Hereditary Episodic Ataxia

Overview and Recommendations

Background

● Hereditary episodic ataxia (EA) describes a group of rare autosomal dominant disorders characterized
by recurrent, discrete episodes of ataxia associated with normal neurologic development.

● Episodes are thought to occur due to genetic mutations a ecting membrane proteins involved in ion
channels and transporters which results in a vulnerability of ion channel regulation.

● There are 7 known types of hereditary episodic ataxia, but only EA1 and EA2 have been found in
multiple families.

● EA2 is the most common type of hereditary episodic ataxia. Incidence is estimated at < 1 in 100,000
families.

Evaluation

● Clinical diagnosis can be made based on a history and physical exam, usually in a child or an
adolescent with recurrent episodes consistent with episodic ataxia type 1 or 2 (EA1 or EA2).
⚬ EA1 is characterized by recurrent, brief episodes (seconds to minutes) of ataxia and jerking
movements of the head, arms, and legs that can occur up to 15 times per day, often associated
with interictal myokymia (spontaneous ne fascicular muscle contractions).
⚬ EA2 is characterized by recurrent, prolonged episodes (hours to days) of ataxia that can occur up to
4 times per week, often associated with interictal nystagmus.
⚬ Common triggers for EA1 and EA1 include physical exertion, stress, and ca eine.

● Genetic testing is recommended for patients with recurrent episodes of ataxia in whom EA is
suspected to con rm the diagnosis.

● Other testing to establish extent of the disease may include:

⚬ magnetic resonance imaging or other head imaging to look for structural lesions and for evidence
of atrophy
⚬ electromyography (EMG) to assess for myokymia
⚬ electroencephalogram (EEG) to assess for seizure activity and other abnormalities
⚬ a metabolic workup including serum ammonia and urine amino acids if the family history is not
consistent with EA2

Management

● Management is based on minimizing the common triggers for episodic ataxia and optimizing lifestyle
factors such as moderate exercise, healthy diet, and adequate sleep.

● Consider acetazolamide or 4-aminopyridine to help decrease the frequency and severity of episodes
of ataxia.

● Consider screening at-risk relatives for episodic ataxia (EA) if it is indicated based on genetic
counseling.
Related Summaries

● Cerebellar ataxia

● Hereditary spinocerebellar ataxia (SCA)

General Information

Description

● group of autosomal dominant disorders characterized by recurrent, discrete episodes of vertigo and

ataxia 1

Also called

● for EA1

⚬ episodic ataxia with myokymia (involuntary muscle movement presenting as spasm, jerking,
twitching, quivering)
⚬ ataxia, episodic with myokymia
⚬ myokymia syndrome
⚬ hereditary paroxysmal ataxia with neuromyotonia
⚬ myokymia with periodic ataxia
⚬ Reference - Online Mendelian Inheritance in Man (OMIM) #160120

● for EA2

⚬ acetazolamide-responsive hereditary paroxysmal cerebellar ataxia

⚬ cerebellar ataxia, paroxysmal, acetazolamide-responsive
⚬ hereditary paroxysmal cerebellopathy
⚬ periodic vestibulocerebellar ataxia
⚬ familial paroxysmal ataxia
⚬ Reference - OMIM #108500

Types

● episodic ataxia (EA) types 1-7 identi ed 1

Epidemiology

Incidence/Prevalence

● rare 1

● incidence likely < 1 in 100,000 families 3

● only episodic ataxia (EA)1 and EA2 described in multiple families 3

● EA2 most common 1

● other types of EA rarely described 4

 ⚬ EA3 described in 2 families from rural North Carolina, United States with European ancestry
⚬ EA4 described in 1 large Mennonite family in Canada
⚬ EA5 described in a French-Canadian family
⚬ EA6 described in 1 family and 1 single patient
⚬ EA7 described in 1 family

Associated conditions

● episodic ataxia (EA)2 associated with 1

⚬ familial hemiplegic migraine type 1 (FHM1)

