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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Fumarate Hydratase Deficiency" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/04/23" /><meta name="citation_author" content="David Coman" /><meta name="citation_author" content="Kamil R Kranc" /><meta name="citation_author" content="John Christodoulou" /><meta name="citation_pmid" content="20301679" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1506/" /><meta name="citation_keywords" content="Fumarase Deficiency" /><meta name="citation_keywords" content="Fumaric Aciduria" /><meta name="citation_keywords" content="Fumaric Aciduria" /><meta name="citation_keywords" content="Fumarase Deficiency" /><meta name="citation_keywords" content="Fumarate hydratase, mitochondrial" /><meta name="citation_keywords" content="FH" /><meta name="citation_keywords" content="Fumarate Hydratase Deficiency" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Fumarate Hydratase Deficiency" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="David Coman" /><meta name="DC.Contributor" content="Kamil R Kranc" /><meta name="DC.Contributor" content="John Christodoulou" /><meta name="DC.Date" content="2020/04/23" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1506/" /><meta name="description" content="Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported." /><meta name="og:title" content="Fumarate Hydratase Deficiency" /><meta name="og:type" content="book" /><meta name="og:description" content="Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. 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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="#__NBK1506_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1506_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/fcmd/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/g6pc3-def/" 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="_NBK1506_"><span class="title" itemprop="name">Fumarate Hydratase Deficiency</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Fumarase Deficiency, Fumaric Aciduria</div><p class="contrib-group"><span itemprop="author">David Coman</span>, MBBS, MPhil, FRAC, <span itemprop="author">Kamil R Kranc</span>, MD, DPhil, and <span itemprop="author">John Christodoulou</span>, MBBS PhD.</p><a data-jig="ncbitoggler" href="#__NBK1506_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1506_ai__"><div class="contrib half_rhythm"><span itemprop="author">David Coman</span>, MBBS, MPhil, FRAC<div class="affiliation small">Professor, Department of Metabolic Medicine
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Queensland Children’s Hospital
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Brisbane, Australia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ua.vog.dlq.htlaeh@namoc.divad" class="oemail">ua.vog.dlq.htlaeh@namoc.divad</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Kamil R Kranc</span>, MD, DPhil<div class="affiliation small">Laboratory of Haematopoietic Stem Cell & Leukaemia Biology
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Centre for Haemato-Oncology
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Barts Cancer Institute
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Queen Mary University of London
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London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lumq@cnark.limak" class="oemail">ku.ca.lumq@cnark.limak</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">John Christodoulou</span>, MBBS PhD<div class="affiliation small">Director, Genetics Research
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Murdoch Children’s Research Institute;
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Chair of Genomic Medicine, Department of Paediatrics
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University of Melbourne
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Melbourne, Australia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ua.ude.ircm@uoluodotsirhc.nhoj" class="oemail">ua.ude.ircm@uoluodotsirhc.nhoj</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">July 5, 2006</span>; Last Update: <span itemprop="dateModified">April 23, 2020</span>.</p><p><em>Estimated reading time: 21 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="fum.Summary" itemprop="description"><h2 id="_fum_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis, combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency. The diagnosis of FH deficiency is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with reduced fumarate hydratase enzyme activity in fibroblasts or leukocytes and/or <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>FH</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Evaluation and management by a pediatric neurologist to treat seizures; gastrostomy tube to optimize nutrition and prevent aspiration in hypotonic or lethargic children; feeding therapy as needed; special needs services to address developmental deficits; physical therapy to minimize contractures; wheelchair and/or other mobility devices; management of scoliosis by orthopedist.</p><p><i>Prevention of primary manifestations:</i> To date, there is limited information regarding use of a high-fat/low-carbohydrate diet with 60% of the dietary energy goals coming from fat, 30% from carbohydrate, and 10% from protein.</p><p><i>Surveillance:</i> At least annual evaluations by pediatric neurology and physical medicine; periodic evaluation by orthopedist to monitor contractures and scoliosis; assessment of visual acuity by ophthalmologist.</p><p><i>Agents/circumstances to avoid</i>: The ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with FH deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.</p><p><i>Evaluation of relatives at risk:</i> If the <i>FH</i> pathogenic variants in the family are known, it is appropriate to consider offering <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> to relatives who may be at risk for hereditary leiomyomatosis and renal cell cancer.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>FH deficiency is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. When both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>FH</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of having FH deficiency, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> <i>FH</i> pathogenic variants. Heterozygotes are at risk of developing hereditary leiomyomatosis and renal cell cancer. Once the <i>FH</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a> detection for at-risk relatives and molecular genetic <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible. Biochemical prenatal testing by measurement of fumarate hydratase enzyme activity is also possible but may be problematic as some affected fetuses have considerable residual fumarate hydratase enzyme activity.</p></div></div><div id="fum.Diagnosis"><h2 id="_fum_Diagnosis_">Diagnosis</h2><div id="fum.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Fumarate hydratase (FH) deficiency <b>should be suspected</b> in individuals with the following clinical, laboratory, and imaging findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor, and coma)</div></li><li class="half_rhythm"><div>Seizures, present in many but not all affected individuals</div></li><li class="half_rhythm"><div>Intellectual disability / developmental delay</div></li><li class="half_rhythm"><div>Dysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes</div></li></ul><p>
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<b>Laboratory findings</b>
