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class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><p class="vip-notice retraction"><strong>This publication is provided for historical reference only and the information may be out of date.</strong></p><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1501_"><span class="title" itemprop="name">Episodic Ataxia Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY</span></h1><p class="contribs">Spacey S.</p><p class="fm-aai"><a href="#_NBK1501_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 24 minutes</em></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="ea2.Summary" itemprop="description"><h2 id="_ea2_Summary_">Summary</h2><p>
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<b>NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.</b>
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</p><div><h4 class="inline">Clinical characteristics.</h4><p>Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia, vertigo, and nausea typically lasting minutes to days in duration. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache. About 50% of individuals with EA2 have migraine headaches. Onset is typically in childhood or early adolescence (age range 2-32 years). Frequency of attacks can range from once or twice a year to three or four times a week. Attacks can be triggered by stress, exertion, caffeine, alcohol, fever, heat, and phenytoin; they can be stopped or decreased in frequency and severity by administration of acetazolamide or 4-aminopyridine. Between attacks, individuals may initially be asymptomatic but commonly develop interictal findings that can include nystagmus, pursuit and saccade alterations, and ataxia.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of EA2 is established by identification of a heterozygous pathogenic variant in <i>CACNA1A</i>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Acetazolamide is effective in controlling or reducing the frequency and severity of attacks in most individuals; typical starting dose is 125 mg a day given orally, but doses as high as 500 mg twice a day may be required. Acetazolamide is generally well tolerated; the most common side effects are paresthesias of the extremities, rash, and renal calculi. Acetazolamide does not appear to prevent the progression of interictal symptoms. Studies have also demonstrated that 4-aminopyridine in doses of 5-10 mg/3x/day can also be effective in reducing attack frequency and duration.</p><p><i>Surveillance:</i> Annual neurologic examination.</p><p><i>Agents/circumstances to avoid:</i> Phenytoin has been reported to exacerbate symptoms.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>EA2 is inherited in an autosomal dominant manner. Most individuals with a diagnosis of EA2 have an affected parent. The proportion of cases caused by <i>de novo</i> pathogenic variants is unknown. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing is possible for pregnancies at increased risk for EA2 if the pathogenic variant has been identified in the family.</p></div></div><div id="ea2.Diagnosis"><h2 id="_ea2_Diagnosis_">Diagnosis</h2><p>There are no formal clinical diagnostic criteria for the diagnosis of episodic ataxia type 2.</p><div id="ea2.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Episodic ataxia type 2 (EA2) <b>should be suspected</b> in individuals with the following clinical, neuroimaging, EMG, and family history findings.</p><p>
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<b>Clinical features</b>
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</p><ul><li class="half_rhythm"><div>Episodic attacks:</div><ul><li class="half_rhythm"><div>Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting</div></li><li class="half_rhythm"><div>Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat</div></li><li class="half_rhythm"><div>Alleviated or prevented by acetazolamide therapy</div></li></ul></li><li class="half_rhythm"><div>Presence of interictal ataxia and nystagmus</div></li><li class="half_rhythm"><div>Absence of myokymia (fine twitching or rippling of muscles) on physical examination</div></li></ul><p>
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<b>Neuroimaging</b>
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</p><ul><li class="half_rhythm"><div>Brain MRI may demonstrate atrophy of the cerebellar vermis [<a class="bibr" href="#ea2.REF.vighetto.1988.547" rid="ea2.REF.vighetto.1988.547">Vighetto et al 1988</a>, <a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>].</div></li><li class="half_rhythm"><div>Nuclear magnetic spectroscopy may demonstrate abnormal cerebellar intracellular pH levels (in those not treated with acetazolamide) [<a class="bibr" href="#ea2.REF.bain.1992.147" rid="ea2.REF.bain.1992.147">Bain et al 1992</a>] and low cerebellar creatine [<a class="bibr" href="#ea2.REF.harno.2005.542" rid="ea2.REF.harno.2005.542">Harno et al 2005</a>].</div></li><li class="half_rhythm"><div>Myokymia is absent on EMG.</div></li><li class="half_rhythm"><div>Single fiber EMG may demonstrate jitter and blocking.</div></li></ul><p><b>Family history</b> consistent with autosomal dominant inheritance</p></div><div id="ea2.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of EA2 <b>is established</b> in a proband by the identification of a heterozygous pathogenic variant in <i>CACNA1A</i> by molecular genetic testing (see <a href="/books/NBK1501/table/ea2.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobea2Tmoleculargenetictestingusedin">Table 1</a>).</p><p>Molecular testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel.</b></p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>CACNA1A</i> is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>CACNA1A</i> and other genes of interest (see <a href="#ea2.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered.</div><div class="half_rhythm">Note: (1) The genes included and sensitivity of multigene panels vary by laboratory and over time. (2) Guidelines for the molecular diagnosis of genetic conditions that cause ataxia have been published [<a class="bibr" href="#ea2.REF.gasser.2010.179" rid="ea2.REF.gasser.2010.179">Gasser et al 2010</a>].</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figea2Tmoleculargenetictestingusedin"><a href="/books/NBK1501/table/ea2.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobea2Tmoleculargenetictestingusedin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="ea2.T.molecular_genetic_testing_used_in"><a href="/books/NBK1501/table/ea2.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobea2Tmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Episodic Ataxia Type 2 </p></div></div></div></div><div id="ea2.Clinical_Characteristics"><h2 id="_ea2_Clinical_Characteristics_">Clinical Characteristics</h2><div id="ea2.Clinical_Description"><h3>Clinical Description</h3><p>Episodic ataxia type 2 (EA2) demonstrates variable expressivity both among and within families [<a class="bibr" href="#ea2.REF.denier.1999.1816" rid="ea2.REF.denier.1999.1816">Denier et al 1999</a>]. Episodic ataxia typically starts in childhood or early adolescence (age range 2-32 years) [<a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>]. Onset as late as age 61 years has been reported [<a class="bibr" href="#ea2.REF.imbrici.2005.944" rid="ea2.REF.imbrici.2005.944">Imbrici et al 2005</a>].</p><p>EA2 is characterized by paroxysmal attacks of ataxia, vertigo, and nausea typically lasting hours to days. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache [<a class="bibr" href="#ea2.REF.nachbauer.2014.983" rid="ea2.REF.nachbauer.2014.983">Nachbauer et al 2014</a>]. One study reported vertigo and weakness accompanying the ataxia in more than half of individuals with genetically confirmed EA2 [<a class="bibr" href="#ea2.REF.jen.2004.17" rid="ea2.REF.jen.2004.17">Jen et al 2004</a>]. Another report suggested that about 50% of individuals with EA2 have migraine headaches without loss of consciousness [<a class="bibr" href="#ea2.REF.baloh.1997.8" rid="ea2.REF.baloh.1997.8">Baloh et al 1997</a>]. Torticollis, intellectual disability, and psychiatric disorders have been described in individuals with genetically confirmed EA2 [<a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>, <a class="bibr" href="#ea2.REF.nachbauer.2014.983" rid="ea2.REF.nachbauer.2014.983">Nachbauer et al 2014</a>].