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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Ethylmalonic Encephalopathy" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2017/09/21" /><meta name="citation_author" content="Ivano Di Meo" /><meta name="citation_author" content="Costanza Lamperti" /><meta name="citation_author" content="Valeria Tiranti" /><meta name="citation_pmid" content="28933811" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK453432/" /><meta name="citation_keywords" content="ETHE1 Deficiency" /><meta name="citation_keywords" content="ETHE1 Deficiency" /><meta name="citation_keywords" content="Persulfide dioxygenase ETHE1, mitochondrial" /><meta name="citation_keywords" content="ETHE1" /><meta name="citation_keywords" content="Ethylmalonic Encephalopathy" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Ethylmalonic Encephalopathy" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Ivano Di Meo" /><meta name="DC.Contributor" content="Costanza Lamperti" /><meta name="DC.Contributor" content="Valeria Tiranti" /><meta name="DC.Date" content="2017/09/21" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK453432/" /><meta name="description" content="Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder characterized by developmental delay / mild-to-severe intellectual disability; generalized infantile hypotonia that evolves into hypertonia, spasticity, and (in some instances) dystonia; generalized tonic-clonic seizures; and generalized microvascular damage (diffuse and spontaneous relapsing petechial purpura, hemorrhagic suffusions of mucosal surfaces, and chronic hemorrhagic diarrhea). Infants sometimes have frequent vomiting and loss of social interaction. Speech is delayed and in some instances absent. Swallowing difficulties and failure to thrive are common. Children may be unable to walk without support and may be wheelchair bound. 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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="#__NBK453432_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK453432_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/tef-ov/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/fam111a-dysp/" 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="_NBK453432_"><span class="title" itemprop="name">Ethylmalonic Encephalopathy</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: ETHE1 Deficiency</div><p class="contrib-group"><span itemprop="author">Ivano Di Meo</span>, PhD, <span itemprop="author">Costanza Lamperti</span>, MD, and <span itemprop="author">Valeria Tiranti</span>, PhD.</p><a data-jig="ncbitoggler" href="#__NBK453432_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK453432_ai__"><div class="contrib half_rhythm"><span itemprop="author">Ivano Di Meo</span>, PhD<div class="affiliation small">Division of Molecular Neurogenetics<br />IRCCS Foundation Carlo Besta Neurological Institute<br />Milano, Italy<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ti.atseb-otutitsi@oemid.onavi" class="oemail">ti.atseb-otutitsi@oemid.onavi</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Costanza Lamperti</span>, MD<div class="affiliation small">Division of Molecular Neurogenetics<br />IRCCS Foundation Carlo Besta Neurological Institute<br />Milano, Italy<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ti.atseb-otutitsi@itrepmal.aznatsoc" class="oemail">ti.atseb-otutitsi@itrepmal.aznatsoc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Valeria Tiranti</span>, PhD<div class="affiliation small">Division of Molecular Neurogenetics<br />IRCCS Foundation Carlo Besta Neurological Institute<br />Milano, Italy<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ti.atseb-otutitsi@itnarit.airelav" class="oemail">ti.atseb-otutitsi@itnarit.airelav</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">September 21, 2017</span>.</p><p><em>Estimated reading time: 15 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="ee.Summary" itemprop="description"><h2 id="_ee_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder characterized by developmental delay / mild-to-severe intellectual disability; generalized infantile hypotonia that evolves into hypertonia, spasticity, and (in some instances) dystonia; generalized tonic-clonic seizures; and generalized microvascular damage (diffuse and spontaneous relapsing petechial purpura, hemorrhagic suffusions of mucosal surfaces, and chronic hemorrhagic diarrhea). Infants sometimes have frequent vomiting and loss of social interaction. Speech is delayed and in some instances absent. Swallowing difficulties and failure to thrive are common. Children may be unable to walk without support and may be wheelchair bound. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of children die in the first decade.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of EE is suggested by clinical findings and the laboratory findings of increased blood lactate levels, C4- and C5-acylcarnitine esters, plasma thiosulphate, and urinary ethylmalonic acid.</p><p>The diagnosis is established by identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>ETHE1</i> on <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> Multi-specialty care that includes child neurology, pediatrics, clinical genetics, nutrition, gastroenterology, pain management, and physical therapy can help with timely detection and treatment of the multiorgan dysfunction that characterizes EE. Treatment is primarily supportive including antispastic medications, muscle relaxants, and anti-seizure medication (ASM). Physical therapy early in the disease course can help prevent contractures. For severe diarrhea, it is important to maintain hydration and caloric intake. Tube feeding is often necessary.</p><p><i>Prevention of secondary complications:</i> Prevention of infections that could be fatal.</p><p><i>Surveillance:</i> Recommendations based on individual patient findings can include: monitoring of feeding and electrolyte status particularly in those with severe diarrhea; monitoring of seizures and response to ASM.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>EE is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. No individuals diagnosed with EE have been known to reproduce. Once the <i>ETHE1</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> for at-risk relatives, <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></div></div><div id="ee.Diagnosis"><h2 id="_ee_Diagnosis_">Diagnosis</h2><div id="ee.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Ethylmalonic encephalopathy (EE) <b>should be suspected</b> in an individual with the following clinical findings, preliminary laboratory findings, and brain MRI findings [<a class="bk_pop" href="#ee.REF.dionisivici.2016.1045">Dionisi-Vici et al 2016</a>].</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Global neurologic impairment</div><ul><li class="half_rhythm"><div>Early-onset progressive psychomotor regression</div></li><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Dystonia</div></li></ul></li><li class="half_rhythm"><div>Diffuse microvasculature injury</div><ul><li class="half_rhythm"><div>Petechiae and/or purpura</div></li><li class="half_rhythm"><div>Orthostatic acrocyanosis</div></li><li class="half_rhythm"><div>Hemorrhagic suffusions of mucosal surfaces</div></li><li class="half_rhythm"><div>Chronic hemorrhagic diarrhea</div></li></ul></li></ul><p>