⚬ spinocerebellar ataxia type 6 (SCA6)

Etiology and Pathogenesis

Causes

● autosomal dominant inheritance of gene mutation a ecting membrane proteins involved in ion

channels and transporters 1

● a ected genes by type 2

⚬ episodic ataxia (EA)1 - KCNA1 at locus 12p13

⚬ EA2 - CACNA1A at locus 19p13
⚬ EA3 - unknown gene at locus 1q42
⚬ EA4 - unknown gene at unknown locus
⚬ EA5 - CACNB4 at locus 2q22-23
⚬ EA6 - SLC1A3 at locus 5p13
⚬ EA7 - unknown gene at locus 19q13

Pathogenesis

● proposed mechanism

⚬ channelopathies (including disorders of potassium and calcium channels) lead to recurrent

episodes of variably disabling neurological manifestations but with normal neurological
development
⚬ possible explanation is that changes in expression or function of some ion channels lead to
neuronal excitability, resulting in compensatory changes in expression or function of other
channels
⚬ genetic changes may lead to vulnerability of ion channel regulation in response to some triggers
⚬ Reference - J Physiol 2010 Jun 1;588(Pt 11):1823 full-text

History and Physical

Clinical presentation

● recurrent, discrete episodes of vertigo and ataxia, sometimes associated with progressive ataxia 1 , 2

⚬ clear onset and clear resolution of symptoms (rather than waxing and waning) distinguishes
episodic ataxia (EA) with progressive features from progressive ataxias
⚬ episodes last for varying amounts of time and have various associated features depending on
subtype
● selected clinical features of major subtypes

⚬ EA1 1 , 4

– recurrent brief episodes of vertigo and ataxia

– episodes last seconds to minutes
– often characterized by jerking movements of head, arms, and legs and loss of balance and
motor coordination
– other symptoms during episodes may include blurred vision, diplopia, nausea, headache,
diaphoresis, incoordination, di culty breathing and talking, and body sti ening
– myokymia (spontaneous ne fascicular muscle contractions) (also called neuromyotonia) may
occur during and between episodes, and may be clinically apparent or only detectable with
electromyographic studies
– association with various types of seizures have been reported
– onset in childhood or early adolescence
– triggers may include

● fever
● physical exertion
● emotional stress
● startle response or abrupt movements (such as avoidance of falling or collision)
● ca eine
● spinning (for example riding merry-go-round)

– frequency of episodes can range from > 15 times/day to < 1 attack per month
– severity of symptoms during episodes may worsen or improve with age

⚬ EA2 1 , 2

– recurrent prolonged episodes of vertigo

– episodes last hours to days
– variably associated with nausea, vomiting, migraine headaches, uctuating weakness
(myasthenia), dystonia, seizures, and interictal nystagmus and ataxia
– onset in childhood or adolescence
– absence of myokymia distinguishes EA2 from EA1
– triggers include

● exertion
● stress
● ca eine
● alcohol
● infection

– frequency of attacks can range from 1 to 2 times/year to 4 times/week (GeneReviews 2011 Dec
8 )

● key features of other subtypes

⚬ EA3 1 , 2

– episodes last minutes

– characterized by vertigo, tinnitus, headache, and ataxia
– age of onset < 20 years old

⚬ EA4 1 , 2

– episodes last hours

– characterized by vertigo and diplopia with ataxia
 – age of onset 20-50 years

⚬ EA5 2

– episodes last hours

– characterized by vertigo with ataxia
– age of onset 20-50 years

⚬ EA6 1 , 2

– episodes last hours

– characterized by episodic and progressive ataxia, seizures, and alternating hemiplegia and
migraine
– age of onset < 10 years old
– associated with fever

⚬ EA7 1 , 2

– episodes last hours to days

– characterized by episodic ataxia associated with weakness, slurring, and vertigo
– age of onset < 20 years old
– triggered by exertion and excitement

History

Past medical history (PMH)

