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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Familial Hemiplegic Migraine" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2024/07/04" /><meta name="citation_author" content="Joanna C Jen" /><meta name="citation_pmid" content="20301562" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1388/" /><meta name="citation_keywords" content="Sodium channel protein type 1 subunit alpha" /><meta name="citation_keywords" content="Sodium/potassium-transporting ATPase subunit alpha-2" /><meta name="citation_keywords" content="Voltage-dependent P/Q-type calcium channel subunit alpha-1A" /><meta name="citation_keywords" content="ATP1A2" /><meta name="citation_keywords" content="CACNA1A" /><meta name="citation_keywords" content="SCN1A" /><meta name="citation_keywords" content="Familial Hemiplegic Migraine" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Familial Hemiplegic Migraine" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Joanna C Jen" /><meta name="DC.Date" content="2024/07/04" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1388/" /><meta name="description" content="Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia." /><meta name="og:title" content="Familial Hemiplegic Migraine" /><meta name="og:type" content="book" /><meta name="og:description" content="Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1388/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/fhm/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1388/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1388_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1388_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/fevr/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/hlh/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1388_"><span class="title" itemprop="name">Familial Hemiplegic Migraine</span></h1><p class="contrib-group"><span itemprop="author">Joanna C Jen</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1388_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1388_ai__"><div class="contrib half_rhythm"><span itemprop="author">Joanna C Jen</span>, MD, PhD<div class="affiliation small">Department of NeurologyIcahn School of Medicine at Mount SinaiNew York, New York<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.mssm@nej.annaoj" class="oemail">ude.mssm@nej.annaoj</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">July 17, 2001</span>; Last Revision: <span itemprop="dateModified">July 4, 2024</span>.</p><p><em>Estimated reading time: 32 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="fhm.Summary" itemprop="description"><h2 id="_fhm_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with <i>CACNA1A</i>-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The clinical diagnosis of FHM can be established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>: (1) who fulfills criteria for migraine with aura; (2) in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms; and (3) who has at least one first- or <a class="def" href="/books/n/gene/glossary/def-item/second-degree-relative/">second-degree relative</a> with similar attacks that fulfill the diagnostic criteria for hemiplegic migraine. The molecular diagnosis can be established in a proband by identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>ATP1A2</i>, <i>CACNA1A</i>, <i>PRRT2</i>, or <i>SCN1A</i>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> A trial of acetazolamide for individuals with <i>CACNA1A-</i>FHM or a trial of prophylactic migraine medications (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, anti-seizure medications) for all FHM types may be warranted for frequent attacks. Anti-seizure treatment may be necessary for seizures, which are prevalent in <i>ATP1A2</i>-FHM. Corticosteroids in children with cerebral edema to reduce life-threatening manifestations.</p><p><i>Surveillance:</i> Neurologic evaluation to assess change in attack frequency and/or seizures, development of movement disorder, developmental delay, and/or learning disability annually or more frequently for worsening symptoms.</p><p><i>Agents/circumstances to avoid:</i> Vasoconstricting agents because of the risk of stroke; cerebral angiography as it may precipitate a severe attack.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>FHM and <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> hemiplegic migraine caused by a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>ATP1A2</i>, <i>CACNA1A</i>, <i>PRRT2</i>, or <i>SCN1A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Because the diagnosis of FHM requires at least one affected <a class="def" href="/books/n/gene/glossary/def-item/first-degree-relative/">first-degree relative</a>, most individuals diagnosed with FHM have an affected parent. Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant or a pathogenic variant inherited from an asymptomatic parent. Each child of an individual with FHM has a 50% chance of inheriting the pathogenic variant. Once an FHM-causing pathogenic variant has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="fhm.Diagnosis"><h2 id="_fhm_Diagnosis_">Diagnosis</h2><p>Consensus clinical diagnostic criteria for <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> hemiplegic migraine (FHM) have been published by the <a class="bk_pop" href="#fhm.REF.headache_classification_committee_of_the_international_headache_society_ihs_.2018.1">Headache Classification Committee of the International Headache Society (IHS) [2018]</a> (<a href="https://ichd-3.org/wp-content/uploads/2018/01/The-International-Classification-of-Headache-Disorders-3rd-Edition-2018.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>).</p><div id="fhm.Suggestive_Findings"><h3>Suggestive Findings</h3><p>FHM is a category of migraine with aura.</p><p>Note: Migraine with aura is a recurring disorder of neurologic symptoms unequivocally localizable to the cerebral cortex or brain stem. The aura usually develops over a period of five to 20 minutes and lasts less than 60 minutes. Headache, nausea, and/or photophobia usually follow neurologic aura symptoms, either immediately or after a symptom-free interval of less than an hour. The headache usually lasts four to 72 hours but may be completely absent (acephalgic migraine).</p><p>
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<b>Diagnostic criteria for HM</b>
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</p><ul><li class="half_rhythm"><div>Headaches that fulfill criteria for migraine with aura</div></li><li class="half_rhythm"><div>Aura consisting of <b>both</b> of the following:</div><ul><li class="half_rhythm"><div>Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness</div></li><li class="half_rhythm"><div>Fully reversible visual, sensory, and/or speech/language symptoms</div></li></ul></li></ul><p>HM is categorized as <b><a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a></b> if at least one <a class="def" href="/books/n/gene/glossary/def-item/first-degree-relative/">first-degree relative</a> (i.e., parent, sib, and/or offspring) or <a class="def" href="/books/n/gene/glossary/def-item/second-degree-relative/">second-degree relative</a> has similar attacks that fulfill the diagnostic criteria for HM.</p><p>Note: HM is <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> if no first- or <a class="def" href="/books/n/gene/glossary/def-item/second-degree-relative/">second-degree relative</a> meets criteria for HM.</p><p>
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<b>Diagnostic criteria for migraine with aura</b>
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</p><ul><li class="half_rhythm"><div>At least two episodes fulfilling criteria for migraine</div></li><li class="half_rhythm"><div>Migraine with at least one of the following fully reversible aura symptoms:</div><ul><li class="half_rhythm"><div>Visual</div></li><li class="half_rhythm"><div>Sensory</div></li><li class="half_rhythm"><div>Speech and/or language</div></li><li class="half_rhythm"><div>Motor</div></li><li class="half_rhythm"><div>Brain stem</div></li><li class="half_rhythm"><div>Retinal</div></li></ul></li><li class="half_rhythm"><div>At least three of the following characteristics:</div><ul><li class="half_rhythm"><div>At least one aura symptom spreads gradually over five minutes.</div></li><li class="half_rhythm"><div>Two or more aura symptoms occur in succession.</div></li><li class="half_rhythm"><div>Each individual aura symptom lasts five to 60 minutes.</div></li><li class="half_rhythm"><div>At least one aura symptom is unilateral.</div></li><li class="half_rhythm"><div>At least one aura symptom is positive.</div></li><li class="half_rhythm"><div>The aura is accompanied – or followed within 60 minutes – by headache.</div></li></ul></li><li class="half_rhythm"><div>Absence of other causes of headache (e.g., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, non-cephalic infection, metabolic disorder, pain associated with other facial or cranial disorders)</div></li></ul></div><div id="fhm.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The clinical diagnosis of FHM can be <b>established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> based on clinical diagnostic criteria described in <a href="#fhm.Suggestive_Findings">Suggestive Findings</a>, or the molecular diagnosis can be established in a proband by identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> in one of the genes listed in <a href="/books/NBK1388/table/fhm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfhmTmoleculargenetictestingusedin">Table 1</a>.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#fhm.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> variant in one of the genes listed in <a href="/books/NBK1388/table/fhm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfhmTmoleculargenetictestingusedin">Table 1</a> of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include <b>serial</b>