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<b>Preliminary laboratory findings</b>
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</p><ul><li class="half_rhythm"><div>Increased blood lactate levels (normal range: 6-22 mg/dL)</div></li><li class="half_rhythm"><div>Increased blood C4-acylcarnitine esters (normal range: <0.9 μmol/L) [<a class="bk_pop" href="#ee.REF.merinero.2006.685">Merinero et al 2006</a>, <a class="bk_pop" href="#ee.REF.zafeiriou.2007.78">Zafeiriou et al 2007</a>] *</div></li><li class="half_rhythm"><div>Increased blood C5-acylcarnitine esters (normal range: <0.3 μmol/L) [<a class="bk_pop" href="#ee.REF.merinero.2006.685">Merinero et al 2006</a>, <a class="bk_pop" href="#ee.REF.zafeiriou.2007.78">Zafeiriou et al 2007</a>] *</div></li><li class="half_rhythm"><div>Increased plasma thiosulphate (normal range: <4 μmol/L)</div></li><li class="half_rhythm"><div>Increased urinary ethylmalonic acid (normal range: <10 μmol/mmol creatinine) evaluated on spot urine [<a class="bk_pop" href="#ee.REF.merinero.2006.685">Merinero et al 2006</a>, <a class="bk_pop" href="#ee.REF.zafeiriou.2007.78">Zafeiriou et al 2007</a>]</div></li></ul><p>* More data are needed to define the range of C4/C5 acylcarnitine elevation in individuals with molecularly proven EE.</p><p><b>Newborn screening (NBS).</b> Tandem mass spectroscopy can identify C4 elevation in a NBS dried blood spot; however, NBS for EE is not available in the US as there is no definitive treatment (see <a href="#ee.Therapies_Under_Investigation">Therapies Under Investigation</a>). Note: (1) NBS may be performed elsewhere in the world. (2) C4 elevation can also be found in <a href="/books/n/gene/scad/">primary short-chain acyl-CoA dehydrogenase (SCAD) deficiency</a> [<a class="bk_pop" href="#ee.REF.mchugh.2011.230">McHugh et al 2011</a>]; an <a href="https://www.acmg.net/PDFLibrary/C4-Elevated-Algorithm.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">algorithm</a> (pdf) from the American College of Medical Genetics can be used to distinguish the two disorders.</p><p>
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<b>Brain MRI</b>
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</p><ul><li class="half_rhythm"><div>Symmetric patchy T<sub>2</sub>-weighted signals in the basal ganglia, periventricular white matter and dentate nuclei, brain stem, and cerebellar white matter. In some instances, cortical atrophy and diffuse leukoencephalopathy are present.</div></li><li class="half_rhythm"><div>Atypical neuroradiologic patterns were also reported [<a class="bk_pop" href="#ee.REF.grosso.2002.1446">Grosso et al 2002</a>, <a class="bk_pop" href="#ee.REF.heberle.2006.329">Heberle et al 2006</a>].</div></li></ul></div><div id="ee.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of ethylmalonic encephalopathy <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive clinical and laboratory findings and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>ETHE1</i> identified on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK453432/table/ee.T.molecular_genetic_testing_used_in_e/?report=objectonly" target="object" rid-ob="figobeeTmoleculargenetictestingusedine">Table 1</a>).</p><p><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> is the <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approach indicated. Sequence analysis of <i>ETHE1</i> is performed first and followed by gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> if only one or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found.</p><div id="ee.T.molecular_genetic_testing_used_in_e" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Ethylmalonic Encephalopathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK453432/table/ee.T.molecular_genetic_testing_used_in_e/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ee.T.molecular_genetic_testing_used_in_e_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ee.T.molecular_genetic_testing_used_in_e_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_ee.T.molecular_genetic_testing_used_in_e_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_ee.T.molecular_genetic_testing_used_in_e_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> in Probands Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_ee.T.molecular_genetic_testing_used_in_e_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ETHE1</i>
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</td><td headers="hd_h_ee.T.molecular_genetic_testing_used_in_e_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_ee.T.molecular_genetic_testing_used_in_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">67/86 <sup>4</sup></td></tr><tr><td headers="hd_h_ee.T.molecular_genetic_testing_used_in_e_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>5</sup></td><td headers="hd_h_ee.T.molecular_genetic_testing_used_in_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19/86 <sup>4, 6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="ee.TF.1.1"><p class="no_margin">See <a href="/books/NBK453432/#ee.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="ee.TF.1.2"><p class="no_margin">See <a href="#ee.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="ee.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="ee.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#ee.REF.tiranti.2006.340">Tiranti et al [2006]</a>, <a class="bk_pop" href="#ee.REF.mineri.2008.473">Mineri et al [2008]</a></p></div></dd><dt>5. </dt><dd><div id="ee.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="ee.TF.1.6"><p class="no_margin">Deletion of <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 4 and <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of exons 1 to 7 have been detected frequently [<a class="bk_pop" href="#ee.REF.tiranti.2006.340">Tiranti et al 2006</a>, <a class="bk_pop" href="#ee.REF.mineri.2008.473">Mineri et al 2008</a>].