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</p><ul><li class="half_rhythm"><div>Finding of isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency.</div></li><li class="half_rhythm"><div>Reduced fumarate hydratase enzyme activity. Fumarate hydratase enzyme activity can be measured in fibroblasts or leukocytes. Fumarate hydratase enzyme activity in severely affected individuals is often less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some affected individuals can be 11%-35% of the control mean. FH deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form (see <a href="#fum.Molecular_Genetics">Molecular Genetics</a>).</div></li></ul><p><b>Imaging findings.</b> Abnormalities on brain MRI examination, including enlarged ventricles and polymicrogyria, may not be present in mildly affected individuals.</p></div><div id="fum.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of FH deficiency <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with reduced fumarate hydratase enzyme activity in fibroblasts or leukocytes and/or <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>FH</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1506/table/fum.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfumTmoleculargenetictestingusedin">Table 1</a>).</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 determines 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 FH deficiency is broad, individuals with the distinctive findings described in <a href="#fum.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#fum.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with seizures and/or neonatal encephalopathy are more likely to be diagnosed using genomic testing (see <a href="#fum.Option_2">Option 2</a>).</p><div id="fum.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of FH deficiency, <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>FH</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. If only one or 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 (multi)exon and whole-gene deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A seizure and/or neonatal encephalopathy</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>FH</i> and other genes of interest (see <a href="#fum.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/NBK1506/table/fum.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfumTmoleculargenetictestingusedin">Table 1</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="fum.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 seizures and/or intellectual disability, <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="fum.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Fumarate Hydratase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1506/table/fum.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fum.T.molecular_genetic_testing_used_in_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_fum.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_fum.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_fum.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FH</i>
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</td><td headers="hd_h_fum.T.molecular_genetic_testing_used_in_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_fum.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99%</td></tr><tr><td headers="hd_h_fum.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>4</sup></td><td headers="hd_h_fum.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 5.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="fum.TF.1.1"><p class="no_margin">See <a href="/books/NBK1506/#fum.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="fum.TF.1.2"><p class="no_margin">See <a href="#fum.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="fum.TF.1.3"><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="fum.TF.1.4"><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 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><dt>5. </dt><dd><div id="fum.TF.1.5"><p class="no_margin">A whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> in an individual with fumarate hydratase deficiency was reported by <a class="bk_pop" href="#fum.REF.mroch.2012.155">Mroch et al [2012]</a> and large <i>FH</i> deletions have been reported in <a href="/books/n/gene/hlrcc/">hereditary leiomyomatosis with renal cell cancer</a> [<a class="bk_pop" href="#fum.REF.tomlinson.2002.406">Tomlinson et al 2002</a>] (see <a href="#fum.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>).</p></div></dd></dl></div></div></div></div></div></div><div id="fum.Clinical_Characteristics"><h2 id="_fum_Clinical_Characteristics_">Clinical Characteristics</h2><div id="fum.Clinical_Description"><h3>Clinical Description</h3><p>To date, approximately 50 individuals have been identified with fumarate hydratase (FH) deficiency [<a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>, <a class="bk_pop" href="#fum.REF.ottolenghi.2011.1046">Ottolenghi et al 2011</a>, <a class="bk_pop" href="#fum.REF.kimonis.2012.241">Kimonis et al 2012</a>, <a class="bk_pop" href="#fum.REF.mroch.2012.155">Mroch et al 2012</a>, <a class="bk_pop" href="#fum.REF.ezgu.2013.403">Ezgu et al 2013</a>, <a class="bk_pop" href="#fum.REF.saini.2013.535">Saini & Singhi 2013</a>, <a class="bk_pop" href="#fum.REF.tregoning.2013.1117">Tregoning et al 2013</a>, <a class="bk_pop" href="#fum.REF.ba_tu_.2014.74">Baştuğ et al 2014</a>, <a class="bk_pop" href="#fum.REF.vara.2014.e32">Vara et al 2014</a>, <a class="bk_pop" href="#fum.REF.ryder.2018.77">Ryder et al 2018</a>, <a class="bk_pop" href="#fum.REF.grocott.2020.504">Grocott et al 2020</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div id="fum.T.select_features_of_fumarate_hydrat" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Select Features of Fumarate Hydratase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1506/table/fum.T.select_features_of_fumarate_hydrat/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.T.select_features_of_fumarate_hydrat_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons<br />w/Feature</th><th id="hd_h_fum.T.select_features_of_fumarate_hydrat_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_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Antenatal manifestations</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12/51 (23%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Oligohydramnios, polyhydramnios, IUGR, maternal intrahepatic cholestasis,& preeclampsia</td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prematurity</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15/51 (30%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DD</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">44/51 (86%) <sup>1</sup></td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mild-moderate ID</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/51 (8%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">35/51 (68%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Seizures</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22/51 (43%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cortical visual impairment</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13/51 (25%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysmorphic facial features</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20/51 (39%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frontal bossing, depressed nasal bridge, anteverted nares</td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Microcephaly</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17/51 (33%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Macrocephaly</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10/51 (20%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Abnormal brain imaging</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">47/51 (92%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl MRI, CT, & antenatal ultrasound findings; most notably: cerebral atrophy, white matter volume loss, polymicrogyria</td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Acute metabolic perturbations</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/51 (8%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metabolic acidosis, lactic acidosis, hypoglycemia, hyperammonemia</td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hematologic abnormalities</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11/51 (22%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonatal polycythemia (9 persons); neutropenia (2 persons)</td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dystonic posturing</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/51 (8%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Excessive irritability</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3/51 (6%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hepatic involvement</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5/51 (10%)</td><td headers="hd_h_fum.T.select_features_of_fumarate_hydrat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cirrhosis, acute hepatic neonatal hepatic failure, biliary atresia</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth retardation</p></div></dd><dt>1. </dt><dd><div id="fum.TF.2.1"><p class="no_margin">Note: Some infants died in the neonatal period.</p></div></dd></dl></div></div></div><div id="fum.Fetal_Manifestations"><h4>Fetal Manifestations</h4><p>Few clinical reports comment on complications of affected pregnancies. However, polyhydramnios, oligohydramnios, intrauterine growth retardation, and premature birth (typically at 33-36 weeks' gestation) are reported in approximately one third of affected pregnancies [<a class="bk_pop" href="#fum.REF.coughlin.1998.254">Coughlin et al 1998</a>, <a class="bk_pop" href="#fum.REF.maradin.2006.683">Maradin et al 2006</a>, <a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>, <a class="bk_pop" href="#fum.REF.saini.2013.535">Saini & Singhi 2013</a>]. Enlarged cerebral ventricles and other brain abnormalities have been identified by fetal ultrasound [<a class="bk_pop" href="#fum.REF.chan.2017.79">Chan et al 2017</a>].