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<b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b>, a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>, or <b><a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a></b>.</p><p>Note: (1) In the majority of persons with adult-onset hemiplegic migraine without nystagmus, seizures, or other unusual associated neurologic features, the yield for genetic testing is low. (2) Multiple studies have shown that pathogenic variants in the genes listed in <a href="/books/NBK1388/table/fhm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfhmTmoleculargenetictestingusedin">Table 1</a> are not a major cause of <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> hemiplegic migraine (i.e., hemiplegic migraine in a single person in a family).</p><ul><li class="half_rhythm"><div class="half_rhythm">
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<b>Serial single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b>
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</div><ul><li class="half_rhythm"><div>In individuals with <b>nystagmus</b>, <b>ataxia</b>, <b>paroxysmal tonic upgaze</b>, <b>or developmental delay</b>, <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <b><i>CACNA1A</i></b> can be performed first. If no variant is detected by the sequencing method used, the next step is to perform <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> and whole-gene deletions or duplications [<a class="bk_pop" href="#fhm.REF.ophoff.1996.543">Ophoff et al 1996</a>].</div></li><li class="half_rhythm"><div>In individuals with <b>epilepsy</b>, <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <b><i>ATP1A2</i></b> can be performed first [<a class="bk_pop" href="#fhm.REF.de_fusco.2003.192">De Fusco et al 2003</a>].</div></li></ul></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes some or all of the genes listed in <a href="/books/NBK1388/table/fhm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfhmTmoleculargenetictestingusedin">Table 1</a> and other genes of interest (see <a href="#fhm.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>Exome sequencing</b> is most commonly used.</div><div class="half_rhythm">For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</div></li></ul><div id="fhm.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Familial Hemiplegic Migraine</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of FHM Attributed to Pathogenic Variants in Gene</th><th id="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>3</sup> Identified by Method</th></tr><tr><th headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence<br />analysis <sup>4</sup></th><th headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATP1A2</i>
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</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~10%</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~99% <sup>6</sup></td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 person <sup>7</sup></td></tr><tr><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CACNA1A</i>
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</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-15%</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~95% <sup>6</sup></td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple families <sup>8</sup></td></tr><tr><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PRRT2</i>
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</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2%-3% <sup>9</sup></td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~75%</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~25%</td></tr><tr><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SCN1A</i>
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</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1%</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>6</sup></td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported</td></tr><tr><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>10</sup></td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">66%-80%</td><td headers="hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_1 hd_h_fhm.T.molecular_genetic_testing_used_in_1_1_2_2" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">NA</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="fhm.TF.1.1"><p class="no_margin">Genes are listed in alphabetic order.</p></div></dd><dt>2. </dt><dd><div id="fhm.TF.1.2"><p class="no_margin">See <a href="/books/NBK1388/#fhm.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>3. </dt><dd><div id="fhm.TF.1.3"><p class="no_margin">See <a href="#fhm.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in these genes.</p></div></dd><dt>4. </dt><dd><div id="fhm.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>5. </dt><dd><div id="fhm.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="fhm.TF.1.6"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#fhm.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>7. </dt><dd><div id="fhm.TF.1.7"><p class="no_margin">An intragenic <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> involving <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 21 was reported in one individual with hemiplegic migraine [<a class="bk_pop" href="#fhm.REF.gagliardi.2017.63">Gagliardi et al 2017</a>].</p></div></dd><dt>8. </dt><dd><div id="fhm.TF.1.8"><p class="no_margin">A 39.5-kb <i>CACNA1A</i> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of the last 16 coding exons was reported in three affected members of one family with episodic ataxia [<a class="bk_pop" href="#fhm.REF.riant.2008.817">Riant et al 2008</a>]. <i>CACNA1A</i> rearrangements have also been reported in families with hemiplegic migraine [<a class="bk_pop" href="#fhm.REF.labrum.2009.786">Labrum et al 2009</a>].</p></div></dd><dt>9. </dt><dd><div id="fhm.TF.1.9"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.riant.2022.e51">Riant et al [2022]</a>
|
||
</p></div></dd><dt>10. </dt><dd><div id="fhm.TF.1.10"><p class="no_margin">A <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>ATP1A4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> was reported in one family; to date, the report has not been confirmed.</p></div></dd></dl></div></div></div></div></div><div id="fhm.Clinical_Characteristics"><h2 id="_fhm_Clinical_Characteristics_">Clinical Characteristics</h2><div id="fhm.Clinical_Description"><h3>Clinical Description</h3><p>In migraine with aura, including <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> hemiplegic migraine (FHM), the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include fully reversible <b>visual disturbance</b> (most common), <b>sensory loss</b> (e.g., numbness or paresthesias of the face or an extremity), and <b>dysphasia</b> (difficulty with speech), and for FHM must include <b>motor involvement</b> (e.g., hemiparesis [weakness of an extremity]):</p><ul><li class="half_rhythm"><div>Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision).</div></li><li class="half_rhythm"><div>Dysphasia usually occurs when hemiplegia is right-sided.</div></li><li class="half_rhythm"><div>Hemiparesis (unilateral weakness), not necessarily hemiplegia (unilateral paralysis), occurs with at least one other symptom during FHM aura.</div></li></ul><p>Some confusion and/or drowsiness may be present even without dysphasia. Impaired consciousness ranging from drowsiness to coma is well described in FHM [<a class="bk_pop" href="#fhm.REF.terwindt.1998.1105">Terwindt et al 1998</a>, <a class="bk_pop" href="#fhm.REF.chabriat.2000.510">Chabriat et al 2000</a>, <a class="bk_pop" href="#fhm.REF.vahedi.2000.1040">Vahedi et al 2000</a>]. Intermittent confusion and psychosis have been reported [<a class="bk_pop" href="#fhm.REF.feely.1982.369">Feely et al 1982</a>], including one probable family with <i>CACNA1A-</i>FHM and ataxia [<a class="bk_pop" href="#fhm.REF.spranger.1999.150">Spranger et al 1999</a>].</p><p>Neurologic deficits with hemiplegic migraine attacks can be prolonged for hours to days and may outlast the associated migrainous headache. Persistent attention and memory loss can last weeks to months [<a class="bk_pop" href="#fhm.REF.kors.2003.684">Kors et al 2003</a>]. Permanent motor, sensory, language, or visual symptoms are extremely rare [<a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al 2001</a>].</p><p>FHM is a rare and extreme <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of migraine with aura. The frequency of attacks ranges from one per day to fewer than five in a lifetime (mean: 2-3/year). Long attack-free intervals are often reported (range: 2-37 years). The frequency of FHM attacks tends to decrease with age. FHM attacks may be provoked by typical migraine triggers (e.g., foods, odors, exertion, stress), cerebral angiography, and minor head trauma.</p><p>The eventual neurologic outcome is often benign in the pure FHM group without interictal deficits (e.g., seizures/epilepsy, ataxia, nystagmus, cognitive impairment / learning disability).</p><p>Note: Cerebral infarction and death have rarely been associated with hemiplegic migraine and should instead raise the possibility of other disorders associated with migraine and stroke (see <a href="#fhm.Differential_Diagnosis">Differential Diagnosis</a>).</p><p><b>Seizures</b> are a recognized feature in those with FHM-related pathogenic variants, which reflects much clinical and mechanistic overlap between epilepsy and migraine. Seizures during severe attacks have been reported in some families with <i>ATP1A2</i>-FHM along with coma and encephalopathy [<a class="bk_pop" href="#fhm.REF.echenne.1999.214">Echenne et al 1999</a>, <a class="bk_pop" href="#fhm.REF.deprez.2008.500">Deprez et al 2008</a>]. Focal seizures during severe attacks have been described in two individuals with <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> <i>CACNA1A-</i>FHM [<a class="bk_pop" href="#fhm.REF.chabriat.2000.510">Chabriat et al 2000</a>], including one with severe intellectual disability, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> ataxia, and early cerebellar atrophy [<a class="bk_pop" href="#fhm.REF.vahedi.2000.1040">Vahedi et al 2000</a>]. <i>De novo</i>
|
||
