Gene dosage influences the age at onset of SCA2 in a family from southern Italy

To the Editor: Spinocerebellar ataxia type 2 (SCA2) is the most common form of autosomal dominant cerebellar ataxia in southern Italy (1). The expansion of a CAG trinucleotide repeat in exon 1 of the SCA2 gene, located on chromosome 12q23-24.1, is responsible for the disease. Normal alleles have 14 to 31 CAG repeats interrupted by one to three CAA trinucleotides, whereas expanded alleles have 33 to over 200 pure repeats, as reported in neonatal cases (2). Clinically, SCA2 is characterized by gait and limb ataxia, dysarthria, slow saccadic eye movements, supranuclear ophthalmoplegia and peripheral neuropathy. Recently, several patients have been described with expansion in the SCA2 gene and an L-dopa responsive parkinsonism (3). In the present study, we reported an Italian SCA2 family in which two brothers and their nephew (the son of another now deceased brother) were affected by progressive ataxia [Fig. 1(a)]. Both parents of these brothers originated from the same isolated village in mid-eastern Sicily (southern Italy); however, no consanguinity was reported between the two parents’ families. Both parents died before the beginning of this study, and the surviving children reported that their father developed gait instability and progressive difficulty in walking when he was 60 and died in an accident at the age of 62. They also recalled that their mother suffered from vertigo; she had fallen many times when she was 80 years of age and died at 82 years for unknown reasons. After having obtained a signed informed consent from three affected family members, genomic DNA was extracted from peripheral blood leukocytes using the standard procedure. The SCA2 gene region containing the CAG repeats was amplified by polymerase chain reaction (PCR). The PCR conditions had been previously published (4). SCA2 genotyping was performed by capillary electrophoresis on ABI 3130XL Avant Apparatus using the GENESCAN software version 3.1 (Applera, Foster City, CA). Each allele was obtained using denaturating high-performance liquid chromatography, and the length of the CAG repeated region was confirmed by direct sequencing on an ABI 3130XL Genetic Analyzer (Applera). In the proband (II-11), SCA2 gene molecular analysis revealed two expanded alleles with 35 and 36 uninterrupted CAG repeats; the proband’s brother (II-6) and the nephew (III-1) were heterozygous for expanded alleles containing 35 and 42 CAG repeats, respectively [Fig. 1(b)]. Considering the clinical features of the affected family members, the proband (35/36 repeats) showed an earlier onset age and a more severe clinical phenotype than his brother (22/35 repeats); the proband developed gait instability at the age of 35 years, dysarthria when he was 40 years and was unable to walk independently at the age of 50 years. At the time of the study (1996), when the proband was 58 years old, he showed dysphagia, severe ataxia in the upper extremities, bilateral Babinski sign and urinary incontinence. Ocular movements were normal. No parkinsonism was noticed in the proband. The severity of disease rating on the inherited ataxia progression scale (IAPS) was 4 (5). T2weighted magnetic resonance imaging (MRI) of the brain, also performed in 1996, showed marked cerebellar atrophy. On contrary, the proband’s brother developed mild ataxia at the age of 65 years; he presented dysarthria, dysphagia and lower motor impairment when he was 67 years old. The IAPS was 2. T2-weighted MRI of the brain performed when this man was 74 years old (1996) revealed a mild cerebellar atrophy. Finally, the age of disease onset and the progression rate and severity of SCA2 symptoms in the nephew (22/42 repeats) were similar to those observed in the proband; the nephew developed gait instability at the age of 30 years and dysarthria at the age of 40 years. The IAPS was 4. The proband’s affected relatives had normal ocular movements and did not show peripheral neuropathy.