</p></div><div id="fum.Neonatal_and_EarlyInfantile_Encephal"><h4>Neonatal and Early-Infantile Encephalopathy</h4><p>Newborns with FH deficiency may be symptomatic immediately following delivery or may appear normal at birth and be discharged home from the nursery without recognized problems [<a class="bk_pop" href="#fum.REF.phillips.2006.150">Phillips et al 2006</a>]. If symptoms are not apparent at birth, affected infants show severe neurologic abnormalities within age one week to one month, including poor feeding, failure to thrive, and hypotonia. These infants have poor eye contact and variable degrees of depressed consciousness including lethargy, stupor, and even coma. Head and neck control may be entirely absent. Infants gain weight slowly and may require tube feedings.</p><p>Epileptic seizures are common (40%-80%), with variable age of onset and seizure type [<a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al 2000</a>, <a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>]. Infantile spasms accompanied by hypsarrhythmia on EEG have been reported [<a class="bk_pop" href="#fum.REF.remes.2004.550">Remes et al 2004</a>, <a class="bk_pop" href="#fum.REF.loeffen.2005.799">Loeffen et al 2005</a>]. Seizures are often resistant to treatment.</p></div><div id="fum.Dysmorphic_Facial_Features"><h4>Dysmorphic Facial Features</h4><p>Abnormal facial features with a spectrum of specific findings have been widely reported and should be regarded as a hallmark feature of this condition (although perhaps not universal). Common features (>50% of affected individuals) include depressed nasal bridge, frontal bossing, and widely spaced eyes [<a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>]. Less frequent features (<50%) include cleft ala nasi or anteverted nares, ear anomalies, or narrow forehead [<a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>].</p></div><div id="fum.Head_Size"><h4>Head Size</h4><p>Head size has been reported as microcephalic in 36% of all affected individuals [<a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>]. However, in one large kindred (8 affected individuals in 1 <a class="def" href="/books/n/gene/glossary/def-item/consanguineous/">consanguineous</a> family), 88% (7 of 8 affected individuals) were reported to have "relative macrocephaly," since head sizes were within the normal range, but in association with brain imaging findings of cerebral atrophy and mild communicating hydrocephalus (enlarged extra-axial CSF spaces) [<a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al 2000</a>]. That is, most children with FH deficiency appear have abnormally limited brain growth.</p></div><div id="fum.Brain_Imaging_Findings"><h4>Brain Imaging Findings</h4><p>The most common finding is a small brain, representative of cerebral underdevelopment. This may be described by the neuroradiologist as cerebral atrophy (73% of all individuals summarized by <a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al [2010]</a>), or ventriculomegaly (82% of all individuals summarized by <a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al [2010]</a>). Brain volume loss (or more likely lack of brain volume development) can be accompanied by a relative decrease in CSF reabsorption, leading to a normal head size with a small brain but modestly expanded CSF compartments. In the series of <a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al [2000]</a>, two such individuals were shunted for possible "hydrocephalus" leading to collapse of the CSF compartments and secondary microcephaly without clinical improvement.</p><p>Additional findings on MRI can include nonspecific white matter abnormalities, described as either delayed myelination or hypomyelination [<a class="bk_pop" href="#fum.REF.phillips.2006.150">Phillips et al 2006</a>], deficient closure of the Sylvian opercula [<a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al 2000</a>, <a class="bk_pop" href="#fum.REF.phillips.2006.150">Phillips et al 2006</a>], and a hypoplastic brain stem [<a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al 2000</a>, <a class="bk_pop" href="#fum.REF.phillips.2006.150">Phillips et al 2006</a>, <a class="bk_pop" href="#fum.REF.tregoning.2013.1117">Tregoning et al 2013</a>]. Abnormalities of the corpus callosum are also reported, including thinning [<a class="bk_pop" href="#fum.REF.maradin.2006.683">Maradin et al 2006</a>, <a class="bk_pop" href="#fum.REF.phillips.2006.150">Phillips et al 2006</a>] and absence [<a class="bk_pop" href="#fum.REF.coughlin.1998.254">Coughlin et al 1998</a>]. Hyperintense basal ganglia lesions in the caudate and thalamic nuclei, and elevated lactate on MRS have also been reported [<a class="bk_pop" href="#fum.REF.tregoning.2013.1117">Tregoning et al 2013</a>]. Diffuse bilateral polymicrogyria of the cerebral cortex has also been reported, a universal feature in the eight affected individuals from one kindred reported by <a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al [2000]</a> but also noted in three additional unrelated individuals [<a class="bk_pop" href="#fum.REF.zeng.2006.1004">Zeng et al 2006</a>, <a class="bk_pop" href="#fum.REF.ottolenghi.2011.1046">Ottolenghi et al 2011</a>].</p></div><div id="fum.Acute_Metabolic_Derangements"><h4>Acute Metabolic Derangements</h4><p>Acute metabolic crises with findings such as hypoglycemia, ketosis, hyperammonemia, or acidosis are rarely observed in individuals with FH deficiency [<a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>, <a class="bk_pop" href="#fum.REF.saini.2013.535">Saini & Singhi 2013</a>, <a class="bk_pop" href="#fum.REF.ba_tu_.2014.74">Baştuğ et al 2014</a>].</p></div><div id="fum.Other_Clinical_Features"><h4>Other Clinical Features</h4><p>Other findings can include neonatal polycythemia [<a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al 2000</a>], recurrent neutropenia [<a class="bk_pop" href="#fum.REF.tregoning.2013.1117">Tregoning et al 2013</a>, <a class="bk_pop" href="#fum.REF.guitart.2017.719">Guitart et al 2017</a>], recurrent vomiting with hepatosplenomegaly [<a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>, <a class="bk_pop" href="#fum.REF.tregoning.2013.1117">Tregoning et al 2013</a>], and pancreatitis [<a class="bk_pop" href="#fum.REF.phillips.2006.150">Phillips et al 2006</a>]. Visual disturbances and optic nerve hypoplasia were described in two families [<a class="bk_pop" href="#fum.REF.kerrigan.2000.583">Kerrigan et al 2000</a>, <a class="bk_pop" href="#fum.REF.saini.2013.535">Saini & Singhi 2013</a>]. Birth defects involving other organ systems are uncommon.</p></div><div id="fum.Clinical_Course"><h4>Clinical Course</h4><p>The clinical outcome for individuals with FH deficiency is not favorable. Many individuals do not survive infancy, or may die of secondary complications (e.g., respiratory failure) during the first decade of life [<a class="bk_pop" href="#fum.REF.loeffen.2005.799">Loeffen et al 2005</a>]. Many children are unable to feed successfully, with failure to gain weight and increased risk for aspiration. Accordingly, feedings administered through gastrostomy tube may be required.</p><p>Over time, severely affected children (usually nonverbal and nonambulatory) develop evidence of spasticity, and consequently are at risk for contractures and orthopedic deformities including scoliosis. Extrapyramidal motor features, including athetosis and dystonic posturing, can also be observed. Epileptic seizures often become more frequent and less responsive to treatment. Seizures may occur daily in some individuals.</p><p>However, less severely affected children, who may be ambulatory and capable of engaging in special needs school programs (despite the presence of bilateral polymicrogyria), have also been reported [<a class="bk_pop" href="#fum.REF.ottolenghi.2011.1046">Ottolenghi et al 2011</a>]. Consequently, counseling of families with children with FH deficiency should include recognition of the range of severity.</p></div><div id="fum.Heterozygotes"><h4>Heterozygotes</h4><p>Most <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parents are healthy. However, the finding of cutaneous leiomyomata without uterine fibroids in the mother of an affected child [<a class="bk_pop" href="#fum.REF.tomlinson.2002.406">Tomlinson et al 2002</a>], a report of a mother with uterine myomas [<a class="bk_pop" href="#fum.REF.maradin.2006.683">Maradin et al 2006</a>], the death of the mother of an affected child from "renal cell carcinoma" in a third family [VE Shih, unpublished], and the detection of renal carcinoma in an asymptomatic obligate heterozygous female raise the possibility of increased risk for HLRCC in the heterozygous relatives of children with FH deficiency (see <a href="/books/n/gene/hlrcc/">Hereditary Leiomyomatosis with Renal Cell Cancer</a>).