<i>CACNA1A</i> pathogenic variants are a common cause of epileptic encephalopathy [<a class="bk_pop" href="#fhm.REF.allen.2016.287">Allen et al 2016</a>], and epileptic encephalopathy may be the presenting <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in an individual who develops <i>CACNA1A-</i>FHM. Heterozygous <i>PRRT2</i> pathogenic variants are a major cause of childhood seizures, including self-limited (<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a>) infantile epilepsy (SeLIE; formerly known as benign familial infantile seizures) and paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC; formerly known as infantile convulsions and choreoathetosis) [<a class="bk_pop" href="#fhm.REF.heron.2012.152">Heron et al 2012</a>, <a class="bk_pop" href="#fhm.REF.schubert.2012.1439">Schubert et al 2012</a>, <a class="bk_pop" href="#fhm.REF.becker.2013.1234">Becker et al 2013</a>].</p><p><b>Paroxysmal movement disorders.</b> Paroxysmal kinesigenic dyskinesia has been reported in individuals with a <i>PRRT2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> with or without presence of hemiplegic migraine (see <a href="/books/n/gene/prrt2-parox/"><i>PRRT2</i>-Related Disorder</a>).</p><p><b>Imaging studies.</b> There are no pathognomonic neuroradiographic findings for FHM. The only abnormalities observed on traditional imaging studies are vermian cerebellar atrophy in some families with <i>CACNA1A-</i>FHM [<a class="bk_pop" href="#fhm.REF.battistini.1999.38">Battistini et al 1999</a>]. Rare ictal studies demonstrated transient diffusion-weighted signal changes on brain MRI, suggesting cytotoxic edema during severe prolonged attacks in individuals with <i>CACNA1A-</i>FHM [<a class="bk_pop" href="#fhm.REF.chabriat.2000.510">Chabriat et al 2000</a>, <a class="bk_pop" href="#fhm.REF.vahedi.2000.1040">Vahedi et al 2000</a>], with hemispheric cerebral atrophy usually contralateral to the hemiparesis [<a class="bk_pop" href="#fhm.REF.hayashi.1998.166">Hayashi et al 1998</a>, <a class="bk_pop" href="#fhm.REF.chabriat.2000.510">Chabriat et al 2000</a>, <a class="bk_pop" href="#fhm.REF.vahedi.2000.1040">Vahedi et al 2000</a>].</p><p>Abnormalities in the cerebellum on magnetic resonance spectroscopy have been reported [<a class="bk_pop" href="#fhm.REF.dichgans.2005.608">Dichgans et al 2005</a>].</p></div><div id="fhm.Phenotype_Correlations_by_Gene"><h3>Phenotype Correlations by Gene</h3><p><b><i>CACNA1A.</i></b> Compared to families without an identified FHM-related <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, families with <i>CACNA1A</i>-FHM have a higher incidence of cerebellar signs ranging from nystagmus to progressive ataxia, which occurs in up to 40%-50% of families with <i>CACNA1A-</i>FHM [<a class="bk_pop" href="#fhm.REF.ducros.2000">Ducros et al 2000</a>]; within such families, up to 60% of affected individuals have permanent cerebellar signs [<a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al 2001</a>].</p><p>Those with identified FHM-related pathogenic variants tend to present with earlier age of onset, more severe symptoms, and associated interictal symptoms and signs (nystagmus, episodic or progressive ataxia, learning disability, epilepsy). In the report of <a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al [2001]</a>, the attacks started at a young age in the majority of individuals with <i>CACNA1A</i>-FHM (mean: 11.7±8 years; range: 1-51 years). Findings from subsequent series confirmed the observation of early age of onset and more severe attacks in those with FHM-related pathogenic variants compared to those with FHM and no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified [<a class="bk_pop" href="#fhm.REF.hiekkala.2018.1849">Hiekkala et al 2018</a>, <a class="bk_pop" href="#fhm.REF.pelzer.2018.e575">Pelzer et al 2018</a>].</p></div><div id="fhm.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>
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<b>
|
||
<i>ATP1A2</i>
|
||
</b>
|
||
</p><ul><li class="half_rhythm"><div>A severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> with seizures, coma, and elevated temperature has been reported with the <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Gly301Arg</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>ATP1A2</i> [<a class="bk_pop" href="#fhm.REF.spadaro.2004.177">Spadaro et al 2004</a>, <a class="bk_pop" href="#fhm.REF.santoro.2011.808">Santoro et al 2011</a>].</div></li><li class="half_rhythm"><div>A severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> with seizures and intellectual disability has been reported with the pathogenic variants <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Asp718Asn</a> and <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Pro979Leu</a> [<a class="bk_pop" href="#fhm.REF.jurkatrott.2004.1857">Jurkat-Rott et al 2004</a>].</div></li></ul><p><b><i>CACNA1A</i>.</b> Although further correlation is needed, some suggestive <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> exist based on limited data regarding <i>CACNA1A</i> pathogenic variants commonly presenting with nystagmus and other cerebellar signs [<a class="bk_pop" href="#fhm.REF.ophoff.1996.543">Ophoff et al 1996</a>, <a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al 2001</a>].</p><ul><li class="half_rhythm"><div><a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Arg192Gln</a> and <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Val1456Leu</a> [<a class="bk_pop" href="#fhm.REF.carrera.1999.26">Carrera et al 1999</a>] are associated with hemiplegic attacks only, whereas unconsciousness occurs commonly during attacks with the <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Val714Ala</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> [<a class="bk_pop" href="#fhm.REF.terwindt.1998.1105">Terwindt et al 1998</a>].</div></li><li class="half_rhythm"><div><a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Thr666Met</a>, <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Ile1810Leu</a>, <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Arg583Gln</a> [<a class="bk_pop" href="#fhm.REF.alonso.2003.610">Alonso et al 2003</a>], and <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Asp715Glu</a> [<a class="bk_pop" href="#fhm.REF.ducros.1999.89">Ducros et al 1999</a>] have been associated with hemiplegic attacks plus ataxia. According to <a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al [2001]</a>, p.Thr666Met was associated with the highest frequency of hemiplegic migraine, severe attacks of coma, and nystagmus. During attacks, unconsciousness sometimes occurs in individuals with the p.Thr666Met or p.Ile1810Leu <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> [<a class="bk_pop" href="#fhm.REF.terwindt.1998.1105">Terwindt et al 1998</a>].</div></li><li class="half_rhythm"><div><a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Arg583Gln</a> can be associated with stupor, fever, and progressive ataxia [<a class="bk_pop" href="#fhm.REF.battistini.1999.38">Battistini et al 1999</a>, <a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al 2001</a>]. Affected individuals were thought to have fewer attacks after treatment with acetazolamide.</div></li><li class="half_rhythm"><div><a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Asp715Glu</a> has the lowest frequency (64%) of attacks of hemiplegic migraine [<a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al 2001</a>].</div></li><li class="half_rhythm"><div><a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Ser218Leu</a> has been associated with delayed cerebral edema and fatal coma after minor head trauma [<a class="bk_pop" href="#fhm.REF.kors.2001.753">Kors et al 2001</a>, <a class="bk_pop" href="#fhm.REF.stam.2009.1125">Stam et al 2009</a>].</div></li></ul></div><div id="fhm.Penetrance"><h3>Penetrance</h3><p>Penetrance appears to be high and is estimated at 80% [<a class="bk_pop" href="#fhm.REF.jurkatrott.2004.1857">Jurkat-Rott et al 2004</a>, <a class="bk_pop" href="#fhm.REF.riant.2005.281">Riant et al 2005</a>].</p></div><div id="fhm.Nomenclature"><h3>Nomenclature</h3><p>Although families with FHM in which attacks are strikingly identical do exist, the term FHM is often used inconsistently to describe families in which different forms of migraine occur, as most individuals with hemiplegic attacks have these attacks intermingled with more frequent attacks of migraine without hemiparesis.</p></div><div id="fhm.Prevalence"><h3>Prevalence</h3><p>In Denmark, <a class="bk_pop" href="#fhm.REF.thomsen.2002.1379">Thomsen et al [2002]</a> found the prevalence of hemiplegic migraine to be 0.01% with a M:F sex ratio of 1:3 and equal prevalence of <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> and <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases.</p></div></div><div id="fhm.Genetically_Related_Allelic_Disorder"><h2 id="_fhm_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>Other phenotypes associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>ATP1A2, CACNA1A</i>, and <i>SCN1A</i> are summarized in <a href="/books/NBK1388/table/fhm.T.allelic_disorders/?report=objectonly" target="object" rid-ob="figobfhmTallelicdisorders">Table 2</a>.</p><div id="fhm.T.allelic_disorders" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Allelic Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.allelic_disorders/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.allelic_disorders_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fhm.T.allelic_disorders_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_fhm.T.allelic_disorders_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Characteristics</th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>
|
||
<i>ATP1A2</i>
|
||
</b>
|
||
</td><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Alternating hemiplegia of childhood (OMIM <a href="https://omim.org/entry/104290" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">104290</a>), characterized by intermittent recurrent prolonged hemiplegic episodes that mimic hemiplegic migraine</td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Polymicrogyric syndrome <sup>1</sup></td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>
|
||
<i>CACNA1A</i>
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||
</b>
|
||
