Clinical features of SCA36
Yoshio IkedaYasuyuki OhtaHatasu KobayashiM. OkamotoKazuhiro TakamatsuTaisei OtaYasuhiro ManabeKoichi OkamotoAkio KoizumiKōji Abe
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To characterize the phenotype of spinocerebellar ataxia type 36 (SCA36), a novel dominant disorder (nicknamed "Asidan") caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene.We investigated the clinical, genetic, and neuropathologic characteristics of 18 patients with SCA36. We performed histologic evaluation of a muscle biopsy specimen from 1 patient with SCA36, and neuropathologic evaluation of an autopsied brain from another patient with SCA36.The (GGCCTG)n expansion was found in 18 ataxic patients from 9 families. The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%). Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration. Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases. Lower motor involvement was confirmed by EMG and muscle biopsy. The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons. Immunohistochemical analysis showed that NOP56 was localized to the nuclei of various neurons. Cytoplasmic or intranuclear inclusion staining of NOP56, TDP-43, and ataxin-2 was not observed in the remaining neurons.This is the first description of the unique clinical features of SCA36, a relatively pure cerebellar ataxia with progressive motor neuron involvement. Thus, SCA36 is a disease that stands at the crossroads of SCA and motor neuron disease.Keywords:
Fasciculation
Cerebellar ataxia
Cerebellar Degeneration
Spinocerebellar ataxias (SCA) are most frequently due to (CAG)
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The repeat expansion detection (RED) method was described to detect expansions of trinucleotide repeats of unknown chromosomal location. We have improved the RED method by the use of 8-mer oligonucleotides and assessed its usefulness in 30 samples from patients with spinocerebellar ataxia type 1 (SCA1), Huntington's disease (HD), and Machado Joseph's disease (MJD), for which the number of CAG/CTG repeats was determined by sequencing. There was a good correlation between the number of repeats detected by sequencing and those identified by RED. However, in 17% of samples, the RED gave additional fragments for ligation products of different size than the CAG/CTG repeat expansion detected in the sample by sequencing. The same was observed in a group of control subjects (n = 78) without known clinical abnormalities in which products of more than 40 repeats were detected in 27% of them, indicating that CAG/CTG repeat expansions are common in the general population. Wether this corresponds to unidentified loci with expansions deserves further investigation. Hum Mutat 10:486–488, 1997. © 1997 Wiley-Liss, Inc.
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Foreword.Introduction.The FRAXA fragile site and fragile X syndrome.Molecular studies of the fragile sites FRAXE and FAXF.Myotonic dystrophy.Spinobulbar musculal atrophy.Polyglutamine tract vs protein context in SCA1 pathogenesis.Spinocerebellar ataxia type 2 (SCA2).Spinocerebellar ataxia type 3/Machado Joseph disease.Spinocerebellar ataxia type 6 (SCA6).Spinocerebellar ataxia type 7 (SCA7). Huntingtons disease.Dentatorubral-pallidoluysian atrophy (DRLPA).Friedrich's ataxia.Anticipation, triplet repeats and psychiatric disorders.Trinucleotide repeat mutation processes.Diagnostic testing for trinucleotide repeat diseases.Predictive testing for trinucleotide repeat diseases.
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Expanded CAG repeat sequences have been identified in the coding region of genes mutated in several neurodegenerative disorders, including spinocerebellar ataxia type 1 and Machado-Joseph disease. In all disorders described to date the CAG expansion codes for an elongated polyglutamine chain. An increased polyglutamine chain size leads to a more severe disease, thus correlating with the genetic anticipation seen in repeat expansion disorders. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant spinocerebellar ataxia with anticipation and a progressive degeneration of the cerebellar cortex. Using repeat expansion detection (RED), a method in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA, we have analyzed 8 SCA7 families for the presence of CAG repeat expansions. RED products of 150-240 bp were found in all affected individuals and found to cosegregate with the disease (P < 0.000001, n = 66), indicating strongly that a CAG expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease, we were able to estimate the average expansion size in SCA7 to be 64 CAG copies.
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Spinocerebellar ataxia type 17 (SCA17) is associated with an expansion of CAG/CAA trinucleotide repeats in the gene encoding TATA-binding protein (TBP). The aim of this study was to characterize eye movements in SCA17 and to localize oculomotor deficits.
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To explore the profile of cytosine/adenine/guanine (CAG) repeat expansion in Omani spinocerebellar ataxia (SCA) patients.Ten SCA patients attending the Sultan Qaboos University Hospital Neurologic clinics, Al-Khoud, Oman in the 3 years starting from January 2000 were recruited for this study. Genomic DNA was extracted from peripheral blood samples and CAG repeat expansion analysis was carried out by polymerase chain reaction and sequencing, when required.The CAG triplet repeats leading to polyglutamine expansion and neurodegeneration are seen in spinocerebellar ataxias 1, 2, 3, 6, 7 and 17. By using primers for SCA 1, 2, 3 and 7, we found the repeats were in the normal range and triplet repeats do not seem to be a common cause for ataxia in Oman.Spinocerebellar ataxia in Oman has the normal range of CAG repeats for the commonly found SCA1, SCA2, SCA3 and SCA7.
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The autosomal dominant spinocerebellar ataxias (ADSCAs) are a heterogeneous group of late-onset neurodegenerative disorders with overlapping clinical features. Genetic linkage studies have identified at least seven distinct loci for the ADSCAs, allowing the genetic classification of these disorders. The spinocerebellar ataxia type 2 (SCA2) locus was mapped to chromosome 12, and a gene responsible for this disorder was recently isolated. The mutation causing SCA2 is an expansion of a trinucleotide CAG repeat contained within the coding region of a novel gene. We describe the results of genotypic analysis for the SCA2 repeat in individuals with ADSCA who were previously found negative for CAG repeat expansions in the SCA1, SCA3, or SCA6 genes. The expanded CAG repeat has been identified in 15 independent families. Repeat instability and anticipation were observed in two large kindreds. The SCA2 mutation was found in 18% of our ADSCA kindreds, confirming the high proportion of SCA2 among this group of disorders.
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