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Episodic Ataxia Type 1

Synonyms: EA1, Episodic Ataxia with Myokymia
, PhD
Section of Physiology and Biochemistry
University of Perugia School of Medicine
Perugia, Italy

Initial Posting: ; Last Update: June 25, 2015.


Clinical characteristics.

Episodic ataxia type 1 (EA1) is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks individuals may experience a number of variable symptoms including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing, among others. EA1 may be associated with epilepsy. Other findings can include delayed motor development, cognitive disability, choreoathetosis, and carpal spasm. Usually, onset is in childhood or early adolescence.


Diagnosis is based on clinical findings, an electrophysiologic test of axonal superexcitability and threshold electrotonus, and/or molecular genetic testing of KCNA1, the only gene in which pathogenic variants are known to cause EA1.


Treatment of manifestations: Acetazolamide (ACTZ), a carbonic-anhydrase (CA) inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Antiepileptic drugs (AEDs) may significantly reduce the frequency of the attacks in some individuals.

Prevention of primary manifestations: In addition to pharmacologic treatments, behavioral measures including avoidance of stress, abrupt movements, loud noises, and caffeine intake may be used to reduce disease manifestations in both symptomatic and asymptomatic individuals.

Prevention of secondary complications: Joint contractures can be prevented by appropriate physiotherapy.

Surveillance: Annual neurologic examination.

Agents/circumstances to avoid: Triggers of attacks, including physical exertion, emotional stress, and changes in environmental temperature; marked generalized myokymia has been reported during induction of anesthesia.

Pregnancy management: Affected women should be made aware that pregnancy may trigger attacks; possible loss of balance and falls could endanger the fetus. Several stressors that trigger attacks may cause breathing difficulties, thus, delivery by C-section should be considered.

Genetic counseling.

EA1 is inherited in an autosomal dominant manner. Most individuals diagnosed with EA1 have an affected parent; however, de novo pathogenic variants have been reported. Each child of an individual with EA1 has a 50% chance of inheriting the KCNA1 pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.


Suggestive Findings

Episodic ataxia type 1 (EA1) should be suspected in individuals with the following clinical, imaging, and laboratory findings:

  • Clinical manifestations including:
    • Episodic attacks of:
      • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs
      • Dysarthria
      • Incoordination of hands
      • Weakness
      • Tremors
      • Muscle twitching/stiffening
      • Dizziness
      • Stiffening of the body
      • Blurred vision, diplopia
      • Nausea, headache, and vomiting
    • Neuromyotonia (muscle cramps and stiffness)
    • Myokymia (muscle twitching with a rippling appearance) occurring in the limbs or especially in the muscles of the face or hands
    • Childhood or early-adolescent disease onset (average age of onset: ~8 years)
  • Normal brain MRI and routine laboratory blood tests including serum concentration of creatine kinase and electrolytes
  • EMG that displays a pattern of either rhythmically or arrhythmically occurring singlets, duplets, or multiplets
    Note: In some individuals myokymic activity on the EMG becomes apparent after the application of regional ischemia.
    • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes).
    • In specialized centers, electrophysiologic assessments of axonal super-excitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac© software; UCL Institute of Neurology [Kiernan et al 2000]) allows differentiation of individuals with EA1 from normal controls with high sensitivity and specificity [Tomlinson et al 2010].
  • Family history consistent with autosomal dominant inheritance

Note: Muscle biopsy is usually not helpful in establishing the diagnosis, although bilateral calf hypertrophy, enlargement of type 1 and type 2 gastrocnemius muscle fibers, and variable glycogen depletion have been observed [VanDyke et al 1975, Kinali et al 2004, Demos et al 2009]. Nevertheless, these changes have not been consistently reported among individuals with EA1.

Establishing the Diagnosis

The diagnosis of EA1 can be established in a proband by means of electrophysiology assessments and/or by the finding of a heterozygous pathogenic variant in KCNA1.

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

Table 1.

