primary episodic ataxias
DESCRIPTION
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.TRANSCRIPT
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Primary Episodic Ataxia
Ryan Crooks, MD PGY3 ● Dept of Neurology ● UF Jacksonville
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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
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Definition
Primary Episodic Ataxia: An autosomal dominant channelopathy
that produces a phenotype of transient attacks of imbalance and incoordination ± progressive ataxia.
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Epidemiology
Onset is typically childhood to adolescence. More rarely may begin in adulthood.
Incidence of any episodic ataxia is less than 1/100,000
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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.
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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)
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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)
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EA1 – Genetics
Chromosome 12q13 (long arm) near a cluster of 3 potassium channel genes
Typically a missense mutation of the gene KCNA1
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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
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EA1 – Pathophysiology
The Kv1.1 potassium channels are primarily expressed within the cerebellum and in the perinodal portions of motor axons.
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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.
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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)
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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
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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.
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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.
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EA2 – Pathophysiology
The mechanism for why those affected have episodic attacks is unknown, similar to other episodic neurologic conditions (epilepsy, migraine, etc)
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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.
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Differential diagnosis
Epilepsy Paroxysmal dyskinesia Migraine Fluctuating symptoms in
spinocerebellar ataxia
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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
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Treatment
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References
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THE END!!!