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Entry
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- #545000 - MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS; MERRF
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- OMIM
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<p>
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<span class="h4">#545000</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="/clinicalSynopsis/545000"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS" 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=64&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="#mimGeneReviewsFold" id="mimGeneReviewsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling."><span id="mimGeneReviewsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Gene Reviews</div>
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<div id="mimGeneReviewsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1224/" title="Primary Mitochondrial Disorders Overview" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Primary Mitochondrial Diso…</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">MERRF</a></div>
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</div>
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<div><a href="https://www.diseaseinfosearch.org/x/5039" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/myoclonic-epilepsy-with-ragged-red-fibers" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=545000[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=551" 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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<div style="display: table-cell;">Animal Models</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:310" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://omia.org/OMIA000344/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:545000" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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 id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 230426003<br />
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<strong>ICD10CM:</strong> E88.42<br />
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<strong>ORPHA:</strong> 551<br />
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<strong>DO:</strong> 310<br />
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">ICD+</a>
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<span class="h3">
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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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545000
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS; MERRF
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</span>
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</h3>
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</div>
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<div>
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<br />
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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MERRF SYNDROME
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<a href="/clinicalSynopsis/545000" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<strong> Neuro </strong>
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- Myoclonus epilepsy. Ataxia. Spasticity.<br />
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<p>A number sign (#) is used with this entry because this syndrome represents a phenotype that can be produced by mutation in more than 1 mitochondrial gene, e.g., MTTK (<a href="/entry/590060">590060</a>), MTTL1 (<a href="/entry/590050">590050</a>), MTTH (<a href="/entry/590040">590040</a>), MTTS1 (<a href="/entry/590080">590080</a>), MTTS2 (<a href="/entry/590085">590085</a>), MTTF (<a href="/entry/590070">590070</a>). Features of the MERRF syndrome have also been associated with mutation in the MTND5 gene (<a href="/entry/516005">516005</a>).</p>
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<p><a href="#4" class="mim-tip-reference" title="Fukuhara, N., Tokiguchi, S., Shirakawa, K., Tsubaki, T. <strong>Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or a syndrome? Light- and electron-microscopic studies of two cases and a review of the literature.</strong> J. Neurol. Sci. 47: 117-133, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6774061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6774061</a>] [<a href="https://doi.org/10.1016/0022-510x(80)90031-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6774061">Fukuhara et al. (1980)</a> provided an early report of myoclonic epilepsy associated with ragged-red fibers (MERRF). For detailed clinical features, see MOLECULAR GENETICS <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6774061" 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="#10" class="mim-tip-reference" title="Rosing, H. S., Hopkins, L. C., Wallace, D. C., Epstein, C. M., Weidenheim, K. <strong>Maternally inherited mitochondrial myopathy and myoclonic epilepsy.</strong> Ann. Neurol. 