Hidenao Sasaki

The hereditary spinocerebellar ataxias in Japan

In Japan, multiple system atrophy (MSA) accounts for 40% of all spinocerebellar ataxias (SCAs) and hereditary disorders account for 30%. Among the latter, autosomal dominant disorders are common and recessive ataxias are rare. Although the frequency of SCA genotypes differs between geographic regions throughout Japan, SCA6, SCA3/MJD, and DRPLA are the three major disorders, while SCA7, SCA8, SCA10, SCA12, and SCA17 are infrequent or almost undetected. SCA1 predominantly occurs in the northern part of Japan. Overall, 20–40% of dominant SCAs are due to unknown mutations. From this cluster, pure cerebellar ataxias linked with the SCA4, SCA14, and SCA16 locus have been isolated. Among the recessive SCAs, patients with AVED and EAOH have been detected. However, FRDA associated with GAA repeat expansion in the frataxin gene has not been reported so far.

Positional vertigo and macroscopic downbeat positioning nystagmus in spinocerebellar ataxia type 6 (SCA6)

Abstract. To investigate the frequency of positioning nystagmus in degenerative ataxic disorders, we examined downbeat positioning nystagmus (DPN) in 25 patients with spinocerebellar ataxia type 6 (SCA6) and 58 patients with other types of degenerative ataxia. DPN was observed in 21 of the 25 patients with SCA6 (84 %) versus only 3 of the 58 patients (5.2 %) with other types of degenerative ataxia, including multiple system atrophy, SCA1, SCA2, SCA3/Machado-Joseph disease, and non-SCA6 late-onset pure cerebellar ataxia. Our findings indicated that DPN is a distinct part of the clinical presentation of SCA6, showing that vestibular cerebellum is more affected in SCA6 than other types of degenerative ataxia.

Spinocerebellar ataxia type 10 is rare in populations other than Mexicans.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by progressive ataxia and seizures that was initially identified in two Mexican families.1-3⇓⇓ It belongs to a heterogenous group of diseases known as autosomal dominant cerebellar ataxias (ADCA). In ADCA, expanded CAG repeats coding for polyglutamine tracts cause SCA1, 2, 3, 6, 7, and 17, whereas expansions of CTG and CAG repeat in noncoding region are considered pathogenic in SCA8 and 12, respectively.4 The chromosomal location of SCA 4, 5, 11, 13, 14, and 16 have been determined although their mutations remain to be identified.4 We recently determined that the SCA-10 mutation is an unstable expansion of a pentanucleotide (ATTCT) repeat in intron 9 of a novel gene, SCA10 , on chromosome 22q13.3. Although the number of the repeat ranges from 10 to 22 in more than 300 healthy individuals,5 …

Physical map and haplotype analysis of 16q-linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan

AbstractAutosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. We previously mapped a gene locus for ADCA with pure cerebellar syndrome (ADCA type III) to a 3-cM region in chromosome 16q, and found a common haplotype among affected individuals. This region was exactly within the locus for another ADCA, spinocerebellar ataxia type 4 (SCA4). To identify the gene causing 16q-linked ADCA type III, we constructed a contig with 38 bacterial artificial chromosome clones between D16S3043 and D16S3095. The size of this contig was estimated to be 4.8Mb. We found more than 500 nucleotide tandem repeats, including 9 CAG/CTG repeats in this candidate region, although none of the 94 tandem repeats analyzed were expanded in affected individuals. However, we found 11 new polymorphic markers, giving 22 markers spanning the candidate region. By typing these markers on eight Japanese families with ADCA type III, including two new families, we found that a common “founder” haplotype is seen in a more restricted 3.8-Mb region, spanning markers GGAA05 and D16S3095. We present here a newly refined critical interval of 16q-ADCA type III/SCA4. Data of 11 new DNA markers on 16q22.1 would also be useful for other research of genes mapped to this region.

Spastin gene mutation in Japanese with hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a cluster of genetically heterogeneous disorders that has spastic paraplegia as the central feature.1 Autosomal dominant HSP (AD-HSP) is also genetically heterogeneous and seven loci have been identified so far on chromosomes 14q (SPG3), 2p (SPG4), 15q (SPG6), 8q (SPG8), 12q (SPG10), 19q (SPG12), and 2q (SPG13).2–9 Among them, the SPG4 gene named spastin (GenBank accession No AJ246001) has recently been identified; it is composed of 17 exons and encodes a putative nuclear member of the AAA (ATPases associated with diverse cellular activities) protein family.10 In the original report, five different mutations were identified in seven families.10 HSP is a rare disorder in the Japanese population and the prevalence of SPG4 among Japanese AD-HSP patients is unknown.11 Only one Japanese family has been reported with an insertion mutation in exon 8 of spastin .12 In order to assess the frequency of spastin mutations in the Japanese, we analysed mutations in probands from 12 Japanese AD-HSP pedigrees. All of the subjects were neurologically evaluated by the present authors. The diagnosis was based on the neurological findings, a progressive course with an insidious onset, and a positive family history indicating …

Late onset ataxia phenotype in dentatorubro-pallidoluysian atrophy (DRPLA)

Abstract We clinically and genetically studied three patients in a family with dentatorubro-pallidoluysian atrophy (DRPLA). The proband patient had 58/24 CAG repeat alleles of the DRPLA gene (normal ≤ 34 repeats). Cerebellar ataxia first developed in the 6–7th decades and was the predominant feature for more than 10 years in all three, after which two of them manifested dementia and choreiform movements in the advanced stage. Atrophy of the cerebellum and brain stem an CT or MRI had suggested dominant spinocerebellar ataxia as a diagnosis in their ataxia-predominant stage, with a diagnosis of DRPLA being impossible based on the clinical findings alone. Our experience implies that DRPLA must be taken into account in the differential diagnosis of late onset ataxic disorders, since it can easily be overlooked.