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Spinocerebellar Atrophy

par Manto, Mario ;Jissendi, Patrice
Référence Encyclopedia of Neuroscience, Elsevier Ltd, page (337-349)
Publication Publié, 2010

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Résumé :

Triplet repeat expansions in the human genome, discovered in 1991, cause a heterogeneous group of disorders which may affect at various degrees the cerebellum, brain stem, and spinal tracts. The pathogenic mechanisms involve either loss of protein function or gain of function at the protein or RNA level. Triplets disorders with spinocerebellar symptoms include autosomal dominant spinocerebellar ataxias (SCAs); fragile X tremor ataxia syndrome (FXTAS), caused by an expansion in the. FMR1 X-linked gene; and the recessive Friedreich ataxia. One main feature of triplet expansion disorders is anticipation, a pattern in which new generations show an increased frequency and severity of the disorder. The phenotypic anticipation is associated with increases in repeat length due to the instability of expanded alleles until a full expansion mutation is transmitted in a classical Mendelian fashion. Clinically, patients usually exhibit a slowly evolving cerebellar syndrome with various combinations of oculomotor disorders, dysarthria, dysmetria/kinetic tremor, and/or ataxic gait. They can also show pigmentary retinopathy, extrapyramidal movement disorders, pyramidal deficits, cortical symptoms, signs of spinal cord involvement, and peripheral neuropathy. Expansions of CAG repeats are found in SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, DRPLA, and SBMA are also classified as polyglutamine expansion disorders. Expansions of CTG repeats occur in SCA8. A pentanucleotide repeat expansion (ATTCT) is associated with SCA10. Missense mutations have been found in SCA14 and fibroblast growth factor (FGF)14. FXTAS syndrome is due to expansions of CGG repeats with a premutation, whereas the full mutation causes fragile X syndrome. Friedreich ataxia results from a triplet expansion (GAA) in an intron, causing a deficiency of frataxin, a mitochondrial protein that plays a role in iron homeostasis. It is estimated that extensive genetic testing leads to the identification of the causative gene in approximately 70-75% of cases. There is currently an intense effort to develop relevant cellular and animal models of triplet repeat expansion disorders. Effective therapies are expected in the coming decade. © 2009 Elsevier Ltd All rights reserved.