● about 50% of patients with episodic ataxia (EA)2 have history of migraine headaches (GeneReviews
2011 Dec 8 )

Family history (FH)

● ask about family history of ataxia 1

Social history (SH)

● ask about association of attacks with exertion, stress, and alcohol (may indicate EA1 or EA2) 1 , 2

Physical

General physical

● minor dysmorphic facial features have been described in patients with episodic ataxia (EA)1 4

HEENT

● interictal nystagmus in EA2, EA4, and EA5 2

● interictal abnormal smooth pursuit in EA4 2

Back

● scoliosis and kyphoscoliosis may be present in patients with EA1 4

Extremities

● with EA1 4

⚬ muscle hypertrophy, especially in calves, may be seen

 ⚬ shorted Achilles tendons can result in tiptoe walking

Neuro

● clinical exam ndings that may con rm cerebellar ataxia

⚬ upper-limb and lower-limb dysmetria

⚬ dysdiadochokinesia (di culty performing rapidly alternating movements)
⚬ hypotonia
⚬ cerebellar dysarthria
⚬ saccadic ocular pursuit
⚬ Reference - N Engl J Med 2012 Feb 16;366(7):636

● clinical exam ndings which indicate ataxia may be due to sensory problems rather than cerebellar
dysfunction
⚬ loss of proprioception and vibration sensation
⚬ loss of re exes
⚬ positive Romberg test
⚬ Reference - Online Mendelian Inheritance in Man (#607364) #607459

● interictal ataxia occurs with EA2, EA5, EA6 2

● interictal myokymia ( ne muscle fasciculation or rippling) in EA1, EA3 2

● delayed expressive and/or receptive language skills and motor delay may be seen with EA1 4

● intellectual disability may be seen with EA2 (GeneReviews 2011 Dec 8 )

Diagnosis

Making the diagnosis

● clinical diagnosis commonly made based on history and physical exam, usually in child or adolescent

with recurrent episodes of ataxia but with normal neurologic development 1 , 2

● genetic testing con rms diagnosis and episodic ataxia (EA) subtype 1

Differential diagnosis

● other causes of episodic neurological disease 3

⚬ epilepsy
⚬ paroxysmal dyskinesia
⚬ migraine

● other causes of ataxia include

⚬ hereditary disorders

– autosomal dominant cerebellar ataxias (ADCAs)

● hereditary spinocerebellar ataxia (SCA) type 1-30 (mutation of SCA genes)

● dentatorubral-pallidoluysian atrophy (DRPLA) (mutation of ATN1 gene)
● hypomyelinating leukoencephalopathy
 ● spastic ataxia type 1

– autosomal recessive ataxias include

● ataxia with oculomotor apraxia type 1

● Friedreich ataxia (FRDA)
● ataxia with vitamin E de ciency
● ataxia-telangiectasia
● infantile-onset spinocerebellar ataxia
● cerebrotendinous xanthomatosis
● Refsum disease
● Boucher-Neuhauser syndrome
● ataxia with oculomotor apraxia type 2
● autosomal recessive spastic ataxia of Charlevoix-Saguenay
● Marinesco-Sjogren syndrome
● Brown-Vialetto-Van Laere syndrome 2
● Wolfram syndrome
● spastic ataxia types 2-5
● spastic paraplegia 7

– X-linked ataxias

● Fragile X tremor/ataxia syndrome (FXTAS)

● X-linked sideroblastic anemia and ataxia
● CASK-related disorders
● X-linked spinocerebellar ataxia 5
● X-linked mental retardation

– Reference - GeneReviews 2015 Apr 2

⚬ mitochondrial disorders 1

⚬ sporadic causes of ataxia

– in ammatory causes include

● paraneoplastic cerebellar degeneration

● celiac disease
● steroid-responsive encephalopathy with antithyroid antibodies (SREAT, Hashimoto
encephalopathy)
● antiglutamic acid decarboxylase ataxia (anti-GAD ataxia)

