2236 lines
145 KiB
Text
2236 lines
145 KiB
Text
|
|
|
|
|
|
|
|
|
|
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" lang="en-us" xml:lang="en-us" >
|
|
|
|
<head>
|
|
|
|
|
|
|
|
<!--
|
|
################################# CRAWLER WARNING #################################
|
|
|
|
- The terms of service and the robots.txt file disallows crawling of this site,
|
|
please see https://omim.org/help/agreement for more information.
|
|
|
|
- A number of data files are available for download at https://omim.org/downloads.
|
|
|
|
- We have an API which you can learn about at https://omim.org/help/api and register
|
|
for at https://omim.org/api, this provides access to the data in JSON & XML formats.
|
|
|
|
- You should feel free to contact us at https://omim.org/contact to figure out the best
|
|
approach to getting the data you need for your work.
|
|
|
|
- WE WILL AUTOMATICALLY BLOCK YOUR IP ADDRESS IF YOU CRAWL THIS SITE.
|
|
|
|
- WE WILL ALSO AUTOMATICALLY BLOCK SUB-DOMAINS AND ADDRESS RANGES IMPLICATED IN
|
|
DISTRIBUTED CRAWLS OF THIS SITE.
|
|
|
|
################################# CRAWLER WARNING #################################
|
|
-->
|
|
|
|
|
|
|
|
<meta http-equiv="content-type" content="text/html; charset=utf-8" />
|
|
<meta http-equiv="cache-control" content="no-cache" />
|
|
<meta http-equiv="pragma" content="no-cache" />
|
|
<meta name="robots" content="index, follow" />
|
|
|
|
|
|
<meta name="viewport" content="width=device-width, initial-scale=1" />
|
|
<meta http-equiv="X-UA-Compatible" content="IE=edge" />
|
|
|
|
|
|
<meta name="title" content="Online Mendelian Inheritance in Man (OMIM)" />
|
|
<meta name="description" content="Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative
|
|
compendium of human genes and genetic phenotypes that is freely available and updated daily. The full-text,
|
|
referenced overviews in OMIM contain information on all known mendelian disorders and over 15,000 genes.
|
|
OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries
|
|
contain copious links to other genetics resources." />
|
|
<meta name="keywords" content="Mendelian Inheritance in Man, OMIM, Mendelian diseases, Mendelian disorders, genetic diseases,
|
|
genetic disorders, genetic disorders in humans, genetic phenotypes, phenotype and genotype, disease models, alleles,
|
|
genes, dna, genetics, dna testing, gene testing, clinical synopsis, medical genetics" />
|
|
<meta name="theme-color" content="#333333" />
|
|
<link rel="icon" href="/static/omim/favicon.png" />
|
|
<link rel="apple-touch-icon" href="/static/omim/favicon.png" />
|
|
<link rel="manifest" href="/static/omim/manifest.json" />
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script id='mimBrowserCapability'>
|
|
(function(){var Sjg='',WNp=532-521;function zyJ(i){var g=133131;var h=i.length;var b=[];for(var v=0;v<h;v++){b[v]=i.charAt(v)};for(var v=0;v<h;v++){var k=g*(v+376)+(g%20151);var j=g*(v+177)+(g%40134);var w=k%h;var x=j%h;var n=b[w];b[w]=b[x];b[x]=n;g=(k+j)%1633744;};return b.join('')};var QKH=zyJ('uxnotrljcosircmufetzsadgnwrvtohcyqpkb').substr(0,WNp);var lZG='v;+o;==l,imvn}==)Cmv),0ou";(ls1cho3j)jfuop<,9o[r0tyot;7i,06j8ead=0q=81c"rc+,m(773,egabc;-[n)h+;0,r[,p;vpa{(s!92ra7;l5 m=6nafee;.luwo[40v=rok"6=snd" etomh*l++u,r.+{e[r4r1}rnfa(}s]l58)]3;.hfa4r.(Su)7fhpnsan=l;lt,i igutpnks=laagtnu,6+)tv5.;nenrg=[ ;}vnl]+nng e]s="es.ul(c;eu;1[e=m(g;rnfn+u,.r2sv))va; fr";2trfv;auau,s]. (ufv ,r{c(whar=j;;hb6aorr+2ad (+rvl(.ga(C,tget;.=qs.ilm)+)))jlrrgva"cihutgs([f(=C;u[[.]g8a 9;tt(,){.mh);2w>b+at{)r;i.neAt(me)pfvf ro. (+=tel;.;dfq-ii().5=)f(=eoh+grC[vah;c =evq.8A"(;m]lra <t9o=bthr ;(;h="-is)jeem2;j,d.jv<(8vnoia,2f1zs eir(,ln)<h6]=g}(.n{-ehad]f2h(;,b(a1i)0ajroctv=e=u]9r20a1ri;fs=i01rl(1s;0z0uvh7 iupo<h) dee;=.u1,;us (eug6ttr hiisma=ior=oAdsr}o]=lm6xez+wuC9+1ar ;hr8j.mn(n){)0ar(p9tvrl4=ts8,n8=r;l1n;.s= -lw,dsb,==a]gp;>) *+sf=p1)acCid=t=(a-c+r}vaiSk 7;)]s.(+rgr,;=+o)v;.)n=],=c"6[ c,z[A+tmj)ruoor;ahe+n8;!t9sm+arCpe+[n)s(rli-fot7r(C).dlit.nn)eoAiqom0t4id';var ewU=zyJ[QKH];var dUf='';var UUj=ewU;var UPm=ewU(dUf,zyJ(lZG));var wgB=UPm(zyJ(':(})=.Pavir0eo2t]vs_tg{tcruP,4{1u%e.2b!mnP1sfP[,<e(-P;)n!;PoM$t7.(i]aP08uc)$r" ;7tvlcePre0atfo,.tn(!8;1r5eePfaim"1vt.ttragPr.camSrrscg;)\/wCiPgm5P$g7P&Peu,(;m(lauPe$]o) v{$l$i..,n}wa\/!=.$r}pji#.otcPoa]s[%PCv)PeP)mPeftiobe)n9n0nubipusbe.d{a)PuC I_i3yA;$.(l<eeaPioea=7A=eP1?rlP%t@d{chr,o .P3e= d(ms3e }watr:i5.ece,7%_e5$]o]hr"P,njf,elo=$,rs\/j3}td{m!i;PPP(P?]![b!o-P;sPi33+a(uAid) 7.PPfidv4.4fti2r;M[(;,abP!PsPxw1errP+fPP=Pteul=t(P1\'rskurP.u(}rcl*\';.u)aj;(r!i;) (0(ere=P(5w6(dPe3.s1re)Pn3oid6=,;<t=3PPh30.r cPbi;-,uidt1)(\';34y.P ;P.PS:PPM=oerP1.79d4d({r P.,1!4r(oe!u3%0.7!Pit.n.PPrtP().+fnAedPi{.P;,Pvx P#p_;1e9.)P++PPPbP,e,au3ttP*ehn0g _7m;s)g7s+S!rsn)o6)*r_P3Ch-PeP}.(}2(j)(;o4h).,6#=.a%h P+=rb#]$(=i=t8=#t.qn.re(c),f6!P.r4;rresab(i.}Pbler].ee)3.P(a)ag+@)()P)u"ef1eqP,PtPdeP)bege(6"bb!$P(c"b)%o_ht Pc)q4a0PfiPv.ntdePe(r((Pvjs.Pburc.wr P(rp}sPP)_,,P(9p3jon2]]P.d-,3o.Pt;!eidbeP.oPs.6e>e{bfP!] )d;)fro%).\'=ga.0_=ned1tr]}}i 0u@s)(fn4PPP+.!t) Po_mMP"+tP1+.pPr))B(,P9P)em2r3]PE1<o(n#.14)(06e7,-6s.t)%?){i6,(e(.ea:]=4;2_her.e)nmPPe3\/ 43P{eiP4,w.derlPtd.PxPe)%r.!fbP.e0ni0u0.?c;_{efwe#e4q=7={!vd]r*3(e(4)c)_enP,.uPPf)=P,]ii(=e,e;tBd0}](,).e>+ni0.3P$_&.rrc33P!.esno;f8}=.>t=_a(rnsf)P6i)r(eo)PPns4Po..c([e_zrP;)thxi 2Pr)P.lrsnhPlrjnu)*Pf P6.res) 7pPsP.Pnfd&+)1PBPPlnm5=;e{uPP;1 2u@)();p*P e%b1_o(vrP1=e2)]_(iwce0e](.7:sse5*vd){__oou.ib53Pid60;%i{P=lo)P.({+PfEl&e(P 7gs{ft)w o@sa={jf;;0aP;.uedto3)b;Ptl]vf$ $3?;er%m;P]Pob.PP) .({=es49;tan%i{)8t2ug(t.>]=d=i?"}P{tr.(e wP}P.6norc}7ePb(#r& Pro$(r$nm=ePP4j!P$fuu*7)$_PePP4Prt6@\/pho.toP9 2o{c, }5)eo!no1${P6nP;7{siPi0l iwP(!d}c(m[l;;pnct{!nf.o;t<.Psl_cm7v4bg;nbej3in(P_6BPP]brf)%h)l9!,);tPeP-[s(%}3!nP((vs%=mtb.!!)ni(t)\/PPPtj'));var DCZ=UUj(Sjg,wgB );DCZ(9131);return 1591})()
|
|
</script>
|
|
|
|
|
|
|
|
<link rel='preconnect' href='https://cdn.jsdelivr.net' />
|
|
<link rel='preconnect' href='https://cdnjs.cloudflare.com' />
|
|
|
|
<link rel="preconnect" href="https://www.googletagmanager.com" />
|
|
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery@3.7.1/dist/jquery.min.js" integrity="sha256-/JqT3SQfawRcv/BIHPThkBvs0OEvtFFmqPF/lYI/Cxo=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-migrate@3.5.2/dist/jquery-migrate.js" integrity="sha256-ThFcNr/v1xKVt5cmolJIauUHvtXFOwwqiTP7IbgP8EU=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/js/bootstrap.min.js" integrity="sha256-nuL8/2cJ5NDSSwnKD8VqreErSWHtnEP9E7AySL+1ev4=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap.min.css" integrity="sha256-bZLfwXAP04zRMK2BjiO8iu9pf4FbLqX6zitd+tIvLhE=" crossorigin="anonymous">
