a>]. However, significant complications can occur. A recent review of the UK NHS Barth Syndrome Service documented infections in 35 affected individuals prior to the introduction of G-CSF therapy: two had complications of acute tubular necrosis secondary to streptococcal septicemia; one developed renal failure requiring transplant due to haemophilus septicemia; two had osteomyelitis; one had septic arthritis; three had soft tissue abscesses; five had cellulitis; two had balanitis; four had lobar consolidation/pneumonia; two had gingivitis; and one had a urinary tract infection [<a class="bk_pop" href="#barth.REF.steward.2019.6">Steward et al 2019</a>]. In the more recent Barth Syndrome Registry study, 60.2% of affected males had mouth ulcers, 28% had pneumonia, and 10% had blood infections.</p><p>This relatively low incidence of bacterial infections despite an ANC persistently below 1,000 cells/µL could be due to the development of a chronic, substantial monocytosis [<a class="bk_pop" href="#barth.REF.kelley.2002">Kelley 2002</a>], which has been reported in two studies:</p><ul><li class="half_rhythm"><div>In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL)</div></li><li class="half_rhythm"><div><a class="bk_pop" href="#barth.REF.vernon.2014.143">Vernon et al [2014]</a> reported an average AMC of 894±449 cells/µL (range: 500-2,400 cells/µL), with five of 17 affected males having monocyte counts at or above 1,000 cells/µL.</div></li><li class="half_rhythm"><div>In a report of 88 individuals with Barth syndrome [<a class="bk_pop" href="#barth.REF.steward.2019.6">Steward et al 2019</a>], monocyte counts greater than 1,000 cells/µL were observed at least once in 75%.</div></li></ul><p>Of note, hematologic parameters neither worsen nor improve with age [<a class="bk_pop" href="#barth.REF.dale.2013">Dale et al 2013</a>]. Patterns of neutropenia seen in people with Barth syndrome can vary between intermittent and unpredictable, chronic and severe, or cyclical with a predictable pattern [<a class="bk_pop" href="#barth.REF.steward.2019.6">Steward et al 2019</a>].</p><p><b>Skeletal myopathy,</b> which predominantly affects the proximal muscles, is non-progressive during childhood [<a class="bk_pop" href="#barth.REF.clarke.2013.23">Clarke et al 2013</a>]. Frequently, affected children are diagnosed with hypotonia.</p><ul><li class="half_rhythm"><div>In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives.</div></li><li class="half_rhythm"><div>In the French study the median age for walking was 19 months (range: 12-24 months).</div></li></ul><p>Some males with Barth syndrome were born with talipes equinovarus, indicating a possible prenatal onset of hypotonia [<a class="bk_pop" href="#barth.REF.ad_s.1993.327">Adès et al 1993</a>, <a class="bk_pop" href="#barth.REF.gedeon.1995.383">Gedeon et al 1995</a>].</p><p>Of note, the exercise intolerance seen in males with Barth syndrome is due to both cardiac impairment and decreased skeletal muscle oxygen utilization [<a class="bk_pop" href="#barth.REF.spencer.2011.h2122">Spencer et al 2011</a>].</p><p>In a study of individuals with Barth syndrome, six-minute walk test (6MWT) distance was abnormal in 33/34 individuals compared to controls [<a class="bk_pop" href="#barth.REF.thompson.2016.1001">Thompson et al 2016</a>]. In a study of functional exercise capacity and strength in 31 individuals with Barth syndrome [<a class="bk_pop" href="#barth.REF.hornby.2019.37">Hornby et al 2019</a>], participants with Barth syndrome demonstrated abnormal 6MWT, increased five times sit-to-stand time (5XSST), and decreased knee extensor strength compared to controls.</p><p><b>Growth delay.</b> Between ages six and 36 months the 50th percentile for length for boys with Barth syndrome is roughly equivalent to the third percentile in the standard curve; between ages 27 and 36 months, the 50th percentile for weight is roughly equal to the third percentile in the standard curve [<a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al 2012</a>].</p><ul><li class="half_rhythm"><div><a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al [2012]</a> published specific growth curves for boys with Barth syndrome [<a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al 2012</a>; see <a href="https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.35609/epdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Figure 1a-d</a>].</div></li><li class="half_rhythm"><div><a class="bk_pop" href="#barth.REF.spencer.2006.e337">Spencer et al [2006]</a> found that males with Barth syndrome show a delayed post-pubertal growth spurt with remarkable "catch-up" growth.</div></li></ul><p>In males younger than age 18 years:</p><ul><li class="half_rhythm"><div>Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile.</div></li><li class="half_rhythm"><div>Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%.</div></li></ul><p>In males older than age 18 years, mean weight was in the 13th percentile (range: <1-63) and mean height in the 50th percentile (range: 8-90).</p><p><b>Dysmorphology.</b> Younger males with Barth syndrome have a characteristic facial gestalt that is most evident during infancy, characterized by a tall and broad forehead, round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes. This appearance persists through childhood, becoming less obvious following puberty. The ears tend to remain prominent and the eyes deep-set.</p><p>At this point and after the late pubertal period of "catch-up" growth the most striking feature is that of gynoid fat distribution [<a class="bk_pop" href="#barth.REF.hastings.2009.185">Hastings et al 2009</a>].</p><p><b>Intellectual development.</b> Cognition in boys with Barth syndrome is characterized by age-appropriate vocabulary and basic reading skills, but a below-average performance in mathematics and selective difficulties in visuospatial skills that are not due to impaired motor functioning from myopathy [<a class="bk_pop" href="#barth.REF.mazzocco.2007.22">Mazzocco et al 2007</a>]. Math difficulties are not evident in preschool but appear to emerge in kindergarten [<a class="bk_pop" href="#barth.REF.raches.2012.328">Raches & Mazzocco 2012</a>].</p><p>In the Barth Syndrome Registry study, 30 of 60 males older than age three years reported delay either in first words or in putting words together; 31 of 67 participated in speech therapy. Twenty-two of 46 males older than age seven years reported some form of "learning disability."</p><p><b>Sensory issues</b> related to feeding and eating are common, and many affected males have a strong preference for salty, cheesy, and spicy foods while having an overall restricted repertoire of foods. Some issues such as a strong gag reflex manifest early in development [<a class="bk_pop" href="#barth.REF.reynolds.2012.1647">Reynolds et al 2012</a>].</p><p><b>Psychosocial functioning.</b> Boys with Barth syndrome experience lower quality of life than both healthy controls and boys with cardiac disease alone [<a class="bk_pop" href="#barth.REF.storch.2009.137">Storch et al 2009</a>]. Nine of 34 children were being monitored by a school psychologist, and eight of 34 children had close contact with a school counselor.</p><p><b>Acute decompensation.</b> An acute metabolic presentation with metabolic acidosis, elevated plasma lactate, elevated transaminases, hypoglycemia, and hyperammonemia has been reported [<a class="bk_pop" href="#barth.REF.donati.2006.684">Donati et al 2006</a>]. Of note, this presentation has been described even in the setting of largely preserved cardiac function [<a class="bk_pop" href="#barth.REF.yen.2008.941">Yen et al 2008</a>, <a class="bk_pop" href="#barth.REF.steward.2010.970">Steward et al 2010</a>]. All four males reported to date with this metabolic presentation had onset of symptoms during the neonatal period (between days 1 and 13). Their subsequent course is not known to differ from that of other males with Barth syndrome.</p><p><b>Other.</b> Based on data collected by the Barth Syndrome Registry study, other observed findings were:</p><ul><li class="half_rhythm"><div>Delayed bone age (in 58%);</div></li><li class="half_rhythm"><div>Scoliosis (in 20%);</div></li><li class="half_rhythm"><div>Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals).</div></li></ul><p><b>Perinatal.</b> In 19 families with Barth syndrome, <a class="bk_pop" href="#barth.REF.steward.2010.970">Steward et al [2010]</a> found that six had serious perinatal issues including male fetal loss, nine stillbirths, and severe neonatal illness or death. The authors noted that Barth syndrome may be an under-recognized cause of male fetal loss. Others have described characteristic cardiac pathology of Barth syndrome (endocardial fibroelastosis and subendocardial vacuolization of myocytes) as early as 18 weeks' gestation [<a class="bk_pop" href="#barth.REF.brady.2006.462">Brady et al 2006</a>].</p><p>In the Barth Syndrome Registry study, preterm birth from 29 to 36 weeks occurred in nine of 65 males; birth weight was below 2.5 kg in nine of 48 males.</p><p>In the French study, median birth weight was 2.77 kg (range: 2.18-3.73 kg) and seven of 22 males had severe intrauterine growth restriction with birth weight below the third percentile.</p><p><b>Prognosis.</b> The two factors that correlate with survival are severe neutropenia at the time of diagnosis and birth year (before 2000 or in/after 2000) [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</p><ul><li class="half_rhythm"><div>Males with an ANC <500 cells/µL at the time of diagnosis have a one-year survival rate of 25% compared to 68% for those with an ANC >500 cells/µL.</div></li><li class="half_rhythm"><div>Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years.</div></li></ul><p>In the French study, the five-year survival rate was 51%, with no deaths reported in males age three years or older; thus, the risk for early mortality appears to peak in the first few years of life.</p><p><a class="bk_pop" href="#barth.REF.ronvelia.2012.428">Ronvelia et al [2012]</a> report a man age 51 years with Barth syndrome, while <a class="bk_pop" href="#barth.REF.mazar.2019.243">Mazar et al [2019]</a> reported seven individuals ages 37.2 to 58.6 years (the latter the oldest living individual with a confirmed diagnosis). Two affected males in their 60s are known [Author, personal observation].</p><p><b>Laboratory findings</b> that may be associated with Barth syndrome include the following.</p><p><b>Plasma 3 methylglutaconic acid (3-MGC).</b> In a single study, 28 of 28 affected individuals ranging in age from ten months to 30 years had elevated plasma 3-MGC levels, with an average of 1,088 nmol/L ± 435 (range: 393-2,326 nmol/L) [<a class="bk_pop" href="#barth.REF.vernon.2014.143">Vernon et al 2014</a>] (see <a href="/books/NBK247162/table/barth.T.urine_and_plasma_organic_acid_le/?report=objectonly" target="object" rid-ob="figobbarthTurineandplasmaorganicacidle">Table 1</a>). In contrast, only eight of 16 individuals in the French cohort had elevated 3-MGC levels [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</p><p><b>Monolysocardiolipin:cardiolipin ratio.</b> Using high-performance liquid chromatography-mass spectrometry (HPLC-MS), <a class="bk_pop" href="#barth.REF.van_werkhoven.2006.2346">van Werkhoven et al [2006]</a> measured monolysocardiolipin (MLCL) and cardiolipin (CL) levels from cultured fibroblasts of males with Barth syndrome and controls. They found that the range of MLCL:CL ratios was 5.41–13.83 in Barth syndrome and 0.03–0.12 in controls.</p><p>Using a screening method in bloodspots, <a class="bk_pop" href="#barth.REF.kulik.2008.371">Kulik et al [2008]</a> found that all males with Barth syndrome had an MLCL:CL ratio greater than 0.40 and all controls had a ratio of lower than 0.23. Using a cutoff of 0.30, they reported a <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> and specificity of 100%. Males with classic Barth syndrome tend to have ratios greater than 1 but those with an intermediate form or atypical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> (mild cardiac involvement, good exercise tolerance, mild/no neutropenia) can have ratios lower than this but greater than 0.4. It is important that the MLCL:CL ratio is used for diagnosis, rather than CL content alone, as false negative results can result for atypical phenotypes if only tetralinoleoyl cardiolipin is measured. [<a class="bk_pop" href="#barth.REF.bowron.2015.279">Bowron et al 2015</a>]. It is also advised to confirm the results from MLCL:CL either through <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> or with a repeat sample, ideally in a different medium.</p><ul><li class="half_rhythm"><div>A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [<a class="bk_pop" href="#barth.REF.houtkooper.2009.230">Houtkooper et al 2009</a>].</div></li><li class="half_rhythm"><div>In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</div></li><li class="half_rhythm"><div>Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L).</div></li><li class="half_rhythm"><div>Plasma amino acids</div><ul><li class="half_rhythm"><div>In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</div></li><li class="half_rhythm"><div>This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [<a class="bk_pop" href="#barth.REF.vernon.2014.143">Vernon et al 2014</a>]. These 28 males also showed significantly higher proline levels (291 μmol/L) than controls (165 μmol/L).</div></li></ul></li><li class="half_rhythm"><div>Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 affected individuals tested [<a class="bk_pop" href="#barth.REF.spencer.2006.e337">Spencer et al 2006</a>]. In another study, only two of 28 were found to be hypocholesterolemic, with a mean cholesterol level of 137±26 mg/dL [<a class="bk_pop" href="#barth.REF.vernon.2014.143">Vernon et al 2014</a>].</div></li><li class="half_rhythm"><div>Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [<a class="bk_pop" href="#barth.REF.kelley.1991.738">Kelley et al 1991</a>, <a class="bk_pop" href="#barth.REF.christodoulou.1994.255">Christodoulou et al 1994</a>] and in at least one case was the presenting complaint [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</div></li><li class="half_rhythm"><div>Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [<a class="bk_pop" href="#barth.REF.spencer.2006.e337">Spencer et al 2006</a>].</div></li><li class="half_rhythm"><div>Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [<a class="bk_pop" href="#barth.REF.spencer.2006.e337">Spencer et al 2006</a>]. In a separate study 13 of 18 affected males showed decreased prealbumin levels with a mean of 16.9±4.0 mg/dL [<a class="bk_pop" href="#barth.REF.vernon.2014.143">Vernon et al 2014</a>].</div></li></ul><p><b>Respiratory chain studies</b> reveal decreased activity of complex III and IV in skeletal muscle [<a class="bk_pop" href="#barth.REF.barth.1983.327">Barth et al 1983</a>] and fibroblasts [<a class="bk_pop" href="#barth.REF.barth.1996.157">Barth et al 1996</a>].</p><p>