</td><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Episodic ataxia type 2 (OMIM <a href="https://www.omim.org/entry/108500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">108500</a>). Episodes of ataxia & sometimes migrainous headache w/interictal nystagmus. In 1 family, affected members experienced hemiplegia; 1 family member had migraine during episodes of ataxia. <sup>2</sup> Assoc pathogenic variants: <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, frameshift, & <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants & multiexon deletions that disrupt the <a class="def" href="/books/n/gene/glossary/def-item/open-reading-frame/">open reading frame</a></td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Progressive cerebellar ataxia. Severe progressive ataxia & cerebellar atrophy. Assoc pathogenic variants: <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants incl p.Gly293Arg in P loop of 1st <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a>; p.Ala454Thr in I-II loop; p.Arg1664Gln</td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/sca6/">Spinocerebellar ataxia type 6</a> (SCA6). Adult-onset, slowly progressive cerebellar ataxia, dysarthria, & nystagmus. Assoc w/a CAG repeat expansion; this expansion has not been observed in families w/FHM <sup>3</sup> but some persons w/SCA6 may have migraine.</td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Developmental & epileptic encephalopathy 42 (OMIM <a href="https://omim.org/entry/617106" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617106</a>). <i>De novo</i> pathogenic variants in <i>CACNA1A</i> are recognized to be an important cause of epileptic encephalopathy. <sup>4</sup></td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>
|
||
<i>PRRT2</i>
|
||
</b>
|
||
</td><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Paroxysmal kinesigenic dyskinesia (see <a href="/books/n/gene/prrt2-parox/"><i>PRRT2</i>-Related Disorder</a>). Paroxysmal attacks are often characterized by dystonia, followed by choreoathetosis, & rarely ballism.</td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Self-limited (<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a>) infantile epilepsy (see <a href="/books/n/gene/prrt2-parox/"><i>PRRT2</i>-Related Disorder</a>). Characterized by complex partial or generalized tonic-clonic seizures in clusters with onset between age three to 12 months.</td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Paroxysmal kinesigenic dyskinesia with infantile convulsions (see <a href="/books/n/gene/prrt2-parox/"><i>PRRT2</i>-Related Disorder</a>)</td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>
|
||
<i>SCN1A</i>
|
||
</b>
|
||
</td><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The vast majority of pathogenic variants in <i>SCN1A</i> cause epilepsy. <a href="/books/n/gene/gefs/"><i>SCN1A</i> seizure disorders</a> encompass a spectrum from simple febrile seizures & generalized epilepsy w/febrile seizures plus to Dravet syndrome & intractable childhood epilepsy w/generalized tonic-clonic seizures. Phenotypes w/intractable seizures incl Dravet syndrome are usually assoc w/progressive cognitive & motor decline.</td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Interstitial deletions of 2q24-q3 (incl a cluster of voltage-gated sodium channel genes: <i>SCN1A</i>, <i>SCN2A</i>, <i>SCN3A</i>, <i>SCN7A</i>, <i>SCN9A</i>) are assoc w/tonic focal & myoclonic jerks that tend to appear in infancy & are later followed by mixed-type seizures, which persist to late childhood & are drug resistant. <sup>5</sup></td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Larger deletions of 2q24.3 are assoc w/<a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features (e.g., microcephaly, ptosis, downslanting palpebral fissures, long eyelashes, micrognathia), <sup>6</sup> & digit anomalies in persons w/2q24-q31 deletions. <sup>7</sup></td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Reported duplications of 2q24.2-q3 involving the cluster of voltage-gated sodium channel genes <i>SCN1A</i>, <i>SCN2A</i>, <i>SCN3A</i>, <i>SCN7A</i>, & <i>SCN9A</i> vary in size. Reported persons presented w/focal seizures & epileptic spasms w/neonatal onset (as early as 3rd day of life). <sup>8</sup></td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Familial autism <sup>9</sup></td></tr><tr><td headers="hd_h_fhm.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Rasmussen encephalitis assoc w/<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> p.Arg1575Cys <sup>10</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="fhm.TF.2.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.chatron.2019.3367">Chatron et al [2019]</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="fhm.TF.2.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.jen.1999.274">Jen [1999]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="fhm.TF.2.3"><p class="no_margin"><a class="bk_pop" href="#fhm.REF.carrera.1999.26">Carrera et al [1999]</a>, <a class="bk_pop" href="#fhm.REF.ducros.1999.89">Ducros et al [1999]</a></p></div></dd><dt>4. </dt><dd><div id="fhm.TF.2.4"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.allen.2016.287">Allen et al [2016]</a>
|
||
</p></div></dd><dt>5. </dt><dd><div id="fhm.TF.2.5"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.grosso.2007.609">Grosso et al [2007]</a>
|
||
</p></div></dd><dt>6. </dt><dd><div id="fhm.TF.2.6"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.pescucci.2007.21">Pescucci et al [2007]</a>
|
||
</p></div></dd><dt>7. </dt><dd><div id="fhm.TF.2.7"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.boles.1995.155">Boles et al [1995]</a>
|
||
</p></div></dd><dt>8. </dt><dd><div id="fhm.TF.2.8"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.goeggel_simonetti.2012.2128">Goeggel Simonetti et al [2012]</a>
|
||
</p></div></dd><dt>9. </dt><dd><div id="fhm.TF.2.9"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.weiss.2003.186">Weiss et al [2003]</a>
|
||
</p></div></dd><dt>10. </dt><dd><div id="fhm.TF.2.10"><p class="no_margin">
|
||
<a class="bk_pop" href="#fhm.REF.ohmori.2008.521">Ohmori et al [2008]</a>
|
||
</p></div></dd></dl></div></div></div><p>Note: In one large family with pathogenic variants in <i>CACNA1A</i>, some individuals had only hemiplegic migraine, some had only ataxia, and some had both [<a class="bk_pop" href="#fhm.REF.alonso.2003.610">Alonso et al 2003</a>].</p></div><div id="fhm.Differential_Diagnosis"><h2 id="_fhm_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Migraine without aura</b> (OMIM <a href="https://omim.org/entry/157300" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">157300</a>) (common migraine) is an <a class="def" href="/books/n/gene/glossary/def-item/idiopathic/">idiopathic</a>, recurring headache disorder manifesting in attacks lasting four to 72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photophobia, and phonophobia. This headache occurs without neurologic aura symptoms and specifically without hemiparesis.</p><p><b>Hemiplegia.</b> The differential diagnosis of hemiplegia includes post-ictal weakness following seizure, transient ischemic attack, stroke, and other non-genetic causes of transient hemiparesis.</p><p><b>Stroke.</b> When family history is positive for hemiparetic attacks with migraine, the presence of infarct on imaging studies raises the possibility of inherited disorders such as <a href="/books/n/gene/melas/">MELAS</a>, <a href="/books/n/gene/cadasil/">CADASIL</a>, or thrombophilia (e.g., <a href="/books/n/gene/factor-v-leiden/">factor V Leiden</a>). Additional stroke risk factors may also be present.</p><p>Caution: Even with normal imaging studies and description of spreading aura, an age-appropriate stroke evaluation should be considered at presentation. Overlap in clinical features, inaccuracies of historical family information, rarity of FHM, and the seriousness of stroke-related disorders warrant this cautious approach. Stroke or other CNS-related disorders should be strongly considered if family history is negative for hemiplegic migraine.</p><p><b>Migrainous headache that may include hemiplegic aura.</b> Other hereditary disorders associated with migrainous headache that may include hemiplegic aura are summarized in <a href="/books/NBK1388/table/fhm.T.hereditary_disorders_with_migraino/?report=objectonly" target="object" rid-ob="figobfhmThereditarydisorderswithmigraino">Table 3</a>.</p><div id="fhm.T.hereditary_disorders_with_migraino" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Hereditary Disorders with Migrainous Headache That May Include Hemiplegic Aura in the Differential Diagnosis of Familial Hemiplegic Migraine</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.hereditary_disorders_with_migraino/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.hereditary_disorders_with_migraino_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Headache Phenotype</th><th id="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Other Clinical Characteristics</th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ACVRL1</i>
|
||
<br />
|
||
<i>ENG</i>
|
||
<br />
|
||
<i>GDF2</i>
|
||
<br />
|
||
<i>SMAD4</i>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<p>
|
||
<a href="/books/n/gene/hht/">Hereditary hemorrhagic telangiectasia</a>
|
||
</p>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Migraine w/aura reported in 50% of affected persons (Migraine headache may be a complication of pulmonary AVMs.)</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple AVMs that lack intervening capillaries & → direct connections between arteries & veins. Small AVMs (telangiectases) close to skin surface or mucous membranes that often rupture & bleed after slight trauma. Most common clinical sign: spontaneous & recurrent nosebleeds from age ~12 yrs.</td></tr><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>APP</i>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<p>Dutch form of hereditary cerebral amyloid angiopathy (OMIM <a href="https://omim.org/entry/605714" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">605714</a>)</p>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Migraines often precede onset of cerebral & cerebellar hemorrhage in 4th or 5th decade.</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Senile plaques & vascular wall amyloid found in the brain in assoc w/amino acid changes in APP beta-amyloid precursor protein, a protease inhibitor</td></tr><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ATP1A2</i>
|
||
<br />
|
||
<p>
|
||
<i>ATP1A3</i>
|
||
</p>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Alternating hemiplegia of childhood (OMIM <a href="https://omim.org/phenotypicSeries/PS104290" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS104290</a>)</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early onset of recurrent transient hemiplegia</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent hemiplegia w/onset age <18 mos, variable other transient neurologic findings, & progressive cognitive decline</td></tr><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CCM2</i>