Molecular Genetic Testing Used in Episodic Ataxia Type 1

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by this Method
KCNA1Sequence analysis 3>90% 4
Gene-targeted deletion/duplication analysis 5Unknown 6; none reported

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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 here.


All affected individuals described thus far are heterozygous for KCNA1 pathogenic variants at amino acid residues highly conserved among the voltage-dependent K+ channel superfamily.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can 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.


No data on detection rate of gene-targeted deletion/duplication analysis are available.

Interpretation of test results. For KCNA1 sequence variants, publications on in vitro assessment of channel function may be useful [D’Adamo et al 1998, D’Adamo et al 1999, Imbrici et al 2008, D’Adamo et al 2015]. Channel function assays are not offered on a clinical testing basis.

Clinical Characteristics

Clinical Description

Episodic ataxia type 1 (EA1), first described in 1975 by VanDyke et al, is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks some individuals may experience vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing [VanDyke et al 1975].

The duration of the attacks is brief, lasting seconds to minutes, although prolonged attacks lasting hours have been described [Lee et al 2004a, D’Adamo et al 2015]. Episode occurrence is variable, with some individuals experiencing severe ataxia more than 15 times per day and others experiencing attacks less often than once a month [VanDyke et al 1975].

The first symptoms typically manifest during childhood (1st or 2nd decade of life). A specific traumatic physical or emotional event may determine the onset and worsening of the disease [Imbrici et al 2008]. Attacks may be brought on by stimuli including stress, emotional upset, anxiety, fatigue, menstruation, pregnancy, environmental temperature, fever, startle response, abrupt movements, sudden postural changes (kinesigenic stimulation), vestibular stimulation (head turning from side to side while standing still; sitting still on a rotating chair; instillation of cold water (i.e., ≤30° C) into either external auditory canal), repeat knee bends, exercise, ingestion of caffeine or alcohol, and riding a merry-go-round. Attacks may occur, for example, when the individual has had to suddenly alter course to avoid falling or potential collision. High temperatures that occur after a hot bath or during use of a hairdryer may also precipitate attacks [Eunson et al 2000]. Whether interictal ataxia develops in individuals with EA1 has not been clearly reported to date.

Myokymia manifests clinically during and between attacks as fine twitching of groups of muscles and intermittent cramps and stiffness. Usually, it is evident as a fine rippling in perioral or periorbital muscles and by lateral finger movements when the hands are held in a relaxed, prone position.

Rarely, episodes of intense myokymic activity during attacks without either ataxia or other neurologic deficits are observed. Myokymic activity is continuous and present in almost all affected patients [Lee et al 2004b, D’Adamo et al 2015].

The exposure of the forearm to warm or cold temperatures may increase or decrease, respectively, the spontaneous activity recorded from a hand muscle.

The severity of some symptoms may either improve or worsen with age [Imbrici et al 2008].

Since the first description of EA1 by VanDyke et al [1975] and the identification and characterization of pathogenic variants in KCNA1, the phenotypic spectrum of EA1 has widened considerably [Graves et al 2014], indicating that it is not a purely cerebellar syndrome. Affected individuals may display delayed motor development, choreoathetosis, carpal spasm, clenching of the fists, and isolated neuromyotonia.

Cognitive dysfunction described in EA1 includes severe receptive and expressive language delay; inability to learn to ride a bicycle; and the need for life-skill programs or schools for children with mild to moderate learning difficulties [Zuberi et al 1999, Demos et al 2009].

Moderate muscle hypertrophy with generalized increase in muscle tone and bilateral calf hypertrophy are observed. Neuromuscular findings secondary to the increased tone include unusual hypercontracted posture; abdominal wall muscle contraction; elbow, hip, and knee contractures; and shortened Achilles tendons that may result in tiptoe walking.

Some individuals display attacks of difficulty in breathing, which can occur during ataxic episodes or as isolated episodes of an inability to inhale without wheezing [Shook et al 2008].