</p></div></div><div id="fum.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been identified.</p></div><div id="fum.Prevalence"><h3>Prevalence</h3><p>FH deficiency is rare. Fewer than 100 individuals have been reported. The disorder occurs in individuals of different ethnic backgrounds.</p></div></div><div id="fum.Genetically_Related_Allelic_Disorder"><h2 id="_fum_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p><a href="/books/n/gene/hlrcc/">Hereditary leiomyomatosis with renal cell cancer</a> (HLRCC) resulting from <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a> of fumarate hydratase caused by <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> <i>FH</i> variants is characterized by cutaneous leiomyomata, uterine leiomyomata (fibroids), and renal cancer. Renal tumors are usually unilateral, solitary, and aggressive and range from type 2 papillary to tubulo-papillary to collecting-duct carcinomas. They occur in about 10%-16% of individuals with HLRCC.</p><p>Sporadic tumors occurring as single tumors in the absence of any other findings of hereditary leiomyomatosis and renal cell cancer were found to have <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> somatic pathogenic variants in <i>FH</i> that were <b>not</b> present in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a>. For more information see <a href="#fum.Cancer_and_Benign_Tumors">Cancer and Benign Tumors</a>.</p></div><div id="fum.Differential_Diagnosis"><h2 id="_fum_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Increased excretion of fumaric acid in urine.</b> Transient excretion of fumaric acid in urine is common in young infants and has been observed in metabolically stressed infants, such as those with cardiac failure resulting from severe <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> cardiac anomalies. When the infant with cardiac failure is in stable condition, urine organic acid analysis should be repeated to confirm the presence of increased isolated fumaric acid excretion.</p><p>Increased excretion of fumaric acid along with other citric acid intermediates is seen in mitochondrial disorders, including subacute necrotizing encephalomyelopathy (see <a href="/books/n/gene/narp/">Mitochondrial DNA-Associated Leigh Syndrome and NARP</a> and <a href="/books/n/gene/leigh-nucl-ov/">Nuclear Gene-Encoded Leigh Syndrome Overview</a>) and deficiencies of the pyruvate dehydrogenase complex [<a class="bk_pop" href="#fum.REF.patel.2012.385">Patel et al 2012</a>] (see <a href="/books/n/gene/pdhc-def-ov/">Primary Pyruvate Dehydrogenase Complex Deficiency Overview</a>).</p><p><b>Polymicrogyria.</b> See <a href="/books/n/gene/poly/">Polymicrogyria Overview</a>.</p></div><div id="fum.Management"><h2 id="_fum_Management_">Management</h2><div id="fum.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with fumarate hydratase (FH) deficiency, the evaluations summarized in <a href="/books/NBK1506/table/fum.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobfumTrecommendedevaluationsfollowing">Table 3</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="fum.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Fumarate Hydratase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1506/table/fum.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.T.recommended_evaluations_following_lrgtbl__"><table><thead><tr><th id="hd_h_fum.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_fum.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_fum.T.recommended_evaluations_following_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_fum.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by pediatric neurologist</td><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval will likely incl brain MRI exam.</td></tr><tr><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Nutrition</b>
|
||
</td><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding assessment & eval of nutritional status</td><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_fum.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></div><div id="fum.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="fum.T.treatment_of_manifestations_in_ind" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Fumarate Hydratase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1506/table/fum.T.treatment_of_manifestations_in_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.T.treatment_of_manifestations_in_ind_lrgtbl__"><table><thead><tr><th id="hd_h_fum.T.treatment_of_manifestations_in_ind_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_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_fum.T.treatment_of_manifestations_in_ind_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_fum.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Seizures</b>
|
||
</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval & mgmt by pediatric neurologist</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ketogenic diet is considered contraindicated.</div></li><li class="half_rhythm"><div>Seizures are often difficult to control.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental</b>
|
||
<br />
|
||
<b>delay</b>
|
||
</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastrostomy tube feeding</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be appropriate in hypotonic &/or lethargic children w/feeding difficulties &/or aspiration</td></tr><tr><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Feeding therapy</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be helpful in some affected persons</td></tr><tr><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Special needs services</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In persons w/significant developmental deficits (incl impairment of motor, language, & social development)</td></tr><tr><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Contractures</b>
|
||
</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical therapy</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To minimize contractures</td></tr><tr><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Wheelchair &/or other mobility device</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Can be useful for some persons</td></tr><tr><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Scoliosis</b>
|
||
</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mgmt per orthopedist</td><td headers="hd_h_fum.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></div><div id="fum.Prevention_of_Primary_Manifestations"><h3>Prevention of Primary Manifestations</h3><p>One individual with FH deficiency has been treated with a high-fat/low-carbohydrate diet with 60% of the dietary energy goals coming from fat, 30% from carbohydrate, and 10% from protein [<a class="bk_pop" href="#fum.REF.ryder.2018.77">Ryder et al 2018</a>]. This child presented at age six months, began the dietary treatment at age 14 months, and remains stable with mild intellectual impairment and well-controlled seizures. Whether the milder disease trajectory is a consequence of the diet remains unclear.</p></div><div id="fum.Surveillance"><h3>Surveillance</h3><div id="fum.T.recommended_surveillance_for_indiv" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Fumarate Hydratase Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1506/table/fum.T.recommended_surveillance_for_indiv/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.T.recommended_surveillance_for_indiv_lrgtbl__"><table><thead><tr><th id="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_fum.T.recommended_surveillance_for_indiv_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_fum.T.recommended_surveillance_for_indiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Seizures</b>
|
||
</td><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by pediatric neurologist</td><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually to monitor for &/or treat epilepsy</td></tr><tr><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal complications</b>
|
||
</td><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical medicine eval</td><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually to monitor for equipment needs & to monitor for &/or treat manifestations of spasticity</td></tr><tr><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Orthopedics eval</td><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed to monitor contractures &/or scoliosis</td></tr><tr><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ophthalmology</b>
