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Episodic Ataxia Type 2

, MD
Department of Neurology
University of British Columbia
Vancouver, British Columbia, Canada

Initial Posting: ; Last Update: December 8, 2011.

Summary

Disease characteristics. 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 and can be stopped or decreased in frequency and severity by administration of acetazolamide. Between attacks, individuals may initially be asymptomatic but eventually develop interictal findings that can include nystagmus and ataxia.

Diagnosis/testing. The diagnosis of EA2 is most commonly made on clinical grounds. MRI can demonstrate atrophy of the cerebellar vermis. Mutations in CACNA1A can cause EA2.

Management. Treatment of manifestations: Acetazolamide is effective in controlling or reducing the frequency and severity of attacks; typical starting dose is 125 mg a day given orally, but doses as high as 500 mg twice a day may be required; although 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. Recent studies have also demonstrated that 4-aminopyridine 5 mg TID can also be effective in reducing attack frequency and duration.

Surveillance: Annual neurologic examination.

Agents/circumstances to avoid: Phenytoin has been reported to exacerbate symptoms.

Genetic counseling. 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 de novo mutations is unknown. Offspring of affected individuals have a 50% chance of inheriting the disease-causing gene mutation. Prenatal testing is possible for pregnancies at increased risk for EA2 if the mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

The 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 heat
  • Attacks 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 Testing

Gene. 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 EA2

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CACNA1ASequence analysis / mutation scanning 4Sequence variants 5>95% 6,7
Deletion / duplication analysis 8Partial- or whole-gene deletionsUnknown 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. 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.

5. 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. For issues to consider in interpretation of sequence analysis results, click here.

6. In families linked to chromosome 19

7. 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.

8. 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.

9. Partial CACNA1A deletions have been described [Labrum et al 2009, Rajakulendran et al 2010, Riant et al 2010].

Testing Strategy

To confirm/establish the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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].

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].

Genotype-Phenotype Correlations

Specific 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].

Penetrance

Penetrance is estimated at 80%-90% [Jen et al 1999, Spacey et al 2005].

Anticipation

Anticipation is not observed.

Nomenclature

EA2 has also been known as periodic vestibulocerebellar ataxia and acetazolamide-responsive episodic ataxia.

Prevalence

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.

Differential Diagnosis

Episodic ataxia can occur sporadically or in a number of hereditary disorders.

Sporadic Disorders

Sporadic causes of episodic ataxia include multiple sclerosis, Arnold Chiari malformation, vertebral basilar insufficiency, basilar migraine, and labyrinthine abnormalities.

Hereditary Disorders

Mitochondrial. 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 is an inborn error of metabolism of the urea cycle that causes hyperammonemia. 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].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 consultation

Treatment of Manifestations

Acetazolamide 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 Manifestations

Treatment 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.

Surveillance

Surveillance should include annual neurologic examination.

Agents/Circumstances to Avoid

Phenytoin has been reported to exacerbate symptoms.

Evaluation of Relatives at Risk

See 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 Investigation

Scoggan 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Episodic ataxia type 2 (EA2) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals with a diagnosis of EA2 have an affected parent.
  • A proband with EA2 may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by a de novo mutation is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient.
  • Recommendations for the evaluation of parents of an individual with EA2 and no known family history of EA2 include clinical assessment.

Note: The family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in an affected parent, or incomplete penetrance.

Sibs of a proband

Offspring of a proband. Offspring of affected individuals have a 50% chance of inheriting the disease-causing mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • 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.

DNA banking 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
    Booklet providing information about Spinocerebellar Ataxia
  • Consortium for Clinical Investigation of Neurologic Channelopathies Contact Registry
  • CoRDS Registry for the National Ataxia Foundation
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: Cords@sanfordhealth.org

Molecular Genetics

Information 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 Databases

Data 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)

108500EPISODIC ATAXIA, TYPE 2; EA2
601011CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A

Normal 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].

Table 2. Selected CACNA1A Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.3841C>T 1p.Arg1281*NM_023035​.2
NP_075461​.2
c.4217T>G 1p.Phe1406Cys
c.4645C>T 1p.Arg1549*

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Associated with fluctuating weakness manifesting as a myasthenic syndrome in individuals with EA2 [Jen et al 2001]. See Genotype-Phenotype Correlations.

Normal 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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 9-12-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 9-12-13.

Literature Cited

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  2. Bain PG, O'Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol. 1992;31:147–54. [PubMed: 1575453]
  3. Baloh RW, Yue Q, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol. 1997;41:8–16. [PubMed: 9005860]
  4. Baloh RW, Winder A. Acetazolamide-responsive vestibulocerebellar syndrome: clinical and oculographic features. Neurology. 1991;41:429–33. [PubMed: 2006014]
  5. Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, Litt M. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet. 1994;8:136–40. [PubMed: 7842011]
  6. Damji KF, Allingham RR, Pollock SC, Small K, Lewis KE, Stajich JM, Yamaoka LH, Vance JM, Pericak-Vance MA. Periodic vestibulocerebellar ataxia, an autosomal dominant ataxia with defective smooth pursuit, is genetically distinct from other autosomal dominant ataxias. Arch Neurol. 1996;53:338–44. [PubMed: 8929156]
  7. 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. Nat Genet. 2003;33:192–6. [PubMed: 12539047]
  8. 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. Arch Neurol. 2009;66:97–101. [PubMed: 19139306]
  9. Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E. Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol. 2001;58:292–5. [PubMed: 11176968]
  10. 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. Neurology. 1999;52:1816–21. [PubMed: 10371528]
  11. 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. Lancet. 2005;366:371–7. [PubMed: 16054936]
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Chapter Notes

Revision History

  • 8 December 2011 (me) Comprehensive update posted live
  • 30 June 2009 (cd) Revision: CACNB4 mutations associated with episodic ataxia type 5
  • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for CACNA1A
  • 17 December 2007 (cd) Revision: prenatal testing available for CACNA1A-related EA2
  • 12 April 2007 (me) Comprehensive update posted to live Web site
  • 21 January 2005 (me) Comprehensive update posted to live Web site
  • 29 December 2003 (me) Revision: change in test availability
  • 24 February 2003 (me) Review posted to live Web site
  • 20 August 2002 (ss) Original submission
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