</p><p>Frequency of attacks can range from one to two times per year to three to four times per week [<a class="bibr" href="#ea2.REF.von_brederlow.1995.279" rid="ea2.REF.von_brederlow.1995.279">von Brederlow et al 1995</a>, <a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>]. Attacks can be triggered by stress, exertion, caffeine, alcohol, and phenytoin. In one kindred, attacks could be provoked by fever or high environmental temperatures [<a class="bibr" href="#ea2.REF.subramony.2003.725" rid="ea2.REF.subramony.2003.725">Subramony et al 2003</a>]. EA2 attacks can be stopped or decreased in frequency and severity by administration of acetazolamide or 4-aminopyridine [<a class="bibr" href="#ea2.REF.strupp.2011.269" rid="ea2.REF.strupp.2011.269">Strupp et al 2011</a>, <a class="bibr" href="#ea2.REF.ilg.2014.248" rid="ea2.REF.ilg.2014.248">Ilg et al 2014</a>]; attacks can recur within 48 to 72 hours of stopping the medication [<a class="bibr" href="#ea2.REF.von_brederlow.1995.279" rid="ea2.REF.von_brederlow.1995.279">von Brederlow et al 1995</a>]. In some cases, attacks remit within one year after onset but in others, they can recur over a 50-year interval [<a class="bibr" href="#ea2.REF.baloh.1997.8" rid="ea2.REF.baloh.1997.8">Baloh et al 1997</a>].</p><p>While individuals with EA2 may initially be asymptomatic between attacks, most eventually develop interictal permanent cerebellar symptoms; 90% have nystagmus and about 80% have ataxia. Other interictal findings include pursuit and saccade alterations and dystonia [<a class="bibr" href="#ea2.REF.spacey.2005.314" rid="ea2.REF.spacey.2005.314">Spacey et al 2005</a>, <a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>].</p></div><div id="ea2.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Specific <i>CACNA1A</i> pathogenic variants do not strictly predict the EA2 phenotype.</p><p>Allelic modifying factors such as number of CAG repeats in exon 47 of CACNA1A do not appear to influence the severity of attacks or the persistence of neurologic symptoms between attacks [<a class="bibr" href="#ea2.REF.denier.1999.1816" rid="ea2.REF.denier.1999.1816">Denier et al 1999</a>]. Furthermore, the EA2 phenotype in individuals with small intragenic deletions or duplications is similar to that of individuals with pathogenic missense, nonsense, or splice-site variants [<a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>].</p><p>Three pathogenic variants – <a href="/books/NBK1501/table/ea2.T.cacna1a_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobea2Tcacna1avariantsdiscussedinthis">c.3841C>T</a> (p.Arg1281Ter), <a href="/books/NBK1501/table/ea2.T.cacna1a_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobea2Tcacna1avariantsdiscussedinthis">c.4217T>G</a> (p.Phe1406Cys), and <a href="/books/NBK1501/table/ea2.T.cacna1a_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobea2Tcacna1avariantsdiscussedinthis">c.4645C>T</a> (p.Arg1549Ter) – have been associated with fluctuating weakness manifesting as a myasthenic syndrome in individuals with EA2 [<a class="bibr" href="#ea2.REF.jen.2001.1843" rid="ea2.REF.jen.2001.1843">Jen et al 2001</a>].</p></div><div id="ea2.Penetrance"><h3>Penetrance</h3><p>Penetrance is estimated at 80%-90% [<a class="bibr" href="#ea2.REF.jen.1999.34" rid="ea2.REF.jen.1999.34">Jen et al 1999</a>, <a class="bibr" href="#ea2.REF.spacey.2005.314" rid="ea2.REF.spacey.2005.314">Spacey et al 2005</a>].</p></div><div id="ea2.Nomenclature"><h3>Nomenclature</h3><p>EA2 has also been known as periodic vestibulocerebellar ataxia and acetazolamide-responsive episodic ataxia.</p></div><div id="ea2.Prevalence"><h3>Prevalence</h3><p>EA2 is rare. The Consortium for Clinical Investigation of Neurological Channelopathies (CLINCH) has estimated the prevalence at lower than 1:100,000 population based on the cases seen by experts in regional centers.</p></div></div><div id="ea2.Genetically_Related_Allelic_Disorder"><h2 id="_ea2_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>Pathogenic variants in <i>CACNA1A</i> can cause other disorders, including:</p><ul><li class="half_rhythm"><div class="half_rhythm"><a href="/books/n/gene/fhm/?report=reader"><b>Familial hemiplegic migraine</b></a>
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<b>(FHM).</b> Approximately 50% of families with FHM, including all those with permanent cerebellar symptoms, have heterozygous pathogenic missense variants in <i>CACNA1A</i> (FHM1) [<a class="bibr" href="#ea2.REF.ophoff.1996.543" rid="ea2.REF.ophoff.1996.543">Ophoff et al 1996</a>, <a class="bibr" href="#ea2.REF.ducros.1999.89" rid="ea2.REF.ducros.1999.89">Ducros et al 1999</a>]. Two other FHM-associated genes have been identified; FHM2 is caused by heterozygous pathogenic variants in <i>ATP1A2</i> [<a class="bibr" href="#ea2.REF.de_fusco.2003.192" rid="ea2.REF.de_fusco.2003.192">De Fusco et al 2003</a>] and FHM3 by heterozygous pathogenic variants in <i>SCN1A</i> [<a class="bibr" href="#ea2.REF.dichgans.2005.371" rid="ea2.REF.dichgans.2005.371">Dichgans et al 2005</a>].</div><div class="half_rhythm">FHM is characterized by an aura of hemiplegia that is always associated with at least one other aura symptom such as hemianopsia, hemisensory deficit, or aphasia. The aura is followed by a moderate to severe headache. Two clinical forms exist: pure FHM (80% of families), in which interictal examination is normal in all family members, and FHM with permanent cerebellar symptoms (20% of families), in which some family members show interictal nystagmus and/or ataxia [<a class="bibr" href="#ea2.REF.ducros.2001.17" rid="ea2.REF.ducros.2001.17">Ducros et al 2001</a>]. Some individuals with FHM – primarily children and adolescents who sustain minor head trauma – develop uncontrollable cerebral edema [<a class="bibr" href="#ea2.REF.mccrory.1998.677" rid="ea2.REF.mccrory.1998.677">McCrory & Berkovic 1998</a>]. Three individuals with delayed cerebral edema were shown to have the pathogenic p.Ser218Leu missense variant in <i>CACNA1A</i> [<a class="bibr" href="#ea2.REF.kors.2001.753" rid="ea2.REF.kors.2001.753">Kors et al 2001</a>]. Inheritance is autosomal dominant.</div></li><li class="half_rhythm"><div class="half_rhythm"><a href="/books/n/gene/sca6/?report=reader"><b>Spinocerebellar ataxia type 6</b></a>
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<b>(SCA6)</b> is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. SCA6 is associated with a CAG expansion in exon 47 of <i>CACNA1A</i> [<a class="bibr" href="#ea2.REF.zhuchenko.1997.62" rid="ea2.REF.zhuchenko.1997.62">Zhuchenko et al 1997</a>]. The normal number of CAG repeats ranges up to 18. Individuals with SCA6 have 20-33 CAG repeats [<a class="bibr" href="#ea2.REF.matsuyama.1997.1283" rid="ea2.REF.matsuyama.1997.1283">Matsuyama et al 1997</a>]. Inheritance is autosomal dominant.</div></li></ul><p>Their well-described phenotypes notwithstanding, clinical overlap exists among EA2, FHM, and SCA6, even within the same family.</p><ul><li class="half_rhythm"><div>In a family with EA2, affected members had hemiplegia, and one affected member had migraine during episodes of ataxia [<a class="bibr" href="#ea2.REF.jen.1999.34" rid="ea2.REF.jen.1999.34">Jen et al 1999</a>].</div></li><li class="half_rhythm"><div>In a study of 11 individuals with EA2 and documented heterozygous pathogenic variants in<i>CACNA1A</i>, four met International Headache Society (HIS) criteria for migraine, but none experienced hemiplegic migraine [<a class="bibr" href="#ea2.REF.mantuano.2004.e82" rid="ea2.REF.mantuano.2004.e82">Mantuano et al 2004</a>].</div></li><li class="half_rhythm"><div>Members of a Portuguese family with a pathogenic missense variant (A>G substitution) in <i>CACNA1A</i> had either hemiplegic migraine with or without cerebellar signs or permanent ataxia without migraines [<a class="bibr" href="#ea2.REF.alonso.2003.610" rid="ea2.REF.alonso.2003.610">Alonso et al 2003</a>].</div></li></ul><p>Individuals with SCA6 can present with episodic ataxia, mostly during the first years of the disorder. In one study, up to 33% of individuals with 21 or more CAG repeats in <i>CACNA1A</i> had episodic features prominent enough to warrant the diagnosis of EA2 [<a class="bibr" href="#ea2.REF.geschwind.1997.1247" rid="ea2.REF.geschwind.1997.1247">Geschwind et al 1997</a>]. In another family with a CAG repeat expansion, some members had episodic ataxia and others had progressive ataxia; in all affected members, the abnormal allele had 23 CAG repeats [<a class="bibr" href="#ea2.REF.jodice.1997.1973" rid="ea2.REF.jodice.1997.1973">Jodice et al 1997</a>].</p></div><div id="ea2.Differential_Diagnosis"><h2 id="_ea2_Differential_Diagnosis_">Differential Diagnosis</h2><p>Episodic ataxia can occur sporadically or in a number of hereditary disorders.