2372 lines
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Entry
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- #500017 - LEIGH SYNDROME, MITOCHONDRIAL; MILS
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- OMIM
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<span class="h4">#500017</span>
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<a href="#inheritance">Inheritance</a>
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<div><a href="https://clinicaltrials.gov/search?cond=LEIGH SYNDROME, MITOCHONDRIAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19809&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1173/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=255210" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 717052002<br />
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<strong>ORPHA:</strong> 255210<br />
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">ICD+</a>
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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500017
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LEIGH SYNDROME, MITOCHONDRIAL; MILS
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that mitochondrial Leigh syndrome (MILS) is caused by mutation in several mitochondrial genes, including MTTV (<a href="/entry/590105">590105</a>), MTTK (<a href="/entry/590060">590060</a>), MTTW (<a href="/entry/590095">590095</a>), MTTL1 (<a href="/entry/590050">590050</a>), and MTATP6 (<a href="/entry/516060">516060</a>).</p>
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<p>Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, sometimes resulting in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by <a href="#8" class="mim-tip-reference" title="Lake, N. J., Compton, A. G., Rahman, S., Thorburn, D. R. <strong>Leigh syndrome: one disorder, more than 75 monogenic causes.</strong> Ann. Neurol. 79: 190-203, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26506407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26506407</a>] [<a href="https://doi.org/10.1002/ana.24551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26506407">Lake et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26506407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Leigh Syndrome</em></strong></p><p>
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Leigh syndrome can be a clinical presentation of a primary deficiency caused by genes involved in any of the mitochondrial respiratory chain complexes, both in the mitochondrial genome and in the nuclear genome.</p><p>See <a href="/entry/256000">256000</a> for discussion of genetic heterogeneity of nuclear Leigh syndrome (NULS).</p>
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<p><strong><em>Patients with Mutations in the MTTV Gene</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="McFarland, R., Clark, K. M., Morris, A. A. M., Taylor, R. W., Macphail, S., Lightowlers, R. N., Turnbull, D. M. <strong>Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation.</strong> Nature Genet. 30: 145-146, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11799391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11799391</a>] [<a href="https://doi.org/10.1038/ng819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11799391">McFarland et al. (2002)</a> reported the case of a 35-year-old woman who had 1 surviving child with mitochondrial Leigh syndrome from 10 pregnancies with 4 unrelated partners. A number of her relatives died in early infancy, including her 3 sibs. She had suffered occasional migraine headaches, and examination demonstrated very mild proximal muscle weakness. In contrast, all of her offspring showed evidence of profound mitochondrial dysfunction. One was delivered by cesarean at 32 weeks' gestation because of deteriorating cardiac function. Despite immediate clinical intervention, the baby died of severe cardiac failure at 21 hours of life. Autopsy showed biventricular hypertrophic cardiomyopathy. Six infants died in the early neonatal period with lacticacidosis, the longest survivor dying 85 hours after birth. Although several changes in mitochondrial DNA were found, <a href="#10" class="mim-tip-reference" title="McFarland, R., Clark, K. M., Morris, A. A. M., Taylor, R. W., Macphail, S., Lightowlers, R. N., Turnbull, D. M. <strong>Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation.</strong> Nature Genet. 30: 145-146, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11799391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11799391</a>] [<a href="https://doi.org/10.1038/ng819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11799391">McFarland et al. (2002)</a> concluded that a C-to-T transition of nucleotide 1624, present in homoplasmic state in the gene encoding mitochondrial tRNA(Val), was responsible for the findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11799391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Patients with Mutations in the MTTW Gene</em></strong></p><p>
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<a href="#15" class="mim-tip-reference" title="Santorelli, F. M., Tanji, K., Sano, M., Shanske, S., El-Shahawi, M., Kranz-Eble, P., DiMauro, S., De Vivo, D. C. <strong>Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene.</strong> Ann. Neurol. 42: 256-260, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9266739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9266739</a>] [<a href="https://doi.org/10.1002/ana.410420220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9266739">Santorelli et al. (1997)</a> reported a family in which the proband had a progressive neurologic disorder and his brother died in infancy of Leigh syndrome. Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. Genetic analysis identified a mutation in the MTTW gene (c.5537insT; <a href="/entry/590095#0002">590095.0002</a>). The mutation was abundant in tissues from the proband and his brother (greater than 92%), and less abundant (42 to 89%) in 4 maternal relatives, 3 of whom had neuropsychiatric disturbances. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9266739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Tulinius, M., Moslemi, A.-R., Darin, N., Westerberg, B., Wiklund, L.-M., Holme, E., Oldfors, A. <strong>Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNA(Trp) gene.</strong> Neuropediatrics 34: 87-91, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12776230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12776230</a>] [<a href="https://doi.org/10.1055/s-2003-39607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12776230">Tulinius et al. (2003)</a> reported a boy with Leigh syndrome who had the 5537insT mutation in the MTTW gene. From infancy, he was irritable and had hypotonia. Later, neurologic features included nystagmus, optic atrophy, seizures, delayed motor development, and mental retardation. Skeletal muscle analysis showed a profound COX deficiency and complex I deficiency. The mutation was found in a high proportion (greater than 95%) in blood, liver, and muscle tissue of the patient, and in blood of the patient's mother (81%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12776230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Patients with Mutations in the MTTL1 Gene</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Sue, C. M., Bruno, C., Andreu, A. L., Cargan, A., Mendell, J. R., Tsao, C.-Y., Luquette, M., Paolicchi, J., Shanske, S., DiMauro, S., De Vivo, D. C. <strong>Infantile encephalopathy associated with the MELAS A3243G mutation.</strong> J. Pediat. 134: 696-700, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10356136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10356136</a>] [<a href="https://doi.org/10.1016/s0022-3476(99)70283-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10356136">Sue et al. (1999)</a> reported 3 unrelated children with a 3243A-G mutation in the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>) who presented with severe psychomotor delay in early infancy. One patient's clinical picture was more consistent with Leigh syndrome, with apneic episodes, ataxia, and bilateral striatal lesions on brain MRI. The proportion of mutant mtDNA in available tissues was relatively low (range, 5 to 51% in muscle and 4 to 39% in blood). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10356136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Patients with Mutations in the MTAPT6 Gene</em></strong></p><p>
