Episodic ataxia is a genetically heterogeneous neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia. Episodic ataxia type 2 is the most common form of EA (Jen et al., 2007).
Parker (1946) may have been the first to describe this disorder. Hill and Sherman (1968) described episodic cerebellar ataxia occurring particularly in children in a large kindred with an autosomal dominant pattern of inheritance. The symptoms ameliorated in ... Parker (1946) may have been the first to describe this disorder. Hill and Sherman (1968) described episodic cerebellar ataxia occurring particularly in children in a large kindred with an autosomal dominant pattern of inheritance. The symptoms ameliorated in later life with no permanent or progressive cerebellar abnormalities. The cases presented by White (1969) showed gradual abatement of symptoms. Donat and Auger (1979) reported ataxia in a 16-year-old boy and his 41-year-old mother, both of whom had 'downbeating nystagmus' of the eyes when in the primary position of gaze. The attacks of dizziness, which began at the age of 9 in the boy, were relieved with acetazolamide. Koller and Bahamon-Dussan (1987) reported a family with affected individuals in 3 generations, including 1 instance of male-to-male transmission. Stress or emotion precipitated attacks. Examination between attacks showed nystagmus, but no other neurologic signs. After adolescence, there was no progression of symptoms. The authors found, as have others (e.g., Zasorin et al., 1983), that acetazolamide therapy successfully abolished the attacks. This disorder may have first been recognized by Parker (1946). Vighetto et al. (1988) indicated that 15 kindreds had been reported. They were the first to report selective atrophy of the cerebellar vermis in all 3 members of 2 affected families that were studied by magnetic resonance imaging. In the family reported by Boel and Casaer (1988), all affected members had their first attacks before the age of 10 and the symptoms usually disappeared during the second decade of life. Ataxia was precipitated by stressful classroom situations or exciting football or tennis contests. Ataxia usually lasted 3 to 8 minutes with no loss of consciousness but was followed by a period of fatigue which often lasted for more than an hour. Bain et al. (1992) reported that in 6 affected members of 2 unrelated families with familial periodic cerebellar ataxia, symptoms were relieved with oral acetazolamide. When untreated, all subjects showed abnormal intracellular pH levels in the cerebellum by (31)P nuclear magnetic resonance (NMR) spectroscopy. These levels returned to normal with treatment. In 1 family studied, cerebral pH values were normal before and after treatment. In 3 additional patients with similar attacks, but without a family history, normal pH values were found in both cerebellum and cerebrum. In the 2 families reported by von Brederlow et al. (1995), physical and emotional stress was the most consistent precipitating factor, although attacks were also triggered occasionally by carbohydrate-rich meals. Attacks lasted between one-half hour and 6 hours. Typical attacks were observed in children as young as age 2 to 5 years, although onset was more common in the second decade. Frequency of the episodes ranged from 3 to 4 times per week to 1 to 2 times per year. Symptoms were fully controlled with acetazolamide. Attacks recurred promptly within 48 to 72 hours upon cessation of medication. Subramony et al. (2003) reported a family with autosomal dominant episodic ataxia type 2 confirmed by mutation in the CACNA1A gene. Nine of 11 affected patients reported that fever or heat triggered ataxic episodes, headaches, weakness, vertigo, or nausea and vomiting. Six patients showed interictal cerebellar deficits. Spacey et al. (2005) reported 2 unrelated patients with EA2 confirmed by genetic analysis who developed dystonia late in the disease, at ages 59 and 47 years, respectively. The authors suggested that dystonia may be a manifestation of a degenerative cerebellar process. Imbrici et al. (2005) reported an Indian man with late-onset EA2 beginning at age 61, followed by a progressive cerebellar syndrome at age 62. The patient's medical history included juvenile-onset complex partial seizures and depression but no headaches. Molecular analysis confirmed a mutation in the CACNA1A gene in the patient and in his asymptomatic son. Imbrici et al. (2005) emphasized the unusual clinical presentation.
Jen et al. (2004) identified a total of 13 mutations in the CACNA1A gene in 9 of 11 families with EA2 showing linkage to chromosome 19p, and in 4 of 9 sporadic cases of EA2. Mutations were identified ... Jen et al. (2004) identified a total of 13 mutations in the CACNA1A gene in 9 of 11 families with EA2 showing linkage to chromosome 19p, and in 4 of 9 sporadic cases of EA2. Mutations were identified in a total of 46 affected and 8 unaffected family members, demonstrating incomplete penetrance. Almost all of the mutation carriers reported episodic ataxia, except 2 related patients who reported only progressive ataxia. Onset was before age 20 years in all cases except 1 with reported ataxia at age 30. Migraine headaches occurred in 24 of 40 mutation carriers, and 15 of 21 treated patients reported good response to acetazolamide. Four patients had episodes of hemiplegia. The mutations were scattered throughout the gene, and there were no obvious genotype/phenotype correlations. Jen et al. (2004) noted the phenotypic overlap between disorders caused by mutations in the CACNA1A gene.