|
||
<br />
|
||
<i>KRIT1</i>
|
||
<br />
|
||
<i>PDCD10</i>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<p>
|
||
<a href="/books/n/gene/ccm/">Familial cerebral cavernous malformations</a>
|
||
</p>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nonspecific headaches</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vascular malformations in brain & spinal cord consisting of closely clustered enlarged capillary channels (caverns) w/a single layer of endothelium w/o normal intervening brain parenchyma or mature vessel wall elements. Typically presents in 2nd-5th decade. ~50%-75% of persons w/CCM have symptoms incl seizures, focal neurologic deficits, & cerebral hemorrhage.</td></tr><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">mtDNA</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/merrf/">MERRF</a> <sup>2</sup></td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mat</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Migraine headaches reported in 5%-14.9% of those w/m.8344A>G in <i>MT-TK</i></td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multisystem disorder characterized by myoclonus followed by generalized epilepsy, ataxia, weakness, & dementia; onset usually in childhood after normal early development</td></tr><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">mtDNA <sup>1</sup></td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/melas/">MELAS</a> <sup>2</sup></td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mat</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Migrainous headaches (recurrent attacks of severe pulsatile headache w/frequent vomiting) are typical & can precipitate stroke-like episodes. Headache episodes are often more severe during stroke-like episodes.</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multisystem disorder w/onset at age ~2-40 yrs. Common clinical manifestations: stroke-like episodes, encephalopathy w/seizures &/or dementia, muscle weakness & exercise intolerance, normal early psychomotor development, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, & short stature</td></tr><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>NOTCH3</i>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<p>
|
||
<a href="/books/n/gene/cadasil/">CADASIL</a>
|
||
</p>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Migraine may be 1st symptom; occurs in 30%-75% of persons, w/1st attack at a mean age of 26-29 yrs. 80%-90% of those w/migraine have migraine w/aura. Migraine auras are sometimes confused w/transient ischemic symptoms, as aura may incl focal neurologic deficits. 60% of those w/migraine w/aura have experienced an atypical migraine attack: prolonged, basilar or hemiplegic aura, confusion, fever, or coma.</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mid-adult onset of recurrent ischemic stroke, cognitive decline progressing to dementia, mood disturbance, apathy, & diffuse white matter lesions & subcortical infarcts on neuroimaging</td></tr><tr><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TREX1</i>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<p>
|
||
<a href="/books/n/gene/rvcl/">Retinal vasculopathy w/cerebral leukoencephalopathy & systemic manifestations</a>
|
||
</p>
|
||
</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Migraine ± aura</td><td headers="hd_h_fhm.T.hereditary_disorders_with_migraino_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Small-vessel disease that affects highly vascularized tissues incl retina, brain, liver, & kidneys. Onset age: ~35-50 yrs. Most common presenting finding: ↓ visual acuity &/or visual field defects. Neurologic manifestations may incl hemiparesis, facial weakness, aphasia, & hemianopsia.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AVM = arteriovenous malformation; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CCM = cerebral cavernous malformation; Mat = maternal; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; mtDNA = mitochondrial DNA</p></div></dd><dt>1. </dt><dd><div id="fhm.TF.3.1"><p class="no_margin">The most common mtDNA <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, present in more than 80% of individuals with typical clinical findings of MELAS, is an A-to-G transition at nucleotide 3243 in the tRNALeu(UUR) of mtDNA.</p></div></dd><dt>2. </dt><dd><div id="fhm.TF.3.2"><p class="no_margin">Other <a href="/books/n/gene/mt-overview/">mitochondrial disorders</a> can also be considered. Common central nervous system findings in mitochondrial disorders are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.</p></div></dd></dl></div></div></div></div><div id="fhm.Management"><h2 id="_fhm_Management_">Management</h2><div id="fhm.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> hemiplegic migraine (FHM) or <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> hemiplegic migraine (i.e., individuals with an FHM-causing <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and an apparently negative family history), the evaluations summarized in this <a href="/books/NBK1388/table/fhm.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobfhmTrecommendedevaluationsfollowing">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="fhm.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Hemiplegic Migraine</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.recommended_evaluations_following_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fhm.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_fhm.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.recommended_evaluations_following_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_fhm.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Quantitative eye movement exam in persons w/nystagmus or complaints of incoordination or imbalance to look for additional clues of cerebellar involvement</div></li><li class="half_rhythm"><div>EEG & neuroimaging studies if seizures are present in order to further characterize seizure disorder</div></li><li class="half_rhythm"><div>Neuroimaging studies in those w/impaired responsiveness to assess for cerebral edema</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_fhm.T.recommended_evaluations_following_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Assess for movement disorder in those w/<i>PRRT2</i>-FHM</td></tr><tr><td headers="hd_h_fhm.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_fhm.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup> to obtain a <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> & inform affected persons & their families re nature, MOI, & implications of FHM in order to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_fhm.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_fhm.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#fhm.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">FHM = <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> hemiplegic migraine; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="fhm.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="fhm.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Symptomatic support during an episode of hemiplegic migraine is the only therapy available.</p><div id="fhm.T.treatment_of_manifestations_in_ind" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Familial Hemiplegic Migraine</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.treatment_of_manifestations_in_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.treatment_of_manifestations_in_ind_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Frequent attacks</b>
|
||
</td><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Trial of acetazolamide for persons w/<i>CACNA1A-</i>FHM</div></li><li class="half_rhythm"><div>Trial of standard migraine prophylactic drugs (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, ASMs)</div></li></ul>
|
||
</td><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Limited correlation exists between drug response & hemiplegic migraine type.</td></tr><tr><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider ASMs incl topiramate, lacosamide, levetiracetam, & valproate, along w/other medications commonly used for migraine prophylaxis.</td><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">There are anecdotal reports of therapeutic response.</td></tr><tr><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Seizures</b>
|
||
</td><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Anti-seizure treatment</td><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cerebral edema</b>
|
||
</td><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Corticosteroids in children w/cerebral edema to reduce life-threatening manifestations</td><td headers="hd_h_fhm.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ASM = anti-seizure medication</p></div></dd></dl></div></div></div></div><div id="fhm.Surveillance"><h3>Surveillance</h3><div id="fhm.T.recommended_surveillance_for_indiv" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Familial Hemiplegic Migraine</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.recommended_surveillance_for_indiv/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.recommended_surveillance_for_indiv_lrgtbl__"><table><thead><tr><th id="hd_h_fhm.T.recommended_surveillance_for_indiv_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_fhm.T.recommended_surveillance_for_indiv_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_fhm.T.recommended_surveillance_for_indiv_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.recommended_surveillance_for_indiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_fhm.T.recommended_surveillance_for_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by neurologist to assess change in attack frequency &/or seizures, development of movement disorder, developmental delay, &/or learning disability</td><td headers="hd_h_fhm.T.recommended_surveillance_for_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually or more frequently for worsening symptoms</td></tr></tbody></table></div></div></div><div id="fhm.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>In general, vasoconstricting agents should be avoided because of the risk of stroke.