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Mutations in the MTAPT6 gene have been identified in multiple families with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; <a href="/entry/500015">500015</a>) resulting in Leigh syndrome. These include c.8993T-G (<a href="/entry/516060#0001">516060.0001</a>) (<a href="#18" class="mim-tip-reference" title="Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B. H. <strong>Heteroplasmic mtDNA mutation (T-to-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.</strong> Am. J. Hum. Genet. 50: 852-858, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1550128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1550128</a>]" pmid="1550128">Tatuch et al., 1992</a>, <a href="#16" class="mim-tip-reference" title="Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., Wallace, D. C. <strong>Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.</strong> Neurology 42: 2168-2174, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1436530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1436530</a>] [<a href="https://doi.org/10.1212/wnl.42.11.2168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1436530">Shoffner et al., 1992</a>, <a href="#3" class="mim-tip-reference" title="Ciafaloni, E., Santorelli, F. M., Shanske, S., Deonna, T., Roulet, E., Janzer, C., Pescia, G., DiMauro, S. <strong>Maternally inherited Leigh syndrome.</strong> J. Pediat. 122: 419-422, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8095070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8095070</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)83431-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8095070">Ciafaloni et al., 1993</a>, <a href="#14" class="mim-tip-reference" title="Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C., DiMauro, S. <strong>The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome.</strong> Ann. Neurol. 34: 827-834, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8250532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8250532</a>] [<a href="https://doi.org/10.1002/ana.410340612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8250532">Santorelli et al., 1993</a>, <a href="#12" class="mim-tip-reference" title="Pastores, G. M., Santorelli, F. M., Shanske, S., Gelb, B. D., Fyfe, B., Wolfe, D., Willner, J. P. <strong>Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G).</strong> Am. J. Med. Genet. 50: 265-271, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8042671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8042671</a>] [<a href="https://doi.org/10.1002/ajmg.1320500310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8042671">Pastores et al., 1994</a>); c.8993T-C (<a href="/entry/516060#0002">516060.0002</a>) (<a href="#5" class="mim-tip-reference" title="de Vries, D. D., van Engelen, B. G. M., Gabreels, F. J. M., Ruitenbeek, W., van Oost, B. A. <strong>A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome.</strong> Ann. Neurol. 34: 410-412, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8395787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8395787</a>] [<a href="https://doi.org/10.1002/ana.410340319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8395787">de Vries et al., 1993</a>, <a href="#20" class="mim-tip-reference" title="Vilarinho, L., Barbot, C., Carrozzo, R., Calado, E., Tessa, A., Dionisi-Vici, C., Guimaraes, A., Santorelli. F. M. <strong>Clinical and molecular findings in 4 new patients harbouring the mtDNA 8993T-C mutation.</strong> J. Inherit. Metab. Dis. 24: 883-884, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11916326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11916326</a>] [<a href="https://doi.org/10.1023/a:1013908728445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11916326">Vilarinho et al., 2001</a>); c.9185T-C (<a href="/entry/516060#0008">516060.0008</a>) (<a href="#2" class="mim-tip-reference" title="Castagna, A. E., Addis, J., McInnes, R. R., Clarke, J. T. R., Ashby, P., Blaser, S., Robinson, B. H. <strong>Late onset Leigh syndrome and ataxia due to a T to C mutation at bp 9,185 of mitochondrial DNA.</strong> Am. J. Med. Genet. 143A: 808-816, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17352390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17352390</a>] [<a href="https://doi.org/10.1002/ajmg.a.31637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17352390">Castagna et al., 2007</a>); and c.9176T-G (<a href="/entry/516060#0011">516060.0011</a>) (<a href="#1" class="mim-tip-reference" title="Carrozzo, R., Tessa, A., Vazquez-Memije, M. E., Piemonte, F., Patrono, C., Malandrini, A., Dionisi-Vici, C., Vilarinho, L., Villanova, M., Schagger, H., Federico, A., Bertini, E., Santorelli, F. M. <strong>The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome.</strong> Neurology 56: 687-690, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245730</a>] [<a href="https://doi.org/10.1212/wnl.56.5.687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11245730">Carrozzo et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8250532+11245730+11916326+8095070+8042671+1436530+8395787+1550128+17352390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B. H. <strong>Heteroplasmic mtDNA mutation (T-to-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.</strong> Am. J. Hum. Genet. 50: 852-858, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1550128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1550128</a>]" pmid="1550128">Tatuch et al. (1992)</a> and <a href="#16" class="mim-tip-reference" title="Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., Wallace, D. C. <strong>Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.</strong> Neurology 42: 2168-2174, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1436530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1436530</a>] [<a href="https://doi.org/10.1212/wnl.42.11.2168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1436530">Shoffner et al. (1992)</a> identified a mutation in the MTAPT6 gene (c.8993T-G; <a href="/entry/516060#0001">516060.0001</a>). <a href="#18" class="mim-tip-reference" title="Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B. H. <strong>Heteroplasmic mtDNA mutation (T-to-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.</strong> Am. J. Hum. Genet. 