Skeletal deformities including scoliosis, kyphoscoliosis, high-arched palate, and minor craniofacial dysmorphism have been described [Kinali et al 2004, Klein et al 2004]. It is now apparent that phenotypic differences exist not only across families, but also among affected individuals within a family.

Tonic-clonic and partial seizures, an isolated episode consisting of photo-sensitive epilepsy [Imbrici et al 2008], as well as head-turning and eyes deviating to the same side, flickering eyelids, lip-smacking, apnea, and cyanosis have been reported [Zuberi et al 1999].

Abnormal electroencephalograms (EEG) have been observed in persons with EA1 [VanDyke et al 1975, Zuberi et al 1999, Lee et al 2004a]. EEG may be characterized by intermittent and generalized slow activity, frequently intermingled with spikes. Zuberi et al [1999] described a boy age three years who presented with an ictal EEG with rhythmic slow-wave activity over the right hemisphere, becoming spike-and-wave complexes that subsequently spread to the left hemisphere.

Neuromimaging with MRI is usually normal; however, Demos et al [2009] reported a family with cerebellar atrophy.

Genotype-Phenotype Correlations

Due to significant interfamilial and intrafamilial phenotypic variability, reliable genotype-phenotype correlations have been extremely difficult to establish. Indeed, differences in severity and frequency of EA1 attacks have been reported even in monozygotic twins [Graves et al 2010].


Most individuals harboring a KCNA1 pathogenic variant exhibit features of EA1; however, penetrance is incomplete.


EA1 has also been known as:

  • Familial paroxysmal kinesigenic ataxia and continuous myokymia
  • Acetazolamide-responsive periodic ataxia
  • Continuous muscle fiber activity
  • Isaacs-Mertens syndrome


EA1 is a rare disease and the prevalence can be estimated only roughly. Several families from Australia, Brazil, Canada, Germany, Italy, Russia, Spain, the Netherlands, United Kingdom, and the United States have been described. Based on limited data, a disease prevalence of 1:500,000 has been proposed. Actual prevalence may well be considerably higher, as the disorder may remain either unrecognized in many families or be incorrectly diagnosed.

The populations that are more or less at risk are also unknown.

Differential Diagnosis

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

Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia, vertigo, and nausea lasting minutes to days. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache. Approximately 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. MRI can demonstrate atrophy of the cerebellar vermis. EA2 is inherited in an autosomal dominant manner. Loss-of-function mutations in CACNA1A, which encodes for a voltage-dependent Ca2+ channel alpha subunit, are causative.

Episodic ataxia type 3 (EA3) (OMIM 606554) has been described in a large Canadian kindred of Mennonite heritage [Steckley et al 2001]. EA3 is an autosomal dominant episodic ataxia prominently characterized by vestibular ataxia, vertigo, tinnitus, and interictal myokymia. The age of onset is variable. The molecular genetic basis of EA3 has not been clearly established. (Steckley et al [2001] referred to this disorder as episodic ataxia type 4 [EA4]; however, the currently preferred designation is EA3.)

Episodic ataxia type 4 (EA4) (OMIM 606552) (also referred to as periodic vestibulocerebellar ataxia [PATX]) has been described in families from North Carolina of northern European origin by Farmer & Mustian [1963] and Vance et al [1984]. EA4 is characterized by recurrent attacks of vertigo, diplopia, and ataxia beginning in early adulthood. In some individuals, slowly progressive cerebellar ataxia occurs. Like EA3, vertigo and tinnitus are prominent in EA4; however, Steckley et al [2001] noted that EA4 differs in having abnormal eye movements, including abnormal smooth pursuit, nystagmus, and abnormal vestibuloocular reflex; no response to acetazolamide; and absence of interictal myokymia. Individuals with EA4 also displaying defective smooth pursuit, gaze-evoked nystagmus, ataxia, and vertigo have been described [Damji et al 1996]. The age of onset ranged from the third to the sixth decade. 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 5 (EA5) (OMIM 613855) can result from heterozygous pathogenic variants in CACNB4, encoding the beta-4 isoform of the regulatory beta subunit of voltage-activated Ca2+ channels. A c.311G>T (p.Cys104Phe; reference sequences NM_000726.3; NP_000717.2) 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. EA5 is allelic with susceptibility to juvenile myoclonic epilepsy 6 (EJM6, OMIM 607682); the semiology of seizures in EA5 is similar to EJM6.