17: 228-237, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3922281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3922281</a>] [<a href="https://doi.org/10.1002/ana.410170303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3922281">Rosing et al. (1985)</a> described an extensive family in which many members showed this combination of abnormalities which goes by the acronymic designation MERRF syndrome. Autosomal dominant, autosomal recessive, and X-linked inheritance could be excluded. Variability of expression and variable characteristics of the inheritance were consistent with mutation in mitochondrial DNA. The clinical spectrum was considered compatible with the proportionality model of mutant and wildtype mtDNAs. Serum levels of pyruvate or pyruvate and lactate were elevated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3922281" 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>Although the genetic defect is transmitted through the maternal lineage, the clinical phenotype varies greatly within a pedigree, consistent with a heteroplasmic population of mtDNAs, some of which are wildtype and others mutant. In skeletal muscle, the biochemical defect is often segmental (<a href="#7" class="mim-tip-reference" title="Matsuoka, T., Goto, Y., Yoneda, M., Nonaka, I. <strong>Muscle histopathology in myoclonus epilepsy with ragged-red fibers (MERRF).</strong> J. Neurol. Sci. 106: 193-198, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1666407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1666407</a>] [<a href="https://doi.org/10.1016/0022-510x(91)90257-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1666407">Matsuoka et al., 1991</a>), suggesting a nonrandom distribution of mutant and wildtype mtDNAs within a muscle cell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1666407" 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 specific mutation in mitochondrial DNA was first demonstrated by <a href="#11" class="mim-tip-reference" title="Shoffner, J. M., Lott, M. T., Lezza, A. M. S., Seibel, P., Ballinger, S. W., Wallace, D. C. <strong>Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA-lys mutation.</strong> Cell 61: 931-937, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2112427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2112427</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90059-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2112427">Shoffner et al. (1990)</a> (MTTK, <a href="/entry/590060#0001">590060.0001</a>). The A-to-G mutation at nucleotide 8344 accounts for 80 to 90% of MERRF cases (<a href="#12" class="mim-tip-reference" title="Shoffner, J. M., Wallace, D. C. <strong>Mitochondrial genetics: principles and practice. (Editorial)</strong> Am. J. Hum. Genet. 51: 1179-1186, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1463005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1463005</a>]" pmid="1463005">Shoffner and Wallace, 1992</a>). Biochemically, the mutation produces multiple deficiencies in the enzyme complexes of the respiratory chain, most prominently involving NADH-CoQ reductase (complex I) in cytochrome c oxidase (COX) (complex IV), consistent with a defect in translation of all mtDNA-encoded genes (<a href="#13" class="mim-tip-reference" title="Wallace, D. C., Zheng, X., Lott, M. T., Shoffner, J. M., Hodge, J. A., Kelley, R. I., Epstein, C. M., Hopkins, L. C. <strong>Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease.</strong> Cell 55: 601-610, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3180221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3180221</a>] [<a href="https://doi.org/10.1016/0092-8674(88)90218-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3180221">Wallace et al., 1988</a>; <a href="#1" class="mim-tip-reference" title="Bindoff, L. A., Desnuelle, C., Birch-Machin, M. A., Pellissier, J.-F., Serratrice, G., Dravet, C., Bureau, M., Howell, N., Turnbull, D. M. <strong>Multiple defects of the mitochondrial respiratory chain in a mitochondrial encephalopathy (MERRF): a clinical, biochemical and molecular study.</strong> J. Neurol. Sci. 102: 17-24, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1649912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1649912</a>] [<a href="https://doi.org/10.1016/0022-510x(91)90088-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1649912">Bindoff et al., 1991</a>). <a href="#3" class="mim-tip-reference" title="Chomyn, A., Meola, G., Bresolin, N., Lai, S. T., Scarlato, G., Attardi, G. <strong>In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria.</strong> Molec. Cell. Biol. 11: 2236-2244, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1848674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1848674</a>] [<a href="https://doi.org/10.1128/mcb.11.4.2236-2244.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1848674">Chomyn et al. (1991)</a> showed that transfer of mtDNAs carrying the mutation to human cell lines lacking their own mitochondrial DNA resulted in a severe defect in mitochondrial translation in the recipient cells, independent of nuclear background, implying that the tRNA mutation itself is sufficient to cause the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1463005+2112427+1649912+3180221+1848674" 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="#5" class="mim-tip-reference" title="Holme, E., Larsson, N.-G., Oldfors, A., Tulinius, M., Sahlin, P., Stenman, G. <strong>Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.</strong> Am. J. Hum. Genet. 52: 551-556, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8447321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8447321</a>]" pmid="8447321">Holme et al. (1993)</a> reported a woman with multiple symmetric lipomas (MSL; see <a href="/entry/151800">151800</a>) in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (<a href="/entry/590060#0001">590060.0001</a>). Her son, who also carried the mutation, had MERRF syndrome; the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. <a href="#5" class="mim-tip-reference" title="Holme, E., Larsson, N.