In a family initially classified as autosomal dominant cerebellar ataxia of unknown type, Jodice et al. (1997) found that an intergenerational allele size change showed that a (CAG)20 allele (601011.0008) was associated with an EA2 phenotype and a ... In a family initially classified as autosomal dominant cerebellar ataxia of unknown type, Jodice et al. (1997) found that an intergenerational allele size change showed that a (CAG)20 allele (601011.0008) was associated with an EA2 phenotype and a (CAG)25 allele with progressive cerebellar ataxia. These results suggested that EA2 and SCA6 (183086) are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggested that the small expansions in the CACNA1A gene may not be as stable as previously reported. Hemiplegic migraine type 1 (141500) has also been mapped to 19p13. Ophoff et al. (1996) found mutations in the calcium ion channel gene CACNL1A4 in both familial hemiplegic migraine (e.g., 601011.0001) and episodic ataxia type 2 (see 601011.0005 and 601011.0006). The CACNL1A4 gene had previously been mapped to 19p13. Riant et al. (2008) identified a heterozygous 39.5-kb deletion in the CACNA1A gene (601011.0026) in 3 affected members of a family with autosomal dominant EA2 in whom initial screening did not identify a point mutation. For a comprehensive review of episodic ataxia type 2 and its causative mutations, see Brandt and Strupp (1997). Jen et al. (2007) provided a detailed review of the pathophysiology and molecular genetics of known episodic ataxia syndromes. Riant et al. (2010) identified 4 different exonic deletions in the CACNA1A gene in 4 (14%) of 27 patients with episodic ataxia, in whom sequencing analysis was negative for CACNA1A point mutations. The EA2 phenotype in patients with deletions was similar to that of patients with point mutations. The findings indicated that screening for deletions in the CACNA1A gene should also be done for a complete genetic workup.
The diagnosis of episodic ataxia type 2 (EA2) is most commonly made on clinical grounds based on the following:...
DiagnosisClinical DiagnosisThe diagnosis of episodic ataxia type 2 (EA2) is most commonly made on clinical grounds based on the following:Attacks of gait ataxia and nystagmus lasting hours in duration, possibly associated with vertigo, nausea, and vomiting Presence of interictal ataxia and nystagmus Attacks that can be provoked by exercise, emotional stress, alcohol, caffeine, fever, and heatAttacks of ataxia that can be reduced in frequency or prevented by acetazolamide Absence of myokymia (fine twitching or rippling of muscles) clinically and electrographically (EMG) Family history consistent with autosomal dominant inheritance Neuroimaging. MRI can demonstrate atrophy of the cerebellar vermis [Vighetto et al 1988]. Nuclear magnetic spectroscopy has demonstrated abnormal cerebellar intracellular pH levels in individuals with EA2 not treated with acetazolamide [Bain et al 1992] and low cerebellar creatine [Harno et al 2005]. Molecular Genetic TestingGene. CACNA1A is the only gene in which mutations are known to cause EA2 [Ophoff et al 1996].Table 1. Summary of Molecular Genetic Testing Used in EA2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1 Test AvailabilityCACNA1ASequence analysis / mutation scanning 2Sequence variants 3>95% 4, 5ClinicalDeletion / duplication analysis 6Partial- or whole-gene deletionsUnknown 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. In families linked to chromosome 195. Sequence analysis has identified a number of CACNA1A mutations [Yue et al 1998, Friend et al 1999, Denier et al 2001]. In the study of Jen et al [2004], nine of 11 families (82%) with episodic ataxia showed linkage to 19p; mutations in CACNA1A 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 CACNA1A mutations.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.7. Partial CACNA1A deletions have been described [Labrum et al 2009, Rajakulendran et al 2010, Riant et al 2010]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandSequence analysis is performed first. If a disease-causing mutation is not identified, deletion/duplication analysis is considered. Some laboratories may perform tiered testing, beginning with sequencing of select exons and then proceeding to sequence the remainder of the gene. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersMutations in CACNA1A can cause other disorders, including: Familial hemiplegic migraine (FHM). Approximately 50% of families with FHM, including all those with permanent cerebellar symptoms, have missense mutations in CACNA1A (FHM1) [Ophoff et al 1996, Ducros et al 1999]. Two other FHM-associated genes have been identified; FHM2 is caused by mutations in ATP1A2 [De Fusco et al 2003] and FHM3 by mutations in SCN1A [Dichgans et al 2005]. 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 [Ducros et al 2001]. Some individuals with FHM, primarily children and adolescents who sustain minor head trauma, develop uncontrollable cerebral edema [McCrory & Berkovic 1998]. Three individuals with delayed cerebral edema were shown to have the p.Ser218Leu missense mutation in CACNA1A [Kors et al 2001]. Inheritance is autosomal dominant.Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. SCA6 is associated with a CAG expansion in exon 47 of CACNA1A [Zhuchenko et al 1997]. The normal number of CAG repeats ranges up to 18. Individuals with SCA6 have 20-33 CAG repeats [Matsuyama et al 1997]. Inheritance is autosomal dominant. Their well-described phenotypes notwithstanding, clinical overlap exists among EA2, FHM, and SCA6, even within the same family.In a family with EA2, affected members had hemiplegia, and one affected member had migraine during episodes of ataxia [Jen et al 1999]. In a study of 11 individuals with EA2 and documented CACNA1A mutations, four met IHS criteria for migraine, but none experienced hemiplegic migraine [Mantuano et al 2004]. Members of a Portuguese family with a missense mutation (A>G substitution) in CACNA1A had either hemiplegic migraine with or without cerebellar signs or permanent ataxia without migraines [Alonso et al 2003]. 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 CACNA1A had episodic features prominent enough to warrant the diagnosis of EA2 [Geschwind et al 1997]. 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 [Jodice et al 1997].
Episodic ataxia type 2 (EA2) demonstrates variable expressivity both between and within families [Denier et al 1999]. Episodic ataxia typically starts in childhood or early adolescence (age range 2-32 years) [Baloh et al 1997]. Onset as late as age 61 years has been reported [Imbrici et al 2005]....
Natural HistoryEpisodic ataxia type 2 (EA2) demonstrates variable expressivity both between and within families [Denier et al 1999]. Episodic ataxia typically starts in childhood or early adolescence (age range 2-32 years) [Baloh et al 1997]. Onset as late as age 61 years has been reported [Imbrici et al 2005].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. One study reported vertigo and weakness accompanying the ataxia in more than half of individuals with genetically confirmed EA2 [Jen et al 2004]. Another report suggested that about 50% of individuals with EA2 have migraine headaches without loss of consciousness [Baloh et al 1997]. Torticollis and intellectual disability [Mantuano et al 2010] have been described in individuals with genetically confirmed EA2.Frequency of attacks can range from one to two times per year to three to four times per week [von Brederlow et al 1995]. Attacks can be triggered by stress, exertion, caffeine, alcohol, and phenytoin. In one kindred, attacks could be provoked by fever or high environmental temperatures [Subramony et al 2003]. EA2 attacks can be stopped or decreased in frequency and severity by administration of acetazolamide [Griggs et al 1978]; attacks can recur within 48 to 72 hours of stopping the medication [von Brederlow et al 1995]. In some cases, attacks remit within one year after onset but in others, they can recur over a 50-year interval [Baloh et al 1997]. While individuals with EA2 may initially be asymptomatic between attacks, most eventually develop interictal permanent cerebellar symptoms. Ninety percent have nystagmus and about 80% have ataxia. Interictal dystonia has also been reported in two individuals with genetically confirmed EA2 [Spacey et al 2005].
Specific CACNA1A mutations do not strictly predict the EA2 phenotype....
Genotype-Phenotype CorrelationsSpecific CACNA1A mutations do not strictly predict the EA2 phenotype.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 [Denier et al 1999].Three mutations (c.3841C>T (p.Arg1281*), c.4217T>G (p.Phe1406Cys), c.4645C>T (p.Arg1549*) have been associated with fluctuating weakness manifesting as a myasthenic syndrome in individuals with EA2 [Jen et al 2001].
Episodic ataxia can occur sporadically or in a number of hereditary disorders. ...