50: 852-858, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1550128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1550128</a>]" pmid="1550128">Tatuch et al. (1992)</a> found the heteroplasmic mtDNA mutation in a female infant showing lactic acidemia, hypotonia, and neurodegenerative disease leading to death at the age of 7 months. Autopsy revealed lesions typical of Leigh disease, both in the basal ganglia and in the brainstem. A maternal uncle and aunt died 5 months and 1 year, respectively, after a similar clinical course, while another maternal uncle, 33 years of age, had retinitis pigmentosa, ataxia, and mental retardation. The index patient had more than 95% abnormal mtDNA in her skin fibroblasts, brain, kidney, and liver tissues, as measured by laser densitometry. The maternal aunt who died at 1 year likewise had more than 95% abnormal mtDNA in her lymphoblasts. The uncle with retinitis pigmentosa had 78% and 79% abnormal mtDNA in his skin fibroblasts and lymphoblasts, respectively, while an asymptomatic maternal aunt and her son had no trace of the mutation. The mother of the index case had 71% and 39% abnormal mtDNA in her skin fibroblasts and lymphoblasts, respectively. <a href="#16" class="mim-tip-reference" title="Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., Wallace, D. C. <strong>Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.</strong> Neurology 42: 2168-2174, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1436530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1436530</a>] [<a href="https://doi.org/10.1212/wnl.42.11.2168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1436530">Shoffner et al. (1992)</a> reported a family which was heteroplasmic for the ATPase 6 nucleotide 8993 mutation in which 2 daughters with Leigh syndrome died at ages 2.5 years and 14 months. Pathologic analyses showed classic basal ganglial lesions, vascular proliferation, and glioses. Two brothers manifested psychomotor retardation, ataxia, hypotonia, and retinal degeneration. The mother had retinal degeneration and experienced migraine headaches. The mother's 2 sisters were normal. The 4 affected children had high levels of mutant mtDNA, in excess of 95% by Southern blot. The mother had a 78% level of mutant mtDNA while her 2 sisters had 100% normal mtDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1550128+1436530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ciafaloni, E., Santorelli, F. M., Shanske, S., Deonna, T., Roulet, E., Janzer, C., Pescia, G., DiMauro, S. <strong>Maternally inherited Leigh syndrome.</strong> J. Pediat. 122: 419-422, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8095070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8095070</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)83431-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8095070">Ciafaloni et al. (1993)</a> described 2 sisters with Leigh syndrome who had a T-to-G transversion at nucleotide 8993 in the MTATP6 gene. The asymptomatic mother had the same mutation. All 3 were heteroplasmic. The proportion of mutant genomes was lower in the mother's blood than in the blood of the more mildly affected sister, whereas all tissues from the other sister were almost homoplasmic for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8095070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C., DiMauro, S. <strong>The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome.</strong> Ann. Neurol. 34: 827-834, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8250532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8250532</a>] [<a href="https://doi.org/10.1002/ana.410340612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8250532">Santorelli et al. (1993)</a> found the T-to-G point mutation at nucleotide 8993 in 12 patients with Leigh syndrome from 10 unrelated families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8250532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Mitochondrial Leigh syndrome shows maternal mitochondrial inheritance.</p><p><a href="#6" class="mim-tip-reference" title="DiMauro, S., De Vivo, D. C. <strong>Genetic heterogeneity in Leigh syndrome. (Letter)</strong> Ann. Neurol. 40: 5-7, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8687192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8687192</a>] [<a href="https://doi.org/10.1002/ana.410400104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8687192">DiMauro and De Vivo (1996)</a> reviewed the genetic heterogeneity of Leigh syndrome and noted that multiple defects had been described in association with Leigh syndrome, including mutations in PDHA1 (<a href="/entry/300502">300502</a>), mutations in the mitochondrial MTATP6 gene, and defects in complex IV (see, e.g., <a href="/entry/220110">220110</a>). Thus, there are at least 3 major causes of Leigh syndrome, each transmitted by a different mode of inheritance: X-linked recessive, mitochondrial, and autosomal recessive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8687192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Ma, H., Folmes, C. D. L., Wu, J., Morey, R., Mora-Castilla, S., Ocampo, A., Ma, L., Poulton, J., Wang, X., Ahmed, R., Kang, E., Lee, Y., and 14 others. <strong>Metabolic rescue in pluripotent cells from patients with mtDNA disease.</strong> Nature 524: 234-238, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26176921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26176921</a>] [<a href="https://doi.org/10.1038/nature14546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26176921">Ma et al. (2015)</a> generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A-G (<a href="/entry/590050#0001">590050.0001</a>), causing MELAS, and 8993T-G (<a href="/entry/516060#0001">516060.0001</a>) and 13513G-A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wildtype or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T-G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wildtype mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wildtype mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. <a href="#9" class="mim-tip-reference" title="Ma, H., Folmes, C. D. L., Wu, J., Morey, R., Mora-Castilla, S., Ocampo, A., Ma, L., Poulton, J., Wang, X., Ahmed, R., Kang, E., Lee, Y., and 14 others. <strong>Metabolic rescue in pluripotent cells from patients with mtDNA disease.</strong> Nature 524: 234-238, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26176921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26176921</a>] [<a href="https://doi.org/10.1038/nature14546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26176921">Ma et al. (2015)</a> concluded that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wildtype mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26176921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="DiMauro, S., De Vivo, D. C. <strong>Genetic heterogeneity in Leigh syndrome. (Letter)</strong> Ann. Neurol. 40: 5-7, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8687192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8687192</a>] [<a href="https://doi.org/10.1002/ana.410400104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8687192">DiMauro and De Vivo (1996)</a> reviewed the genetic heterogeneity of Leigh syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8687192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p><a href="#13" class="mim-tip-reference" title="Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R. <strong>Leigh syndrome: clinical features and biochemical and DNA abnormalities.</strong> Ann. Neurol. 