Clinical 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; 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.

Diagnosis/testing.

The diagnosis of EA2 is established by identification of a heterozygous pathogenic variant in CACNA1A.

Management.

Treatment of manifestations: 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.

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 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.

Suggestive Findings

Episodic ataxia type 2 (EA2) should be suspected in individuals with the following clinical, neuroimaging, EMG, and family history findings.

Clinical features

• Episodic attacks:
  • Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting
  • Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat
  • Alleviated or prevented by acetazolamide therapy
• Presence of interictal ataxia and nystagmus
• Absence of myokymia (fine twitching or rippling of muscles) on physical examination

Neuroimaging

• Brain MRI may demonstrate atrophy of the cerebellar vermis [Vighetto et al 1988, Mantuano et al 2010].
• Nuclear magnetic spectroscopy may demonstrate abnormal cerebellar intracellular pH levels (in those not treated with acetazolamide) [Bain et al 1992] and low cerebellar creatine [Harno et al 2005].
• Myokymia is absent on EMG.
• Single fiber EMG may demonstrate jitter and blocking.

Family history consistent with autosomal dominant inheritance

Establishing the Diagnosis

The diagnosis of EA2 is established in a proband by the identification of a heterozygous pathogenic variant in CACNA1A by molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing or use of a multigene panel.

• Single-gene testing. Sequence analysis of CACNA1A is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes CACNA1A and other genes of interest (see Differential Diagnosis) may also be considered.
  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 [Gasser et al 2010].
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Episodic ataxia type 2 (EA2) demonstrates variable expressivity both among and within families [Denier et al 1999]. Episodic ataxia typically starts in childhood or early adolescence (age range 2-32 years) [Mantuano et al 2010]. 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 [Nachbauer et al 2014]. 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, intellectual disability, and psychiatric disorders have been described in individuals with genetically confirmed EA2 [Mantuano et al 2010, Nachbauer et al 2014].

Frequency of attacks can range from one to two times per year to three to four times per week [von Brederlow et al 1995, Mantuano et al 2010]. 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 or 4-aminopyridine [Strupp et al 2011, Ilg et al 2014]; 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; 90% have nystagmus and about 80% have ataxia. Other interictal findings include pursuit and saccade alterations and dystonia [Spacey et al 2005, Mantuano et al 2010].

Genotype-Phenotype Correlations

Specific CACNA1A pathogenic variants 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]. 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 [Mantuano et al 2010].

Three pathogenic variants – c.3841C>T (p.Arg1281Ter), c.4217T>G (p.Phe1406Cys), and c.4645C>T (p.Arg1549Ter) – 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].

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.

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 is pyruvate carboxylase deficiency. 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. PC is the only gene in which mutation is known to cause PC deficiency.
• Pyruvate dehydrogenase deficiency (OMIM 312170) may also present with episodic ataxia and is caused by hemizygous pathogenic variants in the gene encoding the E1-alpha subunit (PDHA1) in males or by a heterozygous pathogenic variant in PDHA1 in a female. See Mitochondrial Diseases Overview.

X-linked. Ornithine transcarbamylase (OTC) deficiency is an inborn error of metabolism of the urea cycle that causes hyperammonemia. Identification of a hemizygous pathogenic variant OTC in males can confirm the diagnosis. A heterozygous pathogenic variant in OTC 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.

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.
  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.
  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 levels of certain amino acids in plasma and increased excretion of amino acids in the urine.
  • 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, 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 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.

Autosomal dominant

• Episodic ataxia type 1 (EA1) is caused by heterozygous pathogenic variants in KCNA1, 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 [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 a large Canadian Mennonite family [Steckley et al 2001]. 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 [Steckley et al 2001, Cader et al 2005].
• Episodic ataxia type 4 (EA4) (OMIM 606552) has been described in two families of European ancestry from rural North Carolina [Farmer & Mustian 1963, Vance et al 1984]. EA4 is characterized by attacks of vertigo, diplopia, and ataxia beginning in early adulthood. In some individuals, slowly progressive cerebellar ataxia occurs.
• Episodic ataxia type 5 (EA5) (OMIM 613855) can result from a heterozygous pathogenic variant in CACNB4, 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 [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 pathogenic variants in SLC1A3 (OMIM 600111; see .0002). Cellular studies showed that the pathogenic variant 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 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, 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 pathogenic variants were identified in KCNC3 (OMIM 176264) or SLC17A7 (OMIM 605208). 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 [Kerber et al 2007].
• Spinocerebellar ataxia type 6 (SCA6) (See also Genetically Related Disorders.)

See Episodic ataxia: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 (if not performed already), preferably MRI, to evaluate for structural lesions and to look for evidence of atrophy
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Acetazolamide is effective in controlling or reducing the frequency and severity of attacks in two thirds of individuals with EA2 [Mantuano et al 2010, Ilg et al 2014]. 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.

4-aminopyridine, a potassium channel blocker, also reduces attack frequency and duration at doses of 5-10 mg/3x/day [Mantuano et al 2010, Strupp et al 2011].

Generally acetazolomide is used as the firstline therapy, although there are no specific recommendations regarding which medication should be trialed first [Ilg et al 2014].

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 Yue et al [1997] 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.

To date no data regarding whether 4-aminopyridine can prevent the progression of interictal symptoms are available.

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

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 [Spacey 2012].

Therapies Under Investigation

Scoggan et al [2006] reported an individual who responded to a combination of acetazolamide and valproic acid.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 diagnosed with EA2 have an affected parent.
• A proband with EA2 may have the disorder as the result of a de novo CACNA1A pathogenic variant. The proportion of cases caused by a de novo 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.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent Although no instances of germline mosaicism have been reported, it remains a possibility.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include neurologic examination, head MRI, and EMG.
• 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.

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the proband's parents.
• If a parent of a proband is affected, the risk to the sibs is 50%.
• Since EA2 demonstrates incomplete penetrance, a clinically unaffected parent may have a heterozygous CACNA1A pathogenic variant and the sibs of the proband may still be at 50% risk.
• If the CACNA1A 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.

Offspring of a proband. Each child of an individual with EA2 has a 50% chance of inheriting the CACNA1A 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.

Other family members. 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.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with EA2 has the pathogenic variant or clinical evidence of the disorder, the CACNA1A pathogenic variant is likely de novo. However, other possible non-medical explanations that could be explored include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

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

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CACNA1A 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.

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.

Published Guidelines / Consensus Statements

• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 4-13-18.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 4-13-18.

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Revision History

• 22 October 2020 (ma) Chapter retired: extremely rare
• 15 October 2015 (me) Comprehensive update posted live
• 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