</p><div id="ea2.Sporadic_Disorders"><h3>Sporadic Disorders</h3><p>Sporadic causes of episodic ataxia include multiple sclerosis, Arnold Chiari malformation, vertebral basilar insufficiency, basilar migraine, and labyrinthine abnormalities.</p></div><div id="ea2.Hereditary_Disorders"><h3>Hereditary Disorders</h3><p><b>Mitochondrial.</b> Disorders of mitochondrial oxidative metabolism result in a number of neurologic conditions that are associated with episodic ataxia.</p><ul><li class="half_rhythm"><div>The most common of these is <a href="/books/n/gene/pdc/?report=reader">pyruvate carboxylase deficiency</a>. The diagnosis of pyruvate carboxylase (PC) deficiency rests on analysis of amino acids and organic acids and detection of deficient PC enzyme activity measured in cultured fibroblasts. <i>PC</i> is the only gene in which mutation is known to cause PC deficiency.</div></li><li class="half_rhythm"><div>Pyruvate dehydrogenase deficiency (OMIM <a href="http://www.omim.org/entry/312170" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">312170</a>) may also present with episodic ataxia and is caused by hemizygous pathogenic variants in the gene encoding the E1-alpha subunit (<i>PDHA1</i>) in males or by a heterozygous pathogenic variant in <i>PDHA1</i> in a female. See <a href="/books/n/gene/mt-overview/?report=reader">Mitochondrial Diseases Overview</a>.</div></li></ul><p><b>X-linked.</b>
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<a href="/books/n/gene/otc-def/?report=reader">Ornithine transcarbamylase (OTC) deficiency</a> is an inborn error of metabolism of the urea cycle that causes hyperammonemia. Identification of a hemizygous pathogenic variant <i>OTC</i> in males can confirm the diagnosis. A heterozygous pathogenic variant in <i>OTC</i> in a female may lead to partial deficiency. Severely affected males die in the neonatal period and females have varying clinical manifestations ranging from no symptoms to severe deficits. Symptoms can include episodic extreme irritability (100%), episodic vomiting and lethargy (100%), protein avoidance (92%), ataxia (77%), stage II coma (46%), delayed growth (38%), developmental delay (38%), and seizures (23%). OTC deficiency is treatable with supplemental dietary arginine and a low-protein diet.</p><p>
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<b>Autosomal recessive</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Hyperammonemias caused by deficiencies of urea cycle enzymes</b> include carbamoylphosphate synthetase deficiency (OMIM <a href="http://www.omim.org/entry/237300" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">237300</a>), argininosuccinate synthetase deficiency (<a href="/books/n/gene/ctlm/?report=reader">citrullinemia type 1</a>), <a href="/books/n/gene/args-aciduria/?report=reader">argininosuccinase deficiency</a>, and <a href="/books/n/gene/arg1/?report=reader">arginase deficiency</a>. See <a href="/books/n/gene/ucd-overview/?report=reader">Urea Cycle Disorders Overview</a>.</div><div class="half_rhythm">The identification of a significantly elevated blood ammonia concentration requires immediate treatment by hemodialysis and by IV sodium phenylacetate/sodium benzoate; long-term treatment of urea cycle disorders generally includes a high-calorie, low-protein diet supplemented with essential amino acids.</div><div class="half_rhythm">The severe forms of the hyperammonemias present in the first few days of life with lethargy and possible focal and generalized seizures, ultimately leading to coma. The less severe forms develop in early childhood and are characterized by intermittent ataxia, dysarthria, vomiting, headache, ptosis, involuntary movements, seizures, and confusion. These episodes are precipitated by high protein loads and intercurrent illness. Children with argininosuccinase deficiency often have distinctive facial features and brittle hair.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Aminoacidurias,</b> including Hartnup disease, intermittent branched-chain ketoaciduria, and isovaleric acidemia, can be diagnosed by identification of increased levels of certain amino acids in plasma and increased excretion of amino acids in the urine.</div><ul><li class="half_rhythm"><div><b>Hartnup disease</b> (OMIM <a href="http://www.omim.org/entry/234500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">234500</a>) results from defective renal and intestinal transport of monoaminomonocarboxylic acids giving rise to intermittent ataxia, tremor, chorea, and psychiatric disturbances; intellectual disability; and pellagra-like rash. Episodes are triggered by exposure to sunlight, emotional stress, and sulfonamide drugs. Attacks last about two weeks, followed by relative normalcy. The frequency of attacks diminishes with maturation. Treatment is oral administration of nicotinamide.</div></li><li class="half_rhythm"><div><b>Intermittent branched-chain ketoaciduria</b> (OMIM <a href="http://www.omim.org/entry/248600" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">248600</a>) is characterized by intermittent transient ataxia, intellectual disability, physical developmental delay, feeding problems, and elevation of branched-chain amino acids and keto acids in the urine as well as a distinctive odor of maple syrup to the urine. This condition is treated by the elimination of branched-chain amino acids (leucine, isoleucine, valine) from the diet. A variant of this condition may be effectively treated with thiamine. See <a href="/books/n/gene/msud/?report=reader">Maple Syrup Urine Disease</a>.</div></li><li class="half_rhythm"><div><b>Isovaleric acidemia</b> (OMIM <a href="http://www.omim.org/entry/243500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">243500</a>) occurs in two forms. The acute neonatal form is associated with urine that has a sweaty foot odor and massive metabolic acidosis in the first days of life followed by rapid death. The chronic form is associated with periodic attacks of severe ketoacidosis between asymptomatic periods. Treatment consists of protein restriction and supplementation with glycine and carnitine.</div></li></ul></li></ul><p>
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<b>Autosomal dominant</b>
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</p><ul><li class="half_rhythm"><div><a href="/books/n/gene/ea1/?report=reader"><b>Episodic ataxia type 1</b></a>
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<b>(EA1)</b> is caused by heterozygous pathogenic variants in <i>KCNA1,</i> a potassium channel. EA1, also called ataxia with myokymia, is characterized by brief attacks (<15 minutes) of ataxia and dysarthria that can occur up to 15 times per day. Attacks can occur spontaneously or be triggered by anxiety, exercise, startle, and/or intercurrent illness. Onset is typically in late childhood and early adolescence; symptoms usually remit in the second decade. Between attacks, widespread myokymia of the face, hands, arms, and legs occurs [<a class="bibr" href="#ea2.REF.vandyke.1975.109" rid="ea2.REF.vandyke.1975.109">VanDyke et al 1975</a>, <a class="bibr" href="#ea2.REF.hanson.1977.120" rid="ea2.REF.hanson.1977.120">Hanson et al 1977</a>, <a class="bibr" href="#ea2.REF.gancher.1986.239" rid="ea2.REF.gancher.1986.239">Gancher & Nutt 1986</a>]. Electromyographic studies reveal myokymia (neuromyotonia). Phenytoin can control symptoms; acetazolamide is also effective [<a class="bibr" href="#ea2.REF.lubbers.1995.400" rid="ea2.REF.lubbers.1995.400">Lubbers et al 1995</a>].</div></li><li class="half_rhythm"><div><b>Episodic ataxia type 3 (EA3)</b> (OMIM <a href="http://www.omim.org/entry/606554" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606554</a>) has been described in a large Canadian Mennonite family [<a class="bibr" href="#ea2.REF.steckley.2001.1499" rid="ea2.REF.steckley.2001.1499">Steckley et al 2001</a>]. EA3 is characterized by brief acetazolamide-responsive attacks of vestibular ataxia, vertigo, tinnitus, and interictal myokymia. Interictal nystagmus and ataxia are not present. The age of onset is variable. The causative locus has been mapped to a 4 cM region on chromosome 1q42 between markers D1S2712 and D1S2678 [<a class="bibr" href="#ea2.REF.steckley.2001.1499" rid="ea2.REF.steckley.2001.1499">Steckley et al 2001</a>, <a class="bibr" href="#ea2.REF.cader.2005.156" rid="ea2.REF.cader.2005.156">Cader et al 2005</a>].