326 lines
121 KiB
Text
326 lines
121 KiB
Text
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" class="no-js no-jr">
|
|
<head>
|
|
<!-- For pinger, set start time and add meta elements. -->
|
|
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
|
|
|
<!-- Logger begin -->
|
|
<meta name="ncbi_db" content="books">
|
|
<meta name="ncbi_pdid" content="book-part">
|
|
<meta name="ncbi_acc" content="NBK547304">
|
|
<meta name="ncbi_domain" content="gene">
|
|
<meta name="ncbi_report" content="reader">
|
|
<meta name="ncbi_type" content="fulltext">
|
|
<meta name="ncbi_objectid" content="">
|
|
<meta name="ncbi_pcid" content="/NBK547304/?report=reader">
|
|
<meta name="ncbi_pagename" content="ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome - GeneReviews® - NCBI Bookshelf">
|
|
<meta name="ncbi_bookparttype" content="chapter">
|
|
<meta name="ncbi_app" content="bookshelf">
|
|
<!-- Logger end -->
|
|
|
|
<!--component id="Page" label="meta"/-->
|
|
<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome - GeneReviews® - NCBI Bookshelf</title>
|
|
<meta charset="utf-8">
|
|
<meta name="apple-mobile-web-app-capable" content="no">
|
|
<meta name="viewport" content="initial-scale=1,minimum-scale=1,maximum-scale=1,user-scalable=no">
|
|
<meta name="jr-col-layout" content="auto">
|
|
<meta name="jr-prev-unit" content="/books/n/gene/vws/?report=reader">
|
|
<meta name="jr-next-unit" content="/books/n/gene/isca2-mt-dis/?report=reader">
|
|
<meta name="bk-toc-url" content="/books/n/gene/?report=toc">
|
|
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE">
|
|
<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
|
|
<meta name="citation_title" content="ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome">
|
|
<meta name="citation_publisher" content="University of Washington, Seattle">
|
|
<meta name="citation_date" content="2019/10/03">
|
|
<meta name="citation_author" content="Anju Shukla">
|
|
<meta name="citation_author" content="Dhanya Lakshmi Narayanan">
|
|
<meta name="citation_author" content="Parneet Kaur">
|
|
<meta name="citation_author" content="Katta Mohan Girisha">
|
|
<meta name="citation_pmid" content="31580634">
|
|
<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK547304/">
|
|
<meta name="citation_keywords" content="Multiple Mitochondrial Dysfunctions Syndrome 5">
|
|
<meta name="citation_keywords" content="Multiple Mitochondrial Dysfunctions Syndrome 5">
|
|
<meta name="citation_keywords" content="Iron-sulfur cluster assembly 1 homolog, mitochondrial">
|
|
<meta name="citation_keywords" content="ISCA1">
|
|
<meta name="citation_keywords" content="ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome">
|
|
<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
|
|
<meta name="DC.Title" content="ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome">
|
|
<meta name="DC.Type" content="Text">
|
|
<meta name="DC.Publisher" content="University of Washington, Seattle">
|
|
<meta name="DC.Contributor" content="Anju Shukla">
|
|
<meta name="DC.Contributor" content="Dhanya Lakshmi Narayanan">
|
|
<meta name="DC.Contributor" content="Parneet Kaur">
|
|
<meta name="DC.Contributor" content="Katta Mohan Girisha">
|
|
<meta name="DC.Date" content="2019/10/03">
|
|
<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK547304/">
|
|
<meta name="description" content="ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Affected individuals may also demonstrate elevated blood lactate levels with an elevated lipid-lactate peak on brain MR spectroscopy. Further brain MRI findings may include extensive cerebral and cerebellar deep white matter hyperintensities, marked dilatation of the cerebral ventricles, and pachygyria. Prognosis is poor and most individuals succumb to an intercurrent illness in early childhood.">
|
|
<meta name="og:title" content="ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome">
|
|
<meta name="og:type" content="book">
|
|
<meta name="og:description" content="ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Affected individuals may also demonstrate elevated blood lactate levels with an elevated lipid-lactate peak on brain MR spectroscopy. Further brain MRI findings may include extensive cerebral and cerebellar deep white matter hyperintensities, marked dilatation of the cerebral ventricles, and pachygyria. Prognosis is poor and most individuals succumb to an intercurrent illness in early childhood.">
|
|
<meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK547304/">
|
|
<meta name="og:site_name" content="NCBI Bookshelf">
|
|
<meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png">
|
|
<meta name="twitter:card" content="summary">
|
|
<meta name="twitter:site" content="@ncbibooks">
|
|
<meta name="bk-non-canon-loc" content="/books/n/gene/isca1-mmds/?report=reader">
|
|
<link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK547304/">
|
|
<link href="https://fonts.googleapis.com/css?family=Archivo+Narrow:400,700,400italic,700italic&subset=latin" rel="stylesheet" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/libs.min.css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/jr.min.css">
|
|
<meta name="format-detection" content="telephone=no">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css//books_print.min.css" type="text/css" media="print">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_reader.min.css" type="text/css">
|
|
<style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style>
|
|
|
|
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico">
|
|
<meta name="ncbi_phid" content="CE8BD7FB7C87321100000000004C0043.m_5">
|
|
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3849091.css"></head>
|
|
<body>
|
|
<!-- Book content! -->
|
|
|
|
|
|
<div id="jr" data-jr-path="/corehtml/pmc/jatsreader/ptpmc_3.22/"><div class="jr-unsupported"><table class="modal"><tr><td><span class="attn inline-block"></span><br />Your browser does not support the NLM PubReader view.<br />Go to <a href="/pmc/about/pr-browsers/">this page</a> to see a list of supported browsers<br />or return to the <br /><a href="/books/NBK547304/?report=classic">regular view</a>.</td></tr></table></div><div id="jr-ui" class="hidden"><nav id="jr-head"><div class="flexh tb"><div id="jr-tb1"><a id="jr-links-sw" class="hidden" title="Links"><svg xmlns="http://www.w3.org/2000/svg" version="1.1" x="0px" y="0px" viewBox="0 0 70.6 85.3" style="enable-background:new 0 0 70.6 85.3;vertical-align:middle" xml:space="preserve" width="24" height="24">
|
|
<style type="text/css">.st0{fill:#939598;}</style>
|
|
<g>
|
|
<path class="st0" d="M36,0C12.8,2.2-22.4,14.6,19.6,32.5C40.7,41.4-30.6,14,35.9,9.8"></path>
|
|
<path class="st0" d="M34.5,85.3c23.2-2.2,58.4-14.6,16.4-32.5c-21.1-8.9,50.2,18.5-16.3,22.7"></path>
|
|
<path class="st0" d="M34.7,37.1c66.5-4.2-4.8-31.6,16.3-22.7c42.1,17.9,6.9,30.3-16.4,32.5h1.7c-66.2,4.4,4.8,31.6-16.3,22.7 c-42.1-17.9-6.9-30.3,16.4-32.5"></path>
|
|
</g>
|
|
</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"><a href="/books/n/gene/vws/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="body"><div class="t">ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome</div><div class="j">GeneReviews® [Internet]</div></div><div class="tail"><a href="/books/n/gene/isca2-mt-dis/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 h-55.484l-10.662,29.981c-4.065,11.431-12.794,20.627-24.001,25.274c-0.005,0.002-0.009,0.004-0.014,0.005 c-11.235,4.66-23.919,4.333-34.905-0.889l-28.723-13.653l-39.234,39.234l13.653,28.721c5.219,10.979,5.545,23.681,0.889,34.91 c-0.002,0.004-0.004,0.009-0.006,0.013c-4.649,11.214-13.834,19.931-25.271,23.998L50,228.257v55.485l29.98,10.661 c11.431,4.065,20.627,12.794,25.274,24c0.002,0.005,0.003,0.01,0.005,0.014c4.66,11.236,4.334,23.921-0.888,34.906l-13.654,28.723 l39.234,39.234l28.721-13.652c10.979-5.219,23.681-5.546,34.909-0.889c0.005,0.002,0.01,0.004,0.014,0.006 c11.214,4.649,19.93,13.833,23.998,25.271L228.257,462h55.484l10.595-29.79c4.103-11.538,12.908-20.824,24.216-25.525 c0.005-0.002,0.009-0.004,0.014-0.006c11.127-4.628,23.694-4.311,34.578,0.863l28.902,13.738l39.234-39.234l-13.66-28.737 c-5.214-10.969-5.539-23.659-0.886-34.877c0.002-0.005,0.004-0.009,0.006-0.014c4.654-11.225,13.848-19.949,25.297-24.021 L462,283.742z M256,331.546c-41.724,0-75.548-33.823-75.548-75.546s33.824-75.547,75.548-75.547 c41.723,0,75.546,33.824,75.546,75.547S297.723,331.546,256,331.546z"></path></svg></a><a id="jr-fip-sw" class="btn wsprkl hidden" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-rtoc-sw" class="btn wsprkl hidden" title="Table of Contents"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,20h10v8H20V20zM36,20h44v8H36V20zM20,37.33h10v8H20V37.33zM36,37.33h44v8H36V37.33zM20,54.66h10v8H20V54.66zM36,54.66h44v8H36V54.66zM20,72h10v8 H20V72zM36,72h44v8H36V72z"></path></svg></a></div></div></nav><nav id="jr-dash" class="noselect"><nav id="jr-dash" class="noselect"><div id="jr-pi" class="hidden"><a