Episodic ataxia type 6 (EA6) (OMIM 612656) is characterized by attacks of ataxia precipitated by fever, subclinical seizures, slurred speech followed by headache, bouts of arm jerking with concomitant confusion, alternating hemiplegia, and interictal gaze-evoked nystagmus. Attacks can be triggered by stress, fatigue, caffeine, or alcohol. EA6 can result from pathogenic variants in SLC1A3, which encodes the excitatory amino acid transporter 1. In cells expressing mutated proteins, glutamate uptake is reduced, suggesting that glutamate transporter dysfunction underlies the disease [Jen et al 2005, de Vries et al 2009].

Episodic ataxia type 7 (EA7) (OMIM 611907) has been described in a four-generation family whose affected individuals showed episodic ataxia before age 20 years [Kerber et al 2007]. The disease is characterized by attacks associated with weakness, vertigo, and dysarthria lasting hours to days. Attacks may be brought about by exercise and excitement. Frequency ranged from monthly to yearly and tended to decrease with age. A candidate region on chromosome 19q13, termed the EA7 locus, has been identified [Kerber et al 2007].

Episodic ataxia type 8 (EA8) (OMIM 616055). Conroy et al [2014] reported an autosomal dominant episodic ataxia with onset in the second year of life. The attacks were characterized by unsteady gait, generalized weakness, and slurred speech. The duration and number of attacks were variable from two attacks a day (lasting minutes to hours) to two attacks per month. Two women reported improvement of symptoms during pregnancy, while others had a decrease in frequency and severity of the attacks with age. Variable additional features included twitching around the eyes, nystagmus, myokymia, mild dysarthria, and persistent intention tremor. None of the affected individuals had epilepsy, but two had migraine headache without aura. Treatment with clonazepam was effective. Genome-wide linkage analysis found linkage to an 18.5-Mb locus on chromosome 1p36.13-p34.3 between SNPs rs2743201 and rs215791 (lod score of 3.29) [Conroy et al 2014]; no specific gene has been identified.

Spastic ataxia 1 (SPAX1) (OMIM 108600). Affected individuals initially show progressive leg spasticity of variable degree followed by ataxia in the form of involuntary head jerk, dysarthria, dysphagia, and ocular movement abnormalities. Age at onset is from early childhood to early twenties. SPAX1 is caused by heterozygous pathogenic variants in VAMP1.

Familial paroxysmal kinesigenic dyskinesia (PKD) is characterized by unilateral or bilateral involuntary movements precipitated by other sudden movements such as standing up from a sitting position, being startled, or changes in velocity; attacks include combinations of dystonia, choreoathetosis, and ballism, are sometimes preceded by an aura, and do not involve loss of consciousness. Attacks can be as frequent as 100 per day to as few as one per month. Attacks are usually a few seconds to five minutes in duration but can last several hours. Age of onset, severity and combinations of symptoms vary. Age of onset, typically in childhood and adolescence, ranges from four months to 57 years. The phenotype of PKD can include benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), hemiplegic migraine, migraine with and without aura, and episodic ataxia. Familial PKD is predominantly seen in males. Attack frequency is reduced or prevented by the anticonvulsants phenytoin or carbamezepine. Familial PKD is inherited in an autosomal dominant manner. Heterozygous mutations in PRRT2 have been reported as causative of a subset of cases of familial PKD.

Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements; attacks are spontaneous or precipitated by alcohol, caffeine or tea, excitement, stress, fatigue or chocolate. Attacks involve dystonic posturing with choreic and ballistic movements, may be accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and occur a few times per day. Attack frequency, duration, severity, and combinations of symptoms vary within and among families. Age of onset is typically in childhood or early teens, but can be as late as age 50 years. Familial PNKD is inherited in an autosomal dominant manner and can be caused by pathogenic variants in PNKD (MR1).

Isaac’s syndrome (acquired neuromyotonia, NMT) is a rare neuromuscular disorder characterized by hyperexcitability of the motor nerve that results in continuously contracting or twitching muscles (myokymia) and muscle hypertrophy. Individuals also experience cramping, increased sweating, and delayed muscle relaxation. Stiffness is most prominent in limb and trunk muscles. Symptoms are not usually triggered by exercise and occur even during sleep or when individuals are under general anesthesia. A few affected individuals report sleep disorders, anxiety, and memory loss (Morvan syndrome). Onset is between ages 15 and 60 years. The acquired form occasionally develops in association with peripheral neuropathies or after radiation treatment. Twenty percent of affected individuals have an associated thymoma. Antibodies that involves K+ channels have been detected in approximately 40% of affected individuals [Hart et al 2002]. Several of these auto-antibodies do not bind directly with Kv1.1, Kv1.2, or Kv1.6 channels, as previously believed, but rather to associated proteins such as leucine-rich glioma-inactivated protein 1, contactin-associated protein-like 2, contactin-2, or others as yet unidentified [Irani et al 2010, Lai et al 2010, Lancaster et al 2011].

See Episodic Ataxia: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with episodic ataxia type 1, the following evaluations are recommended:

  • Detailed medical history of the individual
  • Neurologic examination
  • Initiation (and observation) of attacks of ataxia by either mild exercise or vestibular stimuli
  • EMG to confirm the presence of myokymia, particularly if it is not visible on examination
  • EEG to evaluate for epilepsy [Zuberi et al 1999, Eunson et al 2000, Chen et al 2007]
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

Several drugs variably improve symptoms in affected individuals but, with the lack of clinical trials comparing the efficacy of these drugs, no single medication has been proven to be very effective. Thus, response to the following treatments may be poor.

Acetazolamide (ACTZ), a carbonic-anhydrase (CA) inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. The mechanism by which ACTZ reduces the frequency and severity of the attacks is unclear. The recommended starting dosage is 125 mg once a day, given orally. However, individuals with good renal function may require higher daily doses, ranging from 8 to 30 mg/kg/day in one to four divided doses (not to exceed 1 g/day). ACTZ should not be prescribed to individuals with liver, renal, or adrenal insufficiency.

Chronic treatment with ACTZ may result in side effects including tiredness, paresthesias, rash, and formation of renal calculi; therefore, for some affected individuals treatment must be discontinued [Graves et al 2014, D’Adamo et al 2015].

Antiepileptic drugs (AEDs) may significantly reduce the frequency of the attacks in responsive individuals; however, the response is heterogeneous as some individuals are particularly resistant to drugs [Eunson et al 2000].

  • Diphenylhydantoin treatment at a dose of 150-300 mg daily resulted in reasonable control of seizures in some individuals [VanDyke et al 1975]. In particular, phenytoin treatment at a dose of 3.7 mg/kg/day may improve muscle stiffness and motor performance [Kinali et al 2004]. Nevertheless, phenytoin should be used with caution in young individuals, as it may cause permanent cerebellar dysfunction and atrophy [De Marcos et al 2003].
  • Sulthiame 50-200 mg daily may reduce the attack rate. During this treatment abortive attacks were still noticed lasting a few seconds and troublesome side effects were paresthesias and intermittent carpal spasm.
  • Carbamazepine has been prescribed in doses up to 1600 mg daily [Eunson et al 2000]. The dose needs to be adjusted according to different factors including, age, weight, the particular carbamazepine product being used, responsiveness of the individual, and other medications being taken.
  • Lamotrigine ameliorates attacks in some affected individuals and therefore it has been proposed as an alternative treatment [Graves et al 2014].