</p><p>Cerebral angiography is hazardous as it may precipitate a severe attack [<a class="bk_pop" href="#fhm.REF.chabriat.2000.510">Chabriat et al 2000</a>].</p></div><div id="fhm.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#fhm.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="fhm.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="fhm.Genetic_Counseling"><h2 id="_fhm_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="fhm.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Familial hemiplegic migraine (FHM) and <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> hemiplegic migraine caused by a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>ATP1A2</i>, <i>CACNA1A</i>, <i>PRRT2</i>, or <i>SCN1A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p><p>Note: The term "<a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> hemiplegic migraine" is used in this section to refer to individuals with hemiplegic migraine and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>ATP1A2</i>, <i>CACNA1A</i>, <i>PRRT2</i>, or <i>SCN1A</i> who do not have a first- or <a class="def" href="/books/n/gene/glossary/def-item/second-degree-relative/">second-degree relative</a> who meets criteria for hemiplegic migraine.</p></div><div id="fhm.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Because the diagnosis of FHM requires at least one affected <a class="def" href="/books/n/gene/glossary/def-item/first-degree-relative/">first-degree relative</a>, most individuals diagnosed with FHM have an affected parent.</div></li><li class="half_rhythm"><div>Individuals with <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> hemiplegic migraine (i.e., individuals with an FHM-causing <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and an apparently negative family history) may have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant [<a class="bk_pop" href="#fhm.REF.terwindt.2002.1016">Terwindt et al 2002</a>, <a class="bk_pop" href="#fhm.REF.de_vries.2007.2170">de Vries et al 2007</a>, <a class="bk_pop" href="#fhm.REF.thomsen.2008.914">Thomsen et al 2008</a>, <a class="bk_pop" href="#fhm.REF.riant.2010.967">Riant et al 2010</a>] or a pathogenic variant inherited from an asymptomatic parent.</div></li><li class="half_rhythm"><div>Recommendations for the evaluation of the parents of an individual who appears to be the only affected family member include clinical interview, neurologic examination, and <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> if a molecular diagnosis has been established in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li><li class="half_rhythm"><div>If a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not identified in either parent, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Note: A pathogenic variant is reported as "<i>de novo</i>" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed <i>de novo</i>" [<a class="bk_pop" href="#fhm.REF.richards.2015.405">Richards et al 2015</a>].</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (or somatic and germline) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ cells only.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with <i>ATP1A2</i>, <i>CACNA1A</i>, <i>PRRT2</i>, or <i>SCN1A</i>-related hemiplegic migraine may appear to be negative because of failure to recognize the disorder in affected family members or reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (to establish that neither parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a causative <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>).</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of a proband depends on the clinical/genetic status of the parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have an FHM-causing <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the risk to the sibs of inheriting the pathogenic variant is 50%. There is a high likelihood that a sib who inherits an FHM-causing pathogenic variant will have clinical manifestations of the disorder. Intrafamilial clinical variability has been observed in age at onset and severity of manifestations, including attack frequency, severity, and associated features.</div><ul><li class="half_rhythm"><div>Of note, the core <i>PRRT2</i>-related phenotypes (i.e., hemiplegic migraine, paroxysmal kinesigenic dyskinesia [PKD], self-limited [<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a>] infantile epilepsy, and PKD with infantile convulsions) can be variably observed in family members with the same <i>PRRT2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (see <a href="/books/n/gene/prrt2-parox/"><i>PRRT2</i>-Related Disorder</a>).</div></li></ul></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a known <i>ATP1A2</i>, <i>CACNA1A</i>, <i>PRRT2</i>, or <i>SCN1A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is estimated to be 1% because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#fhm.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> does not have a known FHM-related <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and both of the proband's parents are clinically unaffected, the risk to the sibs of a proband appears to be low.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> hemiplegic migraine has a 50% chance of inheriting the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the genetic status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents. If a parent is affected, the parent's family members are at risk.</p></div><div id="fhm.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.</div></li></ul><p><b>DNA banking. </b>Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#fhm.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="fhm.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once an FHM-causing <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a>. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="fhm.Resources"><h2 id="_fhm_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>CACNA1A Foundation</b>
|
||
</div><div><b>Email:</b> info@cacna1a.org</div><div>
|
||
<a href="https://www.cacna1a.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cacna1a.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Medline Plus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/familial-hemiplegic-migraine/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Familial hemiplegic migraine</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Headache Foundation</b>
|
||
</div><div><b>Phone:</b> 888-NHF-5552; 888-643-5552</div><div><b>Email:</b> info@headaches.org</div><div>
|
||
<a href="http://www.headaches.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.headaches.org</a>
|
||
</div></li></ul>
|
||
</div><div id="fhm.Molecular_Genetics"><h2 id="_fhm_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="fhm.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Familial Hemiplegic Migraine: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_fhm.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_fhm.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_fhm.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_fhm.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_fhm.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_fhm.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_fhm.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/477" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>ATP1A2</i>
|
||
</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=477" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">1q23<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P50993" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Sodium/potassium-transporting ATPase subunit alpha-2</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.lovd.nl/ATP1A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide (ATP1A2) @ LOVD</a>
|
||
<br />
|
||
<a href="https://databases.lovd.nl/shared/genes/ATP1A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Familial Hemiplegic Migraine (FHM) Variation Database (ATP1A2)</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ATP1A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ATP1A2</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ATP1A2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ATP1A2</a>
|
||
</td></tr><tr><td headers="hd_b_fhm.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>CACNA1A</i>
|
||
</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=773" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">19p13<wbr style="display:inline-block"></wbr>.13</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/O00555" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Voltage-dependent P/Q-type calcium channel subunit alpha-1A</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/CACNA1A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) @ LOVD</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CACNA1A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CACNA1A</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=CACNA1A[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CACNA1A</a>
|
||
</td></tr><tr><td headers="hd_b_fhm.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/6323" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SCN1A</i>
|
||
</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=6323" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">2q24<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P35498" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Sodium channel protein type 1 subunit alpha</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/SCN1A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SCN1A gene database</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SCN1A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SCN1A</a>
|
||