id="jr-pi-prev" class="hidden" title="Previous page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a><div class="pginfo">Page <i class="jr-pg-pn">0</i> of <i class="jr-pg-lp">0</i></div><a id="jr-pi-next" class="hidden" title="Next page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div><div id="jr-is-tb"><a id="jr-is-sw" class="btn wsprkl hidden" title="Switch between Figures/Tables strip and Progress bar"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><rect x="10" y="40" width="20" height="20"></rect><rect x="40" y="40" width="20" height="20"></rect><rect x="70" y="40" width="20" height="20"></rect></svg></a></div><nav id="jr-istrip" class="istrip hidden"><a id="jr-is-prev" href="#" class="hidden" title="Previous"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M80,40 60,65 80,90 70,90 50,65 70,40z M50,40 30,65 50,90 40,90 20,65 40,40z"></path><text x="35" y="25" textLength="60" style="font-size:25px">Prev</text></svg></a><a id="jr-is-next" href="#" class="hidden" title="Next"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,40 40,65 20,90 30,90 50,65 30,40z M50,40 70,65 50,90 60,90 80,65 60,40z"></path><text x="15" y="25" textLength="60" style="font-size:25px">Next</text></svg></a></nav><nav id="jr-progress"></nav></nav></nav><aside id="jr-links-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">NCBI Bookshelf</div></div><div class="cnt lol f1"><a href="/books/">Home</a><a href="/books/browse/">Browse All Titles</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://www.facebook.com/sharer/sharer.php?u=https://www.ncbi.nlm.nih.gov/books/NBK547304/"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24" preserveAspectRatio="none"><g><path d="M 17.996,32L 12,32 L 12,16 l-4,0 l0-5.514 l 4-0.002l-0.006-3.248C 11.993,2.737, 13.213,0, 18.512,0l 4.412,0 l0,5.515 l-2.757,0 c-2.063,0-2.163,0.77-2.163,2.209l-0.008,2.76l 4.959,0 l-0.585,5.514L 18,16L 17.996,32z"></path></g></svg> Share on Facebook</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://twitter.com/intent/tweet?url=https://www.ncbi.nlm.nih.gov/books/NBK547304/&text=ISCA1-Related%20Multiple%20Mitochondrial%20Dysfunctions%20Syndrome"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24"><g><path d="M 32,6.076c-1.177,0.522-2.443,0.875-3.771,1.034c 1.355-0.813, 2.396-2.099, 2.887-3.632 c-1.269,0.752-2.674,1.299-4.169,1.593c-1.198-1.276-2.904-2.073-4.792-2.073c-3.626,0-6.565,2.939-6.565,6.565 c0,0.515, 0.058,1.016, 0.17,1.496c-5.456-0.274-10.294-2.888-13.532-6.86c-0.565,0.97-0.889,2.097-0.889,3.301 c0,2.278, 1.159,4.287, 2.921,5.465c-1.076-0.034-2.088-0.329-2.974-0.821c-0.001,0.027-0.001,0.055-0.001,0.083 c0,3.181, 2.263,5.834, 5.266,6.438c-0.551,0.15-1.131,0.23-1.73,0.23c-0.423,0-0.834-0.041-1.235-0.118 c 0.836,2.608, 3.26,4.506, 6.133,4.559c-2.247,1.761-5.078,2.81-8.154,2.81c-0.53,0-1.052-0.031-1.566-0.092 c 2.905,1.863, 6.356,2.95, 10.064,2.95c 12.076,0, 18.679-10.004, 18.679-18.68c0-0.285-0.006-0.568-0.019-0.849 C 30.007,8.548, 31.12,7.392, 32,6.076z"></path></g></svg> Share on Twitter</a></div></aside><aside id="jr-rtoc-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Table of Content</div></div><div class="cnt lol f1"><a href="/books/n/gene/?report=reader">Title Information</a><a href="/books/n/gene/toc/?report=reader">Table of Contents Page</a></div></aside><aside id="jr-help-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Settings</div></div><div class="cnt f1"><div id="jr-typo-p" class="typo"><div><a class="sf btn wsprkl">A-</a><a class="lf btn wsprkl">A+</a></div><div><a class="bcol-auto btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 200 100" preserveAspectRatio="none"><text x="10" y="70" style="font-size:60px;font-family: Trebuchet MS, ArialMT, Arial, sans-serif" textLength="180">AUTO</text></svg></a><a class="bcol-1 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M15,25 85,25zM15,40 85,40zM15,55 85,55zM15,70 85,70z"></path></svg></a><a class="bcol-2 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M5,25 45,25z M55,25 95,25zM5,40 45,40z M55,40 95,40zM5,55 45,55z M55,55 95,55zM5,70 45,70z M55,70 95,70z"></path></svg></a></div></div><div class="lol"><a class="" href="/books/NBK547304/?report=classic">Switch to classic view</a><a href="/books/NBK547304/pdf/Bookshelf_NBK547304.pdf">PDF (489K)</a><a href="/books/NBK547304/?report=printable">Print View</a></div></div></aside><aside id="jr-bkhelp-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Help</div></div><div class="cnt f1 lol"><a id="jr-helpobj-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/help.xml" href="">Help</a><a href="mailto:info@ncbi.nlm.nih.gov?subject=PubReader%20feedback%20%2F%20NBK547304%20%2F%20sid%3ACE8B5AF87C7FFCB1_0191SID%20%2F%20phid%3ACE8BD7FB7C87321100000000004C0043.4">Send us feedback</a><a id="jr-about-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/about.xml" href="">About PubReader</a></div></aside><aside id="jr-objectbox" class="thidden hidden"><div class="jr-objectbox-close wsprkl">✘</div><div class="jr-objectbox-inner cnt"><div class="jr-objectbox-drawer"></div></div></aside><nav id="jr-pm-left" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Previous Page</text></svg></nav><nav id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK547304_"><span class="title" itemprop="name"><i>ISCA1</i>-Related Multiple Mitochondrial Dysfunctions Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Multiple Mitochondrial Dysfunctions Syndrome 5</div><p class="contribs">Shukla A, Narayanan DL, Kaur P, et al.</p><p class="fm-aai"><a href="#_NBK547304_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 14 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="isca1-mmds.Summary" itemprop="description"><h2 id="_isca1-mmds_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>ISCA1</i>-related multiple mitochondrial dysfunctions syndrome (<i>ISCA1</i>-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Affected individuals may also demonstrate elevated blood lactate levels with an elevated lipid-lactate peak on brain MR spectroscopy. Further brain MRI findings may include extensive cerebral and cerebellar deep white matter hyperintensities, marked dilatation of the cerebral ventricles, and pachygyria. Prognosis is poor and most individuals succumb to an intercurrent illness in early childhood.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>ISCA1</i>-MMDS is established in a proband with suggestive findings and/or biallelic pathogenic variants in <i>ISCA1</i> identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Treatment is primarily supportive. A feeding tube (nasogastric or gastrostomy) may be required. Standard treatment for spasticity, seizures, abnormal vision, and hearing loss.</p><p><i>Prevention of secondary complications:</i> Adequate hydration, stool softeners, and laxatives may help to prevent severe constipation.</p><p><i>Surveillance:</i> Assessment for new neurologic manifestations, safety of oral intake, adequate nutrition, and evidence of respiratory insufficiency and aspiration at each visit. Monitor constipation, developmental progress, growth parameters, and family needs at each visit. Ophthalmologic and audiologic evaluations annually or based on clinical suspicion.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>ISCA1</i>-related multiple mitochondrial dysfunctions syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual with <i>ISCA1</i>-MMDS has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic <i>ISCA1</i> variants in the family are known.</p></div></div><div id="isca1-mmds.Diagnosis"><h2 id="_isca1-mmds_Diagnosis_">Diagnosis</h2><p><i>ISCA1</i>-related multiple mitochondrial dysfunctions syndrome (<i>ISCA1</i>-MMDS) is a severe neurodegenerative condition; consensus clinical diagnostic criteria have not been published.</p><div id="isca1-mmds.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>ISCA1</i>-MMDS <b>should be suspected</b> in individuals with the following neurologic, ophthalmologic, head imaging, and supportive laboratory findings.</p><p>
|
|
<b>Neurologic findings</b>
|
|
</p><ul><li class="half_rhythm"><div>Early-infantile onset and progressive neurologic deterioration</div></li><li class="half_rhythm"><div>Early-onset seizures, often developing before age six months</div></li><li class="half_rhythm"><div>Incessant cry</div></li><li class="half_rhythm"><div>Spasticity</div></li><li class="half_rhythm"><div>Exaggerated deep tendon reflexes</div></li><li class="half_rhythm"><div>Early death</div></li></ul><p>
|
|
<b>Ophthalmologic features</b>
|
|
</p><ul><li class="half_rhythm"><div>Nystagmus</div></li><li class="half_rhythm"><div>Pigmentary retinopathy</div></li></ul><p>
|
|
<b>Head MRI findings</b>
|
|