Prevention of Primary Manifestations

In addition to the pharmacologic treatments mentioned above, behavioral measures such as avoidance of stress, abrupt movements, loud noises or caffeine intake may be used to reduce disease manifestations in either a symptomatic or an asymptomatic person.

Prevention of Secondary Complications

Contractures occur in a small proportion of individuals and can be prevented by appropriate physiotherapy.


Surveillance should include annual neurologic examination.

Agents/Circumstances to Avoid

Known triggers of attacks should be avoided; physical exertion, emotional stress, and changes in environmental temperature are the most common triggers.

Marked generalized myokymia has been reported during induction of anesthesia [Kinali et al 2004].

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic relatives at risk in order to identify as early as possible those who would benefit from behavioral measures and avoidance of caffeine intake. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.

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 EA1 on a fetus. However, affected women should be made aware that pregnancy may trigger attacks [Graves et al 2014] and the possible loss of balance and fall could endanger the fetus’s life. Moreover, several stressors that trigger attacks may cause breathing difficulties, thus, delivery by C-section should be considered.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


Morphologic studies on lateral gastrocnemius (LG) muscles derived from a mouse model of EA1 did not reveal changes in muscle mass, fiber type composition, or vascularization [Brunetti et al 2012].

Homozygous Val408Ala/Val408Ala pathogenic variants are embryonically lethal in an animal model of EA1 [Herson et al 2003], although this has not been reported in humans.

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 1 (EA1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with EA1 have an affected parent.
  • A proband with episodic ataxia type 1 may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.

    When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo.
  • If the KCNA1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. 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 evaluation and sequence analysis of KCNA1.
  • The family history of some individuals diagnosed with EA1 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, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic evaluation and molecular genetic testing have been performed on the parents of the proband.
    Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent.
  • If the KCNA1 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.

Offspring of a proband. Each child of an individual with EA1 has a 50% chance of inheriting the KCNA1 pathogenic variant.

Other family members

  • The risk to other family members depends on the status of the proband’s parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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

Family planning

  • The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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 of being affected.

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

If the KCNA1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory offering either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the KCNA1 pathogenic variant has been identified.


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.

  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
  • Consortium for Clinical Investigation of Neurologic Channelopathies Contact Registry
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423

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 1: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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 1 (View All in OMIM)


Molecular Genetic Pathogenesis

Voltage-gated potassium channels (Kv) play key roles in neurotransmission and nerve cell physiology. Kv channels shorten the duration of action potentials, modulate the release of neurotransmitters, and control the excitability, electrical properties, and firing pattern of central and peripheral neurons [Hille 2001, Pessia 2004]. In particular, Kv1.1 channels (encoded by KCNA1) regulate neuromuscular transmission, control the release of β-aminobutyric acid (GABA) from cerebellar basket cells onto Purkinje cells [Herson et al 2003], and modulate synaptic transmission in hippocampus [Geiger & Jonas 2000].

Nomenclature of Kv channels is organized by subfamilies based on sequence relatedness by using the abbreviation Kvx.y whereby the prefix specifies both the permeating ion (K+) and the voltage-dependence of the channel (v). According to this standardized nomenclature Shaker-related channels have been classified in the subfamily Kv1.x and each member numbered Kv1.1 through Kv1.9. The same criteria have been used to classify auxiliary subunits (Kvβ1.1 and Kvβ1.2) and channels related to the subfamilies Shab (Kv2.1 and Kv2.2), Shaw (Kv3.1 to 3.4) and Shal (Kv4.1 to Kv4.3).