Differential DiagnosisEpisodic ataxia can occur sporadically or in a number of hereditary disorders. Sporadic DisordersSporadic causes of episodic ataxia include multiple sclerosis, Arnold Chiari malformation, vertebral basilar insufficiency, basilar migraine, and labyrinthine abnormalities.Hereditary DisordersMitochondrial. Disorders of mitochondrial oxidative metabolism result in a number of neurologic conditions that are associated with episodic ataxia. The most common of these are pyruvate carboxylase deficiency and pyruvate dehydrogenase deficiency (OMIM 312170). Measurement of serum pyruvate and lactate concentrations following a 1.75-g/kg oral glucose load facilitates diagnosis. Definitive diagnosis requires studies of enzymatic activity in muscle, leukocytes, or fibroblasts. Molecular genetic studies may allow precise characterization of the molecular defects. (See Mitochondrial Diseases Overview.) X-linked. Ornithine transcarbamylase (OTC) deficiency (OMIM 311250) is an inborn error of metabolism of the urea cycle that causes hyperammonemia (see Urea Cycle Disorders Overview). Diagnosis can be facilitated by measurement of serum ammonia concentration. Mutations in the structural gene for ornithine transcarbamylase may lead to partial deficiency in heterozygous females and to complete deficiency in hemizygous males. 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. Autosomal recessive Hyperammonemias caused by deficiencies of urea cycle enzymes include carbamoylphosphate synthetase deficiency (OMIM 237300), argininosuccinate synthetase deficiency (citrullinemia type 1), argininosuccinase deficiency, and arginase deficiency. See Urea Cycle Disorders Overview. Diagnosis is established by the identification of raised blood ammonia concentration. Immediate treatment is by hemodialysis and by IV sodium benzoate; long-term treatment is by a high-calorie, low-protein diet supplemented with essential amino acids. 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. Aminoacidurias, including Hartnup disease, intermittent branched-chain ketoaciduria, and isovaleric acidemia, can be diagnosed by identification of increased excretion of amino acids in the urine and feces. Hartnup disease (OMIM 234500) 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. Intermittent branched-chain ketoaciduria (OMIM 248600) is characterized by intermittent transient ataxia, intellectual disability and physical retardation, 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 branch chain amino acids (leucine, isoleucine, valine) from the diet. A variant of this condition may be effectively treated with thiamine. See Maple Syrup Urine Disease. Isovaleric acidemia (OMIM 243500) 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. See Organic Acidemias Overview. Autosomal dominant Episodic ataxia type 1 (EA1) is the result of mutations in the potassium channel gene KCNA1 [Browne et al 1994], which has been mapped to chromosome 12p13 [Litt et al 1994]. 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 [VanDyke et al 1975, Hanson et al 1977, Gancher & Nutt 1986]. Electromyographic studies reveal myokymia (neuromyotonia). Phenytoin can control symptoms; acetazolamide is also effective [Lubbers et al 1995]. Episodic ataxia type 3 (EA3) (OMIM 606554) has been described in two families of European ancestry from rural North Carolina [Farmer & Mustian 1963, Vance et al 1984]. A relationship between the two kindreds is suspected but has not been established. EA3 is characterized by attacks of vertigo, diplopia, and ataxia beginning in early adulthood. In some individuals, slowly progressive cerebellar ataxia occurs. This condition does not link to loci identified with EA1, EA2, or spinocerebellar ataxia types 1, 2, 3, 4, and 5 [Damji et al 1996]. Episodic ataxia type 4 (EA4) (OMIM 606552) has been described in a large Canadian Mennonite family [Steckley et al 2001]. EA4 is characterized by brief acetazolamide-responsive attacks of vestibular ataxia, vertigo, tinnitus, and interictal myokymia. Interictal nystagmus and ataxia were not identified. The age of onset is variable. EA4 does not link to the EA1 or EA2 loci. Episodic ataxia type 5 (EA5) (OMIM 613855) can result from a mutation in CACNB4, located on chromosome 2q22-23 which encodes the beta-4 isoform of the regulatory beta subunit of voltage-activated Ca(2+) channels. A p.Cys104Phe mutation has been described in a French-Canadian family [Escayg et al 2000]. 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.Episodic ataxia type 6 (EA6) (OMIM 612656) results from heterozygous mutations in SLC1A3 (OMIM 600111.0002). Cellular studies showed that the mutation results in decreased glutamate uptake [Jen et al 2005, de Vries et al 2009]. The phenotype correlates with the extent of glutamate transporter dysfunction [deVries et al 2009] and, as a result, the phenotype is quite variable. Jen et al [2005] reported a ten-year-old boy with a severe form of episodic ataxia with seizures, migraine, and alternating hemiplegia triggered by febrile illness. There was interictal truncal ataxia. In contrast, de Vries et al [2009] 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.Episodic ataxia type 7 (EA7) (OMIM 611907) has been linked to a 10-cM candidate region, between