Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology

Abstract

Major advances have been made in the understanding of autosomal dominant cerebellar ataxias since genetic markers came into use in the 1980s. The subsequent mapping of nine genes, six of which have been identified, involved in this clinically diverse group of disorders highlighted their great genetic heterogeneity. Evidence is now accumulating that, except for SCA8, the same molecular and physiopathological processes underlie these diseases and other neurodegenerative disorders sharing the same mutational basis, the expansion of a (CAG)n-polyglutamine coding sequence. The clinical overlap among the different genetic entities makes prediction of the molecular origin impossible in a single patient so that molecular characterisation is necessary. However, extended clinical and neuropathological comparisons have shown that each genetic entity has a characteristic constellation of signs and symptoms that are related to CAG repeat size and disease duration. The combined genetic and clinical information form the basis of a new classification that will aid better understanding of disease evolution, assure follow up and permit genetic counselling by the clinician.

Efeito Da Adição De Carga No Tronco Sobre a Marcha De Um Sujeito Com Ataxia

“…A ataxia é caracterizada por um desequilíbrio ao caminhar e é um dos principais sintomas da Doença de Machado-Joseph (DMJ) 1 . A DMJ pertence ao grupo das ataxias espinocerebelosas autossômicas dominantes 2 , deve-se à presença de mutação genética constituída de repetições trinucleotídicas instáveis (CAG) que aloca-se no cromossomo 14 3 .…”

Expansion of CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene in idiopathic oligozoospermia patients

“…Some studies have established that the anticipation is typically high for spinocerebellar ataxis and MachoadoJoseph disease [13]. Since the length of the CAG repeats in a gene may increase as they are transmitted to the next generation [13], genetic instability of trinucleotide repeats contributes to anticipation.…”

“…Since the length of the CAG repeats in a gene may increase as they are transmitted to the next generation [13], genetic instability of trinucleotide repeats contributes to anticipation. For instance, CAG repeats in SCA1 tend to lengthen during spermatogenesis, explaining why the severity of the disease frequently increases from one generation to the next [14].…”

Ataxia espinocerebelar tipo 7

“…In the SCA type 7, the cerebellar ataxia is associated with progressive visual loss that results from the retina degeneration (progressive macular degeneration). Pyramidal signs, ophthalmoplegia, Parkinsonism, slow saccades and weakness (3)(4)(5) can also be associated with it. Studies (4,5) have identified the occurrence of olivopontocerebellar degeneration associated with the reduction of retinal ganglion cells and pigmentary macular dystrophy.…”

“…Pyramidal signs, ophthalmoplegia, Parkinsonism, slow saccades and weakness (3)(4)(5) can also be associated with it. Studies (4,5) have identified the occurrence of olivopontocerebellar degeneration associated with the reduction of retinal ganglion cells and pigmentary macular dystrophy. The clinical condition may develop during childhood until the 60 years of age, and the younger the individual affected, the faster the disease progresses (5) .…”