</div></li><li class="half_rhythm"><div><b>Episodic ataxia type 4 (EA4)</b> (OMIM <a href="http://www.omim.org/entry/606552" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606552</a>) has been described in two families of European ancestry from rural North Carolina [<a class="bibr" href="#ea2.REF.farmer.1963.471" rid="ea2.REF.farmer.1963.471">Farmer & Mustian 1963</a>, <a class="bibr" href="#ea2.REF.vance.1984.78s" rid="ea2.REF.vance.1984.78s">Vance et al 1984</a>]. EA4 is characterized by attacks of vertigo, diplopia, and ataxia beginning in early adulthood. In some individuals, slowly progressive cerebellar ataxia occurs.</div></li><li class="half_rhythm"><div><b>Episodic ataxia type 5 (EA5)</b> (OMIM <a href="http://www.omim.org/entry/613855" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613855</a>) can result from a heterozygous pathogenic variant in <i>CACNB4,</i> which encodes the beta-4 isoform of the regulatory beta subunit of voltage-activated Ca(2+) channels. A p.Cys104Phe pathogenic variant has been described in a French-Canadian family [<a class="bibr" href="#ea2.REF.escayg.2000.1531" rid="ea2.REF.escayg.2000.1531">Escayg et al 2000</a>]. The phenotype was characterized by recurrent episodes of vertigo and ataxia that lasted for several hours. Interictal examination showed spontaneous downbeat and gaze-evoked nystagmus and mild dysarthria and truncal ataxia. Acetazolamide prevented the attacks.</div></li><li class="half_rhythm"><div><b>Episodic ataxia type 6 (EA6)</b> (OMIM <a href="http://www.omim.org/entry/612656" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612656</a>) results from heterozygous pathogenic variants in <i>SLC1A3</i> (OMIM <a href="http://www.omim.org/entry/600111" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">600111</a>; see .0002). Cellular studies showed that the pathogenic variant results in decreased glutamate uptake [<a class="bibr" href="#ea2.REF.jen.2005.529" rid="ea2.REF.jen.2005.529">Jen et al 2005</a>, <a class="bibr" href="#ea2.REF.de_vries.2009.97" rid="ea2.REF.de_vries.2009.97">de Vries et al 2009</a>]. The phenotype correlates with the extent of glutamate transporter dysfunction [deVries et al 2009] and, as a result, the phenotype is quite variable. <a class="bibr" href="#ea2.REF.jen.2005.529" rid="ea2.REF.jen.2005.529">Jen et al [2005]</a> reported a boy age ten years with a severe form of episodic ataxia with seizures, migraine, and alternating hemiplegia triggered by febrile illness. There was interictal truncal ataxia. In contrast, <a class="bibr" href="#ea2.REF.de_vries.2009.97" rid="ea2.REF.de_vries.2009.97">de Vries et al [2009]</a> reported a Dutch family with onset in the first or second decade and attacks of ataxia lasting two to three hours associated with nausea, vomiting, photophobia, phonophobia, vertigo, diplopia, and/or slurred speech. Headaches were not a prominent feature and there was no interictal truncal ataxia. Attacks were provoked by emotional stress, fatigue, or consumption of alcohol or caffeine. The attacks could be reduced with acetazolamide.</div></li><li class="half_rhythm"><div><b>Episodic ataxia type 7 (EA7)</b> (OMIM <a href="http://www.omim.org/entry/611907" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">611907</a>) has been linked to a 10-cM candidate region, between <a href="http://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1366444;expand=HGVS_names" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs1366444</a> and <a href="http://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs952108;expand=HGVS_names" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs952108</a> on chromosome 19q13 (maximum lod score of 3.28). No pathogenic variants were identified in <i>KCNC3</i> (OMIM <a href="http://www.omim.org/entry/176264" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">176264</a>) or <i>SLC17A7</i> (OMIM <a href="http://www.omim.org/entry/605208" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">605208</a>). The phenotype was characterized by onset before age 20 years, attacks lasting hours to days, and associated weakness and dysarthria. Triggers included exercise and excitement. Two affected family members reported vertigo during attacks. Frequency ranged from monthly to yearly and tended to decrease with age. Two affected family members had migraine headaches that were not associated with episodic ataxia. No interictal findings were observed on neurologic examination [<a class="bibr" href="#ea2.REF.kerber.2007.749" rid="ea2.REF.kerber.2007.749">Kerber et al 2007</a>].</div></li><li class="half_rhythm"><div><a href="/books/n/gene/sca6/?report=reader"><b>Spinocerebellar ataxia type 6</b></a>
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<b>(SCA6)</b> (See also <a href="#ea2.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>.)</div></li></ul><p>See <a href="http://omim.org/phenotypicSeries/PS160120" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Episodic ataxia: OMIM Phenotypic Series</a> to view genes associated with this phenotype in OMIM.</p></div></div><div id="ea2.Management"><h2 id="_ea2_Management_">Management</h2><div id="ea2.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with episodic ataxia type 2 (EA2), the following evaluations are recommended:</p><ul><li class="half_rhythm"><div>Neurologic examination for signs of interictal ataxia and nystagmus</div></li><li class="half_rhythm"><div>Neuroimaging of the head (if not performed already), preferably MRI, to evaluate for structural lesions and to look for evidence of atrophy</div></li><li class="half_rhythm"><div>Consultation with a clinical geneticist and/or genetic counselor</div></li></ul></div><div id="ea2.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p><b>Acetazolamide</b> is effective in controlling or reducing the frequency and severity of attacks in two thirds of individuals with EA2 [<a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>, <a class="bibr" href="#ea2.REF.ilg.2014.248" rid="ea2.REF.ilg.2014.248">Ilg et al 2014</a>]. The typical starting dose is 125 mg/day given orally, but doses as high as 500 mg/2x/day may be required. This medication is generally well tolerated; the most common side effects are paresthesias of the extremities, rash, and renal calculi.</p><p><b>4-aminopyridine,</b> a potassium channel blocker, also reduces attack frequency and duration at doses of 5-10 mg/3x/day [<a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>, <a class="bibr" href="#ea2.REF.strupp.2011.269" rid="ea2.REF.strupp.2011.269">Strupp et al 2011</a>].</p><p>Generally acetazolomide is used as the firstline therapy, although there are no specific recommendations regarding which medication should be trialed first [<a class="bibr" href="#ea2.REF.ilg.2014.248" rid="ea2.REF.ilg.2014.248">Ilg et al 2014</a>].</p></div><div id="ea2.Prevention_of_Primary_Manifestations"><h3>Prevention of Primary Manifestations</h3><p>Treatment with acetazolamide does not appear to prevent the progression of interictal symptoms [<a class="bibr" href="#ea2.REF.baloh.1991.429" rid="ea2.REF.baloh.1991.429">Baloh & Winder 1991</a>]. It is not clear how acetazolamide prevents attacks of EA2, although <a class="bibr" href="#ea2.REF.yue.1997.1078" rid="ea2.REF.yue.1997.1078">Yue et al [1997]</a> speculated that the mechanism involves a decrease in pH, thus inhibiting ion permeation through open calcium channels. Acetazolamide could stabilize channels that fail to properly inactivate. Acetazolamide may not work in some individuals, particularly if the pathogenic variant distorts the pore region of the channel, altering the stabilizing effect of H+ ions.</p><p>To date no data regarding whether 4-aminopyridine can prevent the progression of interictal symptoms are available.</p></div><div id="ea2.Surveillance"><h3>Surveillance</h3><p>Surveillance should include annual neurologic examination.</p></div><div id="ea2.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Phenytoin has been reported to exacerbate symptoms.</p></div><div id="ea2.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#ea2.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="ea2.Pregnancy_Management"><h3>Pregnancy Management</h3><p>There is limited published literature addressing the management of the pregnancy of an affected woman or the effect of maternal EA2 on a fetus. However, because physical exertion can trigger attacks, it would be prudent for a pregnant woman to be followed closely by her obstetrician and at term to undergo a trial of labor with the intent to proceed to delivery by C-section should the labor trigger an EA2 attack [<a class="bibr" href="#ea2.REF.spacey.2012.s3" rid="ea2.REF.spacey.2012.s3">Spacey 2012</a>].</p></div><div id="ea2.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><a class="bibr" href="#ea2.REF.scoggan.2006.68" rid="ea2.REF.scoggan.2006.68">Scoggan et al [2006]</a> reported an individual who responded to a combination of acetazolamide and valproic acid.</p><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="http://www.ClinicalTrialsRegister.eu" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.ClinicalTrialsRegister.eu</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="ea2.Genetic_Counseling"><h2 id="_ea2_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="ea2.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Episodic ataxia type 2 (EA2) is inherited in an autosomal dominant manner.</p></div><div id="ea2.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with EA2 have an affected parent.</div></li><li class="half_rhythm"><div>A proband with EA2 may have the disorder as the result of a <i>de novo</i>