39: 343-351, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8602753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8602753</a>] [<a href="https://doi.org/10.1002/ana.410390311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8602753">Rahman et al. (1996)</a> investigated Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups: in 80% of the tightly defined group and 41% of the 'Leigh-like' group. Enzyme defects were found in 29 patients: in respiratory chain complex I in 13, in complex IV in 9, and in the pyruvate dehydrogenase complex (PDHC) in 7. Eleven patients had mitochondrial mutations, including point mutations in the MTATP6 gene (e.g., <a href="/entry/516060#0001">516060.0001</a>), a mutation in the gene encoding mitochondrial transfer RNA-lysine (MTTK) (<a href="/entry/590060#0001">590060.0001</a>), which is common in MERRF syndrome (<a href="/entry/545000">545000</a>), and a mitochondrial deletion. <a href="#13" class="mim-tip-reference" title="Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R. <strong>Leigh syndrome: clinical features and biochemical and DNA abnormalities.</strong> Ann. Neurol. 39: 343-351, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8602753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8602753</a>] [<a href="https://doi.org/10.1002/ana.410390311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8602753">Rahman et al. (1996)</a> found no strong correlation between the clinical features and basic defects. An assumption of autosomal recessive inheritance would have been wrong in nearly one-half of those in whom a cause was found: 11 of 28 tightly defined and 18 of 41 total patients. The experience illustrated that a specific defect must be identified if reliable genetic counseling is to be provided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8602753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#4" class="mim-tip-reference" title="Dahl, H.-H. <strong>Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. (Editorial)</strong> Am. J. Hum. Genet. 63: 1594-1597, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9837811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9837811</a>] [<a href="https://doi.org/10.1086/302169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9837811">Dahl (1998)</a> reviewed mutations of respiratory chain-enzyme genes that cause Leigh syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9837811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a review of the mechanisms of mitochondrial respiratory chain diseases, <a href="#7" class="mim-tip-reference" title="DiMauro, S., Schon, E. A. <strong>Mitochondrial respiratory-chain diseases.</strong> New Eng. J. Med. 348: 2656-2668, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12826641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12826641</a>] [<a href="https://doi.org/10.1056/NEJMra022567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12826641">DiMauro and Schon (2003)</a> diagrammed the defects resulting from mutations in complexes I, II, III, IV, and V, all of which had Leigh syndrome as one of their pathologic consequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12826641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Mutations in the MTTV Gene</em></strong>
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<p><a href="#10" class="mim-tip-reference" title="McFarland, R., Clark, K. M., Morris, A. A. M., Taylor, R. W., Macphail, S., Lightowlers, R. N., Turnbull, D. M. <strong>Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation.</strong> Nature Genet. 30: 145-146, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11799391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11799391</a>] [<a href="https://doi.org/10.1038/ng819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11799391">McFarland et al. (2002)</a> concluded that a C-to-T transition of nucleotide 1624, present in homoplasmic state in the MTTV gene (<a href="/entry/590105#0002">590105.0002</a>) encoding mitochondrial tRNA(Val), was responsible for the findings. The change was expected to affect a basepair in the dihydrouridine loop that is highly conserved in species from yeast to human. A marked, selective reduction of the steady-state level of mitochondrial tRNA(Val) in cardiac and skeletal muscle was found in one of the infants that died neonatally and in skeletal muscle from the mother. These and other data suggested that the 1624C-T mutant was rapidly degraded. The marked difference in phenotype between the mother and her offspring was not explained by this defect; the authors suggested that other factors, such as nuclear-encoded components or epigenetic phenomena, might be involved. Given the severe biochemical defect and the low level of mitochondrial tRNA(Val), what was surprising about this family was not that the children were severely affected but that the mother had survived and had so few clinical problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11799391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Mutations in the MTTW Gene</em></strong>
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<p>In a family in which the proband had a progressive neurologic disorder and his brother died in infancy of Leigh syndrome, <a href="#15" class="mim-tip-reference" title="Santorelli, F. M., Tanji, K., Sano, M., Shanske, S., El-Shahawi, M., Kranz-Eble, P., DiMauro, S., De Vivo, D. C. <strong>Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene.</strong> Ann. Neurol. 42: 256-260, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9266739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9266739</a>] [<a href="https://doi.org/10.1002/ana.410420220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9266739">Santorelli et al. (1997)</a> identified a 1-bp insertion (5537insT) in the MTTW gene (<a href="/entry/590095#0002">590095.0002</a>). Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. The mutation was abundant in tissues from the proband and his brother (greater than 92%), and less abundant (42 to 89%) in 4 maternal relatives, 3 of whom had neuropsychiatric disturbances. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9266739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#19" class="mim-tip-reference" title="Tulinius, M., Moslemi, A.-R., Darin, N., Westerberg, B., Wiklund, L.-M., Holme, E., Oldfors, A. <strong>Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNA(Trp) gene.</strong> Neuropediatrics 34: 87-91, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12776230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12776230</a>] [<a href="https://doi.org/10.1055/s-2003-39607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12776230">Tulinius et al. (2003)</a> reported a boy with Leigh syndrome who had the 5537insT mutation. The mutation was found in a high proportion (greater than 95%) in blood, liver, and muscle tissue of the patient, and in blood of the patient's mother (81%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12776230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Mutations in the MTTL1 Gene</em></strong>
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<p><a href="#17" class="mim-tip-reference" title="Sue, C. M., Bruno, C., Andreu, A. L., Cargan, A., Mendell, J. R., Tsao, C.-Y., Luquette, M., Paolicchi, J., Shanske, S., DiMauro, S., De Vivo, D. C. <strong>Infantile encephalopathy associated with the MELAS A3243G mutation.</strong> J. Pediat. 134: 696-700, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10356136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10356136</a>] [<a href="https://doi.org/10.1016/s0022-3476(99)70283-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10356136">Sue et al. (1999)</a> reported 3 unrelated children with a 3243A-G mutation in the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>) who presented with severe psychomotor delay in early infancy. One patient's clinical picture was more consistent with Leigh syndrome, with apneic episodes, ataxia, and bilateral striatal lesions on brain MRI. The proportion of mutant mtDNA in available tissues was relatively low (range, 5 to 51% in muscle and 4 to 39% in blood). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10356136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Mutations in the MTATP6 Gene</em></strong>