|
||
</td><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology eval for visual acuity & nystagmus</td><td headers="hd_h_fum.T.recommended_surveillance_for_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As recommended by ophthalmologist</td></tr></tbody></table></div></div></div><div id="fum.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>The ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with FH deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.</p></div><div id="fum.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>If the <i>FH</i> pathogenic variants in the family are known, it is appropriate to consider offering <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> to relatives who may be at risk for <a href="/books/n/gene/hlrcc/">hereditary leiomyomatosis and renal cell cancer</a> (see <a href="#fum.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>).</p><p>See <a href="#fum.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="fum.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Increasingly sophisticated models of mitochondrial function are being used to study the metabolic derangements associated with identified defects of intermediary metabolism, including FH deficiency [<a class="bk_pop" href="#fum.REF.smith.2011.102">Smith & Robinson 2011</a>]. These models may suggest treatment interventions with supplements or dietary changes that are not presently established.</p><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 access to information on clinical studies for a wide range of diseases and conditions.</p></div><div id="fum.Other"><h3>Other</h3><p>No significant clinical or biochemical improvement was noted by treatment with a protein-restricted diet [unpublished data]. A brief therapeutic trial of a low-protein diet in one mildly affected individual with FH deficiency did not alter urinary excretion of fumaric acid or improve clinical signs [<a class="bk_pop" href="#fum.REF.kimonis.2012.241">Kimonis et al 2012</a>].</p></div></div><div id="fum.Genetic_Counseling"><h2 id="_fum_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="fum.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Fumarate hydratase (FH) deficiency is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="fum.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for one <i>FH</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Two exceptions have been reported:</div><ul><li class="half_rhythm"><div>A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's <i>FH</i> pathogenic variants [<a class="bk_pop" href="#fum.REF.coughlin.1998.254">Coughlin et al 1998</a>]. The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> most likely had FH deficiency as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the paternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>, although <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> was not ruled out.</div></li><li class="half_rhythm"><div>In another family, FH deficiency resulted from partial <a class="def" href="/books/n/gene/glossary/def-item/uniparental-isodisomy/">uniparental isodisomy</a> of <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 1 [<a class="bk_pop" href="#fum.REF.zeng.2006.1004">Zeng et al 2006</a>]. Thus, only one of the parents carried an <i>FH</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li></ul></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> are at risk of developing <a href="/books/n/gene/hlrcc/">hereditary leiomyomatosis and renal cell cancer</a> (HLRCC). Lifelong kidney surveillance of heterozygotes is appropriate and may reduce morbidity and mortality associated with renal cancer (see Clinical Description, <a href="#fum.Heterozygotes">Heterozygotes</a>) [<a class="bk_pop" href="#fum.REF.menko.2014.637">Menko et al 2014</a>, <a class="bk_pop" href="#fum.REF.chan.2017.79">Chan et al 2017</a>].</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>FH</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>:</div><ul><li class="half_rhythm"><div>Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>FH</i>. Each sib also has a 50% chance of being <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a>.</div></li><li class="half_rhythm"><div>Heterozygotes are at risk of developing HLRCC.</div></li></ul></li><li class="half_rhythm"><div>When FH deficiency occurs as the result of an unusual mechanism (e.g., a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in one <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> or <a class="def" href="/books/n/gene/glossary/def-item/uniparental-isodisomy/">uniparental isodisomy</a>), the risk to the sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is based on the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> associated with that mechanism.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Many individuals with FH deficiency do not survive childhood; no affected individuals with offspring have been reported.</p><p><b>Other family members.</b> Sibs of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents are at 50% risk of having a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>FH</i>. Such heterozygotes are at risk of developing HLRCC.</p></div><div id="fum.Heterozygote_Detection"><h3>Heterozygote Detection</h3><p><b>Molecular genetic testing.</b> Heterozygote testing for at-risk relatives requires prior identification of the <i>FH</i> pathogenic variants in the family.</p><p><b>Biochemical testing.</b> Enzyme assay may not be informative for <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a> detection because the heterozygote range and the normal range overlap.</p></div><div id="fum.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#fum.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 of allelic disorders associated with <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic variants in <i>FH</i> (i.e., HLRCC).</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 <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, allelic variants, 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 genetic alteration/s are unknown).</p></div><div id="fum.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>FH</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>
|
||
<b>Biochemical testing</b>
|
||
</p><ul><li class="half_rhythm"><div><b>Fumaric acid detection.</b> Prenatal testing for a pregnancy at increased risk for FH deficiency is possible by detection of increased fumaric acid in amniotic fluid at approximately 15 to 18 weeks' gestation [<a class="bk_pop" href="#fum.REF.manning.2000.757">Manning et al 2000</a>]. However, such studies are not diagnostic, and should be reviewed with extreme caution.</div></li><li class="half_rhythm"><div><b>Fumarate hydratase enzyme activity.</b> Prenatal testing for a pregnancy at increased risk for FH deficiency is possible by measurement of fumarate hydratase enzyme activity in uncultured and cultured chorionic villi. Although analysis of fumarate hydratase enzyme activity can be performed using cultured fetal cells obtained by amniocentesis [<a class="bk_pop" href="#fum.REF.manning.2000.757">Manning et al 2000</a>] or chorionic villus sampling at approximately ten to 12 weeks' gestation [<a class="bk_pop" href="#fum.REF.coughlin.1998.254">Coughlin et al 1998</a>], some affected fetuses have considerable residual fumarate hydratase enzyme activity, making <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> using enzyme testing problematic.</div></li></ul><p>Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.</p><p><b>Ultrasound examination.</b> Enlarged cerebral ventricles and certain fetal brain abnormalities (agenesis of the corpus callosum and Dandy-Walker cyst) associated with FH deficiency can be identified by ultrasound examination [<a class="bk_pop" href="#fum.REF.chan.2017.79">Chan et al 2017</a>].</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 use of prenatal testing is a personal decision, discussion of these issues may be helpful.</p></div></div><div id="fum.Resources"><h2 id="_fum_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>United Mitochondrial Disease Foundation</b>
|
||
</div><div><b>Phone:</b> 888-317-UMDF (8633)</div><div><b>Email:</b> info@umdf.org</div><div>
|
||
<a href="https://www.umdf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">umdf.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Epilepsy Society</b>
|
||
</div><div>
|
||
<a href="https://www.aesnet.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aesnet.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Epilepsy Foundation</b>
|
||
</div><div><b>Phone:</b> 800-332-1000; 866-748-8008</div><div>
|
||