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<i>CACNA1A</i> pathogenic variant. The proportion of cases caused by a <i>de novo</i> pathogenic variant is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient.</div></li><li class="half_rhythm"><div>If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a <i>de novo</i> pathogenic variant in the proband or germline mosaicism in a parent Although no instances of germline mosaicism have been reported, it remains a possibility.</div></li><li class="half_rhythm"><div>Recommendations for the evaluation of parents of a proband with an apparent <i>de novo</i> pathogenic variant include neurologic examination, head MRI, and EMG.</div></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with EA2 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to the sibs of a proband depends on the genetic status of the proband's parents.</div></li><li class="half_rhythm"><div>If a parent of a proband is affected, the risk to the sibs is 50%.</div></li><li class="half_rhythm"><div>Since EA2 demonstrates incomplete penetrance, a clinically unaffected parent may have a heterozygous <i>CACNA1A</i> pathogenic variant and the sibs of the proband may still be at 50% risk.</div></li><li class="half_rhythm"><div>If the <i>CACNA1A</i> pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has not been reported to date.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with EA2 has a 50% chance of inheriting the <i>CACNA1A</i> pathogenic variant. Since EA2 demonstrates incomplete penetrance, it is not possible to predict the age of onset, symptoms, or progression of disease in an individual.</p><p><b>Other family members.</b> The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected or has the pathogenic variant, his or her family members may be at risk.</p></div><div id="ea2.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p><b>Considerations in families with an apparent <i>de novo</i> pathogenic variant.</b> When neither parent of a proband with EA2 has the pathogenic variant or clinical evidence of the disorder, the <i>CACNA1A</i> pathogenic variant is likely <i>de novo</i>. However, other possible non-medical explanations that could be explored include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul><p><b>DNA banking</b> is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.</p></div><div id="ea2.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Diagnosis</h3><p>Once the <i>CACNA1A</i> pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for EA2 are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.</p></div></div><div id="ea2.Resources"><h2 id="_ea2_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>euro-ATAXIA (European Federation of Hereditary Ataxias)</b>
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</div><div>Ataxia UK</div><div>Lincoln House, Kennington Park, 1-3 Brixton Road</div><div>London SW9 6DE</div><div>United Kingdom</div><div><b>Phone:</b> +44 (0) 207 582 1444</div><div><b>Email:</b> smillman@ataxia.org.uk</div><div>
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<a href="https://www.euroataxia.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.euroataxia.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Ataxia Foundation</b>
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</div><div>2600 Fernbrook Lane</div><div>Suite 119</div><div>Minneapolis MN 55447</div><div><b>Phone:</b> 763-553-0020</div><div><b>Email:</b> naf@ataxia.org</div><div>
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<a href="http://www.ataxia.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.ataxia.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing</b>
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</div><div>
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<i>Booklet providing information about Spinocerebellar Ataxia</i>
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</div><div>
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<a href="http://depts.washington.edu/neurolog/images/neurogenetics/ataxia.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">depts.washington.edu/neurolog/images/neurogenetics/ataxia.pdf</a>
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</div></li><li class="half_rhythm"><div>
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<b>CoRDS Registry</b>
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</div><div>Sanford Research</div><div>2301 East 60th Street North</div><div>Sioux Falls SD 57104</div><div><b>Phone:</b> 605-312-6423</div><div><b>Email:</b> sanfordresearch@sanfordhealth.org</div><div>
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<a href="http://www.sanfordresearch.org/SpecialPrograms/cords/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CoRDS Registry</a>
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</div></li></ul>
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</div><div id="ea2.Molecular_Genetics"><h2 id="_ea2_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figea2molgenTA"><a href="/books/NBK1501/table/ea2.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobea2molgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="ea2.molgen.TA"><a href="/books/NBK1501/table/ea2.molgen.TA/?report=objectonly" target="object" rid-ob="figobea2molgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Episodic Ataxia Type 2: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figea2molgenTB"><a href="/books/NBK1501/table/ea2.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobea2molgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="ea2.molgen.TB"><a href="/books/NBK1501/table/ea2.molgen.TB/?report=objectonly" target="object" rid-ob="figobea2molgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Episodic Ataxia Type 2 (View All in OMIM) </p></div></div><p><b>Gene structure.</b> Multiple transcript variants encoding different isoforms have been found for <i>CACNA1A</i>. The variant <a href="/nuccore/NM_023035.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_023035.2</a> represents the longest transcript and encodes the longest isoform <a href="/protein/NP_075461.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_075461.2</a>. The transcript <a href="/nuccore/NM_023035.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_023035.2</a> consists of 48 exons and includes a (CAG)n-repeat in the coding region, resulting in a polyglutamine tract near the C-terminus. For a detailed summary of gene and protein information, see <a href="/books/NBK1501/?report=reader#ea2.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> More than 50 different <i>CACNA1A</i> pathogenic variants associated with EA2 have been described [<a class="bibr" href="#ea2.REF.ophoff.1996.543" rid="ea2.REF.ophoff.1996.543">Ophoff et al 1996</a>, <a class="bibr" href="#ea2.REF.yue.1997.1078" rid="ea2.REF.yue.1997.1078">Yue et al 1997</a>, <a class="bibr" href="#ea2.REF.yue.1998.298" rid="ea2.REF.yue.1998.298">Yue et al 1998</a>, <a class="bibr" href="#ea2.REF.denier.1999.1816" rid="ea2.REF.denier.1999.1816">Denier et al 1999</a>, <a class="bibr" href="#ea2.REF.friend.1999.261" rid="ea2.REF.friend.1999.261">Friend et al 1999</a>, <a class="bibr" href="#ea2.REF.denier.2001.292" rid="ea2.REF.denier.2001.292">Denier et al 2001</a>, <a class="bibr" href="#ea2.REF.van_den_maagdenberg.2002.1515" rid="ea2.REF.van_den_maagdenberg.2002.1515">van den Maagdenberg et al 2002</a>, <a class="bibr" href="#ea2.REF.matsuyama.2003.91" rid="ea2.REF.matsuyama.2003.91">Matsuyama et al 2003</a>, <a class="bibr" href="#ea2.REF.subramony.2003.725" rid="ea2.REF.subramony.2003.725">Subramony et al 2003</a>, <a class="bibr" href="#ea2.REF.jen.2004.17" rid="ea2.REF.jen.2004.17">Jen et al 2004</a>, <a class="bibr" href="#ea2.REF.kaunisto.2004.69" rid="ea2.REF.kaunisto.2004.69">Kaunisto et al 2004</a>, <a class="bibr" href="#ea2.REF.mantuano.2004.e82" rid="ea2.REF.mantuano.2004.e82">Mantuano et al 2004</a>, <a class="bibr" href="#ea2.REF.spacey.2004.213" rid="ea2.REF.spacey.2004.213">Spacey et al 2004</a>, <a class="bibr" href="#ea2.REF.spacey.2005.314" rid="ea2.REF.spacey.2005.314">Spacey et al 2005</a>, <a class="bibr" href="#ea2.REF.mantuano.2010.30" rid="ea2.REF.mantuano.2010.30">Mantuano et al 2010</a>, <a class="bibr" href="#ea2.REF.nachbauer.2014.983" rid="ea2.REF.nachbauer.2014.983">Nachbauer et al 2014</a>].