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<p>Mutations in the MTAPT6 gene have been identified in several families with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; <a href="/entry/500015">500015</a>) resulting in Leigh syndrome. These include c.8993T-G (<a href="/entry/516060#0001">516060.0001</a>) (<a href="#18" class="mim-tip-reference" title="Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B. H. <strong>Heteroplasmic mtDNA mutation (T-to-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.</strong> Am. J. Hum. Genet. 50: 852-858, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1550128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1550128</a>]" pmid="1550128">Tatuch et al., 1992</a>, <a href="#16" class="mim-tip-reference" title="Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., Wallace, D. C. <strong>Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.</strong> Neurology 42: 2168-2174, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1436530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1436530</a>] [<a href="https://doi.org/10.1212/wnl.42.11.2168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1436530">Shoffner et al., 1992</a>, <a href="#3" class="mim-tip-reference" title="Ciafaloni, E., Santorelli, F. M., Shanske, S., Deonna, T., Roulet, E., Janzer, C., Pescia, G., DiMauro, S. <strong>Maternally inherited Leigh syndrome.</strong> J. Pediat. 122: 419-422, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8095070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8095070</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)83431-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8095070">Ciafaloni et al., 1993</a>, <a href="#14" class="mim-tip-reference" title="Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C., DiMauro, S. <strong>The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome.</strong> Ann. Neurol. 34: 827-834, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8250532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8250532</a>] [<a href="https://doi.org/10.1002/ana.410340612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8250532">Santorelli et al., 1993</a>, <a href="#12" class="mim-tip-reference" title="Pastores, G. M., Santorelli, F. M., Shanske, S., Gelb, B. D., Fyfe, B., Wolfe, D., Willner, J. P. <strong>Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G).</strong> Am. J. Med. Genet. 50: 265-271, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8042671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8042671</a>] [<a href="https://doi.org/10.1002/ajmg.1320500310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8042671">Pastores et al., 1994</a>); c.8993T-C (<a href="/entry/516060#0002">516060.0002</a>) (<a href="#5" class="mim-tip-reference" title="de Vries, D. D., van Engelen, B. G. M., Gabreels, F. J. M., Ruitenbeek, W., van Oost, B. A. <strong>A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome.</strong> Ann. Neurol. 34: 410-412, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8395787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8395787</a>] [<a href="https://doi.org/10.1002/ana.410340319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8395787">de Vries et al., 1993</a>, <a href="#20" class="mim-tip-reference" title="Vilarinho, L., Barbot, C., Carrozzo, R., Calado, E., Tessa, A., Dionisi-Vici, C., Guimaraes, A., Santorelli. F. M. <strong>Clinical and molecular findings in 4 new patients harbouring the mtDNA 8993T-C mutation.</strong> J. Inherit. Metab. Dis. 24: 883-884, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11916326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11916326</a>] [<a href="https://doi.org/10.1023/a:1013908728445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11916326">Vilarinho et al., 2001</a>); c.9185T-C (<a href="/entry/516060#0008">516060.0008</a>) (<a href="#2" class="mim-tip-reference" title="Castagna, A. E., Addis, J., McInnes, R. R., Clarke, J. T. R., Ashby, P., Blaser, S., Robinson, B. H. <strong>Late onset Leigh syndrome and ataxia due to a T to C mutation at bp 9,185 of mitochondrial DNA.</strong> Am. J. Med. Genet. 143A: 808-816, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17352390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17352390</a>] [<a href="https://doi.org/10.1002/ajmg.a.31637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17352390">Castagna et al., 2007</a>); and c.9176T-G (<a href="/entry/516060#0011">516060.0011</a>) (<a href="#1" class="mim-tip-reference" title="Carrozzo, R., Tessa, A., Vazquez-Memije, M. E., Piemonte, F., Patrono, C., Malandrini, A., Dionisi-Vici, C., Vilarinho, L., Villanova, M., Schagger, H., Federico, A., Bertini, E., Santorelli, F. M. <strong>The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome.</strong> Neurology 56: 687-690, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245730</a>] [<a href="https://doi.org/10.1212/wnl.56.5.687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11245730">Carrozzo et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8250532+11245730+11916326+8095070+8042671+1436530+8395787+1550128+17352390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M. <strong>Deficiency of respiratory chain complex I is a common cause of Leigh disease.</strong> Ann. Neurol. 40: 25-30, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8687187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8687187</a>] [<a href="https://doi.org/10.1002/ana.410400107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8687187">Morris et al. (1996)</a> reviewed the clinical features and biochemical cause of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of the pedigrees, and in 74% of the 19 pedigrees with pathologically confirmed Leigh disease. Mutation in the MTATP6 gene (<a href="/entry/516060#0001">516060.0001</a>) was found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8687187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.31637" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(05)83431-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302169" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8395787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8395787</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8395787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410340319" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410400104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMra022567" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26506407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26506407</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26506407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.24551" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature14546" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng819" target="_blank">Full Text</a>]
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<a id="Morris1996" class="mim-anchor"></a>
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<div class="">
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Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M.