</p><ul><li class="half_rhythm"><div>Diffuse bilateral symmetric signal abnormality in the deep cerebral and cerebellar white matter; white matter abnormalities may also involve the corpus callosum, pons, and spinal cord.</div></li><li class="half_rhythm"><div>Pachygyria</div></li><li class="half_rhythm"><div>Ventriculomegaly</div></li><li class="half_rhythm"><div>Elevated lipid-lactate peak on MR spectroscopy</div></li></ul><p>
|
|
<b>Supportive laboratory findings</b>
|
|
</p><ul><li class="half_rhythm"><div>Elevated plasma lactate</div></li><li class="half_rhythm"><div>Elevated serum creatinine phosphokinase</div></li></ul></div><div id="isca1-mmds.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>ISCA1</i>-MMDS <b>is established</b> in a proband with suggestive findings and/or biallelic pathogenic variants in <i>ISCA1</i> identified by molecular genetic testing (see <a href="/books/NBK547304/table/isca1-mmds.T.molecular_genetic_testing_u/?report=objectonly" target="object" rid-ob="figobisca1mmdsTmoleculargenetictestingu">Table 1</a>).</p><p>Because the phenotype of <i>ISCA1</i>-MMDS is indistinguishable from many other inherited disorders with neurodegeneration and leukodystrophy, recommended molecular genetic testing approaches include use of a <b>multigene panel</b> or <b>comprehensive genomic testing</b>.</p><p>Note: Single-gene testing (sequence analysis of <i>ISCA1</i>, followed by gene-targeted deletion/duplication analysis) may be considered if the clinical findings are highly suggestive of <i>ISCA1</i>-MMDS.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>A</b>
|
|
<b>multigene panel</b> that includes <i>ISCA1</i> and other genes of interest (see <a href="#isca1-mmds.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is another good option. <b>Exome sequencing</b> (including mitochondrial sequencing) is most commonly used; <b>genome sequencing</b> is also possible.</div><div class="half_rhythm">For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</div></li></ul><div id="isca1-mmds.Further_Testing_to_Consider"><h4>Further Testing to Consider</h4><p>A possible founder variant has been identified in four families (3 families reported in the literature and 1 family with unpublished data) from southwestern India [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>]. Targeted analysis for this variant may be considered in families from this region.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTmoleculargenetictestingu"><a href="/books/NBK547304/table/isca1-mmds.T.molecular_genetic_testing_u/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTmoleculargenetictestingu"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.molecular_genetic_testing_u"><a href="/books/NBK547304/table/isca1-mmds.T.molecular_genetic_testing_u/?report=objectonly" target="object" rid-ob="figobisca1mmdsTmoleculargenetictestingu">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>ISCA1</i>-Related Multiple Mitochondrial Dysfunctions Syndrome </p></div></div></div></div></div><div id="isca1-mmds.Clinical_Characteristics"><h2 id="_isca1-mmds_Clinical_Characteristics_">Clinical Characteristics</h2><div id="isca1-mmds.Clinical_Description"><h3>Clinical Description</h3><p><i>ISCA1</i>-related multiple mitochondrial dysfunctions syndrome (<i>ISCA1</i>-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Seven individuals from five unrelated families with this condition have been identified to date [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>, <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>]. All individuals with <i>ISCA1</i>-MMDS presented with early onset and progressive neurodegeneration.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTfrequencyofclinicalfeatu"><a href="/books/NBK547304/table/isca1-mmds.T.frequency_of_clinical_featu/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTfrequencyofclinicalfeatu"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.frequency_of_clinical_featu"><a href="/books/NBK547304/table/isca1-mmds.T.frequency_of_clinical_featu/?report=objectonly" target="object" rid-ob="figobisca1mmdsTfrequencyofclinicalfeatu">Table 2. </a></h4><p class="float-caption no_bottom_margin">Frequency of Clinical Features Observed in Individuals with <i>ISCA1</i>-Related Multiple Mitochondrial Dysfunctions Syndrome </p></div></div><p>
|
|
<b>Cognitive/motor development</b>
|
|
</p><ul><li class="half_rhythm"><div>Six of the seven affected individuals either did not attain any developmental milestone or showed very early loss of achieved milestones.</div></li><li class="half_rhythm"><div>One individual reported by <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al [2018]</a> showed a milder phenotype. Early regression was seen, followed by slow attainment of milestones and delayed development.</div><ul><li class="half_rhythm"><div>The proband lost head control at age three months.</div></li><li class="half_rhythm"><div>He regained head control and was able to sit with support at 18 months.</div></li><li class="half_rhythm"><div>He achieved the ability to sit without support by age four years.</div></li><li class="half_rhythm"><div>At age six years, he could speak in sentences.</div></li></ul></li></ul><p>
|
|
<b>Neurologic</b>
|
|
</p><ul><li class="half_rhythm"><div class="half_rhythm">Occipitofrontal circumference ranged from normal to -6 SD at the time of evaluation [<a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>].</div><div class="half_rhythm">Progressive microcephaly was noted in only one individual for whom head circumference at birth was available. His head circumference was noted to be normal at birth and fell to -2 SD at six months [<a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">Six of the seven individuals developed seizures between age two and four months.</div></li><li class="half_rhythm"><div class="half_rhythm">Clinical examination revealed spasticity and exaggerated deep tendon reflexes.</div></li><li class="half_rhythm"><div class="half_rhythm">Two of seven had incessant cry.</div></li></ul><p>
|
|
<b>Ophthalmologic</b>
|
|
</p><ul><li class="half_rhythm"><div>Nystagmus was observed in two individuals [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>].</div></li><li class="half_rhythm"><div>Pigmentary retinopathy was seen in one individual.</div></li></ul><p><b>Hearing.</b> Bilateral sensorineural hearing loss was identified by brain stem evoked response audiometry in two individuals [<a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>,<a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>].</p><p><b>Feeding.</b> One of the seven individuals had severe dysphagia necessitating a Nissen fundoplication with gastrostomy tube placement [<a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>].</p><p>
|
|
<b>Biochemical testing results</b>
|
|
</p><ul><li class="half_rhythm"><div>Elevated blood lactate was observed in six of the seven individuals.</div></li><li class="half_rhythm"><div>In one individual, elevated creatine phosphokinase level was observed [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>].</div></li><li class="half_rhythm"><div>Respiratory chain enzyme analysis on fibroblasts revealed deficient levels of mitochondrial complex I and II enzymes [<a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>].</div></li></ul><p>Note: More invasive testing that requires a skin biopsy sample may be bypassed in favor of molecular genetic testing on a peripheral blood sample.</p><p><b>Prognosis.</b> All the affected individuals succumbed during an intercurrent illness. The affected individuals from India did not survive beyond age five years. The affected individual from Italy lived to age 11 years. No definitive treatment other than supportive care is available at present.</p><p><b>Neuroimaging</b> with brain MRI shows a characteristic and recognizable pattern:</p><ul><li class="half_rhythm"><div>Extensive cerebral and cerebellar deep white matter hyperintensities were noted in all individuals.</div></li><li class="half_rhythm"><div>Marked dilatation of the cerebral ventricles and pachygyria were seen in four families (see <a href="#isca1-mmds.GenotypePhenotype_Correlation">Genotype-Phenotype Correlations</a>).</div></li><li class="half_rhythm"><div>Elevated lipid-lactate peak was seen on brain MR spectroscopy [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>].</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTradiologicfeaturesofindi"><a href="/books/NBK547304/table/isca1-mmds.T.radiologic_features_of_indi/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTradiologicfeaturesofindi"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.radiologic_features_of_indi"><a href="/books/NBK547304/table/isca1-mmds.T.radiologic_features_of_indi/?report=objectonly" target="object" rid-ob="figobisca1mmdsTradiologicfeaturesofindi">Table 3. </a></h4><p class="float-caption no_bottom_margin">Radiologic Features of Individuals with <i>ISCA1</i>-related Multiple Mitochondrial Dysfunctions Syndrome </p></div></div></div><div id="isca1-mmds.GenotypePhenotype_Correlation"><h3>Genotype-Phenotype Correlations</h3><p>Though very few individuals are reported with this condition, there appears to be striking similarity in clinical and brain imaging features in individuals with the c.259G>A variant.