<a href="https://www.epilepsy.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">epilepsy.com</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Metabolic Support UK</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> 0845 241 2173</div><div>
|
||
<a href="https://metabolicsupportuk.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">metabolicsupportuk.org</a>
|
||
</div></li></ul>
|
||
</div><div id="fum.Molecular_Genetics"><h2 id="_fum_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="fum.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Fumarate Hydratase Deficiency: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1506/table/fum.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_fum.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_fum.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_fum.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_fum.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_fum.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_fum.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_fum.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/2271" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>FH</i>
|
||
</a>
|
||
</td><td headers="hd_b_fum.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=2271" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">1q43</a>
|
||
</td><td headers="hd_b_fum.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P07954" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Fumarate hydratase, mitochondrial</a>
|
||
</td><td headers="hd_b_fum.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.LOVD.nl/FH" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TCA Cycle Gene Mutation Database (FH)</a>
|
||
</td><td headers="hd_b_fum.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=FH" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FH</a>
|
||
</td><td headers="hd_b_fum.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=FH[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FH</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="fum.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="fum.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Fumarate Hydratase Deficiency (<a href="/omim/136850,606812" 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/NBK1506/table/fum.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/136850" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">136850</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FUMARATE HYDRATASE; FH</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/606812" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">606812</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FUMARASE DEFICIENCY; FMRD</td></tr></tbody></table></div></div><div id="fum.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>FH</i> encodes for both mitochondrial and cytosolic FH enzyme <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a>, which catalyze hydration of fumarate to malate. Mitochondrial FH is an important part of the tricarboxylic acid cycle (TCA cycle, also known as Krebs cycle) and is required for efficient oxidative phosphorylation in the mitochondria. The cytosolic isoform of FH metabolizes fumarate produced in the urea cycle, in the purine nucleotide cycle, and during arginine synthesis.</p><p>FH deficiency results in a genetic block in Krebs cycle and the inability of cells to metabolize fumarate in the cytosol. As a consequence, fumarate is substantially accumulated intracellularly and extracellularly and in excessive levels it is toxic to the cells, thus causing multiple developmental defects.</p><p><b>Mechanism of disease causation.</b> Loss of function. Based on genotypes observed in affected individuals, it is likely that complete loss of enzyme activity is incompatible with life.</p><p><b>Notable <i>FH</i> variants.</b> Most disease-associated variants are concentrated at the C terminus of the FH enzyme [<a class="bk_pop" href="#fum.REF.allegri.2010.411">Allegri et al 2010</a>]. There are currently 281 unique variants reported in the Leiden Open Variation Database (LOVD 3.0), many of which are <a class="def" href="/books/n/gene/glossary/def-item/private/">private</a> (<a href="https://databases.lovd.nl/shared/genes/FH" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">databases.lovd.nl</a>).</p><p>The p.Lys477dup variant is the variant most frequently associated with FH deficiency [<a class="bk_pop" href="#fum.REF.coughlin.1998.254">Coughlin et al 1998</a>]; however, no functional studies have been reported. This variant is present in the population at a frequency higher than expected for a disease-causing variant; it is not associated with HLRCC (see <a href="#fum.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>) [<a class="bk_pop" href="#fum.REF.zhang.2020.103">Zhang et al 2020</a>]. Therefore, the functional consequence of p.Lys477dup is not understood at this time.</p><div id="fum.T.notable_fh_pathogenic_variants" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Notable <i>FH</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1506/table/fum.T.notable_fh_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fum.T.notable_fh_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000143.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000143<wbr style="display:inline-block"></wbr>.2</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000134.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000134<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1431_1433dupAAA <sup>1</sup></td><td headers="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Lys477dup <sup>1</sup></td><td headers="hd_h_fum.T.notable_fh_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common variant assoc w/FH deficiency (30% of fumarate hydratase deficiency-related pathogenic variants)</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="fum.TF.6.1"><p class="no_margin">The numbering system for the <i>FH</i> sequence has changed over the years; hence, the commonly seen AAA <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> in fumarate hydratase deficiency is referred to variously in the literature as 1302insAAA, 435insAAA, 435insK, 1433insAAA, and insK477.</p></div></dd></dl></div></div></div></div><div id="fum.Cancer_and_Benign_Tumors"><h3>Cancer and Benign Tumors</h3><p>Sporadic tumors (including 2 early-onset uterine leiomyomas and a soft tissue sarcoma of the lower limb) occurring as single tumors in the absence of any other findings of hereditary leiomyomatosis and renal cell cancer were found to have <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> somatic pathogenic variants in <i>FH</i> that were <b>not</b> present in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> [<a class="bk_pop" href="#fum.REF.kiuru.2002.4554">Kiuru et al 2002</a>, <a class="bk_pop" href="#fum.REF.lehtonen.2004.17">Lehtonen et al 2004</a>]. In these circumstances predisposition to these tumors is not heritable.</p><p>Loss of FH enzymatic activity leads to the accumulation of intracellular fumarate, which is thought to function as an oncometabolite, an intermediate of cellular metabolism that promotes cancer formation. Fumarate is known to competitively inhibit 2-oxoglutarate (2OG)-dependent oxygenases, including HIF prolyl hydroxylases, thus resulting in an increased stability of HIFs, which are thought to be oncogenic drivers in certain tumors. High levels of cytoplasmic fumarate also result in the modification of protein cysteine residues, forming S-(2-succinyl)-cysteine, in the process called succination, thereby affecting multiple cellular pathways. Furthermore, elevated fumarate succinates glutathione (GSH; a major cellular protection against reactive oxygen species), and by depleting the GSH pool it causes oxidative stress, a common feature of many cancers. While the exact causal mechanism by which elevated fumarate promotes cancer formation is not well defined, it is highly likely that fumarate synergistically affects multiple cellular pathways to exert its pathogenic effects.</p></div></div><div id="fum.References"><h2 id="_fum_References_">References</h2><div id="fum.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="fum.REF.allegri.2010.411">Allegri G, Fernandes MJ, Scalco FB, Correia P, Simoni RE, Llerena JC Jr, de Oliveira ML. Fumaric aciduria: an overview and the first Brazilian case report. <span><span class="ref-journal">J Inherit Metab Dis. </span>2010;<span class="ref-vol">33</span>:411–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20549362" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20549362</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.ba_tu_.2014.74">Baştuğ O, Kardaş F, Öztürk MA, Halis H, Memur Ş, Korkmaz L, Tağ Z, Güneş T. A rare cause of opistotonus; fumaric aciduria: The first case presentation in Turkey. <span><span class="ref-journal">Turk Pediatri Ars. </span>2014;<span class="ref-vol">49</span>:74–6.