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<b>Pathology</b>
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</p><ul><li class="half_rhythm"><div>Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [<a class="bk_pop" href="#barth.REF.barth.1983.327">Barth et al 1983</a>, <a class="bk_pop" href="#barth.REF.ino.1988.511">Ino et al 1988</a>, <a class="bk_pop" href="#barth.REF.kelley.1991.738">Kelley et al 1991</a>]. In at least one case the initial presentation was a lipid storage myopathy [<a class="bk_pop" href="#barth.REF.takeda.2011.1481">Takeda et al 2011</a>].</div></li><li class="half_rhythm"><div>Liver. Lipid storage in the liver has also been described [<a class="bk_pop" href="#barth.REF.ino.1988.511">Ino et al 1988</a>, <a class="bk_pop" href="#barth.REF.kelley.1991.738">Kelley et al 1991</a>, <a class="bk_pop" href="#barth.REF.donati.2006.684">Donati et al 2006</a>].</div></li><li class="half_rhythm"><div>Bone marrow</div><ul><li class="half_rhythm"><div>A maturation arrest at the myelocyte stage was noted in the original description of the disease [<a class="bk_pop" href="#barth.REF.barth.1983.327">Barth et al 1983</a>].</div></li><li class="half_rhythm"><div>More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</div></li></ul></li></ul></div><div id="barth.Female_Heterozygotes"><h4>Female Heterozygotes</h4><p>Heterozygous females typically do not manifest the disease. Biochemical abnormalities have not been found in eight <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> females [<a class="bk_pop" href="#barth.REF.vernon.2014.143">Vernon et al 2014</a>].</p><p>It is proposed that <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> females are asymptomatic due to selection against cells with the mutated <i>TAFAZZIN</i> (formerly <i>TAZ</i>) <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> on the active X <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a>, based on a study of the <a class="def" href="/books/n/gene/glossary/def-item/x-chromosome-inactivation/">X-chromosome inactivation</a> pattern in 16 obligate heterozygotes [<a class="bk_pop" href="#barth.REF.orstavik.1998.1457">Orstavik et al 1998</a>]. In this study, six of the 16 had an extremely skewed pattern of X-chromosome inactivation (≥95:5) and five had a skewed pattern (80:20≤95:5) that was not observed in 148 female controls.</p><p>Two females with Barth syndrome have been reported:</p><ul><li class="half_rhythm"><div>One had <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>TAFAZZIN</i> as a result of (1) a complete <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of the paternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> (associated with a ring X <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with a large deletion that included <i>TAFAZZIN</i>) and (2) a deletion of exons 1-5 in the maternal <i>TAFAZZIN</i> allele [<a class="bk_pop" href="#barth.REF.cosson.2012.115">Cosson et al 2012</a>]. Analysis of lymphocyte and fibroblast cultures showed <a class="def" href="/books/n/gene/glossary/def-item/monosomy/">monosomy</a> X with <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a> for the ring X chromosome; thus, at least in lymphocytes, she lacked a normal <i>TAFAZZIN</i> allele.</div></li><li class="half_rhythm"><div>A second affected female with pathogenic <i>TAFAZZIN</i> variant <a href="/books/NBK247162/table/barth.T.notable_tafazzin_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobbarthTnotabletafazzinpathogenicvari">c.253insC</a> (p.Arg85ProfsTer54) in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 3 had left ventricular noncompaction and hypotonia. Skewed X inactivation (presumably where the X <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the nonmutated <i>TAFAZZIN</i> was preferentially inactivated) was identified in her blood [<a class="bk_pop" href="#barth.REF.avdjievatzavella.2016.495">Avdjieva-Tzavella et al 2016</a>].</div></li></ul></div></div><div id="barth.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>In general, <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have not been found [<a class="bk_pop" href="#barth.REF.johnston.1997.1053">Johnston et al 1997</a>, <a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</p></div><div id="barth.Prevalence"><h3>Prevalence</h3><p>As of 2020, an estimated 230-250 males have been identified with Barth syndrome worldwide [<a class="bk_pop" href="#barth.REF.miller.2020.139">Miller et al 2020</a>]. Estimates of the prevalence of Barth syndrome range from 1:140,000 live births in South West England and South Wales [<a class="bk_pop" href="#barth.REF.clarke.2013.23">Clarke et al 2013</a>] to 1:300,000-1:400,000 based on new diagnoses in the United States each year [<a class="bk_pop" href="#barth.REF.kelley.2002">Kelley 2002</a>], to 1.5 cases per million births (95% CI: 0.2-2.3) based on data from France between 1995 and 2008 [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>]. A Bayesian analysis to estimate Barth syndrome prevalence based on subsets of individuals with Barth syndrome included in publications describing the incidence and prevalence of cardiomyopathy and neutropenia estimates the prevalence of Barth syndrome at 1 per million males [<a class="bk_pop" href="#barth.REF.miller.2020.139">Miller et al 2020</a>].</p></div></div><div id="barth.Genetically_Related_Allelic_Disord"><h2 id="_barth_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>TAFAZZIN</i> (formerly <i>TAZ</i>).</p></div><div id="barth.Differential_Diagnosis"><h2 id="_barth_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Disorders in which excretion of 3-methylglutaconate is increased.</b> Increased urinary excretion of the branched-chain organic acid 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism [<a class="bk_pop" href="#barth.REF.gunayaygun.2005.1">Gunay-Aygun 2005</a>]. 3-MGC is an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA metabolism.</p><p>A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by <a class="bk_pop" href="#barth.REF.wortmann.2013a.923">Wortmann et al [2013a]</a> and <a class="bk_pop" href="#barth.REF.wortmann.2013b.913">Wortmann et al [2013b]</a>. Clinical features (see <a href="/books/NBK247162/table/barth.T.inborn_errors_of_metabolism_with/?report=objectonly" target="object" rid-ob="figobbarthTinbornerrorsofmetabolismwith">Table 4</a>) and biochemical findings of syndromes associated with 3-MGCA vary. Tissues with higher requirements for oxidative metabolism, such as the central nervous system and cardiac and skeletal muscle, are predominantly affected.</p><div id="barth.T.inborn_errors_of_metabolism_with" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Inborn Errors of Metabolism with 3-Methylglutaconic Aciduria as a Discriminative Feature</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.inborn_errors_of_metabolism_with/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.inborn_errors_of_metabolism_with_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Key Clinical Characteristics (in addition to 3-MGCA)</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>AGK</i>
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</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sengers syndrome<br />(See <a href="/books/n/gene/mtdna-md-ov/">Mitochondrial DNA Maintenance Defects Overview</a>.)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cataracts; cardiomyopathy</div></li><li class="half_rhythm"><div>DD <sup>1</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ATAD3A</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Harel-Yoon syndrome (OMIM <a href="https://omim.org/entry/617183" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617183</a>)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DD; hypotonia; optic atrophy; axonal neuropathy; hypertrophic cardiomyopathy <sup>2</sup></td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AUH</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>AUH</i> defect (OMIM <a href="https://omim.org/entry/250950" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">250950</a>)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult-onset progressive spasticity & dementia w/characteristic slowly developing radiologic picture of extensive leukoencephalopathy <sup>3, 4</sup></td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CLPB</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/clpb-def/">CLPB deficiency</a>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cataracts; central hypopnea; DD & ID; movement disorder; neutropenia</div></li><li class="half_rhythm"><div>Epilepsy <sup>1</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>DNAJC19</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>DNAJC19</i> defect (DCMA syndrome) (OMIM <a href="https://omim.org/entry/610198" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610198</a>)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Characteristic combination of childhood-onset dilated cardiomyopathy, nonprogressive cerebellar ataxia, testicular dysgenesis, & growth failure</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>HTRA2</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MGCA8 (OMIM <a href="https://omim.org/entry/617248" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617248</a>)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cataracts; central hypopnea; DD & ID; epilepsy; movement disorder; neutropenia</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>MICOS13</i><br />(<i>C19orf70</i>,<br /><i>QIL1</i>)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Combined oxidative phosphorylation deficiency 37 (OMIM <a href="https://omim.org/entry/618329" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618329</a>)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia; failure to thrive; neurodegeneration w/loss of developmental milestones; liver dysfunction</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>OPA3</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/mga3/">Costeff syndrome</a>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Optic atrophy; movement disorder (ataxia or extrapyramidal disorder)</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SERAC1</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/megdel/">MEGDEL syndrome</a> (SERAC1 defect)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>DD & ID; deafness; movement disorder</div></li><li class="half_rhythm"><div>Epilepsy & optic atrophy <sup>1</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b><i>TAFAZZIN</i> (formerly <i>TAZ</i>)</b>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>XL</b>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Barth syndrome (topic of this <i>GeneReview</i>)</b>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>In males, cardiomyopathy (left ventricular noncompaction), neutropenia, myopathy, typical facial features, hypocholesterolemia, & a cognitive <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a></b>
|
||
</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TIMM50</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MGCA9 (OMIM <a href="https://omim.org/entry/617698" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617698</a>)</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DD & ID; epilepsy</td></tr><tr><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TMEM70</i>
|
||