</p><ul><li class="half_rhythm"><div>In four families with biallelic <a href="/books/NBK547304/table/isca1-mmds.T.notable_isca1_pathogenic_va/?report=objectonly" target="object" rid-ob="figobisca1mmdsTnotableisca1pathogenicva">c.259G>A</a> variants, all affected individuals had marked dilatation of the cerebral ventricles with pachygyria [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>].</div></li><li class="half_rhythm"><div>The individual reported by <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al [2018]</a>, who was homozygous for the <a href="/books/NBK547304/table/isca1-mmds.T.notable_isca1_pathogenic_va/?report=objectonly" target="object" rid-ob="figobisca1mmdsTnotableisca1pathogenicva">c.29T>G</a> variant, did not show ventriculomegaly or any cortical abnormalities.</div></li></ul><p>One affected individual homozygous for the c.29T>G missense variant showed milder clinical as well as radiologic features and succumbed to this condition at age 11 years [<a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>]. It is unclear whether the clinical course in this affected individual was due to the genotype or to baseline phenotypic variability of this condition.</p></div><div id="isca1-mmds.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>ISCA1</i>-MMDS is unknown. Seven affected individuals from five families have been reported [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>, <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>]. Six individuals are reported from the southwestern part of India [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>]; one individual of Italian descent is reported from outside this region [<a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>].</p></div></div><div id="isca1-mmds.Genetically_Related_Allelic_D"><h2 id="_isca1-mmds_Genetically_Related_Allelic_D_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants in <i>ISCA1</i>.</p></div><div id="isca1-mmds.Differential_Diagnosis"><h2 id="_isca1-mmds_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis of neurologic regression with white matter disease in infancy is extensive. Diagnostic algorithms for genetic leukodystrophy disorders have been published. In <i>ISCA1</i>-related multiple mitochondrial dysfunctions syndrome (<i>ISCA1</i>-MMDS), the constellation of extensive leukodystrophy, pigmentary retinopathy, and biochemical evidence of mitochondrial involvement is suggestive of the disorder, but these features can also be seen in other conditions.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTdisorderstoconsiderinth"><a href="/books/NBK547304/table/isca1-mmds.T.disorders_to_consider_in_th/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTdisorderstoconsiderinth"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.disorders_to_consider_in_th"><a href="/books/NBK547304/table/isca1-mmds.T.disorders_to_consider_in_th/?report=objectonly" target="object" rid-ob="figobisca1mmdsTdisorderstoconsiderinth">Table 4. </a></h4><p class="float-caption no_bottom_margin">Disorders to Consider in the Differential Diagnosis of <i>ISCA1</i>-MMDS </p></div></div><p><b>Other leukodystrophies and lysosomal storage diseases.</b> Other progressive degenerative disorders that manifest in infancy can mimic <i>ISCA1</i>-MMDS. In the presence of leukodystrophy, other conditions to consider include Pelizaeus-Merzbacher disease (see <a href="/books/n/gene/pmd/?report=reader"><i>PLP1</i>-Related Disorders</a>) and GM2 gangliosidoses (Tay-Sachs disease [see <a href="/books/n/gene/tay-sachs/?report=reader">Hexosaminidase A Deficiency</a>] and <a href="/books/n/gene/sandhoff/?report=reader">Sandhoff disease</a>).</p><p>See <a href="https://omim.org/phenotypicSeries/PS605711" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM Multiple Mitochondrial Dysfunctions Syndrome Phenotypic Series</a> to view genes associated with this phenotype in OMIM.</p></div><div id="isca1-mmds.Management"><h2 id="_isca1-mmds_Management_">Management</h2><div id="isca1-mmds.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>ISCA1</i>-MMDS, the evaluations summarized in <a href="/books/NBK547304/table/isca1-mmds.T.recommended_evaluations_fol/?report=objectonly" target="object" rid-ob="figobisca1mmdsTrecommendedevaluationsfol">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTrecommendedevaluationsfol"><a href="/books/NBK547304/table/isca1-mmds.T.recommended_evaluations_fol/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTrecommendedevaluationsfol"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.recommended_evaluations_fol"><a href="/books/NBK547304/table/isca1-mmds.T.recommended_evaluations_fol/?report=objectonly" target="object" rid-ob="figobisca1mmdsTrecommendedevaluationsfol">Table 5. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with <i>ISCA1</i>-MMDS </p></div></div></div><div id="isca1-mmds.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>The mainstay of treatment is supportive and is best provided by a multidisciplinary team including a geneticist, pediatric neurologist or neurologist, and dietician. The following recommendations are based on the experience from a small number of affected individuals. The spectrum of disease may evolve with reports of additional affected people. Treatment options should be considered based on the observed phenotype.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTtreatmentofmanifestations"><a href="/books/NBK547304/table/isca1-mmds.T.treatment_of_manifestations/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTtreatmentofmanifestations"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.treatment_of_manifestations"><a href="/books/NBK547304/table/isca1-mmds.T.treatment_of_manifestations/?report=objectonly" target="object" rid-ob="figobisca1mmdsTtreatmentofmanifestations">Table 6. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with <i>ISCA1</i>-MMDS </p></div></div></div><div id="isca1-mmds.Prevention_of_Secondary_Compl"><h3>Prevention of Secondary Complications</h3><p>With the progression of the disease, constipation can be a problem. Adequate hydration, stool softeners, and laxatives may help in avoiding severe constipation.</p></div><div id="isca1-mmds.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTrecommendedsurveillancefo"><a href="/books/NBK547304/table/isca1-mmds.T.recommended_surveillance_fo/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTrecommendedsurveillancefo"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.recommended_surveillance_fo"><a href="/books/NBK547304/table/isca1-mmds.T.recommended_surveillance_fo/?report=objectonly" target="object" rid-ob="figobisca1mmdsTrecommendedsurveillancefo">Table 7. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with <i>ISCA1</i>-MMDS </p></div></div></div><div id="isca1-mmds.Evaluation_of_Relatives_at_Ri"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#isca1-mmds.Related_Genetic_Counseling_Is">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="isca1-mmds.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="isca1-mmds.Genetic_Counseling"><h2 id="_isca1-mmds_Genetic_Counseling_">Genetic Counseling</h2><p>
|
|
<i>Genetic counseling is the process of providing individuals and families with
|
|
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
|
make informed medical and personal decisions. The following section deals with genetic
|
|
risk assessment and the use of family history and genetic testing to clarify genetic
|
|
status for family members; it is not meant to address all personal, cultural, or
|
|
ethical issues that may arise or to substitute for consultation with a genetics
|
|
professional</i>. —ED.</p><div id="isca1-mmds.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>ISCA1</i>-related multiple mitochondrial dysfunctions syndrome (<i>ISCA1</i>-MMDS) is inherited in an autosomal recessive manner.</p><p>
|
|
<b>Parents of a proband</b>
|
|
</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., carriers of one <i>ISCA1</i> pathogenic variant).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
|
<b>Sibs of a proband</b>
|
|
</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> To date, individuals with <i>ISCA1</i>-MMDS are not known to reproduce.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of an <i>ISCA1</i> pathogenic variant.</p></div><div id="isca1-mmds.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>ISCA1</i> pathogenic variants in the family.</p></div><div id="isca1-mmds.Related_Genetic_Counseling_Is"><h3>Related Genetic Counseling Issues</h3><p>
|
|
<b>Family planning</b>
|
|