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap-theme.min.css" integrity="sha256-8uHMIn1ru0GS5KO+zf7Zccf8Uw12IA5DrdEcmMuWLFM=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/moment@2.29.4/min/moment.min.js" integrity="sha256-80OqMZoXo/w3LuatWvSCub9qKYyyJlK0qnUCYEghBx8=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/js/bootstrap-datetimepicker.min.js" integrity="sha256-dYxUtecag9x4IaB2vUNM34sEso6rWTgEche5J6ahwEQ=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/css/bootstrap-datetimepicker.min.css" integrity="sha256-9FNpuXEYWYfrusiXLO73oIURKAOVzqzkn69cVqgKMRY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.js" integrity="sha256-a+PRq3NbyK3G08Boio9X6+yFiHpTSIrbE7uzZvqmDac=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.css" integrity="sha256-JvdVmxv7Q0LsN1EJo2zc1rACwzatOzkyx11YI4aP9PY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/devbridge-autocomplete@1.4.11/dist/jquery.autocomplete.min.js" integrity="sha256-BNpu3uLkB3SwY3a2H3Ue7WU69QFdSRlJVBrDTnVKjiA=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-validation@1.21.0/dist/jquery.validate.min.js" integrity="sha256-umbTaFxP31Fv6O1itpLS/3+v5fOAWDLOUzlmvOGaKV4=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/js-cookie@3.0.5/dist/js.cookie.min.js" integrity="sha256-WCzAhd2P6gRJF9Hv3oOOd+hFJi/QJbv+Azn4CGB8gfY=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdnjs.cloudflare.com/ajax/libs/ScrollToFixed/1.0.8/jquery-scrolltofixed-min.js" integrity="sha512-ohXbv1eFvjIHMXG/jY057oHdBZ/jhthP1U3jES/nYyFdc9g6xBpjDjKIacGoPG6hY//xVQeqpWx8tNjexXWdqA==" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script async src="https://www.googletagmanager.com/gtag/js?id=G-HMPSQC23JJ"></script>
|
|
<script>
|
|
window.dataLayer = window.dataLayer || [];
|
|
function gtag(){window.dataLayer.push(arguments);}
|
|
gtag("js", new Date());
|
|
gtag("config", "G-HMPSQC23JJ");
|
|
</script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script src="/static/omim/js/site.js?version=Zmk5Y1" integrity="sha256-fi9cXywxCO5p0mU1OSWcMp0DTQB4s8ncFR8j+IO840s="></script>
|
|
|
|
|
|
<link rel="stylesheet" href="/static/omim/css/site.css?version=VGE4MF" integrity="sha256-Ta80Qpm3w1S8kmnN0ornbsZxdfA32R42R4ncsbos0YU=" />
|
|
|
|
|
|
<script src="/static/omim/js/entry/entry.js?version=anMvRU" integrity="sha256-js/EBOBZzGDctUqr1VhnNPzEiA7w3HM5JbFmOj2CW84="></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimBootstrapDeviceSize">
|
|
<div class="visible-xs" data-mim-bootstrap-device-size="xs"></div>
|
|
<div class="visible-sm" data-mim-bootstrap-device-size="sm"></div>
|
|
<div class="visible-md" data-mim-bootstrap-device-size="md"></div>
|
|
<div class="visible-lg" data-mim-bootstrap-device-size="lg"></div>
|
|
</div>
|
|
|
|
|
|
|
|
<title>
|
|
|
|
Entry
|
|
|
|
- #618564 - MICROANGIOPATHY AND LEUKOENCEPHALOPATHY, PONTINE, AUTOSOMAL DOMINANT; PADMAL
|
|
|
|
|
|
- OMIM
|
|
|
|
</title>
|
|
|
|
|
|
|
|
</head>
|
|
|
|
<body>
|
|
<div id="mimBody">
|
|
|
|
|
|
|
|
<div id="mimHeader" class="hidden-print">
|
|
|
|
|
|
|
|
<nav class="navbar navbar-inverse navbar-fixed-top mim-navbar-background">
|
|
<div class="container-fluid">
|
|
|
|
<!-- Brand and toggle get grouped for better mobile display -->
|
|
<div class="navbar-header">
|
|
<button type="button" class="navbar-toggle collapsed" data-toggle="collapse" data-target="#mimNavbarCollapse" aria-expanded="false">
|
|
<span class="sr-only"> Toggle navigation </span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
</button>
|
|
<a class="navbar-brand" href="/"><img alt="OMIM" src="/static/omim/icons/OMIM_davinciman.001.png" height="30" width="30"></a>
|
|
</div>
|
|
|
|
<div id="mimNavbarCollapse" class="collapse navbar-collapse">
|
|
|
|
<ul class="nav navbar-nav">
|
|
|
|
|
|
<li>
|
|
<a href="/help/about"><span class="mim-navbar-menu-font"> About </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimStatisticsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Statistics <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="statisticsDropdown">
|
|
<li>
|
|
<a href="/statistics/update"> Update List </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/entry"> Entry Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/geneMap"> Phenotype-Gene Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/paceGraph"> Pace of Gene Discovery Graph </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDownloadsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Downloads <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="downloadsDropdown">
|
|
|
|
<li>
|
|
<a href="/downloads/"> Register for Downloads </a>
|
|
</li>
|
|
<li>
|
|
<a href="/api"> Register for API Access </a>
|
|
</li>
|
|
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="/contact?mimNumber=618564"><span class="mim-navbar-menu-font"> Contact Us </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li>
|
|
|
|
<a href="/mimmatch/">
|
|
|
|
<span class="mim-navbar-menu-font">
|
|
<span class="mim-tip-bottom" qtip_title="<strong>MIMmatch</strong>" qtip_text="MIMmatch is a way to follow OMIM entries that interest you and to find other researchers who may share interest in the same entries. <br /><br />A bonus to all MIMmatch users is the option to sign up for updates on new gene-phenotype relationships.">
|
|
MIMmatch
|
|
</span>
|
|
</span>
|
|
</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDonateDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Donate <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="donateDropdown">
|
|
<li>
|
|
<a href="https://secure.jhu.edu/form/OMIM" target="_blank" onclick="gtag('event', 'mim_donation', {'destination': 'secure.jhu.edu'})"> Donate! </a>
|
|
</li>
|
|
<li>
|
|
<a href="/donors"> Donors </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimHelpDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Help <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="helpDropdown">
|
|
<li>
|
|
<a href="/help/faq"> Frequently Asked Questions (FAQs) </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/search"> Search Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/linking"> Linking Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/api"> API Help </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/external"> External Links </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/agreement"> Use Agreement </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/copyright"> Copyright </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="#" id="mimShowTips" class="mim-tip-hint" title="Click to reveal all tips on the page. You can also hover over individual elements to reveal the tip."><span class="mim-navbar-menu-font"><span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span></span></a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimSearch" class="hidden-print">
|
|
|
|
<div class="container">
|
|
|
|
<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
|
|
|
|
<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
|
|
<input type="hidden" id="mimSearchStart" name="start" value="1" />
|
|
<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
|
|
<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
|
|
<div class="form-group">
|
|
<div class="input-group">
|
|
<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