</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TMEM70</i> defect</td><td headers="hd_h_barth.T.inborn_errors_of_metabolism_with_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Typically neonatal onset w/muscular hypotonia, hypertrophic cardiomyopathy, psychomotor disability, hyperammonemia, & lactic acidosis</div></li><li class="half_rhythm"><div>Children surviving neonatal period later show DD; phenotypic spectrum is variable.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">3-MGCA = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; XL = <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a></p></div></dd><dt></dt><dd><div><p class="no_margin">Adapted from <a href="/books/NBK247162/table/barth.T.urine_and_plasma_organic_acid_le/?report=objectonly" target="object" rid-ob="figobbarthTurineandplasmaorganicacidle">Table 1</a> in <a class="bk_pop" href="#barth.REF.kovacsnagy.2018.373">Kovacs-Nagy et al [2018]</a></p></div></dd><dt>1. </dt><dd><div id="barth.TF.4.1"><p class="no_margin">Seen in some individuals</p></div></dd><dt>2. </dt><dd><div id="barth.TF.4.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#barth.REF.harel.2016.831">Harel et al [2016]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="barth.TF.4.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#barth.REF.wortmann.2010.1079">Wortmann et al [2010]</a>
|
||
</p></div></dd><dt>4. </dt><dd><div id="barth.TF.4.4"><p class="no_margin"><i>AUH</i> defect is the only one of the five inborn errors of metabolism with 3-MGA-uria with a distinct biochemical finding: elevated urinary excretion of 3-hydroxyisovaleric acid (3-HIVA).</p></div></dd></dl></div></div></div><p><b>Cardiomyopathy.</b> Left ventricular noncompaction (LVNC) is seen in other genetic syndromes as an <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> finding or associated with other <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> cardiac malformations.</p><p>Other genes in which pathogenic variants can lead to <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> cardiomyopathy with left ventricular noncompaction include: <i>LDB3</i>, <i>ACTC1</i>, <i>MYH7</i>, <i>MIB1</i>, <i>PRDM16</i>, <i>TNNT2</i>, <i>TPM1</i>, and <i>MYBPC3</i> (OMIM <a href="https://omim.org/phenotypicSeries/PS604169" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS604169</a>)<i>.</i> Given the considerable phenotypic overlap, it can be quite difficult to differentiate the phenotypes on the basis of specific genetic cause. However, as none of these other genes is on the X <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a>, a family history suggestive of <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> inheritance (i.e., affected males related through unaffected females) can point to Barth syndrome. Often, the most efficient way to determine the responsible <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is through <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> using a <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>.</p><p>LVNC and skeletal myopathy can be seen in <a href="/books/n/gene/dbmd/">Duchenne muscular dystrophy</a>, with a prevalence as high as 28% [<a class="bk_pop" href="#barth.REF.statile.2013.67">Statile et al 2013</a>]. However, in Duchenne muscular dystrophy (in contrast to Barth syndrome) the LVNC tends to worsen over time.</p><p><b>Neutropenia.</b> The differential for <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> neutropenia is wide and includes several notable genetic conditions:</p><ul><li class="half_rhythm"><div><a href="/books/n/gene/cyclic-n/"><i>ELANE</i>-related neutropenia</a> is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> disorder associated with either <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> neutropenia or cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy.</div></li><li class="half_rhythm"><div>Kostmann syndrome (OMIM <a href="https://omim.org/entry/610738" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610738</a>) is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> form of severe <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> neutropenia. <a class="bk_pop" href="#barth.REF.klein.2007.86">Klein et al [2007]</a> identified <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> pathogenic variants in <i>HAX1</i> (encoding HCLS1-associated protein X-1) in several individuals with Kostmann syndrome.</div></li><li class="half_rhythm"><div>Mutation of <i>G6PC3</i> (encoding glucose-6-phosphate 3) results in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> form of severe <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> neutropenia [<a class="bk_pop" href="#barth.REF.klein.2011.399">Klein 2011</a>]. (See <a href="/books/n/gene/g6pc3-def/">G6PC3 Deficiency</a>.)</div></li><li class="half_rhythm"><div>Benign <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> neutropenia is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> form of <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> neutropenia with milder neutropenia and less severe symptoms.</div></li></ul></div><div id="barth.Management"><h2 id="_barth_Management_">Management</h2><p>Consensus clinical management recommendations for Barth syndrome have not been published.</p><div id="barth.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in a male diagnosed with Barth syndrome, the evaluations summarized in <a href="/books/NBK247162/table/barth.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobbarthTrecommendedevaluationsfollowin">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><p>Note: In the very rare event that a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> female has signs and/or symptoms of Barth syndrome, evaluation and treatment should follow what is recommended for affected males.</p><div id="barth.T.recommended_evaluations_followin" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in a Male with Barth Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.recommended_evaluations_followin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.recommended_evaluations_followin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Electrocardiography</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for hypertrophy, QTc, & arrythmia</td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Echocardiography</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for cardiac muscle structure (size/noncompaction) strain & function</td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Immune</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete blood count w/differential</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for neutropenia</td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neuromuscular</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic exam for signs of muscle weakness & hypotonia</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of growth parameters</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider plotting on the Barth syndrome specific growth charts. <sup>1</sup></td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastroenterology / nutrition / feeding team eval</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl eval of weight gain & nutritional status</div></li><li class="half_rhythm"><div>Consider eval for gastric tube placement in those w/poor weight gain.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, & cognitive assessments</div></li><li class="half_rhythm"><div>Eval for early intervention/special education based on age</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>2</sup></td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected males & families re nature, MOI, & implications of Barth syndrome to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_barth.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#barth.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="barth.TF.5.1"><p class="no_margin">Derived from <a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al [2012</a>; see <a href="https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.35609/epdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Figure 1a-d</a>]</p></div></dd><dt>2. </dt><dd><div id="barth.TF.5.2"><p class="no_margin">Medical geneticist, certified genetic counselor, or certified advanced genetics nurse</p></div></dd></dl></div></div></div></div><div id="barth.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="barth.T.treatment_of_manifestations_in_i" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Barth Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.treatment_of_manifestations_in_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.treatment_of_manifestations_in_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Heart failure</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment <sup>1</sup> incl careful fluid & volume mgmt & avoidance of overdiuresis & dehydration</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Standard HF medications are used to improve symptoms, effect reverse remodeling of the ventricle, & improve ventricular function as measured by EF. <sup>2</sup></td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>ACE inhibitors & beta blockers for typical outpatient mgmt <sup>3</sup></div></li><li class="half_rhythm"><div>IV inotropes incl milrinone for in-patient mgmt of acute decompensation</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Cardiac transplantation has been successful when HF is severe & intractable. <sup>4</sup></td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Given the natural history of improving ventricular function after infancy, cardiac transplantation should be carefully considered.</td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac</b>
|
||
<br />
|
||
<b>arrhythmia</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consideration of antiarrhythmic medications or implantable cardiac defibrillator</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Use of these therapies prophylactically for prevention of primary arrhythmia has not been clarified. Long-term implantable cardiac monitoring devices can be considered for those at risk.</td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neutropenia</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">G-CSF of 2-3 μg/kg/dose w/frequency of administration ranging from 2x/wk to every other day <sup>5, 6, 7</sup></td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Consider regular administration of G-CSF (i.e., not only during times of high risk, e.g., surgery or infection).</div></li><li class="half_rhythm"><div>Consider prophylactic antibiotics (see <a href="#barth.Prevention_of_Secondary_Complicati">Prevention of Secondary Complications</a>).</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skeletal muscle</b>
|
||
<br />
|
||
<b>weakness</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To aid in attainment of developmental milestones & functional outcomes while monitoring cardiovascular status <sup>8</sup></td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Talipes</b>
|
||
<br />
|
||
<b>equinovarus</b>
|
||
<br />
|
||
<b>&/or scoliosis</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per orthopedist</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Poor weight</b>
|
||
<br />
|
||
<b>gain / Failure</b>
|
||
<br />
|
||
<b>to thrive</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Feeding therapy</div></li><li class="half_rhythm"><div>Gastrostomy tube placement may be required for persistent feeding issues.</div></li></ul>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low threshold for clinical feeding eval when showing poor weight gain</td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypoglycemia/</b>
|
||
<br />
|
||
<b>Nutrition</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Uncooked cornstarch given prior to bedtime</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To avoid muscle protein loss overnight</div></li><li class="half_rhythm"><div>Specific dosing by age & weight can be obtained from the <a href="https://www.barthsyndrome.org/home" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Barth Syndrome Foundation</a>. <sup>9</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>DD/ID</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#barth.Developmental_Delay__Intellectual">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/</b>
|
||
<br />
|
||
<b>Community</b>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
||