</p></div></dd></dl></div></div></div></div></div><div id="ee.Clinical_Characteristics"><h2 id="_ee_Clinical_Characteristics_">Clinical Characteristics</h2><div id="ee.Clinical_Description"><h3>Clinical Description</h3><p>Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder, typically characterized by the following major manifestations: developmental delay, progressive neurologic involvement, seizures, and vascular damage. Findings usually appear in the first years of life, in some instances during metabolic stress such as infection or fever. Affected infants typically have severe neck, trunk, and limb hypotonia and loss of head control, sometimes associated with frequent vomiting and loss of social interaction. In addition, chronic diarrhea and failure to thrive are common.</p><p>Atypical findings have also been reported [<a class="bk_pop" href="#ee.REF.grosso.2002.1446">Grosso et al 2002</a>, <a class="bk_pop" href="#ee.REF.di_rocco.2006.395">Di Rocco et al 2006</a>, <a class="bk_pop" href="#ee.REF.heberle.2006.329">Heberle et al 2006</a>, <a class="bk_pop" href="#ee.REF.pigeon.2009.991">Pigeon et al 2009</a>].</p><p><b>Developmental delay,</b> evident in early infancy, manifests later as intellectual disability that ranges from mild to severe. Speech difficulties are common; in some instances speech is absent.</p><p><b>Progressive neurologic involvement.</b> Hypotonia evolves into spastic quadriparesis and eventually global neurologic impairment including pyramidal signs such as hypertonia and spasticity with increased deep tendon reflexes (in particular in the lower limbs) with paraparesis. Children may be unable to walk without support and in some instances are wheelchair bound. Difficulty in swallowing is common.</p><p>Dystonia, an extrapyramidal finding, generally involves the limbs and trunk.</p><p>Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of patients die in the early years, although some are still alive in the second decade of life.</p><p><b>Generalized seizures</b>. Generalized tonic-clonic seizures are characterized by spasms of the neck, trunk, and arms that could evolve into status epilepticus with decreased level of consciousness.</p><p><b>Microvasculature injury</b> is common and is characterized by diffuse and spontaneous relapsing petechial purpura, especially in the trunk and associated with "cutis marmorata" of the extremities.</p><p>Distal orthostatic acrocyanosis with edema of the extremities is often visible.</p><p>Hemorrhagic suffusions of mucosal surfaces and chronic hemorrhagic diarrhea are common manifestations.</p><div id="ee.Individuals_with_Atypical_Findings"><h4>Individuals with Atypical Findings</h4><p>Of two affected individuals reported by <a class="bk_pop" href="#ee.REF.grosso.2002.1446">Grosso et al [2002]</a>, one had chronic very slow neuromotor deterioration, ataxia, and dysarthria, and the other had acute neonatal onset with severe neuromotor retardation, severe generalized hypotonia, and intractable seizures.</p><p>In one individual with a molecularly confirmed diagnosis, the clinical findings suggested a connective tissue disorder (vascular fragility, joint hyperextensibility, and delayed motor development with normal cognitive development); urinary excretion of ethylmalonic acid was not abnormally increased during intercritical phases [<a class="bk_pop" href="#ee.REF.di_rocco.2006.395">Di Rocco et al 2006</a>].</p><p>One individual who had the typical findings of EE also had hydronephrosis, undescended testes, mild tricuspid regurgitation, and mild dilatation of the pulmonary artery [<a class="bk_pop" href="#ee.REF.heberle.2006.329">Heberle et al 2006</a>].</p><p>Monochorial twins had severe axial hypotonia without petechiae, orthostatic acrocyanosis, or chronic diarrhea. Other clinical findings differed markedly: one twin had an episode of coma at age three years followed by spastic quadriparesis and loss of language; the other had pyramidal involvement (mainly limited to the lower extremities) and spoke two languages [<a class="bk_pop" href="#ee.REF.pigeon.2009.991">Pigeon et al 2009</a>].</p><p><b>MR spectroscopy</b> showed a lactate peak in one patient [<a class="bk_pop" href="#ee.REF.grosso.2004.755">Grosso et al 2004</a>].</p><p><b>Neuropathologic findings</b> in the brain of an infant age nine months showed widespread luminal microthrombi, acute microhemorrhages, and focal perivascular hemosiderin-laden macrophages, the latter being consistent with previous bleeding. These findings were consistent with both acute and chronic ischemic damage and corresponded with abnormal signal intensity lesions observed on repeat MRI [<a class="bk_pop" href="#ee.REF.giordano.2012.451">Giordano et al 2012</a>].</p></div></div><div id="ee.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> are known to be associated with <i>ETHE1</i> <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants.</p></div><div id="ee.Prevalence"><h3>Prevalence</h3><p>The prevalence of ethylmalonic encephalopathy is unknown. More than 80 individuals with features consistent with EE and a molecularly confirmed diagnosis have been reported [<a class="bk_pop" href="#ee.REF.tiranti.2004.239">Tiranti et al 2004</a>, <a class="bk_pop" href="#ee.REF.tiranti.2006.340">Tiranti et al 2006</a>, <a class="bk_pop" href="#ee.REF.mineri.2008.473">Mineri et al 2008</a>].</p><p>To date, families with EE have been from (or could be traced to) different regions of the Mediterranean basin or the Arabian Peninsula; parental <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a> is common.</p></div></div><div id="ee.Genetically_Related_Allelic_Disorders"><h2 id="_ee_Genetically_Related_Allelic_Disorders_">Genetically Related (Allelic) Disorders</h2><p>At present, no phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>ETHE1</i> pathogenic variants.</p></div><div id="ee.Differential_Diagnosis"><h2 id="_ee_Differential_Diagnosis_">Differential Diagnosis</h2><p>Ethylmalonic acid is a dicarboxylic organic acid produced by the carboxylation of butyrate. Ethylmalonic encephalopathy (EE) should be included in the differential diagnosis of other forms of persistent ethylmalonic aciduria, including the following:</p><ul><li class="half_rhythm"><div>Defects of beta-oxidation of fatty acids with similar clinical findings (e.g., vomiting, diarrhea, difficulty with feeding, and developmental delay) such as <a href="/books/n/gene/scad/">short-chain acyl-CoA dehydrogenase (SCAD) deficiency</a> and 3-hydroxyacyl-CoA dehydrogenase (HADH) deficiency (OMIM <a href="https://omim.org/entry/231530" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">231530</a>). Petechiae, purpura, and orthostatic acrocyanosis are specific to EE [<a class="bk_pop" href="#ee.REF.burlina.1994.79">Burlina et al 1994</a>].