-G., Oldfors, A., Tulinius, M., Sahlin, P., Stenman, G. <strong>Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.</strong> Am. J. Hum. Genet. 52: 551-556, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8447321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8447321</a>]" pmid="8447321">Holme et al. (1993)</a> concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8447321" 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>In several affected members of 3-generation Sardinian kindred with a maternally inherited syndrome characterized by features of both MERRF and MELAS (<a href="/entry/540000">540000</a>), <a href="#14" class="mim-tip-reference" title="Zeviani, M., Muntoni, F., Savarese, N., Serra, G., Tiranti, V., Carrara, F., Mariotti, C., DiDonato, S. <strong>A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA-lys gene.</strong> Europ. J. Hum. Genet. 1: 80-87, 1993. Note: Erratum: Europ. J. Hum. Genet. 1: 124 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069654</a>] [<a href="https://doi.org/10.1159/000472390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069654">Zeviani et al. (1993)</a> identified a mutation in the MTTK gene (<a href="/entry/590060#0002">590060.0002</a>). The relative amount of mutant mtDNA in muscle correlated with the severity of the clinical presentation. Clinical features included myoclonic epilepsy, neural deafness, ataxia, and stroke-like episodes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069654" 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>In a mother and daughter with MERFF/MELAS overlap syndrome, <a href="#9" class="mim-tip-reference" title="Nakamura, M., Nakano, S., Gato, Y.-i., Ozawa, M., Nagahama, Y., Fukuyama, H., Akiguchi, I., Kaji, R., Kimura, J. <strong>A novel point mutation in the mitochondrial tRNA (ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome.</strong> Biochem. Biophys. Res. Commun. 214: 86-93, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7669057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7669057</a>] [<a href="https://doi.org/10.1006/bbrc.1995.2260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7669057">Nakamura et al. (1995)</a> identified a heteroplasmic mutation in the MTTS1 gene (<a href="/entry/590080#0001">590080.0001</a>). The proband in their study was a mentally retarded 26-year-old woman who had had epileptic attacks since the age of 15 years. At the age of 20 years, clear symptoms of MERRF syndrome developed, including myoclonic seizures, generalized tonic-clonic seizures, and paroxysmal hearing disturbance. She also showed mental deterioration, muscle atrophy weakness, and truncal ataxia. Lactate levels in both blood and cerebrospinal fluid were elevated. The brain CT scan showed cerebral atrophy and bilateral calcification of the basal ganglia. Muscle biopsies showed many ragged-red fibers and abnormal mitochondria with concentric cristae. The mother was a 55-year-old woman who had myoclonic jerks of the arms and generalized seizures since the age of 37 years. At age 47 years, she was moderately demented. Muscle weakness and ataxia were not apparent. The brain CT scan revealed calcification of the basal ganglia and bilateral occipital lobe atrophy. At age 55 years, she developed blindness after an episode of generalized seizure, and thereafter was bedridden and severely demented; the phenotype suggested stroke-like episodes consistent with MELAS syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7669057" 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="#8" class="mim-tip-reference" title="Melone, M. A. B., Tessa, A., Petrini, S., Lus, G., Sampaolo, S., di Fede, G., Santorelli, F. M., Cotrufo, R. <strong>Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype.</strong> Arch. Neurol. 61: 269-272, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14967777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14967777</a>] [<a href="https://doi.org/10.1001/archneur.61.2.269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14967777">Melone et al. (2004)</a> reported a 20-year-old man who experienced sudden migrainous headache and vomiting, followed by left hemiparesis and lateral homonymous hemianopia. Seizures also occurred. The clinical picture was consistent with MELAS syndrome. At age 25 years, he developed myoclonus and ataxia, suggesting progression to MERRF syndrome. His mother had shown similar stroke-like episodes and had died at age 36 years. Muscle biopsy of the proband showed abnormal mitochondrial proliferation and COX-negative fibers. Genetic analysis identified a heteroplasmic mutation in the MTTH gene (<a href="/entry/590040#0003">590040.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14967777" 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="#6" class="mim-tip-reference" title="Mancuso, M., Filosto, M., Mootha, V. K., Rocchi, A., Pistolesi, S., Murri, L., DiMauro, S., Siciliano, G. <strong>A novel mitochondrial tRNA-phe mutation causes MERRF syndrome.