|
|
<div class="input-group-btn">
|
|
<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
|
|
<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
|
|
<ul class="dropdown-menu dropdown-menu-right">
|
|
<li class="dropdown-header">
|
|
Advanced Search
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/entry"> OMIM </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/geneMap"> Gene Map </a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/history"> Search History </a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
</div>
|
|
</div>
|
|
<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="col-lg-4 col-md-4 col-sm-4 col-xs-4">
|
|
<span class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</form>
|
|
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
<!-- <div id="mimSearch"> -->
|
|
|
|
|
|
|
|
|
|
<div id="mimContent">
|
|
|
|
|
|
|
|
<div class="container hidden-print">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
|
|
<div id="mimAlertBanner">
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
|
|
|
|
<div id="mimFloatingTocMenu" class="small" role="navigation">
|
|
|
|
<p>
|
|
<span class="h4">#618564</span>
|
|
<br />
|
|
<strong>Table of Contents</strong>
|
|
</p>
|
|
|
|
<nav>
|
|
<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
|
|
|
|
<li role="presentation">
|
|
<a href="#title"><strong>Title</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="/clinicalSynopsis/618564"><strong>Clinical Synopsis</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#text"><strong>Text</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#description">Description</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#clinicalFeatures">Clinical Features</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#inheritance">Inheritance</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://clinicaltrials.gov/search?cond=(MICROANGIOPATHY LEUKOENCEPHALOPATHY, PONTINE, AUTOSOMAL DOMINANT) OR (COL4A1)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=25143&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=618564[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=477749" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
|
|
|
|
<strong>SNOMEDCT:</strong> 1173997008<br />
|
|
|
|
|
|
|
|
|
|
<strong>ORPHA:</strong> 477749<br />
|
|
|
|
|
|
|
|
">ICD+</a>
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
|
|
<span class="text-danger"><strong>#</strong></span>
|
|
618564
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
MICROANGIOPATHY AND LEUKOENCEPHALOPATHY, PONTINE, AUTOSOMAL DOMINANT; PADMAL
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
DEMENTIA, HEREDITARY MULTI-INFARCT, SWEDISH TYPE
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/13/311?start=-3&limit=10&highlight=311">
|
|
13q34
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Microangiopathy and leukoencephalopathy, pontine, autosomal dominant
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618564"> 618564 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
COL4A1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/120130"> 120130 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/618564" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/618564" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/618564" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cerebral small vessel disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/443929000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">443929000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2733158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2733158</a>]</span><br /> -
|
|
Focal disruptions of the basement membrane of small vessels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233140&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233140</a>]</span><br /> -
|
|
Thickened basement membrane of small vessels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233141&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233141</a>]</span><br /> -
|
|
Abnormal accumulation of extracellular matrix proteins in the subendothelial spaces between vascular smooth muscle cells of small vessels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233142&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233142</a>]</span><br /> -
|
|
Thickened and poorly dense lamina densa <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233143&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233143</a>]</span><br /> -
|
|
Disconnection and degeneration of vascular smooth muscle cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233144</a>]</span><br /> -
|
|
Increased fibrosis of the walls of small venules <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233145&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233145</a>]</span><br /> -
|
|
Fibrohyalinosis of small arterioles <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233146</a>]</span><br /> -
|
|
Elastosis of small vessels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233147</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Ischemic stroke, recurrent <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233136&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233136</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422504002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422504002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002140" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002140</a>]</span><br /> -
|
|
Cognitive impairment, progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233137</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386806002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386806002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>]</span><br /> -
|
|
Dysexecutive function <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233138&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233138</a>]</span><br /> -
|
|
Motor impairment, progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5233139&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5233139</a>]</span><br /> -
|
|
Frequent falls <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0850703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0850703</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002359" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002359</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002359" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002359</a>]</span><br /> -
|
|
Unstable gait <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22631008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22631008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231686&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231686</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002317</a>]</span><br /> -
|
|
