Primary Episodic Ataxias

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Overview of the genetics, epidemiology, pathophysiology, and clinical presentation of primary episodic ataxia. This is a relatively rare neurologic illness under the purveyance of movement disorders.

Text of Primary Episodic Ataxias

Primary Episodic Ataxias

Primary Episodic AtaxiaRyan Crooks, MD PGY3 Dept of Neurology UF JacksonvilleObjectivesDefine primary episodic ataxiaBe familiar with the various genetic formsUnderstand the pathophysiology of primary episodic ataxiasKnow when to include primary episodic ataxia in your differentialBe able to diagnose a primary episodic ataxiaBe familiar with treatment modalities for primary episodic ataxiaDefinitionPrimary Episodic Ataxia:An autosomal dominant channelopathy that produces a phenotype of transient attacks of imbalance and incoordination progressive ataxia.

EpidemiologyOnset is typically childhood to adolescence. More rarely may begin in adulthood.Incidence of any episodic ataxia is less than 1/100,000

GeneticsThe majority of cases of episodic ataxia are accounted for by two genes:KCNA1 (episodic ataxia 1 EA1)CACNA1A (EA2)There are other rarer forms which do not have identified genes or have not been well characterized yet.

EA1 Clinical featuresOnset: early childhoodAttacks: seconds to minutes, up to 30 times per day.May also see: dysarthria, coarse tremor Precipitants: physical/emotional stress, startle, sudden movements, caffeine, hormonal changes, fatigueMay have aura: feeling of falling or weakness prior to attackBetween attacks: myokymia / neuromyotonia (involuntary low amplitude muscle contractions)EA1 Clinical featuresOther possible associated features:Partial epilepsyShort achilles tendonsTransient postural abnormalities in infancyPeripheral weaknessNeuromyotonia without ataxia (rare)May also have prolonged events in some cases (hours)EA1 GeneticsChromosome 12q13 (long arm) near a cluster of 3 potassium channel genesTypically a missense mutation of the gene KCNA1

EA1 PathophysiologyKCNA1 affects the Kv1.1 voltage-gated potassium channelMost cases will have intermediate dysfunction of the channel leading to increase in voltage threshold for activation, impairing membrane repolarization

Jen et al 2007EA1 PathophysiologyThe Kv1.1 potassium channels are primarily expressed within the cerebellum and in the perinodal portions of motor axons.

EA1 PathophysiologyAnimal models suggest that GABAergic neurons are primarily affected, which affect on their output to cerebellar perkinje cells is primarily responsible for impairment of motor coordination.Eventually, degeneration of these neurons is seen over time due to unclear mechanisms.

EA2 Clinical FeaturesOnset: early life, but possibly into adulthoodIncidence: much more common than any other form of EAAttacks: longer duration than EA1 (hours)May also see: spontaneous nystagmus, nausea, vomiting, vertigo, HA Precipitants: stress, similar to EA1Between attacks: gaze-evoked nystagmus with rebound nystagmus, 1/3 of cases with spontaneous downbeat nystagmus (may start positionally, seen with head-hanging position)

Rebound nystagmus: nystagmus seen following gaze-evoked nystagmus when eye is returned to midline with fast phase toward direction of previous gaze.

12EA2 Clinical FeaturesGaze evoked nystagmus with rebound

Downbeat nystagmus

Rebound nystagmus: nystagmus seen following gaze-evoked nystagmus when eye is returned to midline with fast phase toward direction of previous gaze.

13EA2 Clinical FeaturesAlso associated with:Familiar hemiplegic migraine type 1 (FHM1)Progressive ataxiaFluctuating weaknessEpileptic seizuresDystoniaRebound nystagmus: nystagmus seen following gaze-evoked nystagmus when eye is returned to midline with fast phase toward direction of previous gaze.

14EA2 Genetics

Gene for CACNA1A on chromosome 19p13 (short arm)EA2, FHM1 and spinocerebellar ataxia type 6 (SCA6) are all allelic diseases, involving the CACNA1A gene.EA2 typically due to a truncation (frameshift or splice site) mutation.

EA2 PathophysiologyCACNA1A encodes the Cav2.1 P/Q type voltage-gated calcium channel.Most abundant in the cerebellum and presynapse of the neuromuscular junction.

EA2 PathophysiologyThe mechanism for why those affected have episodic attacks is unknown, similar to other episodic neurologic conditions (epilepsy, migraine, etc)

EA3 EA6All are episodic ataxias described in one or a few families or single individual that did not have a mutation identified in the genes associated with EA1 or EA2.

Differential diagnosisEpilepsyParoxysmal dyskinesiaMigraineFluctuating symptoms in spinocerebellar ataxia

DiagnosisHistory HPI, family hx (may be sporadic)Exam inter-attack signs, weakness, ataxia at baselineGenetic testing only EA1 and EA2 are commercially available

TreatmentReferencesTHE END!!!