</strong> Neurology 62: 2119-2121, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184630</a>] [<a href="https://doi.org/10.1212/01.wnl.0000127608.48406.f1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15184630">Mancuso et al. (2004)</a> reported an Italian woman with MERRF syndrome who experienced panic attacks at age 11 years. In her twenties, she developed migraine and progressive limb myoclonus. In her thirties, she had exercise intolerance, loss of balance, and memory problems, and later developed bilateral sensorineural hearing loss and mild cognitive deficits. Other features included short stature, pes cavus, ataxia, and mild ophthalmoparesis. Skeletal muscle biopsy showed multiple COX-negative fibers and ragged red fibers. Genetic analysis identified a heteroplasmic mutation in the MTTF gene (<a href="/entry/590070#0002">590070.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15184630" 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="#2" class="mim-tip-reference" title="Blakely, E. L., Trip, S. A., Swalwell, H., He, L., Wren, D. R., Rich, P., Turnbull, D. M., Omer, S. E., Taylor, R. W. <strong>A new mitochondrial transfer RNA(pro) gene mutation associated with myoclonic epilepsy with ragged-red fibers and other neurological features.</strong> Arch. Neurol. 66: 399-402, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19273760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19273760</a>] [<a href="https://doi.org/10.1001/archneurol.2008.576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19273760">Blakely et al. (2009)</a> reported a woman who developed myoclonic jerks and generalized seizures at age 27 years, acute bilateral sensorineural hearing loss at age 37, underwent bilateral cataract surgery at age 39, and showed progressive loss of balance and arm weakness at age 47. Physical examination at age 49 showed some retinal pigmentary changes, dysarthria, proximal muscle weakness, and cerebellar ataxia. Skeletal muscle biopsy showed COX deficiency and ragged red fibers, consistent with mitochondrial accumulation. Genetic analysis identified a heteroplasmic mutation in the MTTP gene (<a href="/entry/590075#0003">590075.0003</a>). The mutation segregated with cytochrome c oxidase activity in single muscle fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19273760" 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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Blakely, E. L., Trip, S. A., Swalwell, H., He, L., Wren, D. R., Rich, P., Turnbull, D. M., Omer, S. E., Taylor, R. W.
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<strong>A new mitochondrial transfer RNA(pro) gene mutation associated with myoclonic epilepsy with ragged-red fibers and other neurological features.</strong>
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Arch. Neurol. 66: 399-402, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19273760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19273760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19273760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Mancuso, M., Filosto, M., Mootha, V. K., Rocchi, A., Pistolesi, S., Murri, L., DiMauro, S., Siciliano, G.
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<strong>A novel mitochondrial tRNA-phe mutation causes MERRF syndrome.</strong>
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Neurology 62: 2119-2121, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15184630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15184630</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15184630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3922281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3922281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3922281" 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.410170303" target="_blank">Full Text</a>]
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Shoffner, J. M., Lott, M. T., Lezza, A. M. S., Seibel, P., Ballinger, S. W., Wallace, D. C.
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<strong>Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA-lys mutation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2112427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2112427</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2112427" 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/10.1016/0092-8674(90)90059-n" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1463005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1463005</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1463005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA-lys gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069654</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069654" 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/10.1159/000472390" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 11/19/2014
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Cassandra L. Kniffin - updated : 8/10/2009<br>Cassandra L. Kniffin - updated : 6/27/2005<br>Cassandra L. Kniffin - updated : 1/31/2005<br>Cassandra L. Kniffin - updated : 6/2/2004<br>Victor A. McKusick - updated : 1/7/1998
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Victor A. McKusick : 9/24/1992
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carol : 11/19/2014
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carol : 4/3/2013<br>ckniffin : 5/5/2010<br>wwang : 8/31/2009<br>ckniffin : 8/10/2009<br>wwang : 2/19/2007<br>ckniffin : 2/15/2007<br>ckniffin : 6/27/2005<br>ckniffin : 1/31/2005<br>tkritzer : 6/3/2004<br>ckniffin : 6/3/2004<br>ckniffin : 6/2/2004<br>terry : 4/29/1999<br>alopez : 9/28/1998<br>terry : 1/7/1998<br>mimman : 2/8/1996<br>mimadm : 4/18/1994<br>carol : 10/18/1993<br>carol : 10/14/1993<br>carol : 4/5/1993<br>carol : 3/2/1993<br>carol : 1/27/1993