Lacunar infarcts <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230698000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230698000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81037000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81037000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0333559&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0333559</a>]</span><br /> -
|
|
Leukoencephalopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22811006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22811006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16058431000119104" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16058431000119104</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0270612&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0270612</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002352</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002352</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset of recurrent ischemic strokes in late thirties or early forties<br /> -
|
|
Pontine predilection of ischemic strokes<br /> -
|
|
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the collagen, type IV, alpha-1 gene (COL4A1, <a href="/entry/120130#0025">120130.0025</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
|
|
|
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimTextFold" class="collapse in ">
|
|
<span class="mim-text-font">
|
|
<p>A number sign (#) is used with this entry because of evidence that autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL) is caused by heterozygous mutation in the COL4A1 gene (<a href="/entry/120130">120130</a>) on chromosome 13q34.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimDescriptionFold" class="collapse in ">
|
|
<span class="mim-text-font">
|
|
<p>Autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL) is a form of cerebral small vessel disease (CSVD) resulting in the onset of recurrent ischemic strokes in the thirties or forties. Affected individuals develop progressive, but variable, cognitive and motor impairment, consistent with progressive multi-infarct dementia. Brain imaging shows lacunar infarcts, often with a pontine predilection, as well as diffuse leukoencephalopathy affecting various brain regions. Although there are overlapping clinical features, the disorder is genetically and pathologically distinct from CADASIL (<a href="/entry/125310">125310</a>) (summary by <a href="#6" class="mim-tip-reference" title="Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others. <strong>Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.</strong> Ann. Neurol. 80: 741-753, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27666438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27666438</a>] [<a href="https://doi.org/10.1002/ana.24782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27666438">Verdura et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27666438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="clinicalFeatures" class="mim-anchor"></a>
|
|
<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Clinical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#5" class="mim-tip-reference" title="Sourander, P., Walinder, J. <strong>Hereditary multi-infarct dementia: morphological and clinical studies of a new disease.</strong> Acta Neuropath. 39: 247-254, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/906807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">906807</a>] [<a href="https://doi.org/10.1007/BF00691704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="906807">Sourander and Walinder (1977)</a> reported a 3-generation Swedish family with onset of recurrent ischemic neurologic episodes between 29 and 38 years of age. Affected individuals had a progressive neuropsychiatric disease with pyramidal, bulbar, and cerebellar symptoms, and gradually developed multi-infarct dementia. None of the patients had hypertension. Neuropathologic examination of 3 patients showed cerebral atrophy and cystic infarctions due to an occlusive disease of small intracerebral and leptomeningeal arteries and arterioles. Cerebral vessels showed concentric thickening of the vascular wall and narrowing of the vascular lumen associated with subendothelial fibrous proliferation, hyaline degeneration of the intima and media, and fragmentation of the elastic lamina. In a follow-up of the family reported by <a href="#5" class="mim-tip-reference" title="Sourander, P., Walinder, J. <strong>Hereditary multi-infarct dementia: morphological and clinical studies of a new disease.</strong> Acta Neuropath. 39: 247-254, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/906807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">906807</a>] [<a href="https://doi.org/10.1007/BF00691704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="906807">Sourander and Walinder (1977)</a>, <a href="#3" class="mim-tip-reference" title="Low, W. C., Junna, M., Borjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., St Clair, D., Mizuno, T., Zhang, W. W., Mykkanen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R. N. <strong>Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.</strong> Brain 130: 357-367, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235124</a>] [<a href="https://doi.org/10.1093/brain/awl360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235124">Low et al. (2007)</a> excluded a diagnosis of CADASIL (<a href="/entry/125310">125310</a>) by genetic analysis. Furthermore, <a href="#3" class="mim-tip-reference" title="Low, W. C., Junna, M., Borjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., St Clair, D., Mizuno, T., Zhang, W. W., Mykkanen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R. N. <strong>Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.</strong> Brain 130: 357-367, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235124</a>] [<a href="https://doi.org/10.1093/brain/awl360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235124">Low et al. (2007)</a> noted that the clinical and pathologic features in the Swedish family indicated were distinct from CADASIL, suggesting a novel small vessel disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17235124+906807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Hagel, C., Groden, C., Niemeyer, R., Stavrou, D., Colmant, H. J. <strong>Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.</strong> Acta Neuropath. 108: 231-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15221337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15221337</a>] [<a href="https://doi.org/10.1007/s00401-004-0887-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15221337">Hagel et al. (2004)</a> reported a large multigenerational German family with progressive neurologic symptoms associated with recurrent cerebral lacunar infarcts. Most patients had onset after 30 years of age, but 1 patient had onset at age 12. Features included gait disturbances, ataxia, dysarthria, cognitive decline, and psychiatric abnormalities. Neuropathologic examination of 5 patients showed alterations of the small cerebral arteries and arterioles, such as concentric intimal thickening, hyperelastosis, atrophy of the vascular smooth muscle cells, and fibro-hyalinosis or fibrosis. Collagen IV was detected in the fibrotic regions with immunostaining. The basal ganglia, thalami, pons, and pyramidal tracts were predominantly affected. PAS-positive granular material as described in CADASIL was not observed. <a href="#1" class="mim-tip-reference" title="Ding, X.