</td><td headers="hd_h_barth.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider involvement in adaptive sports or Special Olympics.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACE = angiotensin-converting enzyme; DD = developmental delay; EF = ejection fraction; G-CSF = granulocyte colony-stimulating factor; HF = heart failure; ID = intellectual disability; IV = intravenous; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="barth.TF.6.1"><p class="no_margin">See <a class="bk_pop" href="#barth.REF.kirk.2014.888">Kirk et al [2014]</a> for pediatric heart failure management and <a class="bk_pop" href="#barth.REF.yancy.2017.628">Yancy et al [2017]</a> for adult heart failure management guidelines.</p></div></dd><dt>2. </dt><dd><div id="barth.TF.6.2"><p class="no_margin">Although no studies are available to evaluate the effectiveness of medical therapy in males with Barth syndrome, when medications are stopped a decline in heart function is often observed. However, this can sometimes be difficult to distinguish from the natural fluctuations of the clinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> (<a href="#barth.Clinical_Description">Clinical Description</a>, <b>Heart failure</b>).</p></div></dd><dt>3. </dt><dd><div id="barth.TF.6.3"><p class="no_margin">Therapy received by 22 individuals in the French cohort [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>] included: 16/22 beta blockers, 9/22 beta blockers, 11/22 digoxin, 17/22 diuretics, 5/22 anticoagulants, and 5/22 aspirin.</p></div></dd><dt>4. </dt><dd><div id="barth.TF.6.4"><p class="no_margin"><a class="bk_pop" href="#barth.REF.mangat.2007.327">Mangat et al [2007]</a>, <a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al [2012]</a></p></div></dd><dt>5. </dt><dd><div id="barth.TF.6.5"><p class="no_margin">
|
||
<a class="bk_pop" href="#barth.REF.clarke.2013.23">Clarke et al [2013]</a>
|
||
</p></div></dd><dt>6. </dt><dd><div id="barth.TF.6.6"><p class="no_margin">In 83 affected males, 42 of whom had been treated with G-CSF, the median dose was 2.78±0.78 μg/kg/dose (range: 0.45-12.8 μg/kg/dose) [<a class="bk_pop" href="#barth.REF.dale.2013">Dale et al 2013</a>]. On average, G-CSF was begun at age 5.8 years, with an average exposure of 7.3 years; none developed acute myeloid leukemia, and treatment responses to G-CSF were maintained long-term.</p></div></dd><dt>7. </dt><dd><div id="barth.TF.6.7"><p class="no_margin">Although neutropenia appears to improve with G-CSF treatment, in the French cohort in which six affected males were actively treated with G-CSF, two developed a severe infection, including one episode of septic shock [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</p></div></dd><dt>8. </dt><dd><div id="barth.TF.6.8"><p class="no_margin">
|
||
<a class="bk_pop" href="#barth.REF.jarvis.2001.175">Jarvis et al [2001]</a>
|
||
</p></div></dd><dt>9. </dt><dd><div id="barth.TF.6.9"><p class="no_margin">
|
||
<a class="bk_pop" href="#barth.REF.avery.2006">Avery [2006]</a>
|
||
</p></div></dd></dl></div></div></div><div id="barth.Developmental_Delay__Intellectual"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / learning disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services and special educators. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, or social delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>The excessive fatigue that boys with Barth syndrome experience and the characteristic cognitive <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> (see <a href="#barth.Clinical_Description">Clinical Description</a>) warrant educational support during the early school-age years [<a class="bk_pop" href="#barth.REF.mazzocco.2007.22">Mazzocco et al 2007</a>] with particular attention to mathematics [<a class="bk_pop" href="#barth.REF.raches.2012.328">Raches & Mazzocco 2012</a>].</div></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="barth.Gross_Motor_Dysfunction"><h4>Gross Motor Dysfunction</h4><p>Physical therapy is recommended to maximize strength.</p></div><div id="barth.SocialBehavioral_Concerns"><h4>Social/Behavioral Concerns</h4><p>Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary.</p></div></div><div id="barth.Prevention_of_Secondary_Complicati"><h3>Prevention of Secondary Complications</h3><div id="barth.T.prevention_of_secondary_complica" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Prevention of Secondary Complications in Males with Barth Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.prevention_of_secondary_complica/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.prevention_of_secondary_complica_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Preventive Measure</th><th id="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Blood clot</b>
|
||
<br />
|
||
<b>formation</b>
|
||
</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aspirin therapy
|
||
<ul><li class="half_rhythm"><div>5 mg/kg daily for children</div></li><li class="half_rhythm"><div>81-325 mg daily for adults</div></li></ul>
|
||
</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For prevention of clot formation (& thus ↓ in risk for stroke) in males w/severe cardiac dysfunction &/or marked LVNC</td></tr><tr><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Infections</b>
|
||
</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Antibiotic prophylaxis <sup>1</sup></td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To prevent recurrent infections</td></tr><tr><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypoglycemia</b>
|
||
</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Episodes of fasting (e.g., prior to surgery) should be as short as possible & accompanied by IV glucose infusion.</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#barth.REF.schlame.2013">Schlame [2013]</a>
|
||
</td></tr><tr><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hyperkalemia</b>
|
||
</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Regular monitoring of potassium levels during administration of IV fluids that contain potassium</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Affected males lack normal muscle "reservoir" for potassium & can rapidly develop hyperkalemia when given IV fluids containing potassium.</td></tr><tr><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypokalemia</b>
|
||
</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Regular monitoring of potassium levels during episodes of diarrhea</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Affected males can rapidly become potassium depleted during a GI illness due to marked muscular hypoplasia. <sup>2</sup></td></tr><tr><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Chronic</b>
|
||
<br />
|
||
<b>diarrhea</b>
|
||
<br />
|
||
<b>induced by</b>
|
||
<br />
|
||
<b>overfeeding</b>
|
||
</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/nutritionist/gastroenterologist to determine optimal caloric delivery</td><td headers="hd_h_barth.T.prevention_of_secondary_complica_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Males w/Barth syndrome have lower-than-normal caloric requirements. <sup>2</sup></div></li><li class="half_rhythm"><div>Attempts to induce growth by overfeeding can lead to chronic diarrhea.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">GI = gastrointestinal; IV = intravenous; LVNC = left ventricular noncompaction</p></div></dd><dt>1. </dt><dd><div id="barth.TF.7.1"><p class="no_margin">In the French study of 22 affected males, four received antibiotic prophylaxis [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</p></div></dd><dt>2. </dt><dd><div id="barth.TF.7.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#barth.REF.kelley.2002">Kelley [2002]</a>
|
||
</p></div></dd></dl></div></div></div></div><div id="barth.Surveillance"><h3>Surveillance</h3><div id="barth.T.recommended_surveillance_for_mal" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Recommended Surveillance for Males with Barth Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.recommended_surveillance_for_mal/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.recommended_surveillance_for_mal_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac <sup>1</sup></b>
|
||
</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Electrocardiography w/Holder monitoring</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually</td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Echocardiography</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually or more frequently depending on clinical status</td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Electrophysiologic study to assess for a potentially serious arrhythmia</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed & for eval of symptoms incl palpitations & syncope, abnormal arrhythmia screening tests, or family history of sudden death</td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Immune</b>
|
||
</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete blood count w/differential</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">With all febrile episodes & semi-annually (or more frequently based on history & symptoms)</td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neuromuscular</b>
|
||
</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical assessment of strength & for scoliosis</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of height & weight <sup>2</sup></td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurocognitive</b>
|
||
</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Formal developmental assessments</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 3-5 yrs during childhood</td></tr><tr><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Miscellaneous/</b>
|
||
<br />
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., respite care, home nursing, other local resources) & care coordination.</td><td headers="hd_h_barth.T.recommended_surveillance_for_mal_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="barth.TF.8.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#barth.REF.spencer.2005.632">Spencer et al [2005]</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="barth.TF.8.2"><p class="no_margin">Consideration of Barth syndrome-specific growth patterns [<a class="bk_pop" href="#barth.REF.roberts.2012.2726">Roberts et al 2012</a>].</p></div></dd></dl></div></div></div></div><div id="barth.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Avoid the following:</p><ul><li class="half_rhythm"><div>Prolonged fasting because of a predisposition to hypoglycemia</div></li><li class="half_rhythm"><div>The use of rectal thermometers in those with neutropenia</div></li><li class="half_rhythm"><div>The use of succinylcholine, as nondepolarizing neuromuscular blockers could have a prolonged effect [<a class="bk_pop" href="#barth.REF.schlame.2013">Schlame 2013</a>]</div></li></ul><p>The use of human growth hormone is usually discouraged, as the majority of affected males will attain normal stature by adulthood.</p><p>Although the use of sevoflurane has been reported without adverse effects, the muscular involvement in Barth syndrome may increase the risk for <a href="/books/n/gene/mhs/">malignant hyperthermia</a> compared to the general population [<a class="bk_pop" href="#barth.REF.schlame.2013">Schlame 2013</a>].</p></div><div id="barth.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate the older and younger brothers of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.</p><ul><li class="half_rhythm"><div>If the <i>TAFAZZIN</i> (formerly <i>TAZ</i>) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family is known, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> can be used to clarify the genetic status of at-risk male sibs.</div></li><li class="half_rhythm"><div>If the <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family is not known, testing by means of monolysocardiolipin:cardiolipin (MLCL:CL) ratio (if available) can be used to clarify the genetic status of at-risk male sibs. Note: MLCL:CL measurement is not appropriate for evaluation of the genetic status of females.</div></li><li class="half_rhythm"><div>If MLCL:CL ratio is not available, a combination of urine organic acid analysis, complete blood count with differential, and echocardiogram may be able to clarify the genetic status of at-risk male sibs. However, such testing cannot exclude a diagnosis of Barth syndrome.</div></li></ul><p>See <a href="#barth.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="barth.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Given that Barth syndrome has been variably associated with different prenatal complications including intrauterine growth restriction, oligohydramnios, intrauterine ventricular dysfunction, and hydrops fetalis [<a class="bk_pop" href="#barth.REF.cardonick.1997.983">Cardonick et al 1997</a>, <a class="bk_pop" href="#barth.REF.steward.2010.970">Steward et al 2010</a>], it appears prudent to recommend that pregnancies of male fetuses known to have Barth syndrome be managed by a high-risk maternal fetal obstetrician. Of note, there are no specific recommendations regarding mode, timing, or location of delivery.</p></div><div id="barth.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div><div id="barth.Other"><h3>Other</h3><p><b>Pantothenic acid.</b> The original report of successful treatment of Barth syndrome with pantothenic acid [<a class="bk_pop" href="#barth.REF.ostmansmith.1994.349">Ostman-Smith et al 1994</a>] was not substantiated by later reports [<a class="bk_pop" href="#barth.REF.kelley.2002">Kelley 2002</a>, <a class="bk_pop" href="#barth.REF.rugolotto.2003.408">Rugolotto et al 2003</a>].</p><p><b>Coenzyme Q<sub>10</sub>.