1/8. macular degeneration associated with aberrant expansion of trinucleotide repeat of the SCA7 gene in 2 Japanese families.OBJECTIVE: To evaluate the macular function of Japanese patients with a trinucleotide repeat expansion in the spinocerebellar ataxia type 7 (SCA7) gene. methods: Ophthalmic findings in patients whose dna analysis revealed expanded alleles of the trinucleotide repeat in the SCA7 gene were evaluated. RESULTS: Trinucleotide repeat was expanded from 40 to 48 in affected patients (control subjects, 12 repeats). Affected patients were characterized by different degrees of visual acuity decrease (0.09-0.9), a tritan axis color vision, a coarse granular appearance of the macular region on scanning laser ophthalmoscopy, depression of multifocal electroretinograms, and macular degeneration. However, pigmentary changes were not observed in the retina. The trinucleotide repeat was longer and the onset of macular dysfunction was earlier in the younger generation. One patient in a family manifested decreased visual acuity 10 years preceding other neurologic signs. CONCLUSIONS AND CLINICAL RELEVANCE: patients with SCA7 mutations showed macular dysfunction or degeneration with expansion of CAG repeat in the SCA7 gene. However, the lesions were less pigmented than those previously reported. patients also showed ophthalmologic anticipation, which has not been reported for the ocular changes in other patients who have trinucleotide repeat expansion of the responsible genes.- - - - - - - - - - ranking = 1keywords = anticipation (Clic here for more details about this article) |
2/8. Juvenile dentatorubral-pallidoluysian atrophy: new clinical features.Dentatorubral-pallidoluysian atrophy is a rare autosomal-dominant neurodegenerative disorder caused by an expansion of a CAG repeat in the atrophin-1 gene on chromosome 12. Dentatorubral-pallidoluysian atrophy is characterized clinically by prominent anticipation and a wide variety of symptoms that depend on age of onset and number of trinucleotide repeats. The juvenile type of dentatorubral-pallidoluysian atrophy, like Huntington's disease, is most commonly inherited via paternal transmission of the gene and most frequently presents with early-onset progressive myoclonus epilepsy with mental retardation and ataxia. We present six affected individuals with dentatorubral-pallidoluysian atrophy from a black family living in north america. This pedigree includes two severe juvenile-onset cases, one of maternal transmission and the other of paternal transmission. Both cases of juvenile-onset disease presented with autistic features and seizures. Interestingly, cranial magnetic resonance imaging performed on the more affected child revealed only mild cerebellar atrophy. The present family expands the clinical description of juvenile-onset dentatorubral-pallidoluysian atrophy and emphasizes the importance of considering dentatorubral-pallidoluysian atrophy in children with progressive myoclonus epilepsy.- - - - - - - - - - ranking = 1keywords = anticipation (Clic here for more details about this article) |
3/8. Dentatorubral-pallidoluysian atrophy (DRPLA). Molecular basis for wide clinical features of DRPLA.Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder characterized clinically by various combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, dementia and psychiatric symptoms. Based on the phenomenon of anticipation, the gene for DRPLA was recently identified. DRPLA is caused by unstable expansion of a CAG repeat in the gene located on the short arm of chromosome 12. As have been observed in Huntington's disease and SCA1, there is a strong correlation between the age of onset and the size of CAG repeats. Furthermore, patients with larger repeats tend to show a PME (progressive myoclonus epilepsy) phenotype as well as earlier ages of onset. More prominent anticipation and larger intergenerational increase of CAG repeats in paternal transmission can be accounted for by the meiotic instability of CAG repeats in male gametogenesis. Comparison of size distributions of CAG repeats in Japanese, African-American and white populations revealed that 7.4% of the Japanese alleles had greater than 19 repeats, whereas none of the whites and 1% of the African-American alleles were of this size. The results may account for the ethnic predilection of DRPLA.- - - - - - - - - - ranking = 2keywords = anticipation (Clic here for more details about this article) |
4/8. Dentatorubral-pallidoluysian atrophy (DRPLA): close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation.Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy and dementia as well as various ages of onset. We have identified a specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 as the pathogenic mutation for DRPLA. We investigated how the degree of the expansion of the CAG repeat affects the clinical manifestations of DRPLA. The sizes of the expanded alleles were well correlated with the ages of onset (r = -0.6955, P < 0.001). patients with progressive myoclonus epilepsy (PME) phenotype had larger expansions (62-79 repeats) and earlier ages of onset (onset before age 20). Furthermore, most of the patients with PME phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with non-PME phenotype showed later ages of onset (onset after age 20) and smaller expansions (54-67 repeats). When ages of onset of each clinical symptoms are compared with sizes of the CAG repeat, there is again a remarkably high correlation of the sizes of CAG repeat with each of the clinical symptoms. Thus the wide variation in clinical manifestations of DRPLA can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.- - - - - - - - - - ranking = 4keywords = anticipation (Clic here for more details about this article) |