</div></li><li class="half_rhythm"><div>Defects of the mitochondrial electron-transfer flavoprotein pathway or <a href="/books/n/gene/madd/">glutaric aciduria type II</a></div></li><li class="half_rhythm"><div>Some forms of respiratory chain deficiency</div></li></ul><p>Of note, brain vascular lesions appear to be a specific neuropathologic feature of EE, not seen in other forms of ethylmalonic aciduria or in disorders caused by primary respiratory chain defects such as <a href="/books/n/gene/kss/">Leigh syndrome</a> [<a class="bk_pop" href="#ee.REF.giordano.2012.451">Giordano et al 2012</a>, <a class="bk_pop" href="#ee.REF.tiranti.2013.a011437">Tiranti & Zeviani 2013</a>].</p></div><div id="ee.Management"><h2 id="_ee_Management_">Management</h2><div id="ee.Evaluations_Following_Initial_Diagnos"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with ethylmalonic encephalopathy (EE), the recommended evaluations following diagnosis (if not performed as part of the evaluation that led to the diagnosis) are as summarized in <a href="/books/NBK453432/table/ee.T.recommended_evaluations_following_i/?report=objectonly" target="object" rid-ob="figobeeTrecommendedevaluationsfollowingi">Table 2</a>.</p><div id="ee.T.recommended_evaluations_following_i" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis of Ethylmalonic Encephalopathy (EE)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK453432/table/ee.T.recommended_evaluations_following_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ee.T.recommended_evaluations_following_i_lrgtbl__"><table><thead><tr><th id="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_ee.T.recommended_evaluations_following_i_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_ee.T.recommended_evaluations_following_i_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Particularly if medications are being used to treat spasticity &/or extrapyramidal movement disorders (e.g., dystonia)</td></tr><tr><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Brain MRI</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Indicated in any child w/EE w/seizures or spasticity who has not previously had a brain MRI</td></tr><tr><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">EEG & video EEG</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If seizures are suspected</td></tr><tr><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding eval & nutrition assessment</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to appropriate feeding therapist &/or nutritionist as indicated</td></tr><tr><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment for chronic diarrhea</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to gastroenterologist as needed</td></tr><tr><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedic eval</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to orthopedist as needed</td></tr><tr><td headers="hd_h_ee.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Miscellaneous/</b>
|
||
<br />
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_ee.T.recommended_evaluations_following_i_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_ee.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></div><div id="ee.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Multi-specialty care that includes child neurology, pediatrics, clinical genetics, nutrition, gastroenterology, orthopedic, pain management, and physical therapy can help with timely detection and treatment of the multiorgan dysfunction that characterizes ethylmalonic encephalopathy. Treatment is primarily supportive including anti-spastic medications, muscle relaxants, and anti-seizure medication. Physical therapy early in the disease course can help prevent contractures.</p><div id="ee.T.treatment_of_manifestations_in_indi" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Ethylmalonic Encephalopathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK453432/table/ee.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ee.T.treatment_of_manifestations_in_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ee.T.treatment_of_manifestations_in_indi_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_ee.T.treatment_of_manifestations_in_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/<br />Other</th></tr></thead><tbody><tr><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Spasticity</b>
|
||
</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Antispastic medications</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Dystonia</b>
|
||
</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Muscle relaxants</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Contractures</b>
|
||
</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical therapy</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_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_ee.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Anti-seizure medication</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Severe diarrhea</b>
|
||
</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Maintain hydration & caloric intake</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Tube feeding often necessary</td></tr><tr><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Poor energy</b>
|
||
<br />
|
||
<b>metabolism &</b>
|
||
<br />
|
||
<b>oxidative stress</b>
|
||
</td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">L-carnitine, riboflavin &/or coenzyme Q<sub>10</sub> supplements (a cocktail of drugs generally used in mitochondrial disorders) & other vitamin therapies <sup>1</sup></td><td headers="hd_h_ee.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="ee.TF.3.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#ee.REF.gorman.2016.16080">Gorman et al [2016]</a>
|
||
</p></div></dd></dl></div></div></div><p>Off-label compassionate use of N-acetylcysteine (NAC) in combination with metronidazole may be considered as they are the only drugs known to slow disease progression and improve the metabolic abnormalities of EE [<a class="bk_pop" href="#ee.REF.viscomi.2010.869">Viscomi et al 2010</a>, <a class="bk_pop" href="#ee.REF.k_l__.2017.293">Kılıç et al 2017</a>].</p><ul><li class="half_rhythm"><div>N-acetylcysteine (NAC), a cell-permeable precursor of glutathione, is abundant in mitochondria where it can act as one of the physiologic acceptors of the sulfur atom of hydrogen sulfide (H<sub>2</sub>S), which has deficient clearance in persons with EE.</div></li><li class="half_rhythm"><div>Metronidazole is widely used to combat infections caused by anaerobic bacteria, and can reduce the sulfide-producing bacterial load in the large intestine.</div></li></ul><div id="ee.Developmental_Delay__Intellectual_Dis"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies, and an individualized education plan (IEP) is developed.</p><p>
|
||
<b>Ages 5-21 years</b>
|
||