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<strong>Deficiency of respiratory chain complex I is a common cause of Leigh disease.</strong>
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Ann. Neurol. 40: 25-30, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8687187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8687187</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8687187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410400107" target="_blank">Full Text</a>]
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<a id="Pastores1994" class="mim-anchor"></a>
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Pastores, G. M., Santorelli, F. M., Shanske, S., Gelb, B. D., Fyfe, B., Wolfe, D., Willner, J. P.
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<strong>Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G).</strong>
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Am. J. Med. Genet. 50: 265-271, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8042671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8042671</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8042671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320500310" target="_blank">Full Text</a>]
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<a id="Rahman1996" class="mim-anchor"></a>
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<div class="">
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Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8602753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8602753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8602753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410390311" target="_blank">Full Text</a>]
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<a id="Santorelli1993" class="mim-anchor"></a>
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<div class="">
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Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C., DiMauro, S.
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<strong>The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome.</strong>
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Ann. Neurol. 34: 827-834, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8250532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8250532</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8250532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410340612" target="_blank">Full Text</a>]
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<a id="Santorelli1997" class="mim-anchor"></a>
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Santorelli, F. M., Tanji, K., Sano, M., Shanske, S., El-Shahawi, M., Kranz-Eble, P., DiMauro, S., De Vivo, D. C.
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<strong>Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9266739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9266739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9266739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410420220" target="_blank">Full Text</a>]
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<a id="Shoffner1992" class="mim-anchor"></a>
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Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., Wallace, D. C.
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<strong>Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.</strong>
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Neurology 42: 2168-2174, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1436530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1436530</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1436530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.42.11.2168" target="_blank">Full Text</a>]
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Sue, C. M., Bruno, C., Andreu, A. L., Cargan, A., Mendell, J. R., Tsao, C.-Y., Luquette, M., Paolicchi, J., Shanske, S., DiMauro, S., De Vivo, D. C.
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<strong>Infantile encephalopathy associated with the MELAS A3243G mutation.</strong>
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J. Pediat. 134: 696-700, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10356136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10356136</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10356136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(99)70283-0" target="_blank">Full Text</a>]
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Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B. H.
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<strong>Heteroplasmic mtDNA mutation (T-to-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.</strong>
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Am. J. Hum. Genet. 50: 852-858, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1550128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1550128</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1550128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Tulinius, M., Moslemi, A.-R., Darin, N., Westerberg, B., Wiklund, L.-M., Holme, E., Oldfors, A.
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<strong>Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNA(Trp) gene.</strong>
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Neuropediatrics 34: 87-91, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12776230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12776230</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12776230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1055/s-2003-39607" target="_blank">Full Text</a>]
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Vilarinho, L., Barbot, C., Carrozzo, R., Calado, E., Tessa, A., Dionisi-Vici, C., Guimaraes, A., Santorelli. F. M.
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<strong>Clinical and molecular findings in 4 new patients harbouring the mtDNA 8993T-C mutation.</strong>
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J. Inherit. Metab. Dis. 24: 883-884, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11916326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11916326</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11916326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1023/a:1013908728445" target="_blank">Full Text</a>]
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Cassandra L. Kniffin : 03/21/2024
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carol : 12/17/2024
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carol : 05/15/2024<br>carol : 05/15/2024<br>carol : 05/15/2024<br>ckniffin : 03/23/2024<br>ckniffin : 03/22/2024
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<strong>SNOMEDCT:</strong> 717052002;
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<strong>ORPHA:</strong> 255210;
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<p>A number sign (#) is used with this entry because of evidence that mitochondrial Leigh syndrome (MILS) is caused by mutation in several mitochondrial genes, including MTTV (590105), MTTK (590060), MTTW (590095), MTTL1 (590050), and MTATP6 (516060).</p>
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<p>Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, sometimes resulting in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by Lake et al., 2015). </p><p><strong><em>Genetic Heterogeneity of Leigh Syndrome</em></strong></p><p>
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Leigh syndrome can be a clinical presentation of a primary deficiency caused by genes involved in any of the mitochondrial respiratory chain complexes, both in the mitochondrial genome and in the nuclear genome.</p><p>See 256000 for discussion of genetic heterogeneity of nuclear Leigh syndrome (NULS).</p>