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MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS; MERRF
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MERRF SYNDROME
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<strong>SNOMEDCT:</strong> 230426003;
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<strong>ICD10CM:</strong> E88.42;
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<strong>ORPHA:</strong> 551;
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<strong>DO:</strong> 310;
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<p>A number sign (#) is used with this entry because this syndrome represents a phenotype that can be produced by mutation in more than 1 mitochondrial gene, e.g., MTTK (590060), MTTL1 (590050), MTTH (590040), MTTS1 (590080), MTTS2 (590085), MTTF (590070). Features of the MERRF syndrome have also been associated with mutation in the MTND5 gene (516005).</p>
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<p>Fukuhara et al. (1980) provided an early report of myoclonic epilepsy associated with ragged-red fibers (MERRF). For detailed clinical features, see MOLECULAR GENETICS </p>
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<p>Rosing et al. (1985) described an extensive family in which many members showed this combination of abnormalities which goes by the acronymic designation MERRF syndrome. Autosomal dominant, autosomal recessive, and X-linked inheritance could be excluded. Variability of expression and variable characteristics of the inheritance were consistent with mutation in mitochondrial DNA. The clinical spectrum was considered compatible with the proportionality model of mutant and wildtype mtDNAs. Serum levels of pyruvate or pyruvate and lactate were elevated. </p><p>Although the genetic defect is transmitted through the maternal lineage, the clinical phenotype varies greatly within a pedigree, consistent with a heteroplasmic population of mtDNAs, some of which are wildtype and others mutant. In skeletal muscle, the biochemical defect is often segmental (Matsuoka et al., 1991), suggesting a nonrandom distribution of mutant and wildtype mtDNAs within a muscle cell. </p>
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<strong>Molecular Genetics</strong>
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<p>A specific mutation in mitochondrial DNA was first demonstrated by Shoffner et al. (1990) (MTTK, 590060.0001). The A-to-G mutation at nucleotide 8344 accounts for 80 to 90% of MERRF cases (Shoffner and Wallace, 1992). Biochemically, the mutation produces multiple deficiencies in the enzyme complexes of the respiratory chain, most prominently involving NADH-CoQ reductase (complex I) in cytochrome c oxidase (COX) (complex IV), consistent with a defect in translation of all mtDNA-encoded genes (Wallace et al., 1988; Bindoff et al., 1991). Chomyn et al. (1991) showed that transfer of mtDNAs carrying the mutation to human cell lines lacking their own mitochondrial DNA resulted in a severe defect in mitochondrial translation in the recipient cells, independent of nuclear background, implying that the tRNA mutation itself is sufficient to cause the disease. </p><p>Holme et al. (1993) reported a woman with multiple symmetric lipomas (MSL; see 151800) in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome; the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation. </p><p>In several affected members of 3-generation Sardinian kindred with a maternally inherited syndrome characterized by features of both MERRF and MELAS (540000), Zeviani et al. (1993) identified a mutation in the MTTK gene (590060.0002). The relative amount of mutant mtDNA in muscle correlated with the severity of the clinical presentation. Clinical features included myoclonic epilepsy, neural deafness, ataxia, and stroke-like episodes. </p><p>In a mother and daughter with MERFF/MELAS overlap syndrome, Nakamura et al. (1995) identified a heteroplasmic mutation in the MTTS1 gene (590080.0001). The proband in their study was a mentally retarded 26-year-old woman who had had epileptic attacks since the age of 15 years. At the age of 20 years, clear symptoms of MERRF syndrome developed, including myoclonic seizures, generalized tonic-clonic seizures, and paroxysmal hearing disturbance. She also showed mental deterioration, muscle atrophy weakness, and truncal ataxia. Lactate levels in both blood and cerebrospinal fluid were elevated. The brain CT scan showed cerebral atrophy and bilateral calcification of the basal ganglia. Muscle biopsies showed many ragged-red fibers and abnormal mitochondria with concentric cristae. The mother was a 55-year-old woman who had myoclonic jerks of the arms and generalized seizures since the age of 37 years. At age 47 years, she was moderately demented. Muscle weakness and ataxia were not apparent. The brain CT scan revealed calcification of the basal ganglia and bilateral occipital lobe atrophy. At age 55 years, she developed blindness after an episode of generalized seizure, and thereafter was bedridden and severely demented; the phenotype suggested stroke-like episodes consistent with MELAS syndrome. </p><p>Melone et al. (2004) reported a 20-year-old man who experienced sudden migrainous