</p><ul><li class="half_rhythm"><div>In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.</div></li><li class="half_rhythm"><div>Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.</div></li></ul><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.</p><p>Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</p><p>In the US:</p><ul><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="ee.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures).</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li><li class="half_rhythm"><div>For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox<sup>®</sup>, anti-parkinsonian medications, or orthopedic procedures.</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function (e.g., feeding, grooming, dressing, writing).</p><p><b>Oral motor dysfunction.</b> Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a>) for individuals who have expressive language difficulties.</p></div></div><div id="ee.Prevention_of_Secondary_Complications"><h3>Prevention of Secondary Complications</h3><p>All affected individuals should receive routine immunizations; as well as annual immunizations for influenza.</p><p>Physicians must pay particular attention to the prevention of infections that could be fatal.</p></div><div id="ee.Surveillance"><h3>Surveillance</h3><p>Surveillance should be individualized based on symptoms and organs affected.</p><div id="ee.T.recommended_surveillance_for_indivi" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Ethylmalonic Encephalopathy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK453432/table/ee.T.recommended_surveillance_for_indivi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ee.T.recommended_surveillance_for_indivi_lrgtbl__"><table><thead><tr><th id="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">System/Concern</th><th id="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Evaluation/Action</th><th id="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Growth</b>
|
||
</td><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess growth & monitor for failure to thrive.</td><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor feeding & electrolyte status, particularly in those w/severe diarrhea.</td><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_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_ee.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for epileptic crisis; modify therapy according to clinical presentation & EEG findings.</td><td headers="hd_h_ee.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routine</td></tr></tbody></table></div></div></div><div id="ee.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#ee.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="ee.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>While clearance of circulating sulfide by a transplanted liver could be beneficial, to date only one instance of liver transplantation in EE has been reported [<a class="bk_pop" href="#ee.REF.dionisivici.2016.1045">Dionisi-Vici et al 2016</a>]. Although results were encouraging, follow up of this patient and experience with additional patients are necessary to determine therapeutic efficacy of liver transplantation in EE and possible relevance for national or state-mandated newborn screening, particularly in populations with relatively high prevalence of pathogenic variants.</p><p>Possible future treatments include AAV-mediated <a class="def" href="/books/n/gene/glossary/def-item/gene-therapy/">gene therapy</a> [<a class="bk_pop" href="#ee.REF.di_meo.2012.1008">Di Meo et al 2012</a>] or liver transplantation [<a class="bk_pop" href="#ee.REF.dionisivici.2016.1045">Dionisi-Vici et al 2016</a>].</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><div id="ee.Genetic_Counseling"><h2 id="_ee_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="ee.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Ethylmalonic encephalopathy is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="ee.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 obligate heterozygotes (i.e., carriers of one <i>ETHE1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</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>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> No individuals diagnosed with ethylmalonic encephalopathy have been known to reproduce.</p><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of an <i>ETHE1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="ee.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>ETHE1</i> pathogenic variants in the family.</p></div><div id="ee.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status, and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).</p></div><div id="ee.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>ETHE1</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>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="ee.Resources"><h2 id="_ee_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>National Library of Medicine Genetics Home Reference</b>
|
||
</div><div>
|
||
<a href="https://ghr.nlm.nih.gov/condition/ethylmalonicencephalopathy" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Ethylmalonic encephalopathy</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><li class="half_rhythm"><div>
|
||
<b>Mitocon – Insieme per lo studio e la cura delle malattie mitocondriali Onlus</b>
|
||
</div><div>
|
||
<i>Mitocon is the reference association in Italy for patients suffering from mitochondrial diseases and their families and is the main link between patients and the scientific community.</i>
|
||
</div><div>Italy</div><div><b>Phone:</b> 06 66991333/4</div><div><b>Email:</b> info@mitocon.it</div><div>
|
||
<a href="https://www.mitocon.it/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">mitocon.it</a>
|
||
</div></li></ul>
|
||
</div><div id="ee.Molecular_Genetics"><h2 id="_ee_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="ee.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Ethylmalonic Encephalopathy: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK453432/table/ee.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ee.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_ee.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_ee.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_ee.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_ee.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_ee.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_ee.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_ee.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/23474" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>ETHE1</i>
|
||
</a>
|
||