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).</p></div><div id="isca1-mmds.Prenatal_Testing_and_Preimpla"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>ISCA1</i> pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="isca1-mmds.Resources"><h2 id="_isca1-mmds_Resources_">Resources</h2><p>
|
|
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
|
support organizations and/or registries for the benefit of individuals with this disorder
|
|
and their families. GeneReviews is not responsible for the information provided by other
|
|
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
|
|
<ul><li class="half_rhythm"><div>
|
|
<b>Mito Foundation</b>
|
|
</div><div>Australia</div><div><b>Phone:</b> 61-1-300-977-180</div><div><b>Email:</b> info@mito.org.au</div><div>
|
|
<a href="https://www.mito.org.au/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.mito.org.au</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>Mitocon – Insieme per lo studio e la cura delle malattie mitocondriali Onlus</b>
|
|
</div><div>
|
|
<i>Mitocon is the reference association in Italy for patients suffering from mitochondrial diseases and their families and is the main link between patients and the scientific community.</i>
|
|
</div><div>Italy</div><div><b>Phone:</b> 06 66991333/4</div><div><b>Email:</b> info@mitocon.it</div><div>
|
|
<a href="https://www.mitocon.it/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.mitocon.it</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>The Charlie Gard Foundation</b>
|
|
</div><div>United Kingdom</div><div><b>Email:</b> hello@thecharliegardfoundation.org</div><div>
|
|
<a href="https://www.thecharliegardfoundation.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.thecharliegardfoundation.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>United Mitochondrial Disease Foundation</b>
|
|
</div><div><b>Phone:</b> 888-317-UMDF (8633)</div><div><b>Email:</b> info@umdf.org</div><div>
|
|
<a href="https://www.umdf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.umdf.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium</b>
|
|
</div><div>
|
|
<a href="https://www.rarediseasesnetwork.org/cms/namdc" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Patient Contact Registry</a>
|
|
</div></li></ul>
|
|
</div><div id="isca1-mmds.Molecular_Genetics"><h2 id="_isca1-mmds_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsmolgenTA"><a href="/books/NBK547304/table/isca1-mmds.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobisca1mmdsmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.molgen.TA"><a href="/books/NBK547304/table/isca1-mmds.molgen.TA/?report=objectonly" target="object" rid-ob="figobisca1mmdsmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsmolgenTB"><a href="/books/NBK547304/table/isca1-mmds.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobisca1mmdsmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.molgen.TB"><a href="/books/NBK547304/table/isca1-mmds.molgen.TB/?report=objectonly" target="object" rid-ob="figobisca1mmdsmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome (View All in OMIM) </p></div></div><div id="isca1-mmds.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>ISCA1</i> encodes the 129-amino acid iron-sulfur cluster assembly 1 homolog mitochondrial protein (ISCA1). ISCA1 forms a heterocomplex with ISCA2 and functions in the late iron-sulfur cluster biogenesis and assembly pathway. This protein complex plays a crucial role in formation and integration of iron-sulfur clusters (4Fe-4S) to mitochondrial metalloproteinases including protein subunits of respiratory chain complex I, aconitase, and lipoic acid synthase [<a class="bibr" href="#isca1-mmds.REF.sheftel.2012.1157" rid="isca1-mmds.REF.sheftel.2012.1157">Sheftel et al 2012</a>].</p><p><b>Mechanism of disease causation.</b> The mechanism of disease is not yet established, but appears to be loss of function.</p><p>One pathogenic possible founder variant has been reported in four families to date [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>]. <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al [2018]</a> described a single affected individual born to consanguineous parents with another homozygous missense variant.</p><p>Functional studies by <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al [2018]</a> revealed that p.Val10Gly leads to decreased stability and import of ISCA1 protein to the mitochondria. This results in reduced amounts of respiratory chain complexes I and II, and decreased lipoylation of mitochondrial proteins, indicating that the variant has an impact on the mitochondrial (4Fe–4S) protein assembly.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figisca1mmdsTnotableisca1pathogenicva"><a href="/books/NBK547304/table/isca1-mmds.T.notable_isca1_pathogenic_va/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobisca1mmdsTnotableisca1pathogenicva"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="isca1-mmds.T.notable_isca1_pathogenic_va"><a href="/books/NBK547304/table/isca1-mmds.T.notable_isca1_pathogenic_va/?report=objectonly" target="object" rid-ob="figobisca1mmdsTnotableisca1pathogenicva">Table 8. </a></h4><p class="float-caption no_bottom_margin">Notable <i>ISCA1</i> Pathogenic Variants </p></div></div></div></div><div id="isca1-mmds.Chapter_Notes"><h2 id="_isca1-mmds_Chapter_Notes_">Chapter Notes</h2><div id="isca1-mmds.Acknowledgments"><h3>Acknowledgments</h3><p>Department of Health Research, Ministry of Health and Family Welfare, Government of India for funding the project entitled "Clinical and Molecular Characterization of Leukodystrophies in Indian Children" (V.25011/379/2015-GIA/HR)</p></div><div id="isca1-mmds.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>3 October 2019 (ma) Review posted live</div></li><li class="half_rhythm"><div>3 January 2019 (as) Original submission</div></li></ul></div></div><div id="isca1-mmds.References"><h2 id="_isca1-mmds_References_">References</h2><div id="isca1-mmds.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="isca1-mmds.REF.sheftel.2012.1157">Sheftel AD, Wilbrecht C, Stehling O, Niggemeyer B, Elsasser HP, Muhlenhoff U, Lill R. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation. <span><span class="ref-journal">Molec Biol Cell. </span>2012;<span class="ref-vol">23</span>:1157–66.</span> [<a href="/pmc/articles/PMC3315811/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3315811</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22323289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22323289</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="isca1-mmds.REF.shukla.2017.723">Shukla A, Hebbar M, Srivastava A, Kadavigere R, Upadhyai P, Kanthi A, Brandau O, Bielas S, Girisha KM. Homozygous p.(Glu8Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. <span><span class="ref-journal">J Hum Genet. </span>2017;<span class="ref-vol">62</span>:723–7.</span> [<a href="/pmc/articles/PMC5484744/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5484744</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28356563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28356563</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="isca1-mmds.REF.shukla.2018.130">Shukla A, Kaur P, Girisha KM. Report of the third family with multiple mitochondrial dysfunctions syndrome 5 caused by the founder variant p.(Glu87Lys) in ISCA1. <span><span class="ref-journal">J Pediatr Genet. </span>2018;<span class="ref-vol">7</span>:130–3.</span> [<a href="/pmc/articles/PMC6087475/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6087475</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30105122" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30105122</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="isca1-mmds.REF.torraco.2018.3650">Torraco A, Stehling O, Stümpfig C, Rösser R, De Rasmo D, Fiermonte G, Verrigni D, Rizza T, Vozza A, Di Nottia M, Diodato D, Martinelli D, Piemonte F, Dionisi-Vici C, Bertini E, Lill R, Carrozzo R. ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins. <span><span class="ref-journal">Hum Mol Genet. </span>2018;<span class="ref-vol">27</span>:3650.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30113620" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30113620</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK547304_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Anju Shukla</span>, MD, DM<div class="affiliation small">Associate Professor, Department of Medical Genetics
|
|
Kasturba Medical College
|
|
Manipal Academy of Higher Education
|
|
Manipal, India<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.lapinam@alkuhs.ujna" class="oemail">ude.lapinam@alkuhs.ujna</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Dhanya Lakshmi Narayanan</span>, MD, DM<div class="affiliation small">Assistant Professor, Department of Medical Genetics
|
|
Kasturba Medical College
|
|
Manipal Academy of Higher Education
|
|
