Autosomal dominant episodic ataxia: A heterogeneous syndrome

Gancher, Stephen T.; Nutt, John G.

doi:10.1002/mds.870010404

Cited by 102 publications

(49 citation statements)

References 20 publications

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“…12 Clinically, EA 2 is characterized by recurrent attacks of ataxia lasting for several hours to days, which are provoked by physical exertion, emotional stress, or alcohol. 9,13 Several patients also have mild myasthenic symptoms (due to impaired neuromuscular transmission; see below). Attacks may occur daily or over longer intervals, even years in some patients.…”

Section: Clinical Features Of Episodic Ataxia Typementioning

confidence: 99%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

159

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Summary: Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca V 2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

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Section: Clinical Features Of Episodic Ataxia Typementioning

confidence: 99%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

159

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“…66 The disease is heterogeneous and at least two autosomal dominantly inherited types are distinguished. Episodic ataxia type 1 (EA1) is characterised by brief episodes of ataxia and dysarthria (disturbed articulation) lasting seconds to minutes and is associated with interictal myokymia (twitching of small muscles).…”

Section: Clinical Features and Linkage Datamentioning

confidence: 99%

“…Clinical onset generally occurs in childhood or early adulthood. 66 Episodic ataxia 2 was linked to the same interval on chromosome 19p as FHM. [68][69][70][71] Notwithstanding the clinical differences between EA2 and FHM there are also some similarities.…”

Section: Clinical Features and Linkage Datamentioning

confidence: 99%

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Terwindt

Ophoff²,

Haan

et al. 1998

Eur J Hum Genet

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Clinical and genetic heterogeneity as well as influence of environmental factors have hampered identification of the genetic factors which are involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subtypes, may help to unravel the pathogenesis of the more common forms. Recently, different types of mutation in the brain-specific P/Q type calcium channel α 1A subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebellar ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and without aura. In the tottering and leaner mouse, which are characterised by epilepsy and ataxia, similar mutations were identified in the mouse homologue of the calcium channel α 1A subunit gene. These findings add to the growing list of episodic (and now also chronic) neurological disorders, which are caused by inherited abnormalities of voltage-dependent ion channels. The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.

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“…The disease is characterized by symptomatic attacks of imbalance and uncontrolled movements that may be triggered by physical or emotional stress (3,8,12,22,60). The duration of the attacks of ataxia varies: they may occur several times a day or once a year.…”

Section: -Episodic Ataxia Type 1 (Ea1) Is Amentioning

confidence: 99%

“…Although the symptoms vary between and within families, two symptoms are always observed: an ataxic gait during attacks and myokymia. The latter symptom is characterized by continuous muscle activity that can be detected as a rhythmic electromyography activity with a pattern of repeated duplets and multiplets (12,22). Genetic linkage studies have localized the EA1 locus to chromosome 12p13 (36).…”

Section: -Episodic Ataxia Type 1 (Ea1) Is Amentioning

confidence: 99%