</b> The rationale behind the use of coenzyme Q<sub>10</sub> is based on the fact that both coenzyme Q<sub>10</sub> and 3-methylglutaconic acid (3-MGC) can be produced from dimethylallyl pyrophosphate (DMAPP), an intermediate in the synthesis of cholesterol. Thus, if coenzyme Q<sub>10</sub> production is impaired, more DMAPP could potentially be shunted toward the production of 3-MGC [<a class="bk_pop" href="#barth.REF.costeff.1998.33">Costeff et al 1998</a>]. However, no formal study has been undertaken to prove the efficacy of coenzyme Q<sub>10</sub> therapy in males with Barth syndrome. In a study of 15 males with Barth syndrome, three took coenzyme Q<sub>10</sub> [<a class="bk_pop" href="#barth.REF.spencer.2011.h2122">Spencer et al 2011</a>].</p><p><b>Carnitine.</b> Although early reports claimed significant benefit from carnitine supplementation in males with Barth syndrome [<a class="bk_pop" href="#barth.REF.ino.1988.511">Ino et al 1988</a>], subsequent reports identified rapid deterioration in cardiac function in some cases with carnitine supplementation [<a class="bk_pop" href="#barth.REF.ostmansmith.1994.349">Ostman-Smith et al 1994</a>, <a class="bk_pop" href="#barth.REF.kelley.2002">Kelley 2002</a>]. Thus, unless plasma carnitine levels are low, its supplementation has no role in the treatment of Barth syndrome.</p><p><b>Arginine.</b> Because lower plasma arginine levels detected in males with Barth syndrome [<a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>, <a class="bk_pop" href="#barth.REF.vernon.2014.143">Vernon et al 2014</a>] could contribute to growth delay and cardiac abnormalities by impairing protein synthesis, it has been proposed that oral arginine supplementation be used. Improvements in ventricular function have also been noted concurrently with normalization of the amino acid profile [R Kelley, personal communication]. However, to date no formal assessments of the efficacy of this treatment have been published.</p></div></div><div id="barth.Genetic_Counseling"><h2 id="_barth_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="barth.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Barth syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> manner.</p></div><div id="barth.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The father of an affected male will not have the disorder nor will he be <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> for the <i>TAFAZZIN</i> (formerly <i>TAZ</i>) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; therefore, he does not require further evaluation/testing.</div></li><li class="half_rhythm"><div>In a family with more than one affected individual, the mother of an affected male is an <a class="def" href="/books/n/gene/glossary/def-item/obligate-heterozygote/">obligate heterozygote</a>. Note: If a woman has more than one affected child and no other affected relatives and if the <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> cannot be detected in her leukocyte DNA, she most likely has <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>. Germline mosaicism has been reported in two families with Barth syndrome [<a class="bk_pop" href="#barth.REF.chang.2010.198">Chang et al 2010</a>, <a class="bk_pop" href="#barth.REF.momoi.2012.515">Momoi et al 2012</a>, <a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</div></li><li class="half_rhythm"><div>If a male is the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), the mother may be a <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a> or the affected male may have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, in which case the mother is not a heterozygote. In the experience of one laboratory, the son's pathogenic variant was not identified in the leukocyte DNA of five of 42 mothers of boys with Barth syndrome [<a class="bk_pop" href="#barth.REF.kirwin.2007.976.e5">Kirwin et al 2007</a>].</div></li></ul><p><b>Sibs of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to sibs of a male proband depends on the genetic status of the mother:</p><ul><li class="half_rhythm"><div>If the mother of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and are typically not affected (see Clinical Description, <a href="#barth.Female_Heterozygotes">Female Heterozygotes</a>).</div></li><li class="half_rhythm"><div>If a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> represents a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (i.e., a single occurrence in a family) and if the <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> cannot be detected in the leukocyte DNA of the mother, the risk to sibs is greater than that of the general population because of the possibility of maternal <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#barth.REF.chang.2010.198">Chang et al 2010</a>, <a class="bk_pop" href="#barth.REF.momoi.2012.515">Momoi et al 2012</a>, <a class="bk_pop" href="#barth.REF.rigaud.2013.70">Rigaud et al 2013</a>].</div></li></ul><p><b>Offspring of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Affected males transmit the <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> to:</p><ul><li class="half_rhythm"><div>All of their daughters, who will be heterozygotes and will typically not be affected;</div></li><li class="half_rhythm"><div>None of their sons.</div></li></ul><p><b>Other family members.</b> The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s maternal aunts may be at risk of being heterozygotes and the aunts' offspring, depending on their sex, may be at risk of being heterozygotes or of being affected.</p><p>Note: Molecular genetic testing may be able to identify the family member in whom a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> arose, information that could help determine genetic risk status of the extended family. One laboratory reported that <i>de novo</i> mutation of <i>TAFAZZIN</i> occurs more frequently in a male ancestor than in a female ancestor [<a class="bk_pop" href="#barth.REF.kirwin.2007.976.e5">Kirwin et al 2007</a>].</p></div><div id="barth.Heterozygote_Detection"><h3>Heterozygote Detection</h3><p>Identification of female heterozygotes requires either (1) prior identification of the <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family or, (2) if an affected male is not available for testing, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> first by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, and then, if no pathogenic variant is identified, by <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</p><p>Heterozygous females typically do not manifest the disease. In Barth syndrome, <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> females often demonstrate skewed <a class="def" href="/books/n/gene/glossary/def-item/x-chromosome-inactivation/">X-chromosome inactivation</a> due to preferential inactivation of the X chromosome with the <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> [<a class="bk_pop" href="#barth.REF.orstavik.1998.1457">Orstavik et al 1998</a>]. To date, two females with Barth syndrome have been reported (see Clinical Description, <a href="#barth.Female_Heterozygotes">Female Heterozygotes</a>).</p></div><div id="barth.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#barth.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a>, or are at risk of being heterozygous.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#barth.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="barth.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>TAFAZZIN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for Barth syndrome are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="barth.Resources"><h2 id="_barth_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Barth Syndrome Foundation</b>
|
||
</div><div>PO Box 618</div><div>Larchmont NY 10538</div><div><b>Phone:</b> 850-273-6947</div><div><b>Fax:</b> 518-213-4061</div><div><b>Email:</b> bsfinfo@barthsyndrome.org</div><div>
|
||
<a href="http://www.barthsyndrome.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.barthsyndrome.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Organic Acidemia Association</b>
|
||
</div><div><b>Phone:</b> 763-559-1797</div><div><b>Email:</b> info@oaanews.org</div><div>
|
||
<a href="https://oaanews.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">oaanews.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>European Society for Immunodeficiencies (ESID) Registry</b>
|
||
</div><div><b>Email:</b> esid-registry@uniklinik-freiburg.de</div><div>
|
||
<a href="https://esid.org/Working-Parties/Registry-Working-Party/ESID-Registry" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ESID Registry</a>
|
||
</div></li></ul>
|
||
</div><div id="barth.Molecular_Genetics"><h2 id="_barth_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="barth.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Barth Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_barth.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_barth.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_barth.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_barth.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_barth.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_barth.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_barth.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/6901" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>TAFAZZIN</i>
|
||
</a>
|
||
</td><td headers="hd_b_barth.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=6901" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xq28</a>
|
||
</td><td headers="hd_b_barth.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q16635" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Tafazzin</a>
|
||
</td><td headers="hd_b_barth.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://structure.bmc.lu.se/idbase/TAZbase/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TAZbase: Mutation registry for Barth syndrome</a>
|
||
<br />
|
||
<a href="https://www.barthsyndrome.org/research/tafazzindatabase.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Human Tafazzin Gene Variants Database</a>
|
||
<br />
|
||
<a href="https://lovd.nl/TAZ" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TAZ database</a>
|
||
</td><td headers="hd_b_barth.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=TAFAZZIN" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TAFAZZIN</a>
|
||
</td><td headers="hd_b_barth.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=TAFAZZIN[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TAFAZZIN</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="barth.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="barth.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Barth Syndrome (<a href="/omim/300394,302060" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/300394" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300394</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TAFAZZIN, PHOSPHOLIPID-LYSOPHOSPHOLIPID TRANSACYLASE; TAFAZZIN</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/302060" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">302060</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BARTH SYNDROME; BTHS</td></tr></tbody></table></div></div><div id="barth.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>TAFAZZIN</i> (formerly <i>TAZ</i>) encodes tafazzin, a transacylase located on the inner mitochondrial membrane. Tafazzin catalyzes the remodeling of the acyl chains of immature cardiolipin to a mature, predominantly tetralinoleylcardiolipin. Cardiolipin is important for high energy-requiring tissues such as cardiac muscle; in Barth syndrome, less mature cardiolipin is produced [<a class="bk_pop" href="#barth.REF.schlame.2002.634">Schlame et al 2002</a>, <a class="bk_pop" href="#barth.REF.valianpour.2005.1182">Valianpour et al 2005</a>]. The exact mechanism by which decreased tetralinoleylcardiolipin leads to the pathophysiology of Barth syndrome is unclear. However, cardiolipin is involved in maintaining mitochondrial structure and organizing mitochondrial super complexes and has an important role in apoptosis [<a class="bk_pop" href="#barth.REF.koshkin.2002.317">Koshkin & Greenberg 2002</a>, <a class="bk_pop" href="#barth.REF.brandner.2005.5202">Brandner et al 2005</a>, <a class="bk_pop" href="#barth.REF.gonzalvez.2007.877">Gonzalvez & Gottlieb 2007</a>].</p><p>Almost 45% of the <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> sequence of <i>TAFAZZIN</i> is represented by interspersed repeated sequences (SINES and LINES) and 76% of these (accounting for 35% of the <i>TAFAZZIN</i> genomic sequence) are <i>Alu</i> sequences [<a class="bk_pop" href="#barth.REF.ferri.2013.27">Ferri et al 2013</a>]. <a class="bk_pop" href="#barth.REF.ferri.2013.27">Ferri et al [2013]</a> postulate that because of the high content of repeat sequences in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, <i>TAFAZZIN</i> rearrangements (which may appear to be similar in different patients on the basis of deleted exons) may actually be recurrent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variants.</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div id="barth.T.notable_tafazzin_pathogenic_vari" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Notable <i>TAFAZZIN</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK247162/table/barth.T.notable_tafazzin_pathogenic_vari/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__barth.T.notable_tafazzin_pathogenic_vari_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference<br />Sequences</th><th id="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide<br />Change</th><th id="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000116.