Manipal, India<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.lapinam@imhskal.aynahd" class="oemail">ude.lapinam@imhskal.aynahd</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Parneet Kaur</span>, MSc<div class="affiliation small">PhD Student, Department of Medical Genetics
|
|
Kasturba Medical College
|
|
Manipal Academy of Higher Education
|
|
Manipal, India<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@scitenegruakteenrap" class="oemail">moc.liamg@scitenegruakteenrap</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Katta Mohan Girisha</span>, MD, DM<div class="affiliation small">Professor, Department of Medical Genetics
|
|
Kasturba Medical College
|
|
Manipal Academy of Higher Education
|
|
Manipal, India<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.lapinam@attak.hsirig" class="oemail">ude.lapinam@attak.hsirig</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">October 3, 2019</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
|
|
a registered trademark of the University of Washington, Seattle. All rights
|
|
reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
|
|
hereby granted to reproduce, distribute, and translate copies of content materials for
|
|
noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
|
|
Washington) are included with each copy; (ii) a link to the original material is provided
|
|
whenever the material is published elsewhere on the Web; and (iii) reproducers,
|
|
distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
|
Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
|
|
of GeneReviews chapters for use in lab reports and clinic notes are a permitted
|
|
use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
|
Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
|
|
contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Shukla A, Narayanan DL, Kaur P, et al. ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome. 2019 Oct 3. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/vws/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/isca2-mt-dis/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobisca1mmdsTmoleculargenetictestingu"><div id="isca1-mmds.T.molecular_genetic_testing_u" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>ISCA1</i>-Related Multiple Mitochondrial Dysfunctions Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.molecular_genetic_testing_u/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.molecular_genetic_testing_u_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ISCA1</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Targeted testing for c.259G>A</td><td headers="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/5 <sup>3, 4</sup></td></tr><tr><td headers="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>5</sup></td><td headers="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5/5 <sup>3</sup></td></tr><tr><td headers="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_isca1-mmds.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>7</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="isca1-mmds.TF.1.1"><p class="no_margin">See <a href="/books/n/gene/mult-mt-dys5/?report=reader#mult-mt-dys5.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="isca1-mmds.TF.1.2"><p class="no_margin">See <a href="#isca1-mmds.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="isca1-mmds.TF.1.3"><p class="no_margin"><a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al [2017]</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al [2018]</a>, <a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al [2018]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="isca1-mmds.TF.1.4"><p class="no_margin">The pathogenic c.259G>A (p.Glu87Lys) variant has been proposed as a founder variant in individuals of southwestern Indian descent.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="isca1-mmds.TF.1.5"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="isca1-mmds.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="isca1-mmds.TF.1.7"><p class="no_margin">No data on detection rate of gene-targeted deletion/duplication analysis are available.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobisca1mmdsTfrequencyofclinicalfeatu"><div id="isca1-mmds.T.frequency_of_clinical_featu" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Frequency of Clinical Features Observed in Individuals with <i>ISCA1</i>-Related Multiple Mitochondrial Dysfunctions Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.frequency_of_clinical_featu/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.frequency_of_clinical_featu_lrgtbl__"><table><thead><tr><th id="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clinical Feature</th><th id="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Developmental delay</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7/7 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Spasticity</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7/7 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Elevated plasma lactate</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/6 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Feeding difficulty</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/7 (85.7%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Seizures</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/7 (85.7%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exaggerated deep tendon reflexes</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4/6 (66.67%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hearing loss</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2/5 (40%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Elevated creatine phosphokinase</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2/3 (66.6%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nystagmus</td><td headers="hd_h_isca1-mmds.T.frequency_of_clinical_featu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2/7 (28.5%)</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobisca1mmdsTradiologicfeaturesofindi"><div id="isca1-mmds.T.radiologic_features_of_indi" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Radiologic Features of Individuals with <i>ISCA1</i>-related Multiple Mitochondrial Dysfunctions Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.radiologic_features_of_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.radiologic_features_of_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Radiologic Feature</th><th id="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cerebral white matter abnormalities</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/6 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cerebellar white matter abnormalities</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/6 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Thin corpus callosum w/white matter abnormalities</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/6 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Brain stem white matter abnormalities</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/6 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Spinal cord white matter abnormalities</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6/6 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Elevated lipid lactate peak on MRS</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4/4 (100%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cerebral ventriculomegaly</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5/6 (83.3%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pachygyria</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5/6 (83.3%)</td></tr><tr><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Delayed myelination</td><td headers="hd_h_isca1-mmds.T.radiologic_features_of_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1/6 (16.67%)</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MRS = magnetic resonance spectroscopy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobisca1mmdsTdisorderstoconsiderinth"><div id="isca1-mmds.T.disorders_to_consider_in_th" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of <i>ISCA1</i>-MMDS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.disorders_to_consider_in_th/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.disorders_to_consider_in_th_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Clinical Features of Differential Diagnosis Disorder</th></tr><tr><th headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4" id="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/<i>ISCA1</i>-MMDS</th><th headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4" id="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from <i>ISCA1</i>-MMDS</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple mitochondrial dysfunctions syndrome 1 (OMIM <a