Table 2.

Disorders to Consider in the Differential Diagnosis of Episodic Ataxia Type 1

DisorderGeneMOIClinical FeaturesOnsetFrequency of AttacksAttack TriggersTreatmentInterictal Findings
EA2 1
(OMIM 108500)		 CACNA1A AD
  • Paroxysmal attacks of ataxia, vertigo, nausea lasting minutes to days; can be assoc w/dysarthria, diplopia, tinnitus, dystonia, hemiplegia, & headache (migraine in ~50%)
  • Atrophy of cerebellar vermis on MRI
Typically childhood or early adolescence (range: 2-32 yrs)Range: 1-2/yr to 3-4/wk
  • Stress
  • Exertion
  • Caffeine
  • Alcohol
  • Fever
  • Heat
  • Phenytoin
Acetazolamide can stop or ↓ attack frequency/severity.Initially asymptomatic; may develop interictal findings incl nystagmus & ataxia
EA3 2
(OMIM 606554)		UnknownAD
  • Vestibular ataxia
  • Vertigo
  • Tinnitus
VariableMyokymia
EA4 3, 4, 5
(OMIM 606552)		Unknown
  • Recurrent attacks of vertigo, tinnitus, diplopia, & ataxia
  • Abnormal eye movements (incl abnormal smooth pursuit, nystagmus, & abnormal vestibuloocular reflex)
  • Slowly progressive cerebellar ataxia in some
Early adulthood (range: 3rd-6th decade)No response to acetazolamideAbsence of interictal myokymia
EA5
(OMIM 613855)		CACNB4 6ADRecurrent episodes of vertigo & ataxia lasting several hours 6Acetazolamide prevented attacks.Spontaneous downbeat & gaze-evoked nystagmus, mild dysarthria, & truncal ataxia
EA6
(OMIM 612656)		SLC1A3 7AD
  • Attacks of ataxia precipitated by fever
  • Subclinical seizures
  • Slurred speech followed by headache
  • Bouts of arm jerking w/concomitant confusion
  • Alternating hemiplegia
  • Stress
  • Fatigue
  • Caffeine
  • Alcohol
Gaze-evoked nystagmus
EA7
(OMIM 611907)		Unknown 8ADAttacks assoc w/weakness, vertigo, & dysarthria lasting hrs to daysBefore age 20 yearsRange: 1/mo to 1/yr; frequency tends to ↓ w/age.
  • Exercise
  • Excitement
EA8 9
(OMIM 616055)		UnknownAD
  • Unsteady gait, generalized weakness, & slurred speech lasting mins to hrs
  • In 2 women: improvement during pregnancy; in others: ↓ frequency & severity of attacks w/age
  • Twitching around eyes, nystagmus, myokymia, mild dysarthria, & persistent intention tremor in some
  • Migraine headache w/o aura reported in 2 individuals
  • Epilepsy not reported
2nd year of lifeRange: 2/day to 2/moClonazepam was effective.
Spastic ataxia 1
(OMIM 108600)		 VAMP1 ADInitially, progressive leg spasticity of variable degree followed by ataxia (involuntary head jerk, dysarthria, dysphagia, & ocular movement abnormalities)Early childhood - early 20s
Familial paroxysmal kinesigenic dyskinesia 10 PRRT2 AD
  • Unilateral or bilateral involuntary movements
  • Attacks usually last a few secs to 5 mins but can last several hrs & incl dystonia, choreoathetosis, &/or ballism
  • May be preceded by aura, & do not involve loss of consciousness
  • Severity & combinations of symptoms vary
  • Predominantly seen in males
Typically childhood & adolescence (range 4 mos - 57 yrs)Range: 100/day to as few as 1/moSudden movements (e.g., standing up from sitting position, being startled, or changes in velocity)Phenytoin or carbamezepine can ↓ frequency of (or prevent) attacks.
Familial paroxysmal nonkinesigenic dyskinesia PNKD AD
  • Unilateral or bilateral involuntary movements
  • Attacks lasting mins to hrs: dystonic posturing w/choreic & ballistic movements; may be preceded by aura; occur while awake; are not associated w/seizures
  • Frequency, duration, severity, & combinations of symptoms vary w/in & among families
Typically in childhood or early teens; can be as late as age 50 yrsA few times/dayAttacks are spontaneous or precipitated by:
  • Alcohol
  • Caffeine
  • Excitement
  • Stress
  • Fatigue
  • Chocolate
Isaac syndrome (acquired neuromyotonia, NMT) 11NANA
  • Rare neuromuscular disorder
  • Hyperexcitability of motor nerve → continuously contracting or twitching muscles (myokymia) & muscle hypertrophy
  • Cramping, ↑ sweating, & delayed muscle relaxation
  • Stiffness most prominent in limb & trunk muscles
  • A few persons report sleep disorders, anxiety, & memory loss (Morvan syndrome)
15-60 yearsSymptoms not usually triggered by exercise; occur even during sleep or under general anesthesia

AD = autosomal dominant: MOI = mode of inheritance; NA = not applicable

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

1.
2.

EA3 has been described in a large Canadian kindred of Mennonite heritage [Steckley et al 2001].

3.

EA4 (also referred to as periodic vestibulocerebellar ataxia) has been described in families from North Carolina of northern European origin by Farmer & Mustian [1963] and Vance et al [1984].

4.
5.

EA4 does not link to loci identified with EA1, EA2, or spinocerebellar ataxia types 1, 2, 3, 4, and 5 [Damji et al 1996].

6.

EA5 can result from pathogenic variants in CACNB4 as described in a French-Canadian family [Escayg et al 2000]. EA5 is allelic with susceptibility to juvenile myoclonic epilepsy 6 (EJM6, OMIM 607682); the semiology of seizures in EA5 is similar to EJM6.

7.

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].

8.

EA7 has been described in a four-generation family whose affected individuals showed episodic ataxia [Kerber et al 2007]. A candidate region on chromosome 19q13, termed the EA7 locus, has been identified [Kerber et al 2007].

9.

Genome-wide linkage analysis found linkage to an 18.5-Mb locus on chromosome 1p36.13-p34.3 [Conroy et al 2014].

10.

The phenotype of paroxysmal kinesigenic dyskinesia can include benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), hemiplegic migraine, migraine with and without aura, and episodic ataxia.

11.

The acquired form of Isaac's syndrome occasionally develops in association with peripheral neuropathies or after radiation treatment. Twenty percent of affected individuals have an associated thymoma. Antibodies that involve 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].

From: Episodic Ataxia Type 1

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