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000116<wbr style="display:inline-block"></wbr>.5</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000107.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000107<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.348C>T</td><td headers="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly116= <sup>1</sup></td><td headers="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Causes <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> skipping; infantile onset [<a class="bk_pop" href="#barth.REF.ferri.2016.461">Ferri et al 2016</a>]. See <a href="/books/NBK247162/table/barth.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobbarthTmoleculargenetictestingusedi">Table 2</a>.</td></tr><tr><td headers="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.253insC</td><td headers="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg85ProfsTer54</td><td headers="hd_h_barth.T.notable_tafazzin_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In a female w/Barth syndrome; see <a href="#barth.Female_Heterozygotes">Female Heterozygotes</a> [<a class="bk_pop" href="#barth.REF.avdjievatzavella.2016.495">Avdjieva-Tzavella et al 2016</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="barth.TF.9.1"><p class="no_margin">Denotes silent (no change) in the amino acid</p></div></dd></dl></div></div></div></div></div><div id="barth.Chapter_Notes"><h2 id="_barth_Chapter_Notes_">Chapter Notes</h2><div id="barth.Acknowledgments"><h3>Acknowledgments</h3><p>We would like to acknowledge the Barth Syndrome Foundation for their support.</p></div><div id="barth.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>9 July 2020 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>9 October 2014 (me) Review posted live</div></li><li class="half_rhythm"><div>7 April 2014 (cf) Original submission</div></li></ul></div></div><div id="barth.References"><h2 id="_barth_References_">References</h2><div id="barth.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="barth.REF.ad_s.1993.327">Adès LC, Gedeon AK, Wilson MJ, Latham M, Partington MW, Mulley JC, Nelson J, Lui K, Sillence DO. Barth syndrome: clinical features and confirmation of gene localisation to distal Xq28. <span><span class="ref-journal">Am J Med Genet. </span>1993;<span class="ref-vol">45</span>:327–34.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8434619" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8434619</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.adwani.1997.143">Adwani SS, Whitehead BF, Rees PG, Morris A, Turnball DM, Elliott MJ, de Leval MR. Heart transplantation for Barth syndrome. <span><span class="ref-journal">Pediatr Cardiol. </span>1997;<span class="ref-vol">18</span>:143–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9049131" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9049131</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.avdjievatzavella.2016.495">Avdjieva-Tzavella DM, Todorova AP, Kathom H M, Ivanova MB, Yordanova IT, Todorov TP, Litvinenko IO, Dasheva-Dimitrova AT, Tincheva RS. Barth Syndrome in male and female siblings caused by a novel mutation in the TAZ gene. <span><span class="ref-journal">Genet Couns. </span>2016;<span class="ref-vol">27</span>:495–501.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30226969" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30226969</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.avery.2006">Avery R. Cornstarch. Available <a href="https://www.barthsyndrome.org/file_download/inline/46818476-575c-43b3-9a65-4904aa8af736" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a> (pdf). 2006. Accessed 10-25-22.</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.baban.2020.64">Baban A, Adorisio R, Corica B, Rizzo C, Calì F, Semeraro M, Taurisano R, Magliozzi M, Carrozzo R, Parisi F, Dallapiccola B, Vaz FM, Drago F, Dionisi-Vici C. Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: a potential pitfall for the diagnosis. <span><span class="ref-journal">Am J Med Genet A. </span>2020;<span class="ref-vol">182</span>:64–70.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31729175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31729175</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.barth.1983.327">Barth PG, Scholte HR, Berden JA, Van der Klei-Van Moorsel JM, Luyt-Houwen IE, Van 't Veer-Korthof ET, Van der Harten JJ, Sobotka-Plojhar MA. An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes. <span><span class="ref-journal">J Neurol Sci. </span>1983;<span class="ref-vol">62</span>:327–55.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6142097" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6142097</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.barth.1996.157">Barth PG, Van den Bogert C, Bolhuis PA, Scholte HR, van Gennip AH, Schutgens RB, Ketel AG. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): respiratory-chain abnormalities in cultured fibroblasts. <span><span class="ref-journal">J Inherit Metab Dis. </span>1996;<span class="ref-vol">19</span>:157–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8739954" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8739954</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.barth.1999.273">Barth PG, Wanders RJ, Vreken P. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) - MIM 302060. <span><span class="ref-journal">J Pediatr. </span>1999;<span class="ref-vol">135</span>:273–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10484787" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10484787</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.bowron.2015.279">Bowron A, Honeychurch J, Williams M, Tsai-Goodman B, Clayton N, Jones L, Shortland GJ, Qureshi SA, Heales SJ, Steward CG. Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype. <span><span class="ref-journal">J Inherit Metab Dis. </span>2015;<span class="ref-vol">38</span>:279–86.</span> Erratum in: J Inherit Metab Dis. 2016;39:151. [<a href="/pmc/articles/PMC4341014/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4341014</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25112388" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25112388</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.brady.2006.462">Brady AN, Shehata BM, Fernhoff PM. X-linked fetal cardiomyopathy caused by a novel mutation in the TAZ gene. <span><span class="ref-journal">Prenat Diagn. </span>2006;<span class="ref-vol">26</span>:462–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16548007" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16548007</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.brandner.2005.5202">Brandner K, Mick D, Frazier A, Taylor R, Meisinger C, Rehling P. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth syndrome. <span><span class="ref-journal">Mol Biol Cell. </span>2005;<span class="ref-vol">16</span>:5202–14.</span> [<a href="/pmc/articles/PMC1266419/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1266419</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16135531" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16135531</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.cardonick.1997.983">Cardonick EH, Kuhlman K, Ganz E, Pagotto LT. Prenatal clinical expression of 3-methylglutaconic aciduria: Barth syndrome. <span><span class="ref-journal">Prenat Diagn. </span>1997;<span class="ref-vol">17</span>:983–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9358581" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9358581</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.chang.2010.198">Chang B, Momoi N, Shan L, Mitomo M, Aoyagi Y, Endo K, Takeda I, Chen R, Xing Y, Yu X, Watanabe S, Yoshida T, Kanegane H, Tsubata S, Bowles NE, Ichida F, Miyawaki T., Noncompaction study collaborators. Gonadal mosaicism of a TAZ (G4.5) mutation in a Japanese family with Barth syndrome and left ventricular noncompaction. <span><span class="ref-journal">Mol Genet Metab. </span>2010;<span class="ref-vol">100</span>:198–203.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20303308" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20303308</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.christodoulou.1994.255">Christodoulou J, McInnes RR, Jay V, Wilson G, Becker LE, Lehotay DC, Platt BA, Bridge PJ, Robinson BH, Clarke JT. Barth syndrome: clinical observations and genetic linkage studies. <span><span class="ref-journal">Am J Med Genet. </span>1994;<span class="ref-vol">50</span>:255–64.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8042670" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8042670</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.clarke.2013.23">Clarke SL, Bowron A, Gonzalez IL, Groves SJ, Newbury-Ecob R, Clayton N, Martin RP, Tsai-Goodman B, Garratt V, Ashworth M, Bowen VM, McCurdy KR, Damin MK, Spencer CT, Toth MJ, Kelley RI, Steward CG. Barth syndrome. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2013;<span class="ref-vol">8</span>:23.</span> [<a href="/pmc/articles/PMC3583704/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3583704</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23398819" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23398819</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.cosson.2012.115">Cosson L, Toutain A, Simard G, Kulik W, Matyas G, Guichet A, Blasco H, Maakaroun-Vermesse Z, Vaillant MC, Le Caignec C, Chantepie A, Labarthe F. Barth syndrome in a female patient. <span><span class="ref-journal">Mol Genet Metab. </span>2012;<span class="ref-vol">106</span>:115–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22410210" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22410210</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.costeff.1998.33">Costeff H, Apter N, Elpeleg ON, Prialnic M, Böhles HJ. Ineffectiveness of oral coenzyme Q10 supplementation in 3-methylglutaconic aciduria, type 3. <span><span class="ref-journal">Brain Dev. </span>1998;<span class="ref-vol">20</span>:33–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9533558" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9533558</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.dale.2013">Dale DC, Bolyard AA, Marrero TM, Bonilla MA, Phan L, Steward C. Barth Syndrome and Neutropenia. Poster session. New Orleans, LA: American Society of Hematology Annual Meeting and Exposition. 2013.</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.donati.2006.684">Donati MA, Malvagia S, Pasquini E, Morrone A, La Marca G, Garavaglia B, Toniolo D, Zammarchi E. Barth syndrome presenting with acute metabolic decompensation in the neonatal period. <span><span class="ref-journal">J Inherit Metab Dis. </span>2006;<span class="ref-vol">29</span>:684.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16906470" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16906470</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.ferri.2016.461">Ferri L, Dionisi-Vici C, Taurisano R, Vaz FM, Guerrini R, Morrone A. When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription. <span><span class="ref-journal">Clin Genet. </span>2016;<span class="ref-vol">90</span>:461–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26853223" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26853223</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.ferri.2013.27">Ferri L, Donati MA, Funghini S, Malvagia S, Catarzi S, Lugli L, Ragni L, Bertini E, Vaz FM, Cooper DN, Guerrini R, Morrone A. New clinical and molecular insights on Barth syndrome. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2013;<span class="ref-vol">8</span>:27.</span> [<a href="/pmc/articles/PMC3599367/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3599367</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23409742" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23409742</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.gedeon.1995.383">Gedeon AK, Wilson MJ, Colley AC, Sillence DO, Mulley JC. X linked fatal infantile cardiomyopathy maps to Xq28 and is possibly allelic to Barth syndrome. <span><span class="ref-journal">J Med Genet. </span>1995;<span class="ref-vol">32</span>:383–8.</span> [<a href="/pmc/articles/PMC1050435/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1050435</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7616547" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7616547</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.gonzalvez.2007.877">Gonzalvez F, Gottlieb E. Cardiolipin: Setting the beat of apoptosis. <span><span class="ref-journal">Apoptosis. </span>2007;<span class="ref-vol">12</span>:877–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17294083" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17294083</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.gunayaygun.2005.1">Gunay-Aygun M. 3-Methylglutaconic aciduria: a common biochemical marker in various syndromes with diverse clinical features. <span><span class="ref-journal">Mol Genet Metab. </span>2005;<span class="ref-vol">84</span>:1–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15719488" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15719488</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.harel.2016.831">Harel T, Yoon WH, Garone C, Gu S, Coban-Akdemir Z, Eldomery MK, Posey JE, Jhangiani SN, Rosenfeld JA, Cho MT, Fox S, Withers M, Brooks SM, Chiang T, Duraine L, Erdin S, Yuan B, Shao Y, Moussallem E, Lamperti C, Donati MA, Smith JD, McLaughlin HM, Eng CM, Walkiewicz M, Xia F, Pippucci T, Magini P, Seri M, Zeviani M, Hirano M, Hunter JV, Srour M, Zanigni S, Lewis RA, Muzny DM, Lotze TE, Boerwinkle E., Baylor-Hopkins Center for Mendelian Genomics. University of Washington Center for Mendelian Genomics, Gibbs RA, Hickey SE, Graham BH, Yang Y, Buhas D, Martin DM, Potocki L, Graziano C, Bellen HJ, Lupski JR. Recurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes. <span><span class="ref-journal">Am J Hum Genet. </span>2016;<span class="ref-vol">99</span>:831–45.