</td><td headers="hd_b_ee.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=23474" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">19q13<wbr style="display:inline-block"></wbr>.31</a>
|
||
</td><td headers="hd_b_ee.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/O95571" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Persulfide dioxygenase ETHE1, mitochondrial</a>
|
||
</td><td headers="hd_b_ee.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/ETHE1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ETHE1 database</a>
|
||
</td><td headers="hd_b_ee.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=ETHE1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ETHE1</a>
|
||
</td><td headers="hd_b_ee.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ETHE1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ETHE1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ee.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="ee.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Ethylmalonic Encephalopathy (<a href="/omim/602473,608451" 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/NBK453432/table/ee.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ee.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/602473" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">602473</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ENCEPHALOPATHY, ETHYLMALONIC; EE</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/608451" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608451</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ETHE1 PERSULFIDE DIOXYGENASE; ETHE1</td></tr></tbody></table></div></div><p><b>Gene structure.</b>
|
||
<i>ETHE1</i> comprises seven exons.</p><p><b>Pathogenic variants.</b> To date several <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/missense/">missense</a> pathogenic variants as well as single- and multiexon deletions have been described throughout the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> [<a class="bk_pop" href="#ee.REF.tiranti.2006.340">Tiranti et al 2006</a>, <a class="bk_pop" href="#ee.REF.mineri.2008.473">Mineri et al 2008</a>, <a class="bk_pop" href="#ee.REF.tiranti.2013.a011437">Tiranti & Zeviani 2013</a>].</p><p>Deletion of <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 4 and <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of the entire <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> are the most frequent large deletions [<a class="bk_pop" href="#ee.REF.mineri.2008.473">Mineri et al 2008</a>, <a class="bk_pop" href="#ee.REF.drousiotou.2011.385">Drousiotou et al 2011</a>].</p><div id="ee.T.select_ethe1_pathogenic_variants" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Select <i>ETHE1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK453432/table/ee.T.select_ethe1_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ee.T.select_ethe1_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DNA Nucleotide Change<br />(Alias)</th><th id="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.-83_-79delCGCCC <sup>1</sup></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Met1Ile</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_3" rowspan="9" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_055112.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_055112<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln12Ter</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ile23SerfsTer10</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Tyr38Cys</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu44ValfsTer62</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu55Pro</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln63Ter</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala75SerfsTer32</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asn77IlefsTer68</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.375+5G>A</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_014297.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_014297<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.406A>G</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr136Ala</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_3" rowspan="8" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_014297.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_014297<wbr style="display:inline-block"></wbr>.3</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_055112.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_055112<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.440_450del11</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His147LeufsTer30</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.455C>T</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr152Ile</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.482G>A</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys161Tyr</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.487C>G</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg163Gly</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.487C>T</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg163Trp</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.488G>A</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg163Gln</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.491C>A</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr164Lys</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.505+1G>T</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_014297.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_014297<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.554T>G</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu185Arg</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_014297.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_014297<wbr style="display:inline-block"></wbr>.3</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_055112.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_055112<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.586G>A</td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp196Asn</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.592dupC<br />(592_593insC) <sup>2</sup></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His198fsProTer23</td></tr><tr><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.604dupG<br />(604_605insG) <sup>2</sup></td><td headers="hd_h_ee.T.select_ethe1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val202GlyfsTer19</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="ee.TF.5.1"><p class="no_margin">HGVS nomenclature: <a href="https://www.ncbi.nlm.nih.gov/nuccore/NG_008141.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NG_008141<wbr style="display:inline-block"></wbr>.1</a>:g.4985_4989delCGCCC, as c.