– para (infectious) causes include

● Miller Fisher syndrome

● Epstein-Barr virus-associated infectious mononucleosis
● HIV infection

– structural causes include

● posterior cerebral artery stroke

● brain tumor
● multiple sclerosis (MS)

– toxic causes include

● alcoholic cerebellar degeneration

● toxic

⚬ phenytoin
⚬ lithium
⚬ solvents
 – metabolic causes include

● acquired vitamin E de ciency

● acquired vitamin B1 de ciency
● hypothyroidism
● hypoparathyroidism

– degenerative ataxias

● idiopathic adult-onset cerebellar ataxia

⚬ “pure” (isolated ataxia with no other symptoms)

⚬ with other symptoms/multiple system atrophy - cerebellar type (MSA-C)

● Creutzfeldt-Jakob disease

– siderosis of the central nervous system (also called super cial siderosis)
– complicated migraine including vestibular migraine 2

– Reference - Pract Neurol 2012 Feb;12(1):14 , Neurol Sci 2008 Oct;29 Suppl 3:311

Testing overview

● genetic testing recommended in patients with recurrent episodes of ataxia in whom episodic ataxia

(EA) suspected 1

● other testing to establish extent of disease may include 4

⚬ magnetic resonance imaging or other head imaging to evaluate for structural lesions and evidence
of atrophy
⚬ electromyography (EMG) to assess for myokymia ( ne twitching or rippling of muscles related to
EA1), especially if not evident on clinical exam
⚬ electroencephalogram (EEG) to assess for seizure activity and other abnormalities
⚬ metabolic workup including serum ammonia and urine amino acids to evaluate for alternative
diagnosis if family history not consistent with EA
⚬ Reference - GeneReviews 2011 Dec 8

Genetic testing

● genetic testing for known genotypes in patient with typical history may con rm episodic ataxia (EA)

subtype 1
⚬ analysis of entire coding regions of KCNA1 and CACNA1A genes needed as mutation sites variable
⚬ speci c genotypes associated with each EA subtype

● diagnosis con rmed by genetic testing for known hereditary variants 1 , 2

⚬ EA1 - mutations in KCNA1 gene on chromosome 12q13 (encodes potassium channel Kv1.1)
⚬ EA2 - mutations in CACNA1A gene on chromosome 19p13 (encodes protein for calcium channel
common in cerebellum and at neuromuscular junction)
⚬ EA3 - mutation on locus 1q42
⚬ EA4 - no chromosome identi ed
⚬ EA5 - mutations in gene CACNB4 on chromosome 2q22-23 (encodes protein for a calcium channel
common in cerebellum and at neuromuscular junction)
⚬ EA6 - mutation in SLC1A3 gene on chromosome 5p13 (encodes a glial glutamate [excitatory amino
acid] transporter)
⚬ EA7 - mutation on chromosome 19q13
Imaging studies

● magnetic resonance imaging

⚬ may show atrophy of cerebellar vermis in episodic ataxia (EA)2 (GeneReviews 2011 Dec 8 )
⚬ usually normal in EA1, however, may have cerebellar atrophy 4

Assessment of severity

● standardized severity assessment instruments

⚬ for ataxia symptoms, Scale for Assessment and Rating of Ataxia (SARA) score ranges from 0 to 40 in
increasing severity of symptoms (Neurology 2006 Jun 13;66(11):1717 ), commentary can be
found in Nat Clin Pract Neurol 2007 Mar;3(3):136
⚬ for nonataxia symptoms, Inventory of Non-Ataxia Symptoms (INAS) creates score from 0 to 16
based on presence or absence of 30 items related to 16 symptoms or syndromes (Neurology 2008
Sep 23;71(13):982 )
⚬ spinocerebellar functional index

– composite score based on

● 8-minute walking time (8MW)

● 9-hole peg test (9HPT)
● PATA repetition rate (a timed speech test)

– Reference - Neurology 2008 Aug 12;71(7):486

Management

Management overview

● optimizing lifestyle factors such as moderate exercise, healthy diet, and adequate sleep may help
minimize common triggers for episodic ataxia (EA)