href="https://omim.org/entry/605711" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">605711</a>)</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>NFU1</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Feeding difficulties, muscle weakness, decreasing responsiveness, neurologic regression</div></li><li class="half_rhythm"><div>WM lesions on brain MRI</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Pulmonary hypertension, obstructive vasculopathy</div></li><li class="half_rhythm"><div>Spongiform degeneration, WM necrosis</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple mitochondrial dysfunctions syndrome 2 (OMIM <a href="https://omim.org/entry/614299" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614299</a>)</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>BOLA3</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Visual impairment, spasticity</div></li><li class="half_rhythm"><div>Leukodystrophy</div></li><li class="half_rhythm"><div>Onset in infancy</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cardiomyopathy, hepatomegaly</div></li><li class="half_rhythm"><div>Extrapyramidal signs, ataxia, myoclonus</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple mitochondrial dysfunctions syndrome 3 (OMIM <a href="https://omim.org/entry/615330" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615330</a>)</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>IBA57</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">WM abnormalities</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Onset in utero, IUGR</div></li><li class="half_rhythm"><div>Microcephaly, dysmorphic features (retrognathia, high-arched palate, widely spaced nipples), arthrogryposis, severe hypotonia</div></li><li class="half_rhythm"><div>Hypoplasia of corpus callosum & medulla oblongata</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/isca2-mt-dis/?report=reader"><i>ISCA2</i>-related mitochondrial disorder</a> (multiple mitochondrial dysfunctions syndrome 4)</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ISCA2</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Loss of developmental milestones, spasticity, nystagmus</div></li><li class="half_rhythm"><div>WM abnormalities</div></li><li class="half_rhythm"><div>Lactic acidosis</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ plasma & CSF glycine levels</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metachromatic leukodystrophy (See <a href="/books/n/gene/mld/?report=reader">Arylsulfatase A Deficiency</a> & OMIM <a href="https://omim.org/entry/249900" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">249900</a>.)</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ARSA</i>
|
|
<br />
|
|
<i>PSAP</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neurologic regression</div></li><li class="half_rhythm"><div>Leukodystrophy</div></li><li class="half_rhythm"><div>Spasticity</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ urinary sulfatide excretion</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/krabbe/?report=reader">Krabbe disease</a>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>GALC</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neurologic regression, spasticity</div></li><li class="half_rhythm"><div>Leukodystrophy</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓ galactocerebrosidase activity (See <a href="/books/n/gene/krabbe/?report=reader">Krabbe disease</a>.)</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/lbsl/?report=reader">Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation</a>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>DARS2</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic regression</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spotty or confluent cerebral WM changes w/relative sparing of subcortical WM</div></li><li class="half_rhythm"><div>Involvement of dorsal columns, lateral corticospinal tracts, & medial lemniscus in medulla oblongata</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/cach/?report=reader">Childhood ataxia with central nervous system hypomyelination/vanishing white matter</a>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>EIF2B1</i>
|
|
<br />
|
|
<i>EIF2B2</i>
|
|
<br />
|
|
<i>EIF2B3</i>
|
|
<br />
|
|
<i>EIF2B4</i>
|
|
<br />
|
|
<i>EIF2B5</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neurologic regression, spasticity</div></li><li class="half_rhythm"><div>Leukodystrophy</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Unsteady gait</div></li><li class="half_rhythm"><div><b>MRI findings:</b></div><div>bilateral symmetric diffuse changes in cerebral hemispheres isointense w/CSF;</div><div>cystic breakdown of WM on proton density or FLAIR images;</div><div>mild-to-severe cerebellar atrophy</div></li><li class="half_rhythm"><div>Ovarian dysgenesis in females</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/canavan/?report=reader">Canavan disease</a>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ASPA</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neurologic regression</div></li><li class="half_rhythm"><div>Leukodystrophy</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Macrocephaly</div></li><li class="half_rhythm"><div><b>MRI findings:</b></div><div>symmetric & diffuse WM changes in cerebral cortex & subcortical region;</div><div>less marked involvement of cerebellum & brain stem</div></li><li class="half_rhythm"><div>↑ N-acetyl-L-aspartate in urine</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/alexander/?report=reader">Alexander disease</a>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>GFAP</i>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neurologic regression, spasticity</div></li><li class="half_rhythm"><div>Leukodystrophy</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Macrocephaly</div></li><li class="half_rhythm"><div><b>MRI findings:</b></div><div>cerebral WM abnormalities w/frontal predominance;</div><div>basal ganglia & thalami may incl atrophy &/or altered signal intensity;</div><div>medulla & midbrain involvement</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Leigh syndrome (See <a href="/books/n/gene/narp/?report=reader">Mitochondrial DNA-Associated Leigh Syndrome and NARP</a> & <a href="/books/n/gene/leigh-nucl-ov/?report=reader">Nuclear Gene-Encoded Leigh Syndrome Overview</a>.)</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>75 genes</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />XL<br />mt</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Neurologic regression</div></li><li class="half_rhythm"><div>↑ lactate in MR spectroscopy</div></li></ul>
|
|
</td><td headers="hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_1_4 hd_h_isca1-mmds.T.disorders_to_consider_in_th_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypertrophic cardiomyopathy</div></li><li class="half_rhythm"><div>Hypertrichosis</div></li><li class="half_rhythm"><div>Renal tubulopathy</div></li><li class="half_rhythm"><div>Liver involvement</div></li><li class="half_rhythm"><div><b>MRI findings:</b></div><div>basal ganglia involvement;</div><div>bilateral symmetric T<sub>2</sub>-weighted hyperintensities in basal ganglia &/or brain stem</div></li></ul>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mt = mitochondrial; WM = white matter; XL = X-linked</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobisca1mmdsTrecommendedevaluationsfol"><div id="isca1-mmds.T.recommended_evaluations_fol" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>ISCA1</i>-MMDS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.recommended_evaluations_fol/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.recommended_evaluations_fol_lrgtbl__"><table><thead><tr><th id="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For abnormal tone & spasticity</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral for physical therapy.</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">For possible seizure disorder</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider EEG, head MRI, & MR spectroscopy.</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Eyes</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic evaluation</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For pigmentary retinopathy & visual acuity</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic evaluation</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for hearing loss</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Gastrointestinal/</b>
|
|
<br />
|
|
<b>Feeding</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for feeding issues</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider:
|
|
<ul><li class="half_rhythm"><div>Swallowing study.</div></li><li class="half_rhythm"><div>Eval for gastric tube placement in those w/dysphagia &/or aspiration risk.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment of nutritional status</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl review of growth parameters & serum chemistries (albumin, total protein)</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Miscellaneous/</b>