-83_79delCGCCC is not encompassed in the RefSeq <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_014297.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_014297<wbr style="display:inline-block"></wbr>.3</a>.</p></div></dd><dt>2. </dt><dd><div id="ee.TF.5.2"><p class="no_margin">Originally reported with designation that does not conform to current naming conventions</p></div></dd></dl></div></div></div><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> ETHE1, a 30-kd polypeptide exclusively located in the mitochondrial matrix, is a homodimeric Fe-containing sulfur dioxygenase (SDO). It has a beta-lactamase <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> that is involved in the catabolic oxidation of hydrogen sulfide (H<sub>2</sub>S) to sulfate [<a class="bk_pop" href="#ee.REF.di_meo.2015.1257">Di Meo et al 2015</a>].</p><p><b>Abnormal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b> Impaired activity of ETHE1-SDO in ethylmalonic encephalopathy leads to the accumulation of H<sub>2</sub>S in critical tissues (including colonic mucosa, liver, muscle, and brain) up to concentrations that inhibit short-chain acyl-CoA dehydrogenase (SCAD) and cytochrome <i>c</i> oxidase (COX) activities, thus inducing high plasma levels of C4- and C5-acylcarnitines, ethylmalonic acid, and lactate [<a class="bk_pop" href="#ee.REF.di_meo.2015.1257">Di Meo et al 2015</a>].</p></div><div id="ee.Chapter_Notes"><h2 id="_ee_Chapter_Notes_">Chapter Notes</h2><div id="ee.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>21 September 2017 (bp) Review posted live</div></li><li class="half_rhythm"><div>23 August 2016 (vt) Original submission</div></li></ul></div></div><div id="ee.References"><h2 id="_ee_References_">References</h2><div id="ee.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="ee.REF.burlina.1994.79">Burlina AB, Dionisi-Vici C, Bennett MJ, Gibson KM, Servidei S, Bertini E, Hale DE, Schmidt-Sommerfeld E, Sabetta G, Zacchello F, et al. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. <span><span class="ref-journal">J Pediatr. </span>1994;<span class="ref-vol">124</span>:79–86.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8283379" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8283379</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.di_meo.2012.1008">Di Meo I, Auricchio A, Lamperti C, Burlina A, Viscomi C, Zeviani M. Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy. <span><span class="ref-journal">EMBO Mol Med. </span>2012;<span class="ref-vol">4</span>:1008–14.</span> [<a href="/pmc/articles/PMC3491831/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3491831</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22903887" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22903887</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.di_meo.2015.1257">Di Meo I, Lamperti C, Tiranti V. Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches. <span><span class="ref-journal">EMBO Mol Med. </span>2015;<span class="ref-vol">7</span>:1257–66.</span> [<a href="/pmc/articles/PMC4604682/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4604682</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26194912" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26194912</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.dionisivici.2016.1045">Dionisi-Vici C, Diodato D, Torre G, Picca S, Pariante R, Giuseppe Picardo S, Di Meo I, Rizzo C, Tiranti V, Zeviani M. De GoyetJde V. Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease. <span><span class="ref-journal">Brain. </span>2016;<span class="ref-vol">139</span>:1045–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26917598" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26917598</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.di_rocco.2006.395">Di Rocco M, Caruso U, Briem E, Rossi A, Allegri AE, Buzzi D, Tiranti V. A case of ethylmalonic encephalopathy with atypical clinical and biochemical presentation. <span><span class="ref-journal">Mol Genet Metab. </span>2006;<span class="ref-vol">89</span>:395–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16828325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16828325</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.drousiotou.2011.385">Drousiotou A, DiMeo I, Mineri R, Georgiou T, Stylianidou G, Tiranti V. Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches. <span><span class="ref-journal">Clin Genet. </span>2011;<span class="ref-vol">79</span>:385–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20528888" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20528888</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.giordano.2012.451">Giordano C, Viscomi C, Orlandi M, Papoff P, Spalice A, Burlina A, Di Meo I, Tiranti V, Leuzzi V, d'Amati G, et al. Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy. <span><span class="ref-journal">J Inherit Metab Dis. </span>2012;<span class="ref-vol">35</span>:451–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22020834" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22020834</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.gorman.2016.16080">Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, Suomalainen A, Thorburn DR, Zeviani M, Turnbull DM. Mitochondrial diseases. <span><span class="ref-journal">Nat Rev Dis Primers. </span>2016;<span class="ref-vol">2</span>:16080.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27775730" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27775730</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.grosso.2002.1446">Grosso S, Mostardini R, Farnetani MA, Molinelli M, Berardi R, Dionisi-Vici C, Rizzo C, Morgese G, Balestri P. Ethylmalonic encephalopathy: further clinical and neuroradiological characterization. <span><span class="ref-journal">J Neurol. </span>2002;<span class="ref-vol">249</span>:1446–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12382164" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12382164</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.grosso.2004.755">Grosso S, Balestri P, Mostardini R, Federico A, De Stefano N. Brain mitochondrial impairment in ethylmalonic encephalopathy. <span><span class="ref-journal">J Neurol. </span>2004;<span class="ref-vol">251</span>:755–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15311356" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15311356</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.heberle.2006.329">Heberle LC, Al Tawari AA, Ramadan DG, Ibrahim JK. Ethylmalonic encephalopathy: report of two cases. <span><span class="ref-journal">Brain Dev. </span>2006;<span class="ref-vol">28</span>:329–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16376514" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16376514</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.k_l__.2017.293">Kılıç