primary episodic ataxias

Primary Episodic Ataxia

Ryan Crooks, MD PGY3 ● Dept of Neurology ● UF Jacksonville

Objectives

Define primary episodic ataxia Be familiar with the various genetic forms Understand the pathophysiology of

primary episodic ataxias Know when to include primary episodic

ataxia in your differential Be able to diagnose a primary episodic

ataxia Be familiar with treatment modalities for

primary episodic ataxia

Definition

Primary Episodic Ataxia: An autosomal dominant channelopathy

that produces a phenotype of transient attacks of imbalance and incoordination ± progressive ataxia.

Epidemiology

Onset is typically childhood to adolescence. More rarely may begin in adulthood.

Incidence of any episodic ataxia is less than 1/100,000

Genetics

The 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 features Onset: early childhood Attacks: 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, fatigue

May have aura: feeling of falling or weakness prior to attack

Between attacks: myokymia / neuromyotonia (involuntary low amplitude muscle contractions)

EA1 – Clinical features

Other possible associated features: Partial epilepsy Short achilles tendons Transient postural abnormalities in

infancy Peripheral weakness Neuromyotonia without ataxia (rare) May also have prolonged events in some

cases (hours)

EA1 – Genetics

Chromosome 12q13 (long arm) near a cluster of 3 potassium channel genes

Typically a missense mutation of the gene KCNA1

EA1 – Pathophysiology KCNA1 affects the

Kv1.1 voltage-gated potassium channel

Most cases will have intermediate dysfunction of the channel leading to increase in voltage threshold for activation, impairing membrane repolarization

Jen et al 2007

EA1 – Pathophysiology

The Kv1.1 potassium channels are primarily expressed within the cerebellum and in the perinodal portions of motor axons.

EA1 – Pathophysiology Animal 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 Features Onset: early life, but possibly into adulthood Incidence: much more common than any

other form of EA Attacks: longer duration than EA1 (hours)

May also see: spontaneous nystagmus, nausea, vomiting, vertigo, HA

Precipitants: stress, similar to EA1 Between attacks: gaze-evoked nystagmus

with rebound nystagmus, 1/3 of cases with spontaneous downbeat nystagmus (may start positionally, seen with head-hanging position)

EA2 – Clinical Features

Gaze evoked nystagmus with rebound http://www.youtube.com/watch?v=fUV3z

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Downbeat nystagmus http://www.youtube.com/watch?v=UDfh

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EA2 – Clinical Features

Also associated with: Familiar hemiplegic migraine type 1

(FHM1) Progressive ataxia Fluctuating weakness Epileptic seizures Dystonia

EA2 – GeneticsGene 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 – Pathophysiology

CACNA1A encodes the Cav2.1 P/Q type voltage-gated calcium channel. Most abundant in the cerebellum and

presynapse of the neuromuscular junction.

EA2 – Pathophysiology

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

EA3 – EA6

All 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 diagnosis

Epilepsy Paroxysmal dyskinesia Migraine Fluctuating symptoms in

spinocerebellar ataxia

Diagnosis

History – HPI, family hx (may be sporadic)

Exam – inter-attack signs, weakness, ataxia at baseline

Genetic testing – only EA1 and EA2 are commercially available

Treatment

References

THE END!!!