</td><td headers="hd_b_fhm.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SCN1A[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SCN1A</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="fhm.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="fhm.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Familial Hemiplegic Migraine (<a href="/omim/141500,182340,182389,601011,602481,609634" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/141500" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">141500</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MIGRAINE, FAMILIAL HEMIPLEGIC, 1; FHM1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/182340" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">182340</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/182389" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">182389</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 1; SCN1A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/601011" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">601011</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/602481" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">602481</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MIGRAINE, FAMILIAL HEMIPLEGIC, 2; FHM2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/609634" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">609634</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MIGRAINE, FAMILIAL HEMIPLEGIC, 3; FHM3</td></tr></tbody></table></div></div><div id="fhm.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The three FHM-related genes identified to date encode ion channels and transporters important in regulating neuronal excitability and cortical synaptic transmission. The observation of seizures and epilepsy in individuals with FHM-causing variants further emphasizes the mechanistic overlap between migraine and epilepsy from dysregulation of cortical excitation/inhibition balance.</p><p>Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying migraine aura is cortical spreading depolarization (CSD) of Leão, which is characterized by a slowly propagating wave 2-6 mm/min of hyperexcitation followed by sustained depression. Mouse models generated from <i>ATP1A2</i>-FHM variants <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Trp887Arg</a> or <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Gly301Arg</a> [<a class="bk_pop" href="#fhm.REF.leo.2011.e1002129">Leo et al 2011</a>, <a class="bk_pop" href="#fhm.REF.kros.2018.16959">Kros et al 2018</a>] and <i>CACNA1A</i> variants <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Arg192Gln</a> and <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Ser218Leu</a> [<a class="bk_pop" href="#fhm.REF.van_den_maagdenberg.2004.701">van den Maagdenberg et al 2004</a>, <a class="bk_pop" href="#fhm.REF.van_den_maagdenberg.2010.85">van den Maagdenberg et al 2010</a>] all demonstrated increased susceptibility to induced CSD from decreased glutamate clearance or increased glutamate release, respectively. A newly generated mouse model with the <i>SCN1A</i>-FHM variant <a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object" rid-ob="figobfhmTfamilialhemiplegicmigrainenotab">p.Leu263Val</a> demonstrated spontaneous CSD attributed to overall gain of sodium channel function leading to hyperexcitation of GABAergic inhibitory interneurons [<a class="bk_pop" href="#fhm.REF.jansen.2020.132">Jansen et al 2020</a>].</p><p>
|
||
<b>Mechanism of disease causation</b>
|
||
</p><ul><li class="half_rhythm"><div><b><i>ATP1A2</i>.</b> The two pathogenic variants found by <a class="bk_pop" href="#fhm.REF.de_fusco.2003.192">De Fusco et al [2003]</a>, p.Leu764Pro and p.Trp887Arg, cause loss of function of the α2-subunit leading to <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a>, which appears to be the general rule for <i>ATP1A2-</i>FHM variants. Loss of transporter function would lead to impaired glutamate clearance from the synaptic cleft.</div></li><li class="half_rhythm"><div><b><i>CACNA1A</i>.</b> There is much clinical overlap between FHM and allelic disorders such as episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). In general, FHM-causing variants are thought to lead to gain of channel function, while EA-causing variants are commonly truncation variants and are thought to lead to loss of function. Seizures have been associated with manifestations of hemiplegic migraine and episodic ataxia.</div></li><li class="half_rhythm"><div><b><i>PRRT2.</i></b> FHM-causing variants are largely truncating variants (c.649dupC is the most common) or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions leading to loss of PRRT2 function with disruption of synaptic neurotransmission [<a class="bk_pop" href="#fhm.REF.valente.2016.117">Valente et al 2016</a>] and dysregulation of voltage-gated sodium [<a class="bk_pop" href="#fhm.REF.fruscione.2018.1000">Fruscione et al 2018</a>] and calcium channels [<a class="bk_pop" href="#fhm.REF.ferrante.2021.109248">Ferrante et al 2021</a>].</div></li><li class="half_rhythm"><div><b><i>SCN1A.</i></b> FHM-causing variants generally lead to gain of channel function, which contrasts with <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> variants that account for the vast majority of <i>SCN1A</i> variants causing various epilepsy syndromes including Dravet syndrome.</div></li></ul><div id="fhm.T.familial_hemiplegic_migraine_genes" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Familial Hemiplegic Migraine: Gene-Specific Laboratory Considerations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_genes/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.familial_hemiplegic_migraine_genes_lrgtbl__"><table><thead><tr><th id="hd_h_fhm.T.familial_hemiplegic_migraine_genes_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_fhm.T.familial_hemiplegic_migraine_genes_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Special Consideration</th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<p>
|
||
<i>CACNA1A</i>
|
||
</p>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>CACNA1A</i> is alternatively spliced, notably w/an alternative <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 37 (<a href="/entrez/viewer.fcgi?val=NM_001127221.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001127221<wbr style="display:inline-block"></wbr>.1</a> RefSeq transcript variant 3) & an alternative <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> for <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 47 which contains polymorphic CAG repeats, w/the longer transcript rendering the CAG repeats in frame for polyglutamine. Pathogenic variants have been identified in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 37a & <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 37b. Furthermore, CAG repeat expansions w/>21 repeats cause <a href="/books/n/gene/sca6/">SCA6</a> w/reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>.</td></tr></tbody></table></div></div><div id="fhm.T.familial_hemiplegic_migraine_notab" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Familial Hemiplegic Migraine: Notable Pathogenic Variants by Gene</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1388/table/fhm.T.familial_hemiplegic_migraine_notab/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__fhm.T.familial_hemiplegic_migraine_notab_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ATP1A2</i>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_2" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000702.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000702<wbr style="display:inline-block"></wbr>.4</a>
|
||
<br />
|
||
<a href="/entrez/viewer.fcgi?val=NP_000693.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000693<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.901G>A</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly301Arg</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> reported [<a class="bk_pop" href="#fhm.REF.spadaro.2004.177">Spadaro et al 2004</a>, <a class="bk_pop" href="#fhm.REF.santoro.2011.808">Santoro et al 2011</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2152G>A</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp718Asn</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> reported [<a class="bk_pop" href="#fhm.REF.jurkatrott.2004.1857">Jurkat-Rott et al 2004</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2936C>T</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro979Leu</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2291T>C</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu764Pro</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#fhm.REF.de_fusco.2003.192">De Fusco et al [2003]</a>
|
||
</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2659T>C</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Trp887Arg</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_1" rowspan="8" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CACNA1A</i>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_2" rowspan="8" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001127221.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001127221<wbr style="display:inline-block"></wbr>.2</a><br /><a href="/entrez/viewer.fcgi?val=NP_001120693.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_001120693<wbr style="display:inline-block"></wbr>.1</a><br /><a href="/nuccore/1657332" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">X99897</a> <sup>2</sup></td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.575G>A</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg192Gln</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hemiplegic attacks [<a class="bk_pop" href="#fhm.REF.carrera.1999.26">Carrera et al 1999</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.653C>T</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser218Leu</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bk_pop" href="#fhm.REF.kors.2001.753">Kors et al [2001]</a>, <a class="bk_pop" href="#fhm.REF.stam.2009.1125">Stam et al [2009]</a></td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1748G>A</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg583Gln</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bk_pop" href="#fhm.REF.battistini.1999.38">Battistini et al [1999]</a>, <a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al [2001]</a></td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1997C>T</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr666Met</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> w/no evidence for <a class="def" href="/books/n/gene/glossary/def-item/founder-effect/">founder effect</a> [<a class="bk_pop" href="#fhm.REF.ducros.1999.89">Ducros et al 1999</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2141T>C</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val714Ala</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hemiplegic attacks & unconsciousness [<a class="bk_pop" href="#fhm.REF.terwindt.1998.1105">Terwindt et al 1998</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2145C>G</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp715Glu</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lowest frequency (64%) of attacks of hemiplegic migraine [<a class="bk_pop" href="#fhm.REF.ducros.2001.17">Ducros et al 2001</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.4366G>T<br />(c.4369G>T) <sup>2</sup></td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val1456Leu<br />(p.Val1457Leu) <sup>2</sup></td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hemiplegic attacks [<a class="bk_pop" href="#fhm.REF.carrera.1999.26">Carrera et al 1999</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.5428A>C<br />(c.5431A>C) <sup>2</sup></td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ile1810Leu<br />(p.Ile1811Leu) <sup>2</sup></td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hemiplegic attacks + ataxia [<a class="bk_pop" href="#fhm.REF.ducros.1999.89">Ducros et al 1999</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PRRT2</i>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_145239.