Functional homomeric Kv1.1 channels are tetrameric structures composed of four identical monomers. Each monomer is encoded by KCNA1. However, potassium channel diversity is greatly enhanced by the ability of different types of pore-forming subunits to heteropolymerize and to form channels with properties different from the parental homomeric channels. Kv channels may exhibit fast N-type inactivation that is caused by a “ball-and-chain” mechanism of pore occlusion. Fast inactivation may be conferred to non-inactivating channels by auxiliary subunits such as Kvβ1.1 and Kvβ1.2. Four β subunits participate to the ion channel complex and provide four inactivation particles. Notable examples:

  • Heteromeric channels composed of Kv1.1 and Kv1.2 that are expressed at cerebellar basket cell terminals and at the juxtaparanodal region of motor axons
  • Channels composed of Kv1.1, Kv1.4, and Kvβ1.1 subunits that are expressed in hippocampal mossy fiber boutons

Kv1.1 channels possess a slower process of inactivation, which has been named C-type or P-type depending on the structural determinants of this process that have been located within the C-terminus and pore region.

D’Adamo et al first demonstrated that proteins encoded by KCNA1 pathogenic variants associated with EA1 alter the expression and gating properties of heteromeric channels composed of human Kv1.2 and Kv1.1 subunits [D’Adamo et al 1999, Rea et al 2002]. Successively, it has been shown that proteins encoded by KCNA1 pathogenic variants also impair the function of hetero-oligomeric complexes comprising Kv1.1, Kv1.4, and Kvβ1.x subunits in distinct ways [Imbrici et al 2006, Imbrici et al 2011]. These studies raised the question as to whether other allelic variations, whose gene products may or may not form hetero-oligomeric complexes with Kv1.1 subunits, may underlie a similar channelopathy.

Gene structure. KCNA1 has a transcript of 7983 nucleotides with a coding region of 1488. There are two exons, but the coding region is located entirely within exon 2. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. In 5% of control chromosomes analyzed by Zuberi et al [1999], two silent changes in the coding sequence were observed, c.684T>C and c.804G>C (see Table 2). The reference sequences in Table 2 include the correction of a sequence error published by Ramaswami et al [1990] and reported by Browne et al [1994] and Zuberi et al [1999].

Pathogenic allelic variants. To date, KCNA1 pathogenic variants have been identified by sequence analysis (see Figure 1). Most are missense variants that are distributed throughout the gene; however, nonsense variants and small deletions have also been identified [Eunson et al 2000, Shook et al 2008].

Figure 1. . Schematic drawing of the conventional membrane topology of a human Kv1.

Figure 1.

Schematic drawing of the conventional membrane topology of a human Kv1.1 subunit. Four such subunits comprise a functional homotetrameric channel. Different subunits belonging to the Kv1 subfamily may form heterotetrameric channels. The positions of pathogpenic (more...)

Interestingly, four different variants of the highly conserved threonine 226 residue, located within the second transmembrane segment, have been identified [Rajakulendran et al 2007]. In particular, the amino acid change p.Thr226Arg is associated with epilepsy, infantile contractures, postural abnormalities, and skeletal deformities. Although, the defects caused by the p.Thr226Ala, p.Thr226Arg, and p.Thr226Met amino acid changes on channel functions are virtually identical, they lead to diverse phenotypes.

Table 2.

Selected KCNA1 Allelic Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
p.= 2NM_000217​.2
p.= 2

Note on variant classification: Variants listed in the table have been provided by the authors. 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​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


p.= designates that protein has not been analyzed, but no change is expected.

Normal gene product. KCNA1 encodes the voltage-gated K+ channel Kv1.1. The predicted 496-amino acid Kv1.1 protein contains six hydrophobic segments with the N- and C-termini residing inside the cell. The S4 segment of each Kv1.1 subunit comprises the main voltage sensor that opens the channel by undergoing a conformational rearrangement on membrane depolarization. The S5-S6 loop (H5 region) contributes to the ion-conducting pore. The GYG residues, residing within this loop, control the K+ selectivity of the channel (see also Molecular Genetic Pathogenesis).

