The Clinical Features and Classification of the Late Onset Autosomal Dominant Cerebellar Ataxias

Abstract

The clinical features of 11 families containing 73 individuals with dominantly inherited cerebellar ataxia of late onset are described. Many of the patients had physical signs in addition to cerebellar ataxia, which included dementia, supranuclear ophthalmoplegia, extrapyramidal dysfunction, optic atrophy, pigmentary retinal degeneration, myoclonus and deafness. These associated features were generally very variable within members of the same family. Intrafamilial correlation of age of onset and an analysis of clustering of clinical features within families using X2 tests suggested that there was little evidence of genetic heterogeneity in the eight kindreds where ophthalmoplegia, optic atrophy, dementia, or extrapyramidal signs were found in affected individuals. One of these families contained descendants of the 'Drew family of Walworth' described by Ferguson and Critchley in 1929. The three other families contained patients with clinically distinct syndromes which were: cerebellar ataxia with pigmentary retinal degeneration; a later onset (over 60 years) 'pure' cerebellar syndrome; and an ataxia disorder associated with myoclonus and deafness. A simple classification of the autosomal dominant cerebellar ataxias is proposed and discussed in relation to previous attempts to classify these disorders on clinical and pathological grounds.

A clinical and genetic study in a large cohort of patients with spinocerebellar ataxia type 6

“…Introduction Spinocerebellar ataxia type 6 (SCA6) is one of the autosomal dominant cerebellar ataxias (ADCAs), and its main clinical characteristic is slowly progressive ataxia consistent with ADCA type III (Harding 1982). SCA6 is caused by the expansion of CAG repeats in the gene for the a 1A (P/Q type) subunit of the voltage-gated calcium channel, which is located on the short arm of chromosome 19 (Zhuchenko et al 1997).…”

A família Drew de Walworth: um século após a avaliação inicial finalmente o diagnóstico doença de Machado-Joseph

“…Gowers, Stewart, Collier, Kinnier-Wilson, Turner, Worster-Drought, Ferguson, Critchley, e Anita Harding entre outros, com diferentes hipóteses diagnósticas, tais como paralisia agitante, esclerose múltipla, ataxia locomotora, sífilis e ataxia heredo-familial. O diagnóstico definitivo só foi realizado 100 anos após, em 1995, através dos estudos de genética molecular realizados pelo grupo liderado por Anita Harding [6][7][8][9][10] . O objetivo desta publicação é fazer revisão histórica dos diagnósticos clínicos estabelecidos para os membros da família Drew até o diagnóstico definitivo em 1995.…”

“…Após o estudo das diferentes apresentações clí-nicas das ataxias cerebelares autossômicas dominantes de início tardio (ACADIT), Harding propôs uma nova classificação, que se tornou mundialmente aceita, sendo utilizada até os dias de hoje, e que separa as ACADIT em: tipo 1 -com oftalmoplegia/ atrofia óptica/ demência/características extrapiramidais/amiotrofia; tipo 2 -com degeneração pigmentar de retina +/-oftalmoplegia, demência or características extrapiramidais; tipo 3 -síndrome cerebelar "pura" (sem distúrbios oculares ou extrapiramidais ou demência), com início tardio (acima de 60 anos); tipo 4 -com mioclonia e surdez 8 . Em 1995, Giunti, Sweeney e Harding publicaram interessante estudo com análise genética molecular, para detecção da AEC tipo 3 ou doença de Machado-Joseph, em famílias com desordens motoras autossômicas dominantes, incluindo a família Drew de Walworth 10 .…”

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

“…Autosomal dominant cerebellar ataxia (ADCA) is a clinical entity of heterogeneous neurodegenerative diseases that show dominantly inherited, progressive cerebellar ataxia that can be variably associated with other neurological and systemic features (Harding 1982). ADCA is now classified by the responsible mutations or gene loci.…”