</span> [<a href="/pmc/articles/PMC4462270/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4462270</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26078636" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26078636</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.chan.2017.79">Chan MMY, Barnicoat A, Mumtaz F, Aitchison M, Side L, Brittain H, Bates AWH, Gale DP. Cascade fumarate hydratase mutation screening allows early detection of kidney tumour: a case report. <span><span class="ref-journal">BMC Med Genet. </span>2017;<span class="ref-vol">18</span>:79.</span> [<a href="/pmc/articles/PMC5530463/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5530463</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28747166" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28747166</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.coughlin.1998.254">Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE. Molecular analysis and prenatal diagnosis of human fumarase deficiency. <span><span class="ref-journal">Mol Genet Metab. </span>1998;<span class="ref-vol">63</span>:254–62.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9635293" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9635293</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.ezgu.2013.403">Ezgu F, Krejci P, Wilcox WR. Mild clinical presentation and prolonged survival of a patient with fumarase deficiency due to the combination of a known and a novel mutation in FH gene. <span><span class="ref-journal">Gene. </span>2013;<span class="ref-vol">524</span>:403–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23612258" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23612258</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.grocott.2020.504">Grocott O, Phanor SK, Fung F, Thibert RL, Berkmen MB. Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency. <span><span class="ref-journal">Am J Med Genet A. </span>2020;<span class="ref-vol">182</span>:504–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31746132" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31746132</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.guitart.2017.719">Guitart AV, Panagopoulou TI, Villacreces A, Vukovic M, Sepulveda C, Allen L, Carter RN, van de Lagemaat LN, Morgan M, Giles P, Sas Z, Gonzalez MV, Lawson H, Paris J, Edwards-Hicks J, Schaak K, Subramani C, Gezer D, Armesilla-Diaz A, Wills J, Easterbrook A, Coman D, So CW, O'Carroll D, Vernimmen D, Rodrigues NP, Pollard PJ, Morton NM, Finch A, Kranc KR. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions. <span><span class="ref-journal">J Exp Med. </span>2017;<span class="ref-vol">214</span>:719–35.</span> [<a href="/pmc/articles/PMC5339674/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5339674</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28202494" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28202494</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.kerrigan.2000.583">Kerrigan JF, Aleck KA, Tarby TJ, Bird CR, Heidenreich RA. Fumaric aciduria: clinical and imaging features. <span><span class="ref-journal">Ann Neurol. </span>2000;<span class="ref-vol">47</span>:583–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10805328" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10805328</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.kimonis.2012.241">Kimonis VE, Steller J, Sahai I, Grange DK, Shoemaker J, Zelaya BM, Mandell R, Shih K, Shih V. Mild fumarase deficiency and a trial of low protein diet. <span><span class="ref-journal">Mol Genet Metab. </span>2012;<span class="ref-vol">107</span>:241–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22595425" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22595425</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.kiuru.2002.4554">Kiuru M, Lehtonen R, Arola J, Salovaara R, Järvinen H, Aittomäki K, Sjöberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. <span><span class="ref-journal">Cancer Res. </span>2002;<span class="ref-vol">62</span>:4554–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12183404" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12183404</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.lehtonen.2004.17">Lehtonen R, Kiuru M, Vanharanta S, Sjöberg J, Aaltonen LM, Aittomäki K, Arola J, Butzow R, Eng C, Husgafvel-Pursiainen K, Isola J, Järvinen H, Koivisto P, Mecklin JP, Peltomäki P, Salovaara R, Wasenius VM, Karhu A, Launonen V, Nupponen NN, Aaltonen LA. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. <span><span class="ref-journal">Am J Pathol. </span>2004;<span class="ref-vol">164</span>:17–22.</span> [<a href="/pmc/articles/PMC1602244/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1602244</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14695314" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14695314</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.loeffen.2005.799">Loeffen J, Smeets R, Voit T, Hoffmann G, Smeitink J. Fumarase deficiency presenting with periventricular cysts. <span><span class="ref-journal">J Inherit Metab Dis. </span>2005;<span class="ref-vol">28</span>:799–800.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16151915" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16151915</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.manning.2000.757">Manning NJ, Olpin SE, Pollitt RJ, Downing M, Heeley AF, Young ID. Fumarate hydratase deficiency: increased fumaric acid in amniotic fluid of two affected pregnancies. <span><span class="ref-journal">J Inherit Metab Dis. </span>2000;<span class="ref-vol">23</span>:757–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11117439" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11117439</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.maradin.2006.683">Maradin M, Fumić K, Hansikova H, Tesarova M, Wenchich L, Dorner S, Sarnavka V, Zeman J, Barić I. Fumaric aciduria: mild phenotype in a 8-year-old girl with novel mutations. <span><span class="ref-journal">J Inherit Metab Dis. </span>2006;<span class="ref-vol">29</span>:683.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16972175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16972175</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.menko.2014.637">Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. <span><span class="ref-journal">Fam Cancer. </span>2014;<span class="ref-vol">13</span>:637–44.</span> [<a href="/pmc/articles/PMC4574691/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4574691</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25012257" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25012257</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.mroch.2012.155">Mroch AR, Laudenschlager M, Flanagan JD. Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency. <span><span class="ref-journal">Am J Med Genet A. </span>2012;<span class="ref-vol">158A</span>:155–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22069215" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22069215</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.ottolenghi.2011.1046">Ottolenghi C, Hubert L, Allanore Y, Brassier A, Altuzarra C, Mellot-Draznieks C, Bekri S, Goldenberg A, Veyrieres S, Boddaert N, Barbier V, Valayannopoulos V, Slama A, Chrétien D, Ricquier D, Marret S, Frebourg T, Rabier D, Munnich A, de Keyzer Y, Toulhoat H, de Lonlay P. Clinical and biochemical heterogeneity associated with fumarase deficiency. <span><span class="ref-journal">Hum Mutat. </span>2011;<span class="ref-vol">32</span>:1046–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21560188" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21560188</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.patel.2012.385">Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. <span><span class="ref-journal">Mol Genet Metab. </span>2012;<span class="ref-vol">106</span>:385–94.</span> [<a href="/pmc/articles/PMC4003492/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4003492</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22896851" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22896851</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.phillips.2006.150">Phillips TM, Gibson JB, Ellison DA. Fumarate hydratase deficiency in monozygotic twins. <span><span class="ref-journal">Pediatr Neurol. </span>2006;<span class="ref-vol">35</span>:150–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16876016" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16876016</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.remes.2004.550">Remes AM, Filppula SA, Rantala H, Leisti J, Ruokonen A, Sharma S, Juffer AH, Hiltunen JK. A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency. <span><span class="ref-journal">J Mol Med. </span>2004;<span class="ref-vol">82</span>:550–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15221078" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15221078</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.ryder.2018.77">Ryder B, Moore F, Mitchell A, Thompson S, Christodoulou J, Balasubramaniam S. Fumarase Deficiency: A safe and potentially disease modifying effect of high fat/low carbohydrate diet. <span><span class="ref-journal">JIMD Rep. </span>2018;<span class="ref-vol">40</span>:77–83.