● acetazolamide

⚬ 125-250 mg/day orally with gradual increase up to 500 mg twice daily as needed or as tolerated
⚬ acetazolamide reported to decrease frequency, duration, and severity of attacks of ataxia
DynaMed Level 3

● 4-aminopyridine

⚬ 5 mg orally 3 times daily

⚬ 4-aminopyridine may decrease ataxic episodes in patients with EA2 DynaMed Level 2

● some antiepileptic drugs have been reported to be e ective for EA type 1

Medications

● acetazolamide

⚬ carbonic-anhydrase inhibitor 4

⚬ dose 125-250 mg orally/day with gradual increase up to 500 mg twice daily as needed or as

tolerated 1
⚬ mechanism resulting in symptom reduction with acetazolamide is unclear 4
 STUDY
⚬ SUMMARY
acetazolamide reported to decrease frequency, duration, and severity of attacks of ataxia
DynaMed Level 3

CASE SERIES: Neurology 1978 Dec;28(12):1259

Details
– based on case series
– 8 patients with hereditary episodic ataxia (EA) treated with acetazolamide and followed for up to
5 years
– all patients remained symptom-free
– Reference - Neurology 1978 Dec;28(12):1259

⚬ acetazolamide reported to improve clinical symptoms in 3 patients in family with EA2 (J Neurol
2004 Feb;251(2):232 )
⚬ acetazolamide reported to improve clinical symptoms in case report (J Korean Med Sci 1998
Apr;13(2):196 PDF )
⚬ does not appear to a ect interictal symptoms (GeneReviews 2011 Dec 8 )

● 4-aminopyridine (4AP)

⚬ potassium channel blocker

⚬ reported dosing 5 mg orally 3 times daily 1

⚬ 4-aminopyridine may decrease ataxic episodes in patients with hereditary episodic ataxia
type 2
– based on small randomized trial and 2 case series
– 10 patients with hereditary EA2 (7 patients) or other familial EA randomized to 4AP 5 mg orally 3
times daily vs. placebo for 2 treatment periods (each 3 months long) separated by 1-month-long
washout period
● median monthly attack frequency 1.65 with 4AP vs. 6.5 with placebo (p = 0.03)
● Reference - Neurology 2011 Jul 19;77(3):269 full-text , commentary can be found in J
Neurol 2011 Sep;258(9):1734 , Neurology 2011 Nov 29;77(22):1996
– 3 patients with EA treated with 4AP 5 mg orally 3 times daily for 6 months

● ataxic episodes stopped in all patients during treatment

● ataxic episodes recurred in all patients after treatment discontinued for 1 week and
disappeared again after treatment restarted
● Reference - Neurology 2004 May 11;62(9):1623

– dalfampridine (sustained release 4AP) reported to decrease episodes of ataxia in case series of
2 patients with episodic EA2 (J Neurol 2013 Feb;260(2):668 )

● unarizine (calcium channel blocker not available in United States) reported to be successful in
treatment of 10-year-old boy with episodic ataxia in case report (Neuropediatrics 1988 Nov;19(4):218
)

● antiepileptic drugs have been reported to be e ective for EA type 1, including 3 , 4

⚬ phenytoin
⚬ carbamazepine
⚬ valproic acid
 ⚬ sulthiame (not available in United States)

● avoid phenytoin, as reported to exacerbate symptoms (GeneReviews 2011 Dec 8 )

● treat associated anxiety disorder and panic disorder 1

Consultation and referral

● genetic counseling 4

● referral to physical, occupational, and speech therapy as needed 1

Other management

● lifestyle interventions 1

⚬ encourage patients to stay physically and mentally active

⚬ moderate exercise, healthy diet, and adequate sleep may help minimize common triggers for
episodic ataxia