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<p><strong><em>Patients with Mutations in the MTTV Gene</em></strong></p><p>
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McFarland et al. (2002) reported the case of a 35-year-old woman who had 1 surviving child with mitochondrial Leigh syndrome from 10 pregnancies with 4 unrelated partners. A number of her relatives died in early infancy, including her 3 sibs. She had suffered occasional migraine headaches, and examination demonstrated very mild proximal muscle weakness. In contrast, all of her offspring showed evidence of profound mitochondrial dysfunction. One was delivered by cesarean at 32 weeks' gestation because of deteriorating cardiac function. Despite immediate clinical intervention, the baby died of severe cardiac failure at 21 hours of life. Autopsy showed biventricular hypertrophic cardiomyopathy. Six infants died in the early neonatal period with lacticacidosis, the longest survivor dying 85 hours after birth. Although several changes in mitochondrial DNA were found, McFarland et al. (2002) concluded that a C-to-T transition of nucleotide 1624, present in homoplasmic state in the gene encoding mitochondrial tRNA(Val), was responsible for the findings. </p><p><strong><em>Patients with Mutations in the MTTW Gene</em></strong></p><p>
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Santorelli et al. (1997) reported a family in which the proband had a progressive neurologic disorder and his brother died in infancy of Leigh syndrome. Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. Genetic analysis identified a mutation in the MTTW gene (c.5537insT; 590095.0002). The mutation was abundant in tissues from the proband and his brother (greater than 92%), and less abundant (42 to 89%) in 4 maternal relatives, 3 of whom had neuropsychiatric disturbances. </p><p>Tulinius et al. (2003) reported a boy with Leigh syndrome who had the 5537insT mutation in the MTTW gene. From infancy, he was irritable and had hypotonia. Later, neurologic features included nystagmus, optic atrophy, seizures, delayed motor development, and mental retardation. Skeletal muscle analysis showed a profound COX deficiency and complex I deficiency. The mutation was found in a high proportion (greater than 95%) in blood, liver, and muscle tissue of the patient, and in blood of the patient's mother (81%). </p><p><strong><em>Patients with Mutations in the MTTL1 Gene</em></strong></p><p>
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Sue et al. (1999) reported 3 unrelated children with a 3243A-G mutation in the MTTL1 gene (590050.0001) who presented with severe psychomotor delay in early infancy. One patient's clinical picture was more consistent with Leigh syndrome, with apneic episodes, ataxia, and bilateral striatal lesions on brain MRI. The proportion of mutant mtDNA in available tissues was relatively low (range, 5 to 51% in muscle and 4 to 39% in blood). </p><p><strong><em>Patients with Mutations in the MTAPT6 Gene</em></strong></p><p>
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Mutations in the MTAPT6 gene have been identified in multiple families with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015) resulting in Leigh syndrome. These include c.8993T-G (516060.0001) (Tatuch et al., 1992, Shoffner et al., 1992, Ciafaloni et al., 1993, Santorelli et al., 1993, Pastores et al., 1994); c.8993T-C (516060.0002) (de Vries et al., 1993, Vilarinho et al., 2001); c.9185T-C (516060.0008) (Castagna et al., 2007); and c.9176T-G (516060.0011) (Carrozzo et al., 2001). </p><p>Tatuch et al. (1992) and Shoffner et al. (1992) identified a mutation in the MTAPT6 gene (c.8993T-G; 516060.0001). Tatuch et al. (1992) found the heteroplasmic mtDNA mutation in a female infant showing lactic acidemia, hypotonia, and neurodegenerative disease leading to death at the age of 7 months. Autopsy revealed lesions typical of Leigh disease, both in the basal ganglia and in the brainstem. A maternal uncle and aunt died 5 months and 1 year, respectively, after a similar clinical course, while another maternal uncle, 33 years of age, had retinitis pigmentosa, ataxia, and mental retardation. The index patient had more than 95% abnormal mtDNA in her skin fibroblasts, brain, kidney, and liver tissues, as measured by laser densitometry. The maternal aunt who died at 1 year likewise had more than 95% abnormal mtDNA in her lymphoblasts. The uncle with retinitis pigmentosa had 78% and 79% abnormal mtDNA in his skin fibroblasts and lymphoblasts, respectively, while an asymptomatic maternal aunt and her son had no trace of the mutation. The mother of the index case had 71% and 39% abnormal mtDNA in her skin fibroblasts and lymphoblasts, respectively. Shoffner et al. (1992) reported a family which was heteroplasmic for the ATPase 6 nucleotide 8993 mutation in which 2 daughters with Leigh syndrome died at ages 2.5 years and 14 months. Pathologic analyses showed classic basal ganglial lesions, vascular proliferation, and glioses. Two brothers manifested psychomotor retardation, ataxia, hypotonia, and retinal degeneration. The mother had retinal degeneration and experienced migraine headaches. The mother's 2 sisters were normal. The 4 affected children had high levels of mutant mtDNA, in excess of 95% by Southern blot. The mother had a 78% level of mutant mtDNA while her 2 sisters had 100% normal mtDNA. </p><p>Ciafaloni et al. (1993) described 2 sisters with Leigh syndrome who had a T-to-G transversion at nucleotide 8993 in the MTATP6 gene. The asymptomatic mother had the same mutation. All 3 were heteroplasmic. The proportion of mutant genomes was lower in the mother's blood than in the blood of the more mildly affected sister, whereas all tissues from the other sister were almost homoplasmic for the mutation. </p><p>Santorelli et al. (1993) found the T-to-G point mutation at nucleotide 8993 in 12 patients with Leigh syndrome from 10 unrelated families. </p>
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<p>Mitochondrial Leigh syndrome shows maternal mitochondrial inheritance.</p><p>DiMauro and De Vivo (1996) reviewed the genetic heterogeneity of Leigh syndrome and noted that multiple defects had been described in association with Leigh syndrome, including mutations in PDHA1 (300502), mutations in the mitochondrial MTATP6 gene, and defects in complex IV (see, e.g., 220110). Thus, there are at least 3 major causes of Leigh syndrome, each transmitted by a different mode of inheritance: X-linked recessive, mitochondrial, and autosomal recessive. </p>
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<p>Ma et al. (2015) generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A-G (590050.0001), causing MELAS, and 8993T-G (516060.0001) and 13513G-A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wildtype or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T-G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wildtype mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wildtype mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. Ma et al. (2015) concluded that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wildtype mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease. </p>