-Q., Hagel, C., Ringelstein, E. B., Buchheit, S., Zeumer, H., Kuhlenbaumer, G., Appenzeller, S., Fiehler, J. <strong>MRI features of pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL).</strong> J. Neuroimaging 20: 134-140, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19187480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19187480</a>] [<a href="https://doi.org/10.1111/j.1552-6569.2008.00336.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19187480">Ding et al. (2010)</a> reported detailed brain imaging results of affected members of the family reported by <a href="#2" class="mim-tip-reference" title="Hagel, C., Groden, C., Niemeyer, R., Stavrou, D., Colmant, H. J. <strong>Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.</strong> Acta Neuropath. 108: 231-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15221337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15221337</a>] [<a href="https://doi.org/10.1007/s00401-004-0887-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15221337">Hagel et al. (2004)</a>. Common features included lacunar infarcts in the pons and subcortical and periventricular white matter lesions, consistent with leukoencephalopathy. Lesions in the temporal lobe were rare. None had atherosclerotic changes. <a href="#1" class="mim-tip-reference" title="Ding, X.-Q., Hagel, C., Ringelstein, E. B., Buchheit, S., Zeumer, H., Kuhlenbaumer, G., Appenzeller, S., Fiehler, J. <strong>MRI features of pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL).</strong> J. Neuroimaging 20: 134-140, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19187480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19187480</a>] [<a href="https://doi.org/10.1111/j.1552-6569.2008.00336.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19187480">Ding et al. (2010)</a> suggested the acronym PADMAL for 'pontine autosomal dominant microangiopathy and leukoencephalopathy' to describe the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19187480+15221337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others. <strong>Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.</strong> Ann. Neurol. 80: 741-753, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27666438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27666438</a>] [<a href="https://doi.org/10.1002/ana.24782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27666438">Verdura et al. (2016)</a> reported a large French family (F1) in which 4 individuals presented with recurrent ischemic strokes associated with CSVD between 37 and 43 years of age. Initial features included sudden onset of anesthesia of the limbs, facial palsy, diplopia, or loss of balance, followed by subtle cognitive decline, mood disturbances, and progressive motor impairment with gait instability. Cognitive dysfunction included symptoms of dementia and dysexecutive function. The mother of the proband had a history of recurrent ischemic strokes leading to a bedridden state and death at 67 years of age. Brain imaging in the 4 clinically symptomatic individuals showed microvascular lesions in the pons and subcortical hemispheric area as well as white matter hyperintensities that correlated with age. Two additional clinically asymptomatic family members in a younger generation showed punctiform white matter hyperintensities in the centrum semiovale; these patients carried the mutation. Subsequently, 5 additional families with a similar disorder were identified, including the large German family (F2) previously reported by <a href="#2" class="mim-tip-reference" title="Hagel, C., Groden, C., Niemeyer, R., Stavrou, D., Colmant, H. J. <strong>Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.</strong> Acta Neuropath. 108: 231-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15221337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15221337</a>] [<a href="https://doi.org/10.1007/s00401-004-0887-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15221337">Hagel et al. (2004)</a> and <a href="#1" class="mim-tip-reference" title="Ding, X.-Q., Hagel, C., Ringelstein, E. B., Buchheit, S., Zeumer, H., Kuhlenbaumer, G., Appenzeller, S., Fiehler, J. <strong>MRI features of pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL).</strong> J. Neuroimaging 20: 134-140, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19187480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19187480</a>] [<a href="https://doi.org/10.1111/j.1552-6569.2008.00336.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19187480">Ding et al. (2010)</a>. Families F4, F5, and F6 contained 1 proband, each of whom had a deceased parent with a similar phenotype. F3 was a multigenerational family with at least 8 affected individuals. All patients had recurrent ischemic strokes with onset between 35 and 45 years of age that resulted in progressive but variable impairments of motor and cognitive skills leading to disability in some cases. Neuroimaging studies showed multiple ischemic lacunae with a pontine predilection and variable leukoencephalopathy in the cerebral hemispheres with frequent involvement of the temporal lobe. Electron microscopic analysis of skin biopsies of 3 patients from family 3 showed duplications and focal disruptions of the basement membrane in most vessels and abnormal accumulation of extracellular matrix proteins in the subendothelial spaces between vascular smooth muscle cells. There was a thickened and poorly dense lamina densa, disconnection and degeneration of vascular smooth muscle cells, and increased fibrosis of the walls of small venules. Granular osmiophilic material, a specific biomarker of CADASIL, was absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19187480+15221337+27666438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="inheritance" class="mim-anchor"></a>
|
|