|
|
<br />
|
|
<b>Other</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl genetic counseling</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Family supports/resources</td><td headers="hd_h_isca1-mmds.T.recommended_evaluations_fol_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess:
|
|
<ul><li class="half_rhythm"><div>Use of community or online resources (e.g., Parent to Parent).</div></li><li class="half_rhythm"><div>Need for social work involvement for parental support.</div></li><li class="half_rhythm"><div>Need for home nursing referral.</div></li></ul>
|
|
</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobisca1mmdsTtreatmentofmanifestations"><div id="isca1-mmds.T.treatment_of_manifestations" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>ISCA1</i>-MMDS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.treatment_of_manifestations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.treatment_of_manifestations_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Spasticity</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard therapeutic options may incl use of baclofen &/or botulinum toxin type A.</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider:
|
|
<ul><li class="half_rhythm"><div>PT & rehabilitation therapy.</div></li><li class="half_rhythm"><div>Need for positioning & mobility devices, disability parking placard.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Seizures</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Abnormal</b>
|
|
<br />
|
|
<b>vision</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment as recommended by ophthalmologist</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids may be helpful as per otolaryngologist.</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Community hearing services through early intervention or school district</td></tr><tr><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Feeding</b>
|
|
<br />
|
|
<b>difficulties</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding via nasogastric or gastrostomy tube if needed</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/gastroenterologist &/or feeding specialist</td></tr><tr><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family/</b>
|
|
<br />
|
|
<b>Community</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ongoing assessment of need for palliative care involvement &/or home nursing</td></tr><tr><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies</td><td headers="hd_h_isca1-mmds.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobisca1mmdsTrecommendedsurveillancefo"><div id="isca1-mmds.T.recommended_surveillance_fo" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>ISCA1</i>-MMDS</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.recommended_surveillance_fo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.recommended_surveillance_fo_lrgtbl__"><table><thead><tr><th id="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor those w/seizures.</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As clinically indicated</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Eyes</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic evaluation</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually, or based on clinical suspicion</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic evaluation</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually, or based on clinical suspicion</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Feeding</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation of nutritional status & safety of oral intake</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Gastrointestinal</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for constipation.</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Respiratory</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for evidence of aspiration, respiratory insufficiency.</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Development</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor developmental progress & educational needs.</div></li><li class="half_rhythm"><div>Meaurement of growth parameters</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Miscellaneous/</b>
|
|
<br />
|
|
<b>Other</b>
|
|
</td><td headers="hd_h_isca1-mmds.T.recommended_surveillance_fo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., palliative/respite care, home nursing; other local resources) & care coordination.</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobisca1mmdsmolgenTA"><div id="isca1-mmds.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_isca1-mmds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_isca1-mmds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_isca1-mmds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_isca1-mmds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_isca1-mmds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_isca1-mmds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/81689" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>ISCA1</i>
|
|
</a>
|
|
</td><td headers="hd_b_isca1-mmds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=81689" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9q21<wbr style="display:inline-block"></wbr>​.33</a>
|
|
</td><td headers="hd_b_isca1-mmds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/Q9BUE6" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Iron-sulfur cluster assembly 1 homolog, mitochondrial</a>
|
|
</td><td headers="hd_b_isca1-mmds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ISCA1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ISCA1</a>
|
|
</td><td headers="hd_b_isca1-mmds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ISCA1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ISCA1</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="isca1-mmds.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus from
|
|
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
|
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobisca1mmdsmolgenTB"><div id="isca1-mmds.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome (<a href="/omim/611006,617613" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/611006" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">611006</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IRON-SULFUR CLUSTER ASSEMBLY 1; ISCA1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/617613" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">617613</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 5; MMDS5</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobisca1mmdsTnotableisca1pathogenicva"><div id="isca1-mmds.T.notable_isca1_pathogenic_va" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Notable <i>ISCA1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547304/table/isca1-mmds.T.notable_isca1_pathogenic_va/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__isca1-mmds.T.notable_isca1_pathogenic_va_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_030940.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_030940<wbr style="display:inline-block"></wbr>​.3</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_112202.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_112202<wbr style="display:inline-block"></wbr>​.2</a>
|
|
</td><td headers="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.259G>A</td><td headers="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu87Lys</td><td headers="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Apparent founder variant in southwestern India [<a class="bibr" href="#isca1-mmds.REF.shukla.2017.723" rid="isca1-mmds.REF.shukla.2017.723">Shukla et al 2017</a>, <a class="bibr" href="#isca1-mmds.REF.shukla.2018.130" rid="isca1-mmds.REF.shukla.2018.130">Shukla et al 2018</a>]</td></tr><tr><td headers="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.29T>G</td><td headers="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val10Gly</td><td headers="hd_h_isca1-mmds.T.notable_isca1_pathogenic_va_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Causes decreased stability & import of ISCA1 protein [<a class="bibr" href="#isca1-mmds.REF.torraco.2018.3650" rid="isca1-mmds.REF.torraco.2018.3650">Torraco et al 2018</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
|
|
|
|
|
|
|
|
|
|
<!-- Book content -->
|
|
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js"> </script>
|
|
|
|
|
|
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal104 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
|
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
|
|
|
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3968615.js" snapshot="books"></script></body>
|
|
</html>
|