</span> [<a href="/pmc/articles/PMC5065660/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5065660</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27640307" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27640307</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.hastings.2009.185">Hastings R, Steward C, Tsai-Goodman B, Newbury-Ecob R. Dysmorphology of Barth syndrome. <span><span class="ref-journal">Clin Dysmorphol. </span>2009;<span class="ref-vol">18</span>:185–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19648820" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19648820</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.hornby.2019.37">Hornby B, McClellan R, Buckley L, Carson K, Gooding T, Vernon HJ. Functional exercise capacity, strength, balance and motion reaction time in Barth Syndrome. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2019;<span class="ref-vol">14</span>:37.</span> [<a href="/pmc/articles/PMC6371525/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6371525</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30744648" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30744648</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.houtkooper.2009.230">Houtkooper RH, Rodenburg RJ, Thiels C, van Lenthe H, Stet F, Poll-The BT, Stone JE, Steward CG, Wanders RJ, Smeitink J, Kulik W, Vaz FM. Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes, and tissues using high-performance liquid chromatography-mass spectrometry as a diagnostic test for Barth syndrome. <span><span class="ref-journal">Anal Biochem. </span>2009;<span class="ref-vol">387</span>:230–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19454236" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19454236</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.huang.2022.389">Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. <span><span class="ref-journal">J Community Genet. </span>2022;<span class="ref-vol">13</span>:389–97.</span> [<a href="/pmc/articles/PMC9314484/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9314484</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35834113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35834113</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.ino.1988.511">Ino T, Sherwood WG, Cutz E, Benson LN, Rose V, Freedom RM. Dilated cardiomyopathy with neutropenia, short stature, and abnormal carnitine metabolism. <span><span class="ref-journal">J Pediatr. </span>1988;<span class="ref-vol">113</span>:511–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3411399" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3411399</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.jarvis.2001.175">Jarvis M, Garrett P, Svien L. Gross motor development of a toddler with Barth syndrome, an x-linked recessive disorder: a case report. <span><span class="ref-journal">Pediatr Phys Ther. </span>2001;<span class="ref-vol">13</span>:175–81.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17053636" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17053636</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.johnston.1997.1053">Johnston J, Kelley RI, Feigenbaum A, Cox GF, Iyer GS, Funanage VL, Proujansky R. Mutation characterization and genotype-phenotype correlation in Barth syndrome. <span><span class="ref-journal">Am J Hum Genet. </span>1997;<span class="ref-vol">61</span>:1053–8.</span> [<a href="/pmc/articles/PMC1716030/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1716030</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9345098" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9345098</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.kang.2016.167">Kang SL, Forsey J, Dudley D, Steward CG, Tsai-Goodman B. Clinical characteristics and outcomes of cardiomyopathy in Barth syndrome: the UK experience. <span><span class="ref-journal">Pediatr Cardiol. </span>2016;<span class="ref-vol">37</span>:167–76.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26337810" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26337810</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.kelley.2002">Kelley RI. Barth Syndrome - X-linked Cardiomyopathy and Neutropenia. Johns Hopkins Medicine. 2002.</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.kelley.1991.738">Kelley RI, Cheatham JP, Clark BJ, Nigro MA, Powell BR, Sherwood GW, Sladky JT, Swisher WP. X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria. <span><span class="ref-journal">J Pediatr. </span>1991;<span class="ref-vol">119</span>:738–47.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1719174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1719174</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.kirk.2014.888">Kirk R, Dipchand AI, Rosenthal DN, Addonizio L, Burch M, Chrisant M, Dubin A, Everitt M, Gajarski R, Mertens L, Miyamoto S, Morales D, Pahl E, Shaddy R, Towbin J, Weintraub R. The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: executive summary. <span><span class="ref-journal">J Heart Lung Transplant. </span>2014;<span class="ref-vol">33</span>:888–909.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25110323" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25110323</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.kirwin.2007.976.e5">Kirwin SM, Vinette KM, Schwartz SB, Funanage VL, Gonzalez IL. Multiple transmissions of Barth syndrome through an oocyte donor with a de novo TAZ mutation. <span><span class="ref-journal">Fertil Steril. </span>2007;<span class="ref-vol">87</span>:976.e5–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17241629" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17241629</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.klein.2011.399">Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. <span><span class="ref-journal">Annu Rev Immunol. </span>2011;<span class="ref-vol">29</span>:399–413.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21219176" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21219176</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.klein.2007.86">Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, Rathinam C, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). <span><span class="ref-journal">Nat Genet. </span>2007;<span class="ref-vol">39</span>:86–92.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17187068" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17187068</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.koshkin.2002.317">Koshkin V, Greenberg ML. Cardiolipin prevents rate-dependent uncoupling and provides osmotic stability in yeast mitochondria. <span><span class="ref-journal">Biochem J. </span>2002;<span class="ref-vol">364</span>:317–22.</span> [<a href="/pmc/articles/PMC1222575/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1222575</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11988106" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11988106</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.kovacsnagy.2018.373">Kovacs-Nagy R, Morin G, Nouri MA, Brandau O, Saadi NW, Nouri MA, van den Broek F, Prokisch H, Mayr JA, Wortmann SB. HTRA2 defect: a recognizable inborn error of metabolism with 3-methylglutaconic aciduria as discriminating feature characterized by neonatal movement disorder and epilepsy-report of 11 patients. <span><span class="ref-journal">Neuropediatrics. </span>2018;<span class="ref-vol">49</span>:373–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30114719" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30114719</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.kulik.2008.371">Kulik W, van Lenthe H, Stet FS, Germeshausen M, Sandrock I, Schäffer AA, Rathinam C, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K. Bloodspot assay using HPLC-tandem mass spectrometry for detection of Barth syndrome. <span><span class="ref-journal">Clin Chem. </span>2008;<span class="ref-vol">54</span>:371–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18070816" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18070816</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.mangat.2007.327">Mangat J, Lunnon-Wood T, Rees P, Elliot M, Burch M. Successful cardiac transplantation in Barth syndrome--single-centre experience of four patients. <span><span class="ref-journal">Pediatr Transplant. </span>2007;<span class="ref-vol">11</span>:327–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17430492" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17430492</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.mazar.2019.243">Mazar I, Stokes J, Ollis S, Love E, Espensen A, Barth PG, Powers JH 3rd, Shields AL. Understanding the life experience of Barth syndrome from the perspective of adults: a qualitative one-on-one interview study. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2019;<span class="ref-vol">14</span>:243.</span> [<a href="/pmc/articles/PMC6836365/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6836365</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31699126" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31699126</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.mazzocco.2007.22">Mazzocco MM, Henry AE, Kelly RI. Barth syndrome is associated with a cognitive phenotype. <span><span class="ref-journal">J Dev Behav Pediatr. </span>2007;<span class="ref-vol">28</span>:22–30.</span> [<a href="/pmc/articles/PMC2813702/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2813702</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17353728" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17353728</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.miller.2020.139">Miller PC, Ren M, Schlame M, Toth MJ, Phoon CKL. A Bayesian analysis to determine the prevalence of Barth syndrome in the pediatric population. <span><span class="ref-journal">J Pediatr. </span>2020;<span class="ref-vol">217</span>:139–44.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31732128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31732128</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.momoi.2012.515">Momoi N, Chang B, Takeda I, Aoyagi Y, Endo K, Ichida F. Differing clinical courses and outcomes in two siblings with Barth syndrome and left ventricular noncompaction. <span><span class="ref-journal">Eur J Pediatr. </span>2012;<span class="ref-vol">171</span>:515–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21987083" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21987083</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.orstavik.1998.1457">Orstavik KH, Orstavik RE, Naumova AK, D'Adamo P, Gedeon A, Bolhuis PA, Barth PG, Toniolo D. X chromosome inactivation in carriers of Barth syndrome. <span><span class="ref-journal">Am J Hum Genet. </span>1998;<span class="ref-vol">63</span>:1457–63.</span> [<a href="/pmc/articles/PMC1377557/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1377557</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9792874" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9792874</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.ostmansmith.1994.349">Ostman-Smith I, Brown G, Johnson A, Land JM. Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid. <span><span class="ref-journal">Br Heart J. </span>1994;<span class="ref-vol">72</span>:349–53.</span> [<a href="/pmc/articles/PMC1025545/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1025545</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7833193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7833193</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.raches.2012.328">Raches D, Mazzocco MM. Emergence and nature of mathematical difficulties in young children with Barth syndrome. <span><span class="ref-journal">J Dev Behav Pediatr. </span>2012;<span class="ref-vol">33</span>:328–35.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22566029" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22566029</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.reynolds.2012.1647">Reynolds S, Kreider CM, Bendixen R. A mixed-methods investigation of sensory response patterns in Barth syndrome: a clinical phenotype? <span><span class="ref-journal">Am J Med Genet A. </span>2012;<span class="ref-vol">158A</span>:1647–53.