headache and vomiting, followed by left hemiparesis and lateral homonymous hemianopia. Seizures also occurred. The clinical picture was consistent with MELAS syndrome. At age 25 years, he developed myoclonus and ataxia, suggesting progression to MERRF syndrome. His mother had shown similar stroke-like episodes and had died at age 36 years. Muscle biopsy of the proband showed abnormal mitochondrial proliferation and COX-negative fibers. Genetic analysis identified a heteroplasmic mutation in the MTTH gene (590040.0003). </p><p>Mancuso et al. (2004) reported an Italian woman with MERRF syndrome who experienced panic attacks at age 11 years. In her twenties, she developed migraine and progressive limb myoclonus. In her thirties, she had exercise intolerance, loss of balance, and memory problems, and later developed bilateral sensorineural hearing loss and mild cognitive deficits. Other features included short stature, pes cavus, ataxia, and mild ophthalmoparesis. Skeletal muscle biopsy showed multiple COX-negative fibers and ragged red fibers. Genetic analysis identified a heteroplasmic mutation in the MTTF gene (590070.0002). </p><p>Blakely et al. (2009) reported a woman who developed myoclonic jerks and generalized seizures at age 27 years, acute bilateral sensorineural hearing loss at age 37, underwent bilateral cataract surgery at age 39, and showed progressive loss of balance and arm weakness at age 47. Physical examination at age 49 showed some retinal pigmentary changes, dysarthria, proximal muscle weakness, and cerebellar ataxia. Skeletal muscle biopsy showed COX deficiency and ragged red fibers, consistent with mitochondrial accumulation. Genetic analysis identified a heteroplasmic mutation in the MTTP gene (590075.0003). The mutation segregated with cytochrome c oxidase activity in single muscle fibers. </p>
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<strong>REFERENCES</strong>
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Bindoff, L. A., Desnuelle, C., Birch-Machin, M. A., Pellissier, J.-F., Serratrice, G., Dravet, C., Bureau, M., Howell, N., Turnbull, D. M.
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<strong>Multiple defects of the mitochondrial respiratory chain in a mitochondrial encephalopathy (MERRF): a clinical, biochemical and molecular study.</strong>
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J. Neurol. Sci. 102: 17-24, 1991.
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[PubMed: 1649912]
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[Full Text: https://doi.org/10.1016/0022-510x(91)90088-o]
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Blakely, E. L., Trip, S. A., Swalwell, H., He, L., Wren, D. R., Rich, P., Turnbull, D. M., Omer, S. E., Taylor, R. W.
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<strong>A new mitochondrial transfer RNA(pro) gene mutation associated with myoclonic epilepsy with ragged-red fibers and other neurological features.</strong>
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Arch. Neurol. 66: 399-402, 2009.
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[PubMed: 19273760]
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[Full Text: https://doi.org/10.1001/archneurol.2008.576]
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Chomyn, A., Meola, G., Bresolin, N., Lai, S. T., Scarlato, G., Attardi, G.
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<strong>In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria.</strong>
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Molec. Cell. Biol. 11: 2236-2244, 1991.
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[PubMed: 1848674]
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[Full Text: https://doi.org/10.1128/mcb.11.4.2236-2244.1991]
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Fukuhara, N., Tokiguchi, S., Shirakawa, K., Tsubaki, T.
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<strong>Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or a syndrome? Light- and electron-microscopic studies of two cases and a review of the literature.</strong>
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J. Neurol. Sci. 47: 117-133, 1980.
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[PubMed: 6774061]
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[Full Text: https://doi.org/10.1016/0022-510x(80)90031-3]
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Holme, E., Larsson, N.-G., Oldfors, A., Tulinius, M., Sahlin, P., Stenman, G.
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<strong>Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.</strong>
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Am. J. Hum. Genet. 52: 551-556, 1993.
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[PubMed: 8447321]
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Mancuso, M., Filosto, M., Mootha, V. K., Rocchi, A., Pistolesi, S., Murri, L., DiMauro, S., Siciliano, G.
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<strong>A novel mitochondrial tRNA-phe mutation causes MERRF syndrome.</strong>
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Neurology 62: 2119-2121, 2004.
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[PubMed: 15184630]
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[Full Text: https://doi.org/10.1212/01.wnl.0000127608.48406.f1]
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Matsuoka, T., Goto, Y., Yoneda, M., Nonaka, I.
