Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease

Abstract

DNA tests in normal subjects and patients with ataxia and Parkinson's disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA-binding protein gene and suggests that SCA8 may also be a cause of typical PD.

SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications

“…It is also notable that the age diVerence was statistically signiWcant between cases and controls, which may result in a sampling bias toward the underestimated frequency of larger allele in the controls. Nevertheless, that SCA8 expanded alleles detected in PD or atypical parkinsonism patients from the present, our previous (Wu et al 2004) and other studies (Worth et al 2000;Izumi et al 2003;Baba et al 2005) suggests that SCA8 CTG repeat expansion may play a role in the development of sporadic PD or atypical parkinsonism. The expression of transcripts containing SCA8 CTG repeats in various brain tissues (Koob et al 1999;Nemes et al 2000) as well as the reported white (Kumar and Miller 2008) reinforce the notion that the molecular pathology in SCA8 extends beyond the cerebellum.…”

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

“…Although these Parkinson-like symptoms are most intriguing in view of the association of Klhl1 with mdDA neuronal pathology, they have been mainly attributed to Klhl1-related deficits in Purkinje cells of the cerebellum (He et al, 2006). However, in humans, a direct link between abnormal expansions of trinucleotide repeats within the SCA8 locus, where KLHL1 is located, and cases of Parkinson's disease have been reported (Worth et al, 2000;Izumi et al, 2003;Wu et al, 2004). The expression of Klhl1 in mdDA neurons of the SNc and VTA and the notion that Klhl1 is linked to mdDA pathology in Nurr1-and Pitx3-deficient embryos provide a new basis for studying the role of Klhl1 in the mdDA system.…”

Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease

“…Mutations in other genes were also reported to cause PD, although most of them were not replicated by other groups [1]. Moreover, levodopa-responsive parkinsonism was reported in families with trinucleotide repeat expansions in ATXN2 (SCA2), ATXN3 (SCA3), SCA8, or TBP (SCA17) [2,3]. Besides PDcausing genes inherited in Mendelian fashion, G2385R polymorphism in LRRK2 was found significantly more common among PD patients than controls in some Asian populations, suggesting that this genetic variant acts as a risk factor for sporadic PD.…”