</span> [<a href="/pmc/articles/PMC3383655/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3383655</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22711649" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22711649</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.rigaud.2013.70">Rigaud C, Lebre A-S, Touraine R, Beaupain B, Ottolenghi C, Chabli A, Ansquer H, Ozsahin H, Di Filippo S, De Lonlay P, Borm B, Rivier F, Vaillant MC, Mathieu-Dramard M, Goldenberg A, Viot G, Charron P, Rio M, Bonnet D, Donadieu J. Natural history of Barth syndrome: a national cohort study of 22 patients. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2013;<span class="ref-vol">8</span>:70.</span> [<a href="/pmc/articles/PMC3656783/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3656783</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23656970" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23656970</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.roberts.2012.2726">Roberts AE, Nixon C, Steward CG, Gauvreau K, Maisenbacher M, Fletcher M, Geva J, Byrne BJ, Spencer CT. The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study. <span><span class="ref-journal">Am J Med Genet A. </span>2012;<span class="ref-vol">158A</span>:2726–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23045169" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23045169</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.ronvelia.2012.428">Ronvelia D, Greenwood J, Platt J, Hakim S, Zaragoza MV. Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle. <span><span class="ref-journal">Mol Genet Metab. </span>2012;<span class="ref-vol">107</span>:428–32.</span> [<a href="/pmc/articles/PMC3483384/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3483384</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23031367" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23031367</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.rugolotto.2003.408">Rugolotto S, Prioli MD, Toniolo D, Pellegrino P, Catuogno S, Burlina AB. Long-term treatment of Barth syndrome with pantothenic acid: a retrospective study. <span><span class="ref-journal">Mol Genet Metab. </span>2003;<span class="ref-vol">80</span>:408–11.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14654353" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14654353</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.schlame.2013">Schlame M. Information for anaesthesiologists and surgeons taking care of patients with Barth syndrome. Available <a href="https://www.barthsyndrome.org/file_download/a5ef434e-7a0b-4f53-b33c-969f45cd1611" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a> (pdf). 2013. Accessed 10-25-22.</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.schlame.2002.634">Schlame M, Towbin JA, Heerdt PM, Jehle R, DiMauro S, Blanck TJ. Deficiency of tetralinoleoyl-cardiolipin in Barth syndrome. <span><span class="ref-journal">Ann Neurol. </span>2002;<span class="ref-vol">51</span>:634–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12112112" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12112112</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.spencer.2006.e337">Spencer CT, Bryant RM, Day J, Gonzalez IL, Colan SD, Thompson WR, Berthy J, Redfearn SP, Byrne BJ. Cardiac and clinical phenotype in Barth syndrome. <span><span class="ref-journal">Pediatrics. </span>2006;<span class="ref-vol">118</span>:e337–46.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16847078" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16847078</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.spencer.2011.h2122">Spencer CT, Byrne BJ, Bryant RM, Margossian R, Maisenbacher M, Breitenger P, Benni PB, Redfearn S, Marcus E, Cade WT. Impaired cardiac reserve and severely diminished skeletal muscle O2 utilization mediate exercise intolerance in Barth syndrome. <span><span class="ref-journal">Am J Physiol Heart Circ Physiol. </span>2011;<span class="ref-vol">301</span>:H2122–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21873497" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21873497</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.spencer.2005.632">Spencer CT, Byrne BJ, Gewitz MH, Wechsler SB, Kao AC, Gerstenfeld EP, Merliss AD, Carboni MP, Bryant RM. Ventricular arrhythmia in the X-linked cardiomyopathy Barth syndrome. <span><span class="ref-journal">Pediatr Cardiol. </span>2005;<span class="ref-vol">26</span>:632–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16235007" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16235007</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.statile.2013.67">Statile CJ, Taylor MD, Mazur W, Cripe LH, King E, Pratt J, Benson DW, Hor KN. Left ventricular noncompaction in Duchenne muscular dystrophy. <span><span class="ref-journal">J Cardiovasc Magn Reson. </span>2013;<span class="ref-vol">15</span>:67.</span> [<a href="/pmc/articles/PMC3750745/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3750745</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23914774" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23914774</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.steward.2019.6">Steward CG, Groves SJ, Taylor CT, Maisenbacher MK, Versluys B, Newbury-Ecob RA, Ozsahin H, Damin MK, Bowen VM, McCurdy KR, Mackey MC, Bolyard AA, Dale DC. Neutropenia in Barth syndrome: characteristics, risks, and management. <span><span class="ref-journal">Curr Opin Hematol. </span>2019;<span class="ref-vol">26</span>:6–15.</span> [<a href="/pmc/articles/PMC6392059/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6392059</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30451719" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30451719</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.steward.2010.970">Steward CG, Newbury-Ecob RA, Hastings R, Smithson SF, Tsai-Goodman B, Quarrell OW, Kulik W, Wanders R, Pennock M, Williams M, Cresswell JL, Gonzalez IL, Brennan P. Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth. <span><span class="ref-journal">Prenat Diagn. </span>2010;<span class="ref-vol">30</span>:970–6.</span> [<a href="/pmc/articles/PMC2995309/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2995309</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20812380" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20812380</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.storch.2009.137">Storch EA, Keeley M, Merlo LJ, St Amant JB, Jacob M, Storch JF, Spencer C, Byrne BJ. Psychosocial functioning in youth with Barth syndrome. <span><span class="ref-journal">Child Health Care. </span>2009;<span class="ref-vol">38</span>:137–56.</span> [<a href="/pmc/articles/PMC2929969/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2929969</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20808735" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20808735</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.takeda.2011.1481">Takeda A, Sudo A, Yamada M, Yamazawa H, Izumi G, Nishino I, Ariga T. Barth syndrome diagnosed in the subclinical stage of heart failure based on the presence of lipid storage myopathy and isolated noncompaction of the ventricular myocardium. <span><span class="ref-journal">Eur J Pediatr. </span>2011;<span class="ref-vol">170</span>:1481–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21932011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21932011</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.thompson.2016.1001">Thompson WR, DeCroes B, McClellan R, Rubens J, Vaz FM. New targets for monitoring and therapy in Barth syndrome. Kristaponis K, Avramopoulos D, Vernon HJ. <span><span class="ref-journal">Genet Med. </span>2016;<span class="ref-vol">18</span>:1001–10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26845103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26845103</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.valianpour.2005.1182">Valianpour F, Mitsakos V, Schlemmer D, Towbin JA, Taylor JM, Ekert PG, Thorburn DR, Munnich A, Wanders RJ, Barth PG, Vaz FM. Monolysocardiolipins accumulate in Barth syndrome but do not lead to enhanced apoptosis. <span><span class="ref-journal">J Lipid Res. </span>2005;<span class="ref-vol">46</span>:1182–95.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15805542" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15805542</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.van_werkhoven.2006.2346">van Werkhoven MA, Thorburn DR, Gedeon AK, Pitt JJ. Monolysocardiolipin in cultured fibroblasts is a sensitive and specific marker for Barth Syndrome. <span><span class="ref-journal">J Lipid Res. </span>2006;<span class="ref-vol">47</span>:2346–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16873891" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16873891</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.vernon.2013">Vernon H, McClellan R, Cordova A, Kelley RI, Sandlers Y. Biochemical and hematologic laboratory studies in a cohort of patients with Barth syndrome. Boston, MA: American Society of Human Genetics Annual Meeting. Abstract available <a href="https://www.barthsyndrome.org/file_download/inline/51dabe81-de22-44ee-bc4a-b962dc99cc77" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a>. 2013. Accessed 10-25-22.</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.vernon.2014.143">Vernon HJ, Sandlers Y, McClellan R, Kelley RI. Clinical laboratory studies in Barth Syndrome. <span><span class="ref-journal">Mol Genet Metab. </span>2014;<span class="ref-vol">112</span>:143–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24751896" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24751896</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.wortmann.2013a.923">Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. <span><span class="ref-journal">J Inherit Metab Dis. </span>2013a;<span class="ref-vol">36</span>:923–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23296368" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23296368</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.wortmann.2013b.913">Wortmann SB, Kluijtmans LA, Rodenburg RJ, Sass JO, Nouws J, van Kaauwen EP, Kleefstra T, Tranebjaerg L, de Vries MC, Isohanni P, Walter K, Alkuraya FS, Smuts I, Reinecke CJ, van der Westhuizen FH, Thorburn D, Smeitink JA, Morava E, Wevers RA. 3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients. <span><span class="ref-journal">J Inherit Metab Dis. </span>2013b;<span class="ref-vol">36</span>:913–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23355087" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23355087</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.wortmann.2010.1079">Wortmann SB, Kremer BH, Graham A, Willemsen MA, Loupatty FJ, Hogg SL, Engelke UF, Kluijtmans LA, Wanders RJ, Illsinger S, Wilcken B, Cruysberg JR, Das AM, Morava E, Wevers RA. 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. <span><span class="ref-journal">Neurology. </span>2010;<span class="ref-vol">75</span>:1079–83.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20855850" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20855850</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.yancy.2017.628">Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. <span><span class="ref-journal">J Card Fail. </span>2017;<span class="ref-vol">23</span>:628–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28461259" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28461259</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="barth.REF.yen.2008.941">Yen TY, Hwu W-L, Chien Y-H, Wu MH, Lin MT, Tsao LY, Hsieh WS, Lee NC. Acute metabolic decompensation and sudden death in Barth syndrome: report of a family and a literature review. <span><span class="ref-journal">Eur J Pediatr. </span>2008;<span class="ref-vol">167</span>:941–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17846786" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17846786</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK247162/?report=reader">PubReader</a></li><li><a href="/books/NBK247162/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK247162" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK247162" style="display:none" title="Cite this Page"><div class="bk_tt">Ferreira C, Pierre G, Thompson R, et al. Barth Syndrome. 2014 Oct 9 [Updated 2020 Jul 9]. 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Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK247162/pdf/Bookshelf_NBK247162.pdf">PDF version of this page</a> (632K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#barth.Abstract" ref="log$=inpage&link_id=inpage">Abstract</a></li><li><a href="#barth.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#barth.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#barth.Genetically_Related_Allelic_Disord" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#barth.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#barth.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#barth.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#barth.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#barth.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#barth.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#barth.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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