</p><ul><li class="half_rhythm"><div>The majority of the pathogenic variants in <i>CACNA1A</i> are nonsense or small insertion and/or deletion (indel) variants that disrupt the open reading frame leading to truncation of the protein. Intronic variants that presumably disrupt the reading frame through abnormal splicing (exon skipping or intron inclusion) of the gene product have also been reported [<a class="bibr" href="#ea2.REF.eunson.2005.308" rid="ea2.REF.eunson.2005.308">Eunson et al 2005</a>, <a class="bibr" href="#ea2.REF.wan.2005.131" rid="ea2.REF.wan.2005.131">Wan et al 2005</a>]. However, 21 <i>CACNA1A</i> pathogenic variants do not disrupt the reading frame, including 18 pathogenic missense variants resulting in substitutions of conserved amino acids mostly located in the pore regions of the channel [<a class="bibr" href="#ea2.REF.pietrobon.2010.375" rid="ea2.REF.pietrobon.2010.375">Pietrobon 2010</a>]. A number of pathogenic non-truncating variants that appear to cluster in the S5-S6 linkers and their borders have also been described [<a class="bibr" href="#ea2.REF.mantuano.2004.e82" rid="ea2.REF.mantuano.2004.e82">Mantuano et al 2004</a>, <a class="bibr" href="#ea2.REF.spacey.2004.213" rid="ea2.REF.spacey.2004.213">Spacey et al 2004</a>].</div></li><li class="half_rhythm"><div>Large-scale exon deletions or duplications involving one or more exons in <i>CACNA1A</i> have been reported in several families with EA2 [<a class="bibr" href="#ea2.REF.labrum.2009.786" rid="ea2.REF.labrum.2009.786">Labrum et al 2009</a>, <a class="bibr" href="#ea2.REF.riant.2010.101" rid="ea2.REF.riant.2010.101">Riant et al 2010</a>]. The rearrangements are likely to be pathogenic given their segregation with the disease in large families with EA2.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figea2Tcacna1avariantsdiscussedinthis"><a href="/books/NBK1501/table/ea2.T.cacna1a_variants_discussed_in_this/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobea2Tcacna1avariantsdiscussedinthis"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="ea2.T.cacna1a_variants_discussed_in_this"><a href="/books/NBK1501/table/ea2.T.cacna1a_variants_discussed_in_this/?report=objectonly" target="object" rid-ob="figobea2Tcacna1avariantsdiscussedinthis">Table 2. </a></h4><p class="float-caption no_bottom_margin"><i>CACNA1A</i> Variants Discussed in This <i>GeneReview</i> </p></div></div><p><b>Normal gene product.</b>
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<i>CACNA1A</i> encodes an α<sub>1A</sub> subunit that serves as the pore-forming subunit of a voltage-dependent P/Q-type calcium channel [<a class="bibr" href="#ea2.REF.hofmann.1994.399" rid="ea2.REF.hofmann.1994.399">Hofmann et al 1994</a>, <a class="bibr" href="#ea2.REF.greenberg.1997.275" rid="ea2.REF.greenberg.1997.275">Greenberg 1997</a>]. Voltage-dependent calcium channels are made up of the pore-forming alpha1 subunit and accessory subunits alpha2-delta, beta, and gamma. The α<sub>1A</sub> subunits are membrane glycoproteins of approximately 2400 amino acids in length in which primary structure predicts the presence of four homologous domains, each consisting of six transmembrane domains and a pore-forming P loop. P/Q-type calcium channels are high voltage-activated calcium channels that are found primarily on neurons and are expressed at high levels in granule cells and Purkinje cells of the cerebellar cortex. Their principal role is believed to be in synaptic transmission. The <a href="/protein/NP_075461.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_075461.2</a> isoform has 2512 amino acids. The function of the different <i>CACNA1A</i> isoforms remains to be demonstrated, although differences have been measured in phosphorylation acceptor sites [<a class="bibr" href="#ea2.REF.sakurai.1996.511" rid="ea2.REF.sakurai.1996.511">Sakurai et al 1996</a>].</p><p><b>Abnormal gene product.</b> Pathogenic variants in <i>CACNA1A</i> appear to cause a loss of function.</p></div><div id="ea2.References"><h2 id="_ea2_References_">References</h2><div id="ea2.Published_Guidelines__Consensus_Stat"><h3>Published Guidelines / Consensus Statements</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF1">American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available <a href="http://jco.ascopubs.org/content/28/5/893.long" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a>. 2010. Accessed 4-13-18.</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF2">National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available <a href="https://www.nsgc.org/Policy-Research-and-Publications/Position-Statements/Position-Statements/Post/genetic-testing-of-minors-for-adult-onset-conditions" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">online</a>. 2012. Accessed 4-13-18.</div></p></li></ul></div><div id="ea2.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ea2.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. <span><span class="ref-journal">Arch Neurol. </span>2003;<span class="ref-vol">60</span>:610–4.</span> [<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></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.bain.1992.147">Bain PG, O'Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. <span><span class="ref-journal">Ann Neurol. </span>1992;<span class="ref-vol">31</span>:147–54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1575453" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1575453</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.baloh.1991.429">Baloh RW, Winder A. Acetazolamide-responsive vestibulocerebellar syndrome: clinical and oculographic features. <span><span class="ref-journal">Neurology. </span>1991;<span class="ref-vol">41</span>:429–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2006014" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2006014</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.baloh.1997.8">Baloh RW, Yue Q, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. <span><span class="ref-journal">Ann Neurol. </span>1997;<span class="ref-vol">41</span>:8–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9005860" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9005860</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.cader.2005.156">Cader MZ, Steckley JL, Dyment DA, McLachlan RS, Ebers GC. A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia. <span><span class="ref-journal">Neurology. </span>2005;<span class="ref-vol">65</span>:156–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16009908" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16009908</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.de_fusco.2003.192">De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. <span><span class="ref-journal">Nat Genet. </span>2003;<span class="ref-vol">33</span>:192–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12539047" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12539047</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.de_vries.2009.97">de Vries B, Mamsa H, Stam AH, Wan J, Bakker SL, Vanmolkot KR, Haan J, Terwindt GM, Boon EM, Howard BD, Frants RR, Baloh RW, Ferrari MD, Jen JC, van den Maagdenberg AM. Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. <span><span class="ref-journal">Arch Neurol. </span>2009;<span class="ref-vol">66</span>:97–101.