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_145239<wbr style="display:inline-block"></wbr>.3</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_660282.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_660282<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.649dupC</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg217Glufs</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hemiplegic migraine [<a class="bk_pop" href="#fhm.REF.dale.2012.958">Dale et al 2012</a>]</td></tr><tr><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SCN1A</i>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001165963.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001165963<wbr style="display:inline-block"></wbr>.4</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_001159435.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_001159435<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.787C>G</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu263Val</td><td headers="hd_h_fhm.T.familial_hemiplegic_migraine_notab_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#fhm.REF.jansen.2020.132">Jansen et al [2020]</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the author. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="fhm.TF.8.1"><p class="no_margin">Genes from <a href="/books/NBK1388/table/fhm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobfhmTmoleculargenetictestingusedin">Table 1</a> in alphabetic order</p></div></dd><dt>2. </dt><dd><div id="fhm.TF.8.2"><p class="no_margin">Variant designations are given for an alternate reference sequence. X99897 is an alternate <a class="def" href="/books/n/gene/glossary/def-item/cdna/">cDNA</a> commonly used in the literature. Compared to NM_001127221.2, it has an extra three nucleotides (AAG) at nucleotide 3623_3625, resulting in an additional Glu residue.</p></div></dd></dl></div></div></div></div></div><div id="fhm.Chapter_Notes"><h2 id="_fhm_Chapter_Notes_">Chapter Notes</h2><div id="fhm.Author_History"><h3>Author History</h3><p>Kathy Lou Gardner, MD; University of Pittsburgh (2001-2009)<br />Joanna C Jen, MD, PhD (2009-present)</p></div><div id="fhm.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>4 July 2024 (sw) Revision: information regarding <i>PRRT2</i> added</div></li><li class="half_rhythm"><div>29 April 2021 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 May 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>8 September 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 March 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>17 July 2001 (me) Review posted live</div></li><li class="half_rhythm"><div>October 2000 (kg) Original submission</div></li></ul></div></div><div id="fhm.References"><h2 id="_fhm_References_">References</h2><div id="fhm.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.allen.2016.287">Allen
|
||
AS, Berkovic
|
||
SF, Cossette
|
||
P, Delanty
|
||
N, Dlugos
|
||
D, Eichler
|
||
EE, Epstein
|
||
MP, Glauser
|
||
T; Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.
|
||
Am J Hum Genet.
|
||
2016;99:287–98.
|
||
[<a href="/pmc/articles/PMC4974067/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4974067</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27476654" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27476654</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.alonso.2003.610">Alonso
|
||
I, Barros
|
||
J, Tuna
|
||
A, Coelho
|
||
J, Sequeiros
|
||
J, Silveira
|
||
I, Coutinho
|
||
P. Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family.
|
||
Arch Neurol.
|
||
2003;60:610–4.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/12707077" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12707077</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.battistini.1999.38">Battistini
|
||
S, Stenirri
|
||
S, Piatti
|
||
M, Gelfi
|
||
C, Righetti
|
||
PG, Rocchi
|
||
R, Giannini
|
||
F, Battistini
|
||
N, Guazzi
|
||
GC, Ferrari
|
||
M, Carrera
|
||
P. A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.
|
||
Neurology.
|
||
1999;53:38–43.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/10408534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10408534</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.becker.2013.1234">Becker
|
||
F, Schubert
|
||
J, Striano
|
||
P, Anttonen
|
||
AK, Liukkonen
|
||
E, Gaily
|
||
E, Gerloff
|
||
C, Müller
|
||
S, Heußinger
|
||
N, Kellinghaus
|
||
C, Robbiano
|
||
A, Polvi
|
||
A, Zittel
|
||
S, von Oertzen
|
||
TJ, Rostasy
|
||
K, Schöls
|
||
L, Warner
|
||
T, Münchau
|
||
A, Lehesjoki
|
||
AE, Zara
|
||
F, Lerche
|
||
H, Weber
|
||
YG. PRRT2-related disorders: further PKD and ICCA cases and review of the literature.
|
||
J Neurol.
|
||
2013;260:1234-44.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/23299620" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23299620</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.boles.1995.155">Boles
|
||
RG, Pober
|
||
BR, Gibson
|
||
LH, Willis
|
||
CR, McGrath
|
||
J, Roberts
|
||
DJ, Yang-Feng
|
||
TL. Deletion of chromosome 2q24-q31 causes characteristic digital anomalies: case report and review.
|
||
Am J Med Genet.
|
||
1995;55:155–60.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/7717414" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7717414</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.carrera.1999.26">Carrera
|
||
P, Piatti
|
||
M, Stenirri
|
||
S, Grimaldi
|
||
LM, Marchioni
|
||
E, Curcio
|
||
M, Righetti
|
||
PG, Ferrari
|
||
M, Gelfi
|
||
C. Genetic heterogeneity in Italian families with familial hemiplegic migraine.
|
||
Neurology.
|
||
1999;53:26–33.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/10408532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10408532</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.chabriat.2000.510">Chabriat
|
||
H, Vahedi
|
||
K, Clark
|
||
CA, Poupon
|
||
C, Ducros
|
||
A, Denier
|
||
C, Le Bihan
|
||
D, Bousser
|
||
MG. Decreased hemispheric water mobility in hemiplegic migraine related to mutation of CACNA1A gene.
|
||
Neurology.
|
||
2000;54:510–2.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/10668728" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10668728</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.chatron.2019.3367">Chatron
|
||
N, Cabet
|
||
S, Alix
|
||
E, Buenerd
|
||
A, Cox
|
||
P, Guibaud
|
||
L, Labalme
|
||
A, Marks
|
||
P, Osio
|
||
D, Putoux
|
||
A, Sanlaville
|
||
D, Lesca
|
||
G, Vasiljevic
|
||
A.
|
||
A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.
|
||
Brain.
|
||
2019;142:3367–74.
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N, Plomp
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JJ, Pietrobon
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D, Ferrari
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MD. High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice.
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Ann Neurol.
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2010;67:85–98.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/20186955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20186955</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="fhm.REF.weiss.2003.186">Weiss
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LA, Escayg
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A, Kearney
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JA, Trudeau
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M, MacDonald
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BT, Mori
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M, Reichert
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J, Buxbaum
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JD, Meisler
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MH. Sodium channels SCN1A, SCN2A and SCN3A in familial autism.
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Mol Psychiatry.
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2003;8:186–94.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/12610651" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12610651</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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class="invert">Review</span> Acute Intermittent Porphyria.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Acute Intermittent Porphyria.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Sardh E, Barbaro M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301512" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hypokalemic Periodic Paralysis.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hypokalemic Periodic Paralysis.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Weber F, Lehmann-Horn F. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301294" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> ATP1A3-Related Disorder.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> ATP1A3-Related Disorder.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Brashear A, Sweadner KJ, Haq I, Napoli E, Ozelius L. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301510" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span 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