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<p>DiMauro and De Vivo (1996) reviewed the genetic heterogeneity of Leigh syndrome. </p><p>Rahman et al. (1996) investigated Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups: in 80% of the tightly defined group and 41% of the 'Leigh-like' group. Enzyme defects were found in 29 patients: in respiratory chain complex I in 13, in complex IV in 9, and in the pyruvate dehydrogenase complex (PDHC) in 7. Eleven patients had mitochondrial mutations, including point mutations in the MTATP6 gene (e.g., 516060.0001), a mutation in the gene encoding mitochondrial transfer RNA-lysine (MTTK) (590060.0001), which is common in MERRF syndrome (545000), and a mitochondrial deletion. Rahman et al. (1996) found no strong correlation between the clinical features and basic defects. An assumption of autosomal recessive inheritance would have been wrong in nearly one-half of those in whom a cause was found: 11 of 28 tightly defined and 18 of 41 total patients. The experience illustrated that a specific defect must be identified if reliable genetic counseling is to be provided. </p><p>Dahl (1998) reviewed mutations of respiratory chain-enzyme genes that cause Leigh syndrome. </p><p>In a review of the mechanisms of mitochondrial respiratory chain diseases, DiMauro and Schon (2003) diagrammed the defects resulting from mutations in complexes I, II, III, IV, and V, all of which had Leigh syndrome as one of their pathologic consequences. </p><p><strong><em>Mutations in the MTTV Gene</em></strong></p><p>
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McFarland et al. (2002) concluded that a C-to-T transition of nucleotide 1624, present in homoplasmic state in the MTTV gene (590105.0002) encoding mitochondrial tRNA(Val), was responsible for the findings. The change was expected to affect a basepair in the dihydrouridine loop that is highly conserved in species from yeast to human. A marked, selective reduction of the steady-state level of mitochondrial tRNA(Val) in cardiac and skeletal muscle was found in one of the infants that died neonatally and in skeletal muscle from the mother. These and other data suggested that the 1624C-T mutant was rapidly degraded. The marked difference in phenotype between the mother and her offspring was not explained by this defect; the authors suggested that other factors, such as nuclear-encoded components or epigenetic phenomena, might be involved. Given the severe biochemical defect and the low level of mitochondrial tRNA(Val), what was surprising about this family was not that the children were severely affected but that the mother had survived and had so few clinical problems. </p><p><strong><em>Mutations in the MTTW Gene</em></strong></p><p>
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In a family in which the proband had a progressive neurologic disorder and his brother died in infancy of Leigh syndrome, Santorelli et al. (1997) identified a 1-bp insertion (5537insT) in the MTTW gene (590095.0002). Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. The mutation was abundant in tissues from the proband and his brother (greater than 92%), and less abundant (42 to 89%) in 4 maternal relatives, 3 of whom had neuropsychiatric disturbances. </p><p>Tulinius et al. (2003) reported a boy with Leigh syndrome who had the 5537insT mutation. The mutation was found in a high proportion (greater than 95%) in blood, liver, and muscle tissue of the patient, and in blood of the patient's mother (81%). </p><p><strong><em>Mutations in the MTTL1 Gene</em></strong></p><p>
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Sue et al. (1999) reported 3 unrelated children with a 3243A-G mutation in the MTTL1 gene (590050.0001) who presented with severe psychomotor delay in early infancy. One patient's clinical picture was more consistent with Leigh syndrome, with apneic episodes, ataxia, and bilateral striatal lesions on brain MRI. The proportion of mutant mtDNA in available tissues was relatively low (range, 5 to 51% in muscle and 4 to 39% in blood). </p><p><strong><em>Mutations in the MTATP6 Gene</em></strong></p><p>
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Mutations in the MTAPT6 gene have been identified in several families with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015) resulting in Leigh syndrome. These include c.8993T-G (516060.0001) (Tatuch et al., 1992, Shoffner et al., 1992, Ciafaloni et al., 1993, Santorelli et al., 1993, Pastores et al., 1994); c.8993T-C (516060.0002) (de Vries et al., 1993, Vilarinho et al., 2001); c.9185T-C (516060.0008) (Castagna et al., 2007); and c.9176T-G (516060.0011) (Carrozzo et al., 2001). </p><p>Morris et al. (1996) reviewed the clinical features and biochemical cause of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of the pedigrees, and in 74% of the 19 pedigrees with pathologically confirmed Leigh disease. Mutation in the MTATP6 gene (516060.0001) was found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate </p>
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<strong>REFERENCES</strong>
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Carrozzo, R., Tessa, A., Vazquez-Memije, M. E., Piemonte, F., Patrono, C., Malandrini, A., Dionisi-Vici, C., Vilarinho, L., Villanova, M., Schagger, H., Federico, A., Bertini, E., Santorelli, F. M.
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Ma, H., Folmes, C. D. L., Wu, J., Morey, R., Mora-Castilla, S., Ocampo, A., Ma, L., Poulton, J., Wang, X., Ahmed, R., Kang, E., Lee, Y., and 14 others.
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Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M.
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<strong>Deficiency of respiratory chain complex I is a common cause of Leigh disease.</strong>
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Pastores, G. M., Santorelli, F. M., Shanske, S., Gelb, B. D., Fyfe, B., Wolfe, D., Willner, J. P.
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<strong>Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G).</strong>
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Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R.
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Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C., DiMauro, S.
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<strong>The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome.</strong>
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Santorelli, F. M., Tanji, K., Sano, M., Shanske, S., El-Shahawi, M., Kranz-Eble, P., DiMauro, S., De Vivo, D. C.
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<strong>Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene.</strong>
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Shoffner, J. M., Fernhoff, P. M., Krawiecki, N. S., Caplan, D. B., Holt, P. J., Koontz, D. A., Takei, Y., Newman, N. J., Ortiz, R. G., Polak, M., Ballinger, S. W., Lott, M. T., Wallace, D. C.
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Sue, C. M., Bruno, C., Andreu, A. L., Cargan, A., Mendell, J. R., Tsao, C.-Y., Luquette, M., Paolicchi, J., Shanske, S., DiMauro, S., De Vivo, D. C.
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Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J. T. R., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B. H.
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<strong>Heteroplasmic mtDNA mutation (T-to-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.</strong>
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<strong>Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNA(Trp) gene.</strong>
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Vilarinho, L., Barbot, C., Carrozzo, R., Calado, E., Tessa, A., Dionisi-Vici, C., Guimaraes, A., Santorelli. F. M.
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<strong>Clinical and molecular findings in 4 new patients harbouring the mtDNA 8993T-C mutation.</strong>
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information that you need at your fingertips.
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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