High frequency of Machado-Joseph disease identified in Southeastern Chinese kindreds with spinocerebellar ataxia

Abstract

BackgroundMachado-Joseph disease (MJD), caused by a CAG repeat expansion located in exon10 of the ATXN3 gene, is now regarded as one of the most common spinocerebellar ataxia (SCA) in the world. The relative frequency of MJD among SCA has previously been estimated at about 50% in the Chinese population and has been reported to be related to the frequency of large normal alleles in some populations. Taq polymerase has been used for PCR in nearly all studies reported previously.MethodsNormal and expanded alleles of ATXN3 were detected via PCR using LA Taq DNA polymerase (better for GC-rich sequences) and denaturing polyacrylamide gel electrophoresis in 150 normal individuals and 138 unrelated probands from autosomal dominant SCA families. To compare reaction efficiency, 12 MJD patients' expanded alleles were amplified with La Taq and Taq polymerase respectively in the same amplifying systems and reaction conditions.ResultsNormal alleles ranged from 12 to 42 CAG repeats. The most common allele contained 14 repeats with a frequency of 23.3%, which corroborates previous reports. The frequency of large normal alleles (>27 repeats) was 0.28, which was very high relative to previous reports. The frequency of MJD in SCA patients was 72.5%, which was significantly higher than those in previous reports about the Chinese and other Asian populations. This frequency was one of the highest reported worldwide, with only Portuguese and Brazilian populations exhibiting higher proportions. All 12 expanded alleles were amplified in PCR with La Taq polymerase, whereas only 2 expanded alleles were amplified with Taq polymerase.ConclusionWe have first reported the highest relative frequency of MJD in Asia, and we attribute this high frequency to a more efficient PCR using LA Taq polymerase and hypothesized that large ANs may act as a reservoir for expanded alleles in the Southeastern Chinese population.

Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients

“…The number of CAG repeats in the subjects was determined by polymerase chain reaction (PCR) amplification combined with Sanger sequencing as described previously [2]. …”

“…Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of SCA in China [1, 2]. The pathological cytosine-adenine-guanine (CAG) repeats located in exon10 of the ATXN3 gene on chromosome 14q32.1 are the major genetic factors supporting SCA3 [3].…”

Chinese patients with spinocerebellar ataxia type 3 presenting with rare clinical symptoms

“…Patient 1 had involuntary face movement, gait difficulty with fluctuation and an extra long CAG repeat expansion of 81. Combined with Nandagopal's and Münchau's reports [14,15], and the CAG repeat number (68-84) of SCA3 patients in our former investigation [3], the long CAG repeat number might contribute to dystonic phenotype in SCA3 patients. However, the patients reported by Nandagopal and Münchau [14,15] didn't have fluctuation and were responsive to levodopa.…”

“…Two hundred and one unrelated SCA3 patients identified by the previously reported genetic testing [3] were recruited in the study. They were enrolled in the Genetic Clinic of Huashan Hospital, a generalservice hospital in Shanghai, from February 2008 to March 2011.…”

“…The spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD) [1], is the most common subtype of spinocerebellar ataxia in China [2,3] and is caused by a CAG trinucleotide repeat expansion in exon 10 of ATXN3 gene on chromosome 14q32.1 [4]. The clinical onset typically happens in the second to fourth decade and its presentations mainly consist of cerebellar ataxia and a variety of neuropathies, pyramidal and extrapyramidal signs [5].…”