Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients.
ABSTRACT Expansions of trinucleotide repeats have been discovered in spinocerebellar ataxia (SCA) types 1, 2, 6, 7, 12, and 17, Machado-Joseph disease (MJD/SCA3), and dentatorubropallidoluysian atrophy (DRPLA). However, the frequency of familial SCA in Japan remains unclear. The number of trinucleotide repeats was determined for 1,286 patients. Three hundred and thirty families (523 cases) were autosomal dominant group (A), and 165 families were positive for family history but not autosomal dominant group (B), while the remaining 598 cases were the sporadic group (C). The frequency of SCA subtypes in autosomal dominant group was: 1) 5.5% for SCA1; 2) 2.4% for SCA2; 3) 27.6% for MJD/SCA3; 4) 25.5% for SCA6; 5) 0.3% for SCA17; and 6) 7.3% for DRPLA. Abnormal expansion of SCA12 was not detected. Another 31.5% of the patients in the autosomal dominant group had unknown genetic abnormalities. Within group B, SCA6 was the most prominent and within the sporadic group MJD/SCA3 and SCA6 were the most common subtypes observed. The disease-free survival curve of SCA6 was different from that of other SCAs and the mean age at onset for SCA6 was found to be later than that of the other types. Regional differences were observed in the relative rate of SCA subtypes. MJD/SCA3 appears more common in the Kanto and Kyushu districts of Japan, whereas SCA6 is most common in the Chugoku district. In order to establish an effective social welfare system for SCA patients, clinical course and regional differences in the prevalence of SCA subtypes must be taken into consideration.
Article: High frequency of Machado-Joseph disease identified in southeastern Chinese kindreds with spinocerebellar ataxia.[show abstract] [hide abstract]
ABSTRACT: Machado-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. Normal 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. Normal 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. We 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.BMC Medical Genetics 03/2010; 11:47. · 2.33 Impact Factor
Article: Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics.[show abstract] [hide abstract]
ABSTRACT: Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.Orphanet Journal of Rare Diseases 01/2011; 6:33. · 5.83 Impact Factor
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ABSTRACT: Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), represents the most common form of SCA worldwide. MJD is an autosomal dominant neurodegenerative disorder of late onset, involving predominantly the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems; although sharing features with other SCAs, the identification of minor, but more specific signs, facilitates its differential diagnosis. MJD presents strong phenotypic heterogeneity, which has justified the classification of patients into three main clinical types. Main pathological lesions are observed in the spinocerebellar system, as well as in the cerebellar dentate nucleus. MJD's causative mutation consists in an expansion of an unstable CAG tract in exon 10 of the ATXN3 gene, located at 14q32.1. Haplotype-based studies have suggested that two main founder mutations may explain the present global distribution of the disease; the ancestral haplotype is of Asian origin, and has an estimated age of around 5,800 years, while the second mutational event has occurred about 1,400 years ago. The ATXN3 gene encodes for ataxin-3, which is ubiquitously expressed in neuronal and non-neuronal tissues, and, among other functions, is thought to participate in cellular protein quality control pathways. Mutated ATXN3 alleles consensually present about 61 to 87 CAG repeats, resulting in an expanded polyglutamine tract in ataxin-3. This altered protein gains a neurotoxic function, through yet unclear mechanisms. Clinical variability of MJD is only partially explained by the size of the CAG tract, which leaves a residual variance that should be explained by still unknown additional factors. Several genetic tests are available for MJD, and Genetic Counseling Programs have been created to better assist the affected families, namely on what concerns the possibility of pre-symptomatic testing. The main goal of this review was to bring together updated knowledge on MJD, covering several aspects from its initial descriptions and clinical presentation, through the discovery of the causative mutation, its origin and dispersion, as well as molecular genetics aspects considered essential for a better understanding of its neuropathology. Issues related with molecular testing and Genetic Counseling, as well as recent progresses and perspectives on genetic therapy, are also addressed.Orphanet Journal of Rare Diseases 01/2011; 6:35. · 5.83 Impact Factor