The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates

Abstract

The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2 mutation in 31 out of 38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA III or ILOCA confirms the specificity of this mutation. A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes. However, these neurological signs were also seen in an ADCA I family in which the SCA2 mutation was not identified, illustrating the importance of a direct genetic test. The SCA2 families were from different geographical and ethnic backgrounds. However, haplotype analysis failed to show evidence of a founder mutation, even in families from the same geographical origin. The range of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for the pathological alleles. Similar to the other diseases caused by unstable trinucleotide repeats, a significant inverse correlation has been found between the number of repeats and age of onset, and there is a significantly higher paternal instability of repeat length on transmission to offspring. The SCA2 mutation is the most frequent amongst ADCA I patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectively.

Relative Frequencies of CAG Expansions in Spinocerebellar Ataxia and Dentatorubropallidoluysian Atrophy in 116 Italian Families

“…This value is close to those reported by Schöls et al [31], Silveira et al [33]and Takano et al [42], and falls between those reported by Giunti et al [32]and Geschwind et al [34]. Mutations in new loci or different mutations in already known loci should be responsible for this subset of families, which are exclusively found in Central and Southern Italy.…”

“…SCA3/MJD is the commonest dominant ataxia in France [30], Germany [31], Portugal [33], two American [34, 36]and two Japanese studies [41, 42]. SCA2 was the commonest dominant ataxia in a British study [32], which collected a heterogeneous population with a 39% Italian component, and in a recent American study [35]. Finally, SCA6 may be the prevalent form in Western Japan [38].…”

“…Different patterns of distribution have been reported in Europe, the US and Japan [30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]. …”

Genetic and clinical analysis in a Chinese parkinsonism-predominant spinocerebellar ataxia type 2 family

“…An inverse correlation has been established between age of SCA2 onset and CAG repeat length, with repeat length accounting for 54-80% of variance. 21,22 However, such inverse correlation was not observed in our pedigree. In the branches of III-1 and III-2, the age of onset in affected individuals who carried the 38 CAG repeats ranged from 22 to 37.…”

Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients

“…An exonic unstable CAG repeat expansion is the most frequent mutation associated with this group of neurodegenerative disorders 1 . Machado Joseph disease (MJD) or spinocerebellar ataxia type 3 (MJD/SCA3) seems to be the most common late-onset spinocerebellar ataxia in many world regions, including Germany, Brazil, Portugal, India, France, North America, Japan, China and Taiwan [1][2][3][4][5] . In normal individuals, the gene contains between 12 and 44 CAG repeats, whereas most patients have between 61 to 87 CAG repeats 6 .…”