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19139306" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19139306</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.denier.2001.292">Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E. Missense CACNA1A mutation causing episodic ataxia type 2. <span><span class="ref-journal">Arch Neurol. </span>2001;<span class="ref-vol">58</span>:292–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11176968" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11176968</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.denier.1999.1816">Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, Castelnovo G, Deonna T, Gerard P, Devoize JL, Gayou A, Perrouty B, Soisson T, Autret A, Warter JM, Vighetto A, Van Bogaert P, Alamowitch S, Roullet E, Tournier-Lasserve E. High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. <span><span class="ref-journal">Neurology. </span>1999;<span class="ref-vol">52</span>:1816–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10371528" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10371528</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.dichgans.2005.371">Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. <span><span class="ref-journal">Lancet. </span>2005;<span class="ref-vol">366</span>:371–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16054936" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16054936</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.ducros.2001.17">Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser MG, Tournier-Lasserve E. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. <span><span class="ref-journal">N Engl J Med. </span>2001;<span class="ref-vol">345</span>:17–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11439943" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11439943</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.ducros.1999.89">Ducros A, Denier C, Joutel A, Vahedi K, Michel A, Darcel F, Madigand M, Guerouaou D, Tison F, Julien J, Hirsch E, Chedru F, Bisgard C, Lucotte G, Despres P, Billard C, Barthez MA, Ponsot G, Bousser MG, Tournier-Lasserve E. Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. <span><span class="ref-journal">Am J Hum Genet. </span>1999;<span class="ref-vol">64</span>:89–98.</span> [<a href="/pmc/articles/PMC1377706/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1377706</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9915947" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9915947</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.escayg.2000.1531">Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, Johnston J, Baloh R, Sander T, Meisler MH. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. <span><span class="ref-journal">Am J Hum Genet. </span>2000;<span class="ref-vol">66</span>:1531–9.</span> [<a href="/pmc/articles/PMC1378014/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1378014</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10762541" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10762541</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.eunson.2005.308">Eunson LH, Graves TD, Hanna MG. New calcium channel mutations predict aberrant RNA splicing in episodic ataxia. <span><span class="ref-journal">Neurology. </span>2005;<span class="ref-vol">65</span>:308–10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16043807" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16043807</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.farmer.1963.471">Farmer TW, Mustian VM. Vestibulo-cerebellar ataxia: a newly defined hereditary syndrome with periodic manifestations. <span><span class="ref-journal">Arch Neurol. </span>1963;<span class="ref-vol">8</span>:471–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/13944410" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 13944410</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.friend.1999.261">Friend KL, Crimmins D, Phan TG, Sue CM, Colley A, Fung VS, Morris JG, Sutherland GR, Richards RI. Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. <span><span class="ref-journal">Hum Genet. </span>1999;<span class="ref-vol">105</span>:261–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10987655" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10987655</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.gancher.1986.239">Gancher ST, Nutt JG. Autosomal dominant episodic ataxia: a heterogeneous syndrome. <span><span class="ref-journal">Mov Disord. </span>1986;<span class="ref-vol">1</span>:239–53.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3504247" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3504247</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.gasser.2010.179">Gasser T, Finsterer J, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schöls L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Harbo HF, et al. EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. <span><span class="ref-journal">Eur J Neurol. </span>2010;<span class="ref-vol">17</span>:179–88.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20050888" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20050888</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.geschwind.1997.1247">Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM. Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. <span><span class="ref-journal">Neurology. </span>1997;<span class="ref-vol">49</span>:1247–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9371902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9371902</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.greenberg.1997.275">Greenberg DA. Calcium channels in neurological disease. <span><span class="ref-journal">Ann Neurol. </span>1997;<span class="ref-vol">42</span>:275–82.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9307247" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9307247</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.hanson.1977.120">Hanson PA, Martinez LB, Cassidy R. 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Mapping the gene for acetazolamide responsive hereditary paryoxysmal cerebellar ataxia to chromosome 19p. <span><span class="ref-journal">Hum Mol Genet. </span>1995;<span class="ref-vol">4</span>:279–84.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7757080" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7757080</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.wan.2005.131">Wan J, Carr JR, Baloh RW, Jen JC. Nonconsensus intronic mutations cause episodic ataxia. <span><span class="ref-journal">Ann Neurol. </span>2005;<span class="ref-vol">57</span>:131–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15622542" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15622542</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.yue.1997.1078">Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium-channel gene. <span><span class="ref-journal">Am J Hum Genet. </span>1997;<span class="ref-vol">61</span>:1078–87.</span> [<a href="/pmc/articles/PMC1716037/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1716037</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9345107" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9345107</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.yue.1998.298">Yue Q, Jen JC, Thwe MM, Nelson SF, Baloh RW. De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia. <span><span class="ref-journal">Am J Med Genet. </span>1998;<span class="ref-vol">77</span>:298–301.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9600739" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9600739</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ea2.REF.zhuchenko.1997.62">Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. <span><span class="ref-journal">Nat Genet. </span>1997;<span class="ref-vol">15</span>:62–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8988170" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8988170</span></a>]</div></p></li></ul></div></div><div id="ea2.Chapter_Notes"><h2 id="_ea2_Chapter_Notes_">Chapter Notes</h2><div id="ea2.