ATAXIAS, EPISODIC

CACNA1A, CACNB4, KCNA1, SCN2A, SLC1A3, UBR4

Description

Scientific Background

The clinically and genetically heterogeneous disease group of autosomal dominant episodic ataxia (EA) is divided into 7 subtypes. The genetic cause is not yet known for all subtypes. The leading symptom of all subtypes is paroxysmal ataxia that lasts seconds to minutes or hours to days, often associated with nystagmus and dysarthria.

 

The most common form is episodic ataxia type 2 (EA2, CACNA1A) with a prevalence of approximately 1:100,000, followed by EA1 (KCNA1) with an estimated prevalence of 1:500,000.

 

Further subtypes are the rarer forms EA3, EA4, EA5 (CACNB4), EA6 (SLC1A3) and EA7, which are partly documented only for individual families. Recently EA8 was discovered in a large Irish family whose members have been affected for 3 generations with an early manifesting form (in the 2nd year of life) that is unusual for EA, and all affected persons showed a pathogenic variant in the UBR4 gene. All the genes identified so far code for ion channel proteins, therefore this group of diseases also belongs to the so-called “channelopathies”. The ion channel proteins are located on membranes of glial cells or neurons and have important functions in excitatory neurotransmission.

 

References

Orsucci et al. 2019, Drugs Context 8:212576 / Choi et al. 2016, J Mov Disord. 9:129 / Conroy et al. 2014, Eur J Hum Genet 22:505

 

 

EPISODIC ATAXIA TYPE 2

The clinically and genetically heterogeneous disease group of autosomal dominant episodic ataxia is divided into 7 subtypes. The genetic cause is not yet known for all subtypes. The leading symptom of all subtypes is paroxysmal ataxia that lasts seconds to minutes or hours to days, often associated with nystagmus and dysarthria.

 

With a prevalence of approximately 1:100,000, the most common form is episodic ataxia type 2 (EA2). It is characterized by recurrent phases lasting hours to days of poor balance and gait ataxia, vertigo or swaying dizziness and nausea, which can be triggered by physical exertion or emotional stress. This can be accompanied by dysarthria, oscillopsia, tinnitus, dystonia, migraine-like headaches (in about 50% of cases) and mild myasthenic symptoms. In the periods between seizures, patients are initially asymptomatic, but 90% develop oculomotor disorders and nystagmus. The symptoms usually begin in childhood or early adulthood (2-32 years old), but people with late manifestation after the age of 63 have also been described. There is variable clinical expression, even within a family.

 

EA2 is caused by pathogenic variants in the CACNA1A gene. This gene encodes the alpha-1A subunit of the voltage-gated calcium channel CaV2.1, which is predominantly expressed in the brain stem and cerebellar Purkinje cells. Pathogenic variants in this gene have also been described as the cause of familial hemiplegic migraine. In addition, the expansion of a CAG triplet in the coding region of this gene is the cause of spinocerebellar ataxia type 6 (SCA6).

 

References

Sintas et al. 2017, Sci Rep 7, Article number: 2514 / Guterman et al. 2016, Neurol 86: e239 / Nachbauer et al. 2014, J Neurol 261:983 / Tomlinsen et al. 2009, Clin Neurophysiol 120:1768 / Wan et al. 2001, Front Neuro 2:51 / Ophoff et al. 1996, Cell 87:543

GENES

CACNA1A, CACNB4, KCNA1, SCN2A, SLC1A3, UBR4
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