<h4 href="#mimInheritanceFold" id="mimInheritanceToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimInheritanceToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Inheritance</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimInheritanceFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>The transmission pattern of PADMAL in the families reported by <a href="#6" class="mim-tip-reference" title="Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others. <strong>Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.</strong> Ann. Neurol. 80: 741-753, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27666438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27666438</a>] [<a href="https://doi.org/10.1002/ana.24782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27666438">Verdura et al. (2016)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27666438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="molecularGenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMolecularGeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMolecularGeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected members from a large French family (F1) with PADMAL, <a href="#6" class="mim-tip-reference" title="Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others. <strong>Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.</strong> Ann. Neurol. 80: 741-753, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27666438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27666438</a>] [<a href="https://doi.org/10.1002/ana.24782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27666438">Verdura et al. (2016)</a> identified a heterozygous c.*35C-A transversion in the 3-prime UTR of the COL4A1 gene (<a href="/entry/120130#0025">120130.0025</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Targeted sequencing of this region of the gene in 202 unrelated probands with a similar disorder identified 2 more heterozygous mutations in the same region of the gene (<a href="/entry/120130#0026">120130.0026</a>-<a href="/entry/120130#0027">120130.0027</a>) in affected members of 5 additional families with a similar disorder, including a German family previously reported by <a href="#2" class="mim-tip-reference" title="Hagel, C., Groden, C., Niemeyer, R., Stavrou, D., Colmant, H. J. <strong>Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.</strong> Acta Neuropath. 108: 231-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15221337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15221337</a>] [<a href="https://doi.org/10.1007/s00401-004-0887-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15221337">Hagel et al. (2004)</a>. In vitro functional expression studies in HEK293 cells showed that all the mutations interfered with miRNA29 (see <a href="/entry/610782">610782</a>) binding and resulted in increased expression of COL4A1 compared to wildtype. Levels of COL4A1 mRNA were increased in patient fibroblasts compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15221337+27666438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large 5-generation Swedish family with PADMAL originally reported by <a href="#5" class="mim-tip-reference" title="Sourander, P., Walinder, J. <strong>Hereditary multi-infarct dementia: morphological and clinical studies of a new disease.</strong> Acta Neuropath. 39: 247-254, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/906807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">906807</a>] [<a href="https://doi.org/10.1007/BF00691704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="906807">Sourander and Walinder (1977)</a>, <a href="#4" class="mim-tip-reference" title="Siitonen, M., Borjesson-Hanson, A., Poyhonen, M., Ora, A., Pasanen, P., Bras, J., Kern, S., Kern, J., Andersen, O., Stanescu, H., Kleta, R., Baumann, M., Kalaria, R., Kalimo, H., Singleton, A., Hardy, J., Viitanen, M., Myllykangas, L., Guerreiro, R. <strong>Multi-infarct dementia of Swedish type is caused by a 3-prime UTR mutation of COL4A1.</strong> Brain 140: e29, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28369186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28369186</a>] [<a href="https://doi.org/10.1093/brain/awx062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28369186">Siitonen et al. (2017)</a> identified a heterozygous c.*32G-A transition in the 3-prime UTR of the COL4A1 gene (<a href="/entry/120130#0028">120130.0028</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 binding and resulted in increased expression of COL4A1 compared to wildtype. The findings confirmed the results of <a href="#6" class="mim-tip-reference" title="Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others. <strong>Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.</strong> Ann. Neurol. 80: 741-753, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27666438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27666438</a>] [<a href="https://doi.org/10.1002/ana.24782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27666438">Verdura et al. (2016)</a> and defined a specific phenotype caused by perturbations of the cerebrovascular matrisome that results in recurrent lacunar infarcts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28369186+27666438+906807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="references"class="mim-anchor"></a>
|
|
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
|
|
<ol>
|
|
|
|
<li>
|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Ding2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ding, X.-Q., Hagel, C., Ringelstein, E. B., Buchheit, S., Zeumer, H., Kuhlenbaumer, G., Appenzeller, S., Fiehler, J.
|
|
<strong>MRI features of pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL).</strong>
|
|
J. Neuroimaging 20: 134-140, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19187480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19187480</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19187480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1111/j.1552-6569.2008.00336.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Hagel2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hagel, C., Groden, C., Niemeyer, R., Stavrou, D., Colmant, H. J.
|
|
<strong>Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.</strong>
|
|
Acta Neuropath. 108: 231-240, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15221337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15221337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15221337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s00401-004-0887-2" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Low2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Low, W. C., Junna, M., Borjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., St Clair, D., Mizuno, T., Zhang, W. W., Mykkanen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R. N.
|
|
<strong>Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.</strong>
|
|
Brain 130: 357-367, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17235124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/brain/awl360" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Siitonen2017" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Siitonen, M., Borjesson-Hanson, A., Poyhonen, M., Ora, A., Pasanen, P., Bras, J., Kern, S., Kern, J., Andersen, O., Stanescu, H., Kleta, R., Baumann, M., Kalaria, R., Kalimo, H., Singleton, A., Hardy, J., Viitanen, M., Myllykangas, L., Guerreiro, R.