</span> [<a href="/pmc/articles/PMC6122040/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6122040</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29052812" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29052812</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.saini.2013.535">Saini AG, Singhi P. Infantile metabolic encephalopathy due to fumarase deficiency. <span><span class="ref-journal">J Child Neurol. </span>2013;<span class="ref-vol">28</span>:535–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22772160" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22772160</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.smith.2011.102">Smith AC, Robinson AJ. A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle. <span><span class="ref-journal">BMC Syst Biol. </span>2011;<span class="ref-vol">5</span>:102.</span> [<a href="/pmc/articles/PMC3152903/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3152903</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21714867" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21714867</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.tomlinson.2002.406">Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomäki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. <span><span class="ref-journal">Nat Genet. </span>2002;<span class="ref-vol">30</span>:406–10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11865300" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11865300</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.tregoning.2013.1117">Tregoning S, Salter W, Thorburn DR, Durkie M, Panayi M, Wu JY, Easterbrook A, Coman DJ. Fumarase deficiency in dichorionic diamniotic twins. <span><span class="ref-journal">Twin Res Hum Genet. </span>2013;<span class="ref-vol">16</span>:1117–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24182348" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24182348</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.vara.2014.e32">Vara R, Grammatikopoulos T, Gallagher C, Agalou S, Zen Y, Davenport M, Hadzic N. Fumarase deficiency associated with noninflammatory biliary atresia. <span><span class="ref-journal">J Pediatr Gastroenterol Nutr. </span>2014;<span class="ref-vol">58</span>:e32–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22922375" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22922375</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.zeng.2006.1004">Zeng WQ, Gao H, Brueton L, Hutchin T, Gray G, Chakrapani A, Olpin S, Shih VE. Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1. <span><span class="ref-journal">Am J Med Genet A. </span>2006;<span class="ref-vol">140</span>:1004–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16575891" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16575891</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fum.REF.zhang.2020.103">Zhang L, Walsh MF, Jairam S, Mandelker D, Zhong Y, Kemel Y, Chen YB, Musheyev D, Zehir A, Jayakumaran G, Brzostowski E, Birsoy O, Yang C, Li Y, Somar J, DeLair D, Pradhan N, Berger MF, Cadoo K, Carlo MI, Robson ME, Stadler ZK, Iacobuzio-Donahue CA, Joseph V, Offit K. Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma. <span><span class="ref-journal">Hum Mutat. </span>2020;<span class="ref-vol">41</span>:103–9.</span> [<a href="/pmc/articles/PMC6930334/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6930334</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31444830" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31444830</span></a>]</div></li></ul></div></div><div id="fum.Chapter_Notes"><h2 id="_fum_Chapter_Notes_">Chapter Notes</h2><div id="fum.Author_History"><h3>Author History</h3><p>Kirk Aleck, MD; Phoenix Children's Hospital (2013-2020)<br />John Christodoulou, MBBS, PhD (2020-present)<br />David Coman, MBBS, MPhil, FRAC (2020-present)<br />Clifton Ewbank, MD; University of California San Francisco – East Bay (2013-2020)<br />John F Kerrigan, MD; Phoenix Children's Hospital (2013-2020)<br />Kamil R Kranc, MD, DPhil (2020-present)<br />Roseann Mandell, BA; Massachusetts General Hospital (2006-2013)<br />Vivian E Shih, MD; Massachusetts General Hospital (2006-2013)</p></div><div id="fum.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>23 April 2020 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>4 April 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 June 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 August 2006 (cd) Revision: Prenatal diagnosis clinically available by enzyme assay and molecular testing</div></li><li class="half_rhythm"><div>5 July 2006 (me) Review posted live</div></li><li class="half_rhythm"><div>2 February 2005 (ves) Original submission</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/NBK1506/?report=reader">PubReader</a></li><li><a href="/books/NBK1506/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK1506" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK1506" style="display:none" title="Cite this Page"><div class="bk_tt">Coman D, Kranc KR, Christodoulou J. Fumarate Hydratase Deficiency. 2006 Jul 5 [Updated 2020 Apr 23]. 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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Variations in ClinVar</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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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=NBK1506+AND+genereviews[submitter]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri">Variations from this GeneReview in ClinVar</a>
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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=medgen&DbFrom=books&Cmd=Link&LinkName=books_medgen&IdsFromResult=1463816" ref="log$=recordlinks">MedGen</a><div class="brieflinkpop offscreen_noflow">Related information in MedGen</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=1463816" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=1463816" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=1463816" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=1463816" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301409" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Isolated Methylmalonic Acidemia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Isolated Methylmalonic Acidemia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Manoli I, Sloan JL, Venditti CP. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24404629" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Familial Hypercholesterolemia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Familial Hypercholesterolemia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Ison HE, Clarke SL, Knowles JW. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301790" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ataxia-Telangiectasia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ataxia-Telangiectasia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Veenhuis S, van Os N, Weemaes C, Kamsteeg EJ, Willemsen M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/35862567" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Carnitine-Acylcarnitine Translocase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Carnitine-Acylcarnitine Translocase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Morales Corado JA, Lee CU, Enns GM. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301679" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301679" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2ac30b15b832ebc1cd596">Fumarate Hydratase Deficiency - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Fumarate Hydratase Deficiency - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d2ac2c84f3725e593913f8">FKTN fukutin [Homo sapiens]</a><div class="ralinkpop offscreen_noflow">FKTN fukutin [Homo sapiens]<div class="brieflinkpopdesc">Gene ID:2218</div></div><div class="tertiary">Gene</div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d2ac2aa68b6b5afc82324b">Fukuyama Congenital Muscular Dystrophy - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Fukuyama 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