rs1366444 and rs952108 on chromosome 19q13 (maximum lod score of 3.28). No mutations were identified in KCNC3 (OMIM 176264) or SLC17A7 (OMIM 605208). The phenotype was characterized by onset before age 20 years and attacks lasting hours to days associated with 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 [Kerber et al 2007].Spinocerebellar ataxia type 6 (SCA6) (see also Genetically Related Disorders) Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with episodic ataxia type 2 (EA2), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with episodic ataxia type 2 (EA2), the following evaluations are recommended:Neurologic examination for signs of interictal ataxia and nystagmus Neuroimaging of the head, preferably MRI, to evaluate for structural lesions and to look for evidence of atrophy EMG to look for myokymia (associated with EA1) If family history is not clearly consistent with EA2, a metabolic work-up that includes serum ammonia concentration and assessment of urine amino acids Medical genetics consultationTreatment of ManifestationsAcetazolamide is effective in controlling or reducing the frequency and severity of attacks [Griggs et al 1978]. A trial of acetazolamide is worthwhile in any individual who has episodic ataxia and reports a family history of similar episodes. The typical starting dose is 125 mg a day given orally, but doses as high as 500 mg twice a day may be required. This medication is generally well tolerated; the most common side effects are paresthesias of the extremities, rash, and renal calculi.4 aminopyridine, a potassium channel blocker, also reduces attack frequency and duration at doses of 5 mg TID [Strupp et al 2011]. Prevention of Primary ManifestationsTreatment with acetazolamide does not appear to prevent the progression of interictal symptoms [Baloh & Winder 1991]. It is not clear how acetazolamide prevents attacks of EA2, although it is speculated that it acts by altering intra/intercellular pH.SurveillanceSurveillance should include annual neurologic examination.Agents/Circumstances to AvoidPhenytoin has been reported to exacerbate symptoms.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management No published literature addresses management of the pregnancy of an affected mother or the effect of maternal EA2 on a fetus. However, because physical exertion can trigger attacks, it would be prudent for the mother 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 mother’s labor trigger an EA2 attack [Author personal observation].Therapies Under InvestigationScoggan et al [2006] reported an individual who responded to a combination of acetazolamide and valproic acid.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Episodic Ataxia Type 2: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCACNA1A19p13.2Voltage-dependent P/Q-type calcium channel subunit alpha-1ACalcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) @ LOVDCACNA1AData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Episodic Ataxia Type 2 (View All in OMIM) View in own window 108500EPISODIC ATAXIA, TYPE 2; EA2 601011CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1ANormal allelic variants. Multiple transcript variants encoding different isoforms have been found for CACNA1A. The variant NM_023035.2 represents the longest transcript and encodes the longest isoform NP_075461.2. The transcript NM_023035.2 consists of 48 exons and includes a (CAG)n-repeat in the coding region, resulting in a polyglutamine tract near the C-terminus.Pathologic allelic variants. More than 30 different CACNA1A mutations associated with EA2 have been described [Ophoff et al 1996, Yue et al 1997, Yue et al 1998, Denier et al 1999, Friend et al 1999, Denier et al 2001, van den Maagdenberg et al 2002, Matsuyama et al 2003, Subramony et al 2003, Jen et al 2004, Kaunisto et al 2004, Mantuano et al 2004, Spacey et al 2004, Spacey et al 2005]. The majority are nonsense mutations resulting in a truncated protein product. A number of non-truncating mutations that appear to cluster in the S5-S6 linkers and their borders have been described [Mantuano et al 2004, Spacey et al 2004].Intronic mutations causing exon skipping and abnormal splicing have been reported [Eunson et al 2005, Wan et al 2005]. Table 2. Selected CACNA1A Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.3841C>T 1p.Arg1281*NM_023035.2 NP_075461.2c.4217T>G 1p.Phe1406Cysc.4645C>T 1p.Arg1549*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Associated with fluctuating weakness manifesting as a myasthenic syndrome in individuals with EA2 [Jen et al 2001]. See Genotype-Phenotype CorrelationsNormal gene product. CACNA1A encodes an α1A subunit that serves as the pore-forming subunit of a voltage-dependent P/Q-type calcium channel [Hofmann et al 1994, Greenberg 1997]. Voltage-dependent calcium channels are made up of the pore-forming alpha1 subunit and accessory subunits alpha2-delta, beta, and gamma. The α1A 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 NP_075461.2 isoform has 2512 amino acids. The function of the different CACNA1A isoforms remains to be demonstrated, although differences have been measured in phosphorylation acceptor sites [Sakurai et al 1996]. Abnormal gene product. CACNA1A mutations appear to cause a loss of function.