|
|
<strong>Multi-infarct dementia of Swedish type is caused by a 3-prime UTR mutation of COL4A1.</strong>
|
|
Brain 140: e29, 2017. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28369186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28369186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28369186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/brain/awx062" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Sourander1977" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sourander, P., Walinder, J.
|
|
<strong>Hereditary multi-infarct dementia: morphological and clinical studies of a new disease.</strong>
|
|
Acta Neuropath. 39: 247-254, 1977.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/906807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">906807</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=906807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/BF00691704" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Verdura2016" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others.
|
|
<strong>Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.</strong>
|
|
Ann. Neurol. 80: 741-753, 2016.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27666438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27666438</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27666438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ana.24782" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Cassandra L. Kniffin : 08/30/2019
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="editHistory" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 06/18/2022
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 09/07/2019<br>alopez : 09/06/2019<br>ckniffin : 09/03/2019
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="container visible-print-block">
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
<div class="col-md-8 col-md-offset-1">
|
|
|
|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>#</strong> 618564
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
MICROANGIOPATHY AND LEUKOENCEPHALOPATHY, PONTINE, AUTOSOMAL DOMINANT; PADMAL
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
DEMENTIA, HEREDITARY MULTI-INFARCT, SWEDISH TYPE
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 1173997008;
|
|
|
|
|
|
|
|
|
|
<strong>ORPHA:</strong> 477749;
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
13q34
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Microangiopathy and leukoencephalopathy, pontine, autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
618564
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
COL4A1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
120130
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>A number sign (#) is used with this entry because of evidence that autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL) is caused by heterozygous mutation in the COL4A1 gene (120130) on chromosome 13q34.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Autosomal dominant pontine microangiopathy and leukoencephalopathy (PADMAL) is a form of cerebral small vessel disease (CSVD) resulting in the onset of recurrent ischemic strokes in the thirties or forties. Affected individuals develop progressive, but variable, cognitive and motor impairment, consistent with progressive multi-infarct dementia. Brain imaging shows lacunar infarcts, often with a pontine predilection, as well as diffuse leukoencephalopathy affecting various brain regions. Although there are overlapping clinical features, the disorder is genetically and pathologically distinct from CADASIL (125310) (summary by Verdura et al., 2016). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Clinical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Sourander and Walinder (1977) reported a 3-generation Swedish family with onset of recurrent ischemic neurologic episodes between 29 and 38 years of age. Affected individuals had a progressive neuropsychiatric disease with pyramidal, bulbar, and cerebellar symptoms, and gradually developed multi-infarct dementia. None of the patients had hypertension. Neuropathologic examination of 3 patients showed cerebral atrophy and cystic infarctions due to an occlusive disease of small intracerebral and leptomeningeal arteries and arterioles. Cerebral vessels showed concentric thickening of the vascular wall and narrowing of the vascular lumen associated with subendothelial fibrous proliferation, hyaline degeneration of the intima and media, and fragmentation of the elastic lamina. In a follow-up of the family reported by Sourander and Walinder (1977), Low et al. (2007) excluded a diagnosis of CADASIL (125310) by genetic analysis. Furthermore, Low et al. (2007) noted that the clinical and pathologic features in the Swedish family indicated were distinct from CADASIL, suggesting a novel small vessel disease. </p><p>Hagel et al. (2004) reported a large multigenerational German family with progressive neurologic symptoms associated with recurrent cerebral lacunar infarcts. Most patients had onset after 30 years of age, but 1 patient had onset at age 12. Features included gait disturbances, ataxia, dysarthria, cognitive decline, and psychiatric abnormalities. Neuropathologic examination of 5 patients showed alterations of the small cerebral arteries and arterioles, such as concentric intimal thickening, hyperelastosis, atrophy of the vascular smooth muscle cells, and fibro-hyalinosis or fibrosis. Collagen IV was detected in the fibrotic regions with immunostaining. The basal ganglia, thalami, pons, and pyramidal tracts were predominantly affected. PAS-positive granular material as described in CADASIL was not observed. Ding et al. (2010) reported detailed brain imaging results of affected members of the family reported by Hagel et al. (2004). Common features included lacunar infarcts in the pons and subcortical and periventricular white matter lesions, consistent with leukoencephalopathy. Lesions in the temporal lobe were rare. None had atherosclerotic changes. Ding et al. (2010) suggested the acronym PADMAL for 'pontine autosomal dominant microangiopathy and leukoencephalopathy' to describe the disorder. </p><p>Verdura et al. (2016) reported a large French family (F1) in which 4 individuals presented with recurrent ischemic strokes associated with CSVD between 37 and 43 years of age. Initial features included sudden onset of anesthesia of the limbs, facial palsy, diplopia, or loss of balance, followed by subtle cognitive decline, mood disturbances, and progressive motor impairment with gait instability. Cognitive dysfunction included symptoms of dementia and dysexecutive function. The mother of the proband had a history of recurrent ischemic strokes leading to a bedridden state and death at 67 years of age. Brain imaging in the 4 clinically symptomatic individuals showed microvascular lesions in the pons and subcortical hemispheric area as well as white matter hyperintensities that correlated with age. Two additional clinically asymptomatic family members in a younger generation showed punctiform white matter hyperintensities in the centrum semiovale; these patients carried the mutation. Subsequently, 5 additional families with a similar disorder were identified, including the large German family (F2) previously reported by Hagel et al. (2004) and Ding et al. (2010). Families F4, F5, and F6 contained 1 proband, each of whom had a deceased parent with a similar phenotype. F3 was a multigenerational family with at least 8 affected individuals. All patients had recurrent ischemic strokes with onset between 35 and 45 years of age that resulted in progressive but variable impairments of motor and cognitive skills leading to disability in some cases. Neuroimaging studies showed multiple ischemic lacunae with a pontine predilection and variable leukoencephalopathy in the cerebral hemispheres with frequent involvement of the temporal lobe. Electron microscopic analysis of skin biopsies of 3 patients from family 3 showed duplications and focal disruptions of the basement membrane in most vessels and abnormal accumulation of extracellular matrix proteins in the subendothelial spaces between vascular smooth muscle cells. There was a thickened and poorly dense lamina densa, disconnection and degeneration of vascular smooth muscle cells, and increased fibrosis of the walls of small venules. Granular osmiophilic material, a specific biomarker of CADASIL, was absent. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Inheritance</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The transmission pattern of PADMAL in the families reported by Verdura et al. (2016) was consistent with autosomal dominant inheritance. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected members from a large French family (F1) with PADMAL, Verdura et al. (2016) identified a heterozygous c.*35C-A transversion in the 3-prime UTR of the COL4A1 gene (120130.0025). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Targeted sequencing of this region of the gene in 202 unrelated probands with a similar disorder identified 2 more heterozygous mutations in the same region of the gene (120130.0026-120130.0027) in affected members of 5 additional families with a similar disorder, including a German family previously reported by Hagel et al. (2004). In vitro functional expression studies in HEK293 cells showed that all the mutations interfered with miRNA29 (see 610782) binding and resulted in increased expression of COL4A1 compared to wildtype. Levels of COL4A1 mRNA were increased in patient fibroblasts compared to controls. </p><p>In affected members of a large 5-generation Swedish family with PADMAL originally reported by Sourander and Walinder (1977), Siitonen et al. (2017) identified a heterozygous c.*32G-A transition in the 3-prime UTR of the COL4A1 gene (120130.0028). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the mutation interfered with miRNA29 binding and resulted in increased expression of COL4A1 compared to wildtype. The findings confirmed the results of Verdura et al. (2016) and defined a specific phenotype caused by perturbations of the cerebrovascular matrisome that results in recurrent lacunar infarcts. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ding, X.-Q., Hagel, C., Ringelstein, E. B., Buchheit, S., Zeumer, H., Kuhlenbaumer, G., Appenzeller, S., Fiehler, J.
|
|
<strong>MRI features of pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL).</strong>
|
|
J. Neuroimaging 20: 134-140, 2010.
|
|
|
|
|
|
[PubMed: 19187480]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1552-6569.2008.00336.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hagel, C., Groden, C., Niemeyer, R., Stavrou, D., Colmant, H. J.
|
|
<strong>Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.</strong>
|
|
Acta Neuropath. 108: 231-240, 2004.
|
|
|
|
|
|
[PubMed: 15221337]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00401-004-0887-2]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Low, W. C., Junna, M., Borjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., St Clair, D., Mizuno, T., Zhang, W. W., Mykkanen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R. N.
|
|
<strong>Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.</strong>
|
|
Brain 130: 357-367, 2007.
|
|
|
|
|
|
[PubMed: 17235124]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/brain/awl360]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Siitonen, M., Borjesson-Hanson, A., Poyhonen, M., Ora, A., Pasanen, P., Bras, J., Kern, S., Kern, J., Andersen, O., Stanescu, H., Kleta, R., Baumann, M., Kalaria, R., Kalimo, H., Singleton, A., Hardy, J., Viitanen, M., Myllykangas, L., Guerreiro, R.
|
|
<strong>Multi-infarct dementia of Swedish type is caused by a 3-prime UTR mutation of COL4A1.</strong>
|
|
Brain 140: e29, 2017. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 28369186]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/brain/awx062]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sourander, P., Walinder, J.
|
|
<strong>Hereditary multi-infarct dementia: morphological and clinical studies of a new disease.</strong>
|
|
Acta Neuropath. 39: 247-254, 1977.
|
|
|
|
|
|
[PubMed: 906807]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/BF00691704]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Verdura, E., Herve, D., Bergametti, F., Jacquet, C., Morvan, T., Prieto-Morin, C., Mackowiak, A., Manchon, E., Hosseini, H., Cordonnier, C., Girard-Buttaz, I., Rosenstingl, S., and 9 others.
|
|
<strong>Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.</strong>
|
|
Ann. Neurol. 80: 741-753, 2016.
|
|
|
|
|
|
[PubMed: 27666438]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.24782]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Cassandra L. Kniffin : 08/30/2019
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Edit History:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 06/18/2022<br>carol : 09/07/2019<br>alopez : 09/06/2019<br>ckniffin : 09/03/2019
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div id="mimFooter">
|
|
|
|
|
|
<div class="container ">
|
|
<div class="row">
|
|
<br />
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="hidden-print mim-footer">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="visible-print-block mim-footer" style="position: relative;">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
<br />
|
|
Printed: March 13, 2025
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="modal fade" id="mimDonationPopupModal" tabindex="-1" role="dialog" aria-labelledby="mimDonationPopupModalTitle">
|
|
<div class="modal-dialog" role="document">
|
|
<div class="modal-content">
|
|
<div class="modal-header">
|
|
<button type="button" id="mimDonationPopupCancel" class="close" data-dismiss="modal" aria-label="Close"><span aria-hidden="true">×</span></button>
|
|
<h4 class="modal-title" id="mimDonationPopupModalTitle">
|
|
OMIM Donation:
|
|
</h4>
|
|
</div>
|
|
<div class="modal-body">
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Dear OMIM User,
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
To ensure long-term funding for the OMIM project, we have diversified
|
|
our revenue stream. We are determined to keep this website freely
|
|
accessible. Unfortunately, it is not free to produce. Expert curators
|
|
review the literature and organize it to facilitate your work. Over 90%
|
|
of the OMIM's operating expenses go to salary support for MD and PhD
|
|
science writers and biocurators. Please join your colleagues by making a
|
|
donation now and again in the future. Donations are an important
|
|
component of our efforts to ensure long-term funding to provide you the
|
|
information that you need at your fingertips.
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Thank you in advance for your generous support, <br />
|
|
Ada Hamosh, MD, MPH <br />
|
|
Scientific Director, OMIM <br />
|
|
</p>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div class="modal-footer">
|
|
<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
</body>
|
|
|
|
</html>
|
|
|
|
|