Follow-up

● annual neurologic exam 4

Complications and Prognosis

Complications

● episodic ataxia (EA)1

⚬ permanent cerebellar dysfunction reported in 26% of patients in prospective cohort of 39 patients

with EA1 (Brain 2014 Apr;137(Pt 4):1009 full-text )
⚬ contractures 4

● EA2

⚬ progression of ataxia and nystagmus in EA2 (GeneReviews 2011 Dec 8 )

⚬ cerebral edema due to common infection in patient with presumed EA2 in case report (Acta Neurol
Belg 2009 Mar;109(1):38 )
⚬ de cits in memory, executive function, and vision have been reported (J Neurol 2014
May;261(5):983 )
⚬ anxiety disorders have been reported (J Neurol 2014 May;261(5):983 )

Prognosis

● most patients with hereditary episodic ataxia (EA)2 respond to acetazolamide, but experience slow
progression of permanent cerebellar signs over time (Neurotherapeutics 2007 Apr;4(2):267 )

● patients with EA1 have variable prognosis; severity of symptoms can improve or worsen with age 4

Prevention and Screening

Screening

● decision to screen at-risk relatives of patients with hereditary episodic ataxia type 2 should be based
on genetic counseling (GeneReviews 2011 Dec 8 )

Guidelines and Resources

Guidelines

● European Federation of Neurological Societies/European Neurological Society (EFNS/ENS) consensus

guideline on diagnosis and management of chronic ataxias in adulthood can be found in Eur J Neurol
2014 Apr;21(4):552 full-text

● American College of Radiology (ACR) Appropriateness Criteria for ataxia can be found at ACR 2012

● European Federation of Neurological Societies (EFNS) guidelines on the molecular diagnosis of ataxias
and spastic paraplegias can be found in Eur J Neurol 2010 Feb;17(2):179

Review articles

● review can be found in Rev Neurol (Paris) 2011 May;167(5):401 [French]

● review of the clinical spectrum of autosomal dominant episodic ataxias can be found in Mov Dis Clin
Pract 2014 Dec;1(4);285

● review of episodic ataxia (EA)1 and EA2 can be found in Handb Clin Neurol 2012;103:595

● review of EA1 can be found in Neurotherapeutics 2007 Apr;4(2):258

● reviews of EA2 can be found in

⚬ GeneReviews 2011 Dec 8

⚬ J Neurol 2014 May;261(5):983
⚬ J Assoc Physicians India 2011 Oct;59:668
⚬ Neurotherapeutics 2007 Apr;4(2):267

● review of acetazolamide-responsive ataxia can be found in Semin Neurol 2012 Nov;32(5):533

● review of hereditary ataxia can be found at GeneReviews 2015 Apr 2

● review of hereditary ataxia can be found in Genet Med 2013 Sep;15(9):673

MEDLINE search

● to search MEDLINE for (Episodic ataxia) with targeted search (Clinical Queries), click therapy ,
diagnosis , or prognosis

Patient Information

● handouts from National Ataxia Foundation on

⚬ episodic ataxia PDF

 ⚬ gene testing for hereditary ataxia PDF

● handout on ataxias and cerebellar or spinocerebellar degeneration from National Institute of

Neurological Disorders and Stroke or in Spanish

● handout on ataxia from Mayo Clinic

ICD Codes

ICD-10 codes

● G11.8 other hereditary ataxias

● G11.9 hereditary ataxia, unspeci ed

References

General references used

1. Jen JC. Hereditary episodic ataxias. Ann N Y Acad Sci. 2008 Oct;1142:250-3

2. Gazquez I, Lopez-Escamez JA. Genetics of recurrent vertigo and vestibular disorders. Curr Genomics.
2011 Sep;12(6):443-50 full-text

3. Jen JC, Graves TD, Hess EJ, et al; CINCH investigators. Primary episodic ataxias: diagnosis, pathogenesis
and treatment. Brain. 2007 Oct;130(Pt 10):2484-93 full-text

4. D’Adamo MC, Hanna MG, Di Giovanni G, Pessia M. Episodic ataxia type 1. GeneReviews 2012 Aug 16

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