M, Dedeoğlu Ö, Göçmen R, Kesici S, Yüksel D. Successful treatment of a patient with ethylmalonic encephalopathy by intravenous N-acetylcysteine. <span><span class="ref-journal">Metabolic Brain Disease. </span>2017;<span class="ref-vol">32</span>:293–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27830356" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27830356</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.mchugh.2011.230">McHugh D, et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. <span><span class="ref-journal">Genet Med. </span>2011;<span class="ref-vol">13</span>:230–54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21325949" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21325949</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.merinero.2006.685">Merinero B, Pérez-Cerdá C, Ruiz Sala P, Ferrer I, García MJ, Martínez Pardo M, Belanger-Quintana A, de la Mota JL, Martin-Hernández E, Vianey-Saban C, Bischoff C, Gregersen N, Ugarte M. Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy. <span><span class="ref-journal">J Inherit Metab Dis. </span>2006;<span class="ref-vol">29</span>:685.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16906473" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16906473</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.mineri.2008.473">Mineri R, Rimoldi M, Burlina AB, Koskull S, Perletti C, Heese B, von Döbeln U, Mereghetti P, Di Meo I, Invernizzi F, Zeviani M, Uziel G, Tiranti V. Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. <span><span class="ref-journal">J Med Genet. </span>2008;<span class="ref-vol">45</span>:473–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18593870" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18593870</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.pigeon.2009.991">Pigeon N, Campeau PM, Cyr D, Lemieux B, Clarke JT. Clinical heterogeneity in ethylmalonic encephalopathy. <span><span class="ref-journal">J Child Neurol. </span>2009;<span class="ref-vol">24</span>:991–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19289697" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19289697</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.tiranti.2006.340">Tiranti V, Briem E, Lamantea E, Mineri R, Papaleo E, De Gioia L, Forlani F, Rinaldo P, Dickson P, Abu-Libdeh B, Cindro-Heberle L, Owaidha M, Jack RM, Christensen E, Burlina A, Zeviani M. ETHE1 mutations are specific to ethylmalonic encephalopathy. <span><span class="ref-journal">J Med Genet. </span>2006;<span class="ref-vol">43</span>:340–6.</span> [<a href="/pmc/articles/PMC2563233/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2563233</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16183799" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16183799</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.tiranti.2004.239">Tiranti V, D'Adamo P, Briem E, Ferrari G, Mineri R, Lamantea E, et al. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. <span><span class="ref-journal">Am J Hum Genet. </span>2004;<span class="ref-vol">74</span>:239–52.</span> [<a href="/pmc/articles/PMC1181922/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1181922</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14732903" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14732903</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.tiranti.2013.a011437">Tiranti V, Zeviani M. Altered sulfide (H(2)S) metabolism in ethylmalonic encephalopathy. <span><span class="ref-journal">Cold Spring Harb Perspect Biol. </span>2013;<span class="ref-vol">5</span>:a011437. </span> [<a href="/pmc/articles/PMC3579397/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3579397</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23284046" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23284046</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.viscomi.2010.869">Viscomi C, Burlina AB, Dweikat I, Savoiardo M, Lamperti C, Hildebrandt T, Tiranti V, Zeviani M. Combined treatment with oral metronidazole and N-ace-tylcysteine is effective in ethylmalonic encephalopathy. <span><span class="ref-journal">Nat Med. </span>2010;<span class="ref-vol">16</span>:869–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20657580" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20657580</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ee.REF.zafeiriou.2007.78">Zafeiriou DI, Augoustides-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Sewell AC, Vianey-Saban C, Gregersen N. Ethylmalonic encephalopathy: clinical and biochemical observations. <span><span class="ref-journal">Neuropediatrics. </span>2007;<span class="ref-vol">38</span>:78–82.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17712735" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17712735</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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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=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=4449940" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=4449940" ref="log$=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=4449940" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=4449940" ref="log$=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/20301631" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Lee KN. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=2&log$=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> 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/35862567" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Carnitine-Acylcarnitine Translocase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Carnitine-Acylcarnitine Translocase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Morales Corado JA, Lee CU, Enns GM. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301601" ref="ordinalpos=1&linkpos=4&log$=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> Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.</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> Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Mole SE, Williams RE. </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/24851285" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> KCNQ3-Related Disorders.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> KCNQ3-Related Disorders.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Miceli F, Soldovieri MV, Weckhuysen S, Cooper EC, Taglialatela M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=28933811" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=28933811" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See 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