spinocerebellar ataxias

Spinocerebellar ataxias form a group of genetically distinct diseases characterized by signs and symptoms referable to the cerebellum (progressive ataxia), brainstem, spinal cord, and peripheral nerves, as well as other brain regions in different subtypes.

Pathologically, they are characterized by neuronal loss from the affected areas with secondary degeneration of white matter tracts. The clinically identified spinocerebellar ataxias can be separated on the basis of inheritance pattern into autosomal dominant and recessive types; the genetic understanding of this large and diverse group of diseases continues to evolve.

Among dominantly inherited forms, there are many that are associated with trinucleotide (or larger) repeat expansion. In those forms in which there is expansion of a CAG repeat encoding polyglutamine tract (SCA1-3,6,7,17), neuronal intranuclear inclusions containing the abnormal protein can be found, similar to Huntington disease.

As with HD, these forms of spinocerebellar ataxia show correlation between the degree of repeat expansion and age of onset. All but SCA6 also show anticipation, with expansion of the repeat length during gametogenesis.

Curiously, SCA6 shares its genetic locus with another cerebellar disorder-episodic ataxia type 2 (EA-2)-which is associated with point mutations. The other form of episodic ataxia (EA-1) is also a channelopathy, being caused by mutations in the delayed rectifier potassium channel subunit Kv1.1.

Hereditary spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders for which more than 14 different genetic loci have been identified.

Classification

21 identified loci

SCA1	SCA2	SCA3	SCA4	SCA5	SCA6	SCA7	SCA8	SCA9	SCA10
SCA11	SCA12	SCA13	SCA14	SCA15	SCA16	SCA17	SCA18	SCA19	SCA20
SCA21

Etiology

In some SCAs, expanded tri- or pentanucleotide repeats have been identified, and the length of these expansions correlates with the age at onset and with the severity of the clinical phenotype.

 autosomal dominant cerebellar ataxia

• mutation in the fibroblast growth factor 14 gene (13q34)(12489043)

 autosomal dominant nonepisodic cerebellar ataxia

• missense mutations in the regulatory domain of PKC gamma

Videos

 Mouse model of spinocerebellar ataxia

< object width="425" height="350"> < param name="movie" value="http://www.youtube.com/v/He4mwIPTuDM"> < /param> < param name="wmode" value="transparent"> < /param> < embed src="http://www.youtube.com/v/He4mwIPTuDM" type="application/x-shockwave-flash" wmode="transparent" width="425" height="350"> < /embed> < /object>

References

 Orr HT, Zoghbi HY. SCA1 molecular genetics: a history of a 13 year collaboration against glutamines. Hum Mol Genet. 2001 Oct 1;10(20):2307-11. PMID: 11673415