Abnormal gene product. The molecular mechanisms underlying episodic ataxia type 1 have been established by determining the functional properties of wild-type and several mutant channels in Xenopus oocytes or mammalian cell lines [Adelman et al 1995, D’Adamo et al 1998, Zerr et al 1998, D’Adamo et al 1999, Zuberi et al 1999, Eunson et al 2000, Manganas et al 2001, Imbrici et al 2003, Cusimano et al 2004, Imbrici et al 2006, Imbrici et al 2007, Imbrici et al 2008, Imbrici et al 2009, Imbrici et al 2011, D’Adamo et al 2015]. Overall, these studies have shown that allelic variations underlying EA1 impair channel function and reduce the outward K+ flux through the channel, although with highly variable effects on aspects of channel expression and gating.

Regarding channel gating, KCNA1 pathogenic variants may alter the protein structure and affect the kinetics of opening and closing, voltage dependence, and N- and C-type inactivation [D’Adamo et al 1998, D’Adamo et al 1999, Maylie et al 2002, Imbrici et al 2006, Imbrici et al 2009, Imbrici et al 2011, D’Adamo et al 2015].

Individuals with EA1 are heterozygous for a KCNA1 pathogenic variant, possessing a normal and a mutated allele, which may be equally expressed. Therefore, channels composed of wild-type and mutated subunits may be formed. Co-expression systems, which mimic the heterozygous condition, have shown that some mutant subunits exert dominant negative effects on wild-type subunits, resulting in less than half the normal current, whereas others have virtually no effect on surface expression. It has been shown that KCNA1 allelic variations also alter the function of heteromeric channels containing different subunits, demonstrating that pathogenic variants in a single gene disrupt the functions of other closely related proteins [D’Adamo et al 1999, Rea et al 2002, Imbrici et al 2006]. Based on these findings, a model accounting for the cerebellar symptoms of EA1 was proposed by D’Adamo and colleagues (see Figure 2).

Figure 2. . Proposed effects of EA1-causing pathogenic variants on basket cell and Purkinje cell inhibitory outputs.

Figure 2.

Proposed effects of EA1-causing pathogenic variants on basket cell and Purkinje cell inhibitory outputs. The diagram shows a basket cell which has synapses on the initial segment and soma of a number of Purkinje cells from the cerebellar cortex of a (more...)

A mouse model of EA1 has been generated by introducing a pathogenic variant analogous to the human p.Val408Ala pathogenic variant into the murine ortholog, Kcna1. These animals showed impaired motor performance and altered cerebellar GABAergic transmission from the basket cells to the Purkinje cells [Herson et al 2003]. Such Kv1.1 knock-in ataxic mice also exhibited spontaneous myokymic activity exacerbated by fatigue, ischemia, and low temperature [Brunetti et al 2012]. Spontaneous myokymic discharges were present despite motor nerve axotomy, suggesting that the motor nerve is an important generator of myokymic activity. This study also showed that altered Ca2+ homeostasis in motor axons of mutant animals may contribute to spontaneous myokymic activity [Brunetti et al 2012].

The causes that trigger the paroxysms of ataxia remain elusive, although a phenomenon akin to spreading acidification of the cerebellar cortex has been suggested [Chen et al 2005].


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Chapter Notes


The financial support of Telethon (GGP11188), Ministero della Salute (GR-2009-1580433), and Fondazione Cassa di Risparmio di Perugia to MP is gratefully acknowledged. MGH is supported by an MRC Centre Grant (G0601943).

Author History

Maria Cristina D’Adamo, PhD (2010-present)
Giuseppe Di Giovanni, PhD; Istituto Euro-Mediterraneo di Scienza e Tecnologia (2012-2015)
Michael G Hanna, BSc (Hons), MD, FRCP; UCL Institute of Neurology (2010-2015)
Mauro Pessia, PhD; Istituto Euro-Mediterraneo di Scienza e Tecnologia (2010-2015)

Revision History

  • 25 June 2015 (me) Comprehensive update posted live
  • 16 August 2012 (me) Comprehensive update posted live
  • 9 February 2010 (me) Review posted live
  • 21 April 2009 (mp) Initial submission
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