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<strong>Muscle histopathology in myoclonus epilepsy with ragged-red fibers (MERRF).</strong>
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J. Neurol. Sci. 106: 193-198, 1991.
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[PubMed: 1666407]
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[Full Text: https://doi.org/10.1016/0022-510x(91)90257-8]
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Melone, M. A. B., Tessa, A., Petrini, S., Lus, G., Sampaolo, S., di Fede, G., Santorelli, F. M., Cotrufo, R.
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<strong>Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype.</strong>
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Arch. Neurol. 61: 269-272, 2004.
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[PubMed: 14967777]
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[Full Text: https://doi.org/10.1001/archneur.61.2.269]
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Nakamura, M., Nakano, S., Gato, Y.-i., Ozawa, M., Nagahama, Y., Fukuyama, H., Akiguchi, I., Kaji, R., Kimura, J.
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<strong>A novel point mutation in the mitochondrial tRNA (ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome.</strong>
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Biochem. Biophys. Res. Commun. 214: 86-93, 1995.
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[PubMed: 7669057]
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[Full Text: https://doi.org/10.1006/bbrc.1995.2260]
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Rosing, H. S., Hopkins, L. C., Wallace, D. C., Epstein, C. M., Weidenheim, K.
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<strong>Maternally inherited mitochondrial myopathy and myoclonic epilepsy.</strong>
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Ann. Neurol. 17: 228-237, 1985.
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[PubMed: 3922281]
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[Full Text: https://doi.org/10.1002/ana.410170303]
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Shoffner, J. M., Lott, M. T., Lezza, A. M. S., Seibel, P., Ballinger, S. W., Wallace, D. C.
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<strong>Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA-lys mutation.</strong>
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Cell 61: 931-937, 1990.
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[PubMed: 2112427]
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[Full Text: https://doi.org/10.1016/0092-8674(90)90059-n]
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Shoffner, J. M., Wallace, D. C.
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<strong>Mitochondrial genetics: principles and practice. (Editorial)</strong>
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Am. J. Hum. Genet. 51: 1179-1186, 1992.
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Wallace, D. C., Zheng, X., Lott, M. T., Shoffner, J. M., Hodge, J. A., Kelley, R. I., Epstein, C. M., Hopkins, L. C.
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<strong>Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease.</strong>
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Cell 55: 601-610, 1988.
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[PubMed: 3180221]
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[Full Text: https://doi.org/10.1016/0092-8674(88)90218-8]
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Zeviani, M., Muntoni, F., Savarese, N., Serra, G., Tiranti, V., Carrara, F., Mariotti, C., DiDonato, S.
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<strong>A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA-lys gene.</strong>
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Europ. J. Hum. Genet. 1: 80-87, 1993. Note: Erratum: Europ. J. Hum. Genet. 1: 124 only, 1993.
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[PubMed: 8069654]
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[Full Text: https://doi.org/10.1159/000472390]
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Cassandra L. Kniffin - updated : 11/19/2014<br>Cassandra L. Kniffin - updated : 8/10/2009<br>Cassandra L. Kniffin - updated : 6/27/2005<br>Cassandra L. Kniffin - updated : 1/31/2005<br>Cassandra L. Kniffin - updated : 6/2/2004<br>Victor A. McKusick - updated : 1/7/1998
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Victor A. McKusick : 9/24/1992
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carol : 11/19/2014<br>carol : 4/3/2013<br>ckniffin : 5/5/2010<br>wwang : 8/31/2009<br>ckniffin : 8/10/2009<br>wwang : 2/19/2007<br>ckniffin : 2/15/2007<br>ckniffin : 6/27/2005<br>ckniffin : 1/31/2005<br>tkritzer : 6/3/2004<br>ckniffin : 6/3/2004<br>ckniffin : 6/2/2004<br>terry : 4/29/1999<br>alopez : 9/28/1998<br>terry : 1/7/1998<br>mimman : 2/8/1996<br>mimadm : 4/18/1994<br>carol : 10/18/1993<br>carol : 10/14/1993<br>carol : 4/5/1993<br>carol : 3/2/1993<br>carol : 1/27/1993
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