5/8. Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias.Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinical and genetic heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia. One defective gene responsible for the disease was first localised to 6p (SCA1, spinocerebellar ataxia type 1) and the mutation has been more recently characterised. We have analysed the CAG-repeat mutation responsible for the SCA1 phenotype in a large Spanish kindred with 41 affected members, in which positive linkage with D6S89 was previously shown. All (10) clinically affected members analysed were heterozygous with one disease allele being between 41 to 57 CAG repeats, and the other in the normal range, from 6 to 39 repeats. Nine clinically unaffected individuals who were between the ages of 18 and 40, were found to have expansions of the CAG repeat (41 to 59), and 22 other 'at risk' individuals were found to have inherited the SCA1 gene with copies of the CAG repeat in the normal range. We have also observed that affected fathers passed on the mutated SCA1 gene with larger increases in the number of CAG repeats than affected mothers did. In one case a decrease in the number of CAG repeats (51 to 50) was detected in the transmission from the affected mother, and in two cases no change was observed in the transmission of a 41 allele repeat by a mother. As in the other disorders in which knowledge of the mutation has been obtained, analysis of the repeat expansion dramatically changes diagnosis of SCA1.- - - - - - - - - - ranking = 4keywords = anticipation (Clic here for more details about this article) |
6/8. Clinical and molecular analysis of neurodegenerative diseases.Clinical and molecular analyses of neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 1 (SCA1) were performed. In the present study, a Japanese family of AD with an Ala285Val substitution in exon 8 of the presenilin-1 (PS-1) gene was found. This family was characterized by relatively late onset (mean age at 50 years) in familial AD with PS-1 gene mutation and by absence of myoclonus, seizure or paratonia. Magnetic resonance image (MRI) study showed marked linear signal abnormalities in white matter of parietoocctipital lobes, suggesting a presence of cortical amyloid angiopathy of the patient with PS-1 gene mutation. Clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with four different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene were reported. Although features of progressive neurogenic muscular atrophy was common in patients of these families, patients of each family showed characteristic clinical features. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and Babinski sign was not observed in any cases. Bulbar palsy was frequent with a mutation, but not present with another mutation. SOD activity of red blood cells was generally reduced with minor variations. CAG trinucleotide repeat expansion was analyzed in 25 families with hereditary ataxia of Menzel type in the northeast of japan. Twenty of 38 patients in 12 families had expanded allele for spinocerebellar ataxia type 1 (SCA1). Study of the number of CAG repeats in various tissues showed no differences in the repeat length in lymphocytes, muscle or brain; sperm, however, showed an obvious expansion. This may be a clue to a possible mechanism for the molecular basis of paternal anticipation of the disease. These results suggest that clinical features of some familial cases of neurodegenerative diseases such as AD, ALS, and SCA1 are well correlated with their genetic mutations.- - - - - - - - - - ranking = 1keywords = anticipation (Clic here for more details about this article) |
7/8. Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6.Using a molecular diagnostic approach, we investigated 101 kindreds with autosomal dominant cerebellar ataxias (ADCAs) from the central Honshu island of japan, including spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), machado-joseph disease (MJD), dentatorubral and pallidoluysian atrophy (DRPLA) and spinocerebellar ataxia type 6 (SCA6). In our unselected series, MJD was the most common type of ADCA, accounting for 33.7% followed by DRPLA (19.8%), SCA2 (5.9%) and SCA6 (5.9%). No SCA1 mutations were identified. We analysed the clinical features of six molecular confirmed SCA6 kindreds: in each family, there was an expanded allele in the alpha1A-voltage dependent calcium channel comprising between 23 and 25 CAG repeats. The mean age at onset of symptoms was 43 /-13 years. The clinical features consisted predominantly of cerebellar ataxia, dysarthria and horizontal nystagmus, which was generally consistent with ADCA type 3. However several new clinical features were found in some patients: dramatic anticipation, rapid disease progression, severe ataxia associated with action tremor or action myoclonus, and very early onset, which are not described as the classical features of ADCA type 3.- - - - - - - - - - ranking = 1keywords = anticipation (Clic here for more details about this article) |
8/8. Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia.OBJECTIVE: To characterize a distinct form of spinocerebellar ataxia (SCA) clinically and genetically. BACKGROUND: The SCAs are a genetically heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. The mutations for SCA1, 2, 3, 6, and 7 have been identified and shown to be due to expansion of a CAG repeat in the coding region of these genes. Two additional SCA loci on chromosomes 16 and 11 have been designated SCA4 and SCA5. However, up to 20% of individuals with autosomal dominant forms of ataxias cannot be assigned any of these genotypes, implying the presence of other unidentified genes that may be involved in the development of ataxia. methods: We ascertained and clinically characterized a six-generation pedigree segregating an autosomal dominant trait for SCA. We performed direct mutation analysis and linkage analysis for all known SCA loci. RESULTS: The mutation analysis excludes SCA1, 2, 3, 6, and 7, and genetic linkage analysis excludes SCA4 and SCA5 (multipoint location scores < -2 across the candidate region). Clinical analysis of individuals in this family shows that all affected members have dysarthria, gait and limb ataxia, and nystagmus. No individuals have major brainstem or long-tract findings. Analysis of age at disease onset through multiple generations suggests anticipation. CONCLUSION: This pedigree represents a genetically distinct form of SCA with a phenotype characterized by predominantly cerebellar symptoms and signs.- - - - - - - - - - ranking = 1keywords = anticipation (Clic here for more details about this article) |