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>22 October 2020 (ma) Chapter retired: extremely rare</div></li><li class="half_rhythm"><div>15 October 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>8 December 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>30 June 2009 (cd) Revision: <i>CACNB4</i> mutations associated with episodic ataxia type 5</div></li><li class="half_rhythm"><div>24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for CACNA1A</div></li><li class="half_rhythm"><div>17 December 2007 (cd) Revision: prenatal testing available for CACNA1A-related EA2</div></li><li class="half_rhythm"><div>12 April 2007 (me) Comprehensive update posted to live Web site</div></li><li class="half_rhythm"><div>21 January 2005 (me) Comprehensive update posted to live Web site</div></li><li class="half_rhythm"><div>29 December 2003 (me) Revision: change in test availability</div></li><li class="half_rhythm"><div>24 February 2003 (me) Review posted to live Web site</div></li><li class="half_rhythm"><div>20 August 2002 (ss) Original submission</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1501_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Sian Spacey</span>, MD<div class="affiliation small">Division of Neurology<br />University of British Columbia<br />Vancouver, British Columbia, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.cbu.liam@yecaps" class="oemail">ac.cbu.liam@yecaps</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">February 24, 2003</span>; Last Update: <span itemprop="dateModified">October 15, 2015</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Spacey S. Episodic Ataxia Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2003 Feb 24 [Updated 2015 Oct 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/ea1/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/epp-ar/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobea2Tmoleculargenetictestingusedin"><div id="ea2.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 Episodic Ataxia Type 2</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1501/table/ea2.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ea2.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ea2.T.molecular_genetic_testing_used_in_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_ea2.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Test Method</th><th id="hd_h_ea2.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by This Method</th></tr></thead><tbody><tr><td headers="hd_h_ea2.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" 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_ea2.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_ea2.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>95% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_ea2.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_ea2.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>7</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="ea2.TF.1.1"><p class="no_margin">See <a href="/books/NBK1501/?report=reader#ea2.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="ea2.TF.1.2"><p class="no_margin">See <a href="#ea2.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="ea2.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="ea2.TF.1.4"><p class="no_margin">In families linked to chromosome 19</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="ea2.TF.1.5"><p class="no_margin">Sequence analysis has identified a number of <i>CACNA1A</i> pathogenic variants [<a class="bibr" href="#ea2.REF.yue.1998.298" rid="ea2.REF.yue.1998.298">Yue et al 1998</a>, <a class="bibr" href="#ea2.REF.friend.1999.261" rid="ea2.REF.friend.1999.261">Friend et al 1999</a>, <a class="bibr" href="#ea2.REF.denier.2001.292" rid="ea2.REF.denier.2001.292">Denier et al 2001</a>]. In the study of <a class="bibr" href="#ea2.REF.jen.2004.17" rid="ea2.REF.jen.2004.17">Jen et al [2004]</a>, nine (82%) of 11 families with episodic ataxia showed linkage to 19p; pathogenic variants in <i>CACNA1A</i> were identified in all nine families. In the same study, four of nine simplex cases (i.e., individuals with no family history of EA2) had identifiable <i>CACNA1A</i> pathogenic variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="ea2.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="ea2.TF.1.7"><p class="no_margin">Partial <i>CACNA1A</i> deletions and duplications have been described [<a class="bibr" href="#ea2.REF.labrum.2009.786" rid="ea2.REF.labrum.2009.786">Labrum et al 2009</a>, <a class="bibr" href="#ea2.REF.rajakulendran.2010.1905" rid="ea2.REF.rajakulendran.2010.1905">Rajakulendran et al 2010</a>, <a class="bibr" href="#ea2.REF.riant.2010.101" rid="ea2.REF.riant.2010.101">Riant et al 2010</a>]; however, no data on the overall detection rate of gene-targeted deletion/duplication analysis are available.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobea2molgenTA"><div id="ea2.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Episodic Ataxia Type 2: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1501/table/ea2.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ea2.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_ea2.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_ea2.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_ea2.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_ea2.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_ea2.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_ea2.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_ea2.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/773" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>CACNA1A</i>
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</a>
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</td><td headers="hd_b_ea2.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<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>
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</td><td headers="hd_b_ea2.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<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>
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</td><td headers="hd_b_ea2.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<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>
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</td><td headers="hd_b_ea2.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CACNA1A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CACNA1A</a>
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</td><td headers="hd_b_ea2.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=CACNA1A[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CACNA1A</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ea2.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobea2molgenTB"><div id="ea2.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Episodic Ataxia Type 2 (<a href="/omim/108500,601011" 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/NBK1501/table/ea2.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ea2.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/108500" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">108500</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EPISODIC ATAXIA, TYPE 2; EA2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<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></tbody></table></div></div></article><article data-type="table-wrap" id="figobea2Tcacna1avariantsdiscussedinthis"><div id="ea2.T.cacna1a_variants_discussed_in_this" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>CACNA1A</i> Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1501/table/ea2.T.cacna1a_variants_discussed_in_this/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ea2.T.cacna1a_variants_discussed_in_this_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.3841C>T <sup>1</sup></td><td headers="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg1281Ter</td><td headers="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/nuccore/NM_023035.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_023035<wbr style="display:inline-block"></wbr>​.2</a>
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<br />
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<a href="/protein/NP_075461.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_075461<wbr style="display:inline-block"></wbr>​.2</a>
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</td></tr><tr><td headers="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.4217T>G <sup>1</sup></td><td headers="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Phe1406Cys</td></tr><tr><td headers="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.4645C>T <sup>1</sup></td><td headers="hd_h_ea2.T.cacna1a_variants_discussed_in_this_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg1549Ter</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Note on variant classification: 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></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Note on nomenclature: <i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="http://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="ea2.TF.2.1"><p class="no_margin">Associated with fluctuating weakness manifesting as a myasthenic syndrome in individuals with EA2 [<a class="bibr" href="#ea2.REF.jen.2001.1843" rid="ea2.REF.jen.2001.1843">Jen et al 2001</a>]. See <a href="#ea2.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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