SCA12 is an autosomal dominant cerebellar ataxia (ADCA) with onset in the 4th decade, clinically characterized by the association of action tremor of arms and heads, mild ataxia, dysmetria and hyperreflexia. Bradikinesia, and sensory/motor neuropathy are also present, and older subjects may develop cognitive decline. The genetic mutation underlying SCA12 is a ≥51 CAG expansion in the 5’ region of the brain-specific regulatory subunit B of the protein phosphatase 2A gene (PPP2R2B). SCA12 is very rare, and no patient has been identified in Europe, except for a single ethnic group in India where it accounts for up to 16% of ADCAs probably due to a founder effect. As part of our diagnostic routine, we screened 181 ataxic patients for expansion in the SCA12 gene between 2003 and 2008. The survey comprised cases with autosomal dominant, probably recessive and unknown transmission. We found two carriers of an expanded SCA12 allele (57 CAG). One patient belonged to a family with a clear autosomal dominant transmission; the other was apparently sporadic. Clinical and genetic analyses in the two families revealed the presence of a symptomatic subject carrying the expansion in one and two asymptomatic carriers, aged 68 and 37 yrs, in the other. The two families originated from the Ferrara province, in northeastern Italy: haplotype reconstruction showed that both shared a common haplotype of four microsatellites (one of which was internal to the PPP2R2B gene) and four intragenic SNPs, different from that described in Indian SCA12 patients. In the three affected patients, the disease onset at 53±7,6 yrs (range 45-60) with either action tremor of head and hands, or fine hands movement impairment, or gait instability. Cognitive impairment and psychiatric disorders were not reported. MRI, performed in symptomatic patients, showed mild cortical atrophy in two, associated with mild cerebellar atrophy in the third. These data indicate that, although rare, SCA12 can be found in Italy: considering the results of a previous survey of 225 ataxic patients, performed by our group (Brusco et al., 2004), SCA12 may count for up to 0.5% (2/406) of Italian SCAs. The age at onset and variability of symptoms are in agreement with those already described. Because of the late age at onset and slow progression, SCA12 subjects may be classified as sporadic ataxia: this suggests that SCA12 testing, due to its simplicity, should be routinely extended both to sporadic and familial cases.
Spinocerebellar ataxia type 12 identified in two Italian families
BRUSSINO, Alessandro;FERRONE, Marina Maria Teresa;MIGONE, Nicola;BRUSCO, Alfredo
2009-01-01
Abstract
SCA12 is an autosomal dominant cerebellar ataxia (ADCA) with onset in the 4th decade, clinically characterized by the association of action tremor of arms and heads, mild ataxia, dysmetria and hyperreflexia. Bradikinesia, and sensory/motor neuropathy are also present, and older subjects may develop cognitive decline. The genetic mutation underlying SCA12 is a ≥51 CAG expansion in the 5’ region of the brain-specific regulatory subunit B of the protein phosphatase 2A gene (PPP2R2B). SCA12 is very rare, and no patient has been identified in Europe, except for a single ethnic group in India where it accounts for up to 16% of ADCAs probably due to a founder effect. As part of our diagnostic routine, we screened 181 ataxic patients for expansion in the SCA12 gene between 2003 and 2008. The survey comprised cases with autosomal dominant, probably recessive and unknown transmission. We found two carriers of an expanded SCA12 allele (57 CAG). One patient belonged to a family with a clear autosomal dominant transmission; the other was apparently sporadic. Clinical and genetic analyses in the two families revealed the presence of a symptomatic subject carrying the expansion in one and two asymptomatic carriers, aged 68 and 37 yrs, in the other. The two families originated from the Ferrara province, in northeastern Italy: haplotype reconstruction showed that both shared a common haplotype of four microsatellites (one of which was internal to the PPP2R2B gene) and four intragenic SNPs, different from that described in Indian SCA12 patients. In the three affected patients, the disease onset at 53±7,6 yrs (range 45-60) with either action tremor of head and hands, or fine hands movement impairment, or gait instability. Cognitive impairment and psychiatric disorders were not reported. MRI, performed in symptomatic patients, showed mild cortical atrophy in two, associated with mild cerebellar atrophy in the third. These data indicate that, although rare, SCA12 can be found in Italy: considering the results of a previous survey of 225 ataxic patients, performed by our group (Brusco et al., 2004), SCA12 may count for up to 0.5% (2/406) of Italian SCAs. The age at onset and variability of symptoms are in agreement with those already described. Because of the late age at onset and slow progression, SCA12 subjects may be classified as sporadic ataxia: this suggests that SCA12 testing, due to its simplicity, should be routinely extended both to sporadic and familial cases.
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