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Y Ouyang,
K Sakoe,
H Shimazaki,
M Namekawa, T Ogawa,
Y Ando,
T Kawakami,
J Kaneko,
Y Hasegawa,
K Yoshizawa,
T Amino,
K Ishikawa,
H Mizusawa,
I Nakano,
Y Takiyama
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ABSTRACT: The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.
Journal of the Neurological Sciences 10/2006; 247(2):180-6. · 2.35 Impact Factor
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ABSTRACT: The authors describe a Japanese autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patient with a compound heterozygous mutation (32627-32636delACACTGTTAC and 31760delT) in a new exon of the SACS gene. The new exons upstream of the gigantic one should be analyzed when a case is clinically compatible with ARSACS, even without any mutation in the gigantic exon.
Neurology 05/2006; 66(7):1103-4. · 8.31 Impact Factor
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ABSTRACT: The authors describe two patients in a Japanese family with autosomal recessive spastic ataxia of Charlevoix-Saguenay. They presented early onset spastic ataxia, sensorimotor neuropathy, nystagmus, slurred speech, and hypermyelinated retinal nerve fibers. The authors identified a homozygous missense mutation (T7492C) in the SACS gene, which resulted in the substitution of arginine for tryptophan at amino acid residue 2498 (W2498R).
Neurology 02/2004; 62(1):107-9. · 8.31 Impact Factor
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H Shimazaki,
Y Takiyama,
K Sakoe,
K Ikeguchi,
K Niijima,
J Kaneko,
M Namekawa, T Ogawa,
H Date,
S Tsuji,
I Nakano,
M Nishizawa
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ABSTRACT: Early-onset ataxia with hypoalbuminemia is regarded as a variant form of Friedreich ataxia in Japan. Early-onset ataxia with hypoalbuminemia and ataxia with ocular motor apraxia have been considered as the same clinical entity because of the recent identification of a common mutation in the aprataxin gene. A new clinical entity named early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) has been proposed to explain these two diseases.
To disclose the clinical features of EAOH and to identify the mutations in the aprataxin gene in six patients in four Japanese families with EAOH.
The clinical features, laboratory findings, sural nerve biopsy results, and brain MRI or CT findings for these patients were evaluated, and molecular analysis was performed, which involved sequencing of the aprataxin gene directly or use of the subcloning method.
Cerebellar ataxia and peripheral neuropathy were noted in all six patients. Ocular motor apraxia was observed in five patients; two of these patients had obvious head thrust. Choreiform movements of the limbs and mental deterioration were observed in five patients. Although foot deformity was noted in five patients, kyphoscoliosis was noted only in one patient. In all patients, hypoalbuminemia and hypercholesterolemia were evident, and brain MRI or CT showed marked cerebellar atrophy. Nerve biopsy revealed depletion of large myelinated fibers in three of the five patients examined. Molecular analysis of the aprataxin gene revealed an insertion mutation (insT at nt167) and two missense mutations (A-to-G transition at nt80 and C-to-T transition at nt95, the former being novel).
We found clinical heterogeneity in the patients with EAOH in this study. With the disease course, the choreiform movements tended to reduce in degree, and hypoalbuminemia became evident. Molecular analysis identified one insertion and two missense mutations including a novel missense one, which was located at a highly conserved amino acid residue in the aprataxin gene product.
Neurology 09/2002; 59(4):590-5. · 8.31 Impact Factor
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ABSTRACT: A 49-year-old woman with diabetes mellitus developed progressive weakness and atrophy of both thighs rendering her wheelchair-bound within two months. The neurological findings and electrophysiological test results were compatible with diabetic amyotrophy (DA). Immediately after intravenous immunoglobulin (IVIg) therapy (20 g x 3 days), she became able to walk with a cane. After the next course of the therapy, she could walk without assistance. This dramatic effect of IVIg therapy together with the recent observation of vasculitic neuropathy in DA indicates an inflammatory process in this condition, and gives support to this treatment for DA.
Internal Medicine 05/2001; 40(4):349-52. · 0.94 Impact Factor
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ABSTRACT: Dentatorubral-pallidoluysian atrophy (DRPLA) is known to show the most prominent genetic anticipation among CAG repeat diseases. To investigate the mechanism underlying the meiotic instability of expanded CAG repeats in the gene for DRPLA, we determined the CAG repeat sizes of 427 single sperm from two individuals with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38. 5), Huntington's disease (69.0) and spinal and bulbar muscular atrophy (16.3), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance of the change in CAG repeat size was significantly different between the two DRPLA patients (F-test, P < 0.0001). However, the segregation ratio of single sperm with an expanded allele to ones with a normal allele is not statistically different ( P = 0.161) from the expected 1:1 segregation ratio, and thus segregation distortion of expanded alleles in meiosis in male patients with DRPLA was not demonstrated.
Human Molecular Genetics 03/1999; 8(3):453-7. · 7.64 Impact Factor
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ABSTRACT: We describe a Japanese family which includes 13 patients in five generations who have dominantly inherited ataxia. Molecular testing revealed that in these patients the SCA6/CACNL1A4 gene carries the smallest known expanded CAG repeat (21 repeat units). The clinical features of these patients exhibited predominantly cerebellar ataxia with onset late in adult life and a very slowly progressive disease course. In addition, this SCA6 family showed some characteristic clinical and genetic features, including (1) apparent lack of genetic anticipation, with an intergenerationally stable CAG repeat size and (2) down-beat nystagmus and diabetes mellitus in some of the SCA6 patients. We identified three individuals homozygous for an expanded CAG repeat (21/21) in the SCA6/CACNL1A4 gene, two of whom were symptomatic. There were no apparent differences in clinical phenotype between the individuals homozygous and those heterozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene.
Journal of the Neurological Sciences 07/1998; 158(2):141-7. · 2.35 Impact Factor
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Y Takiyama,
K Sakoe,
M Soutome,
M Namekawa, T Ogawa,
I Nakano,
S Igarashi,
M Oyake,
H Tanaka,
S Tsuji,
M Nishizawa
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ABSTRACT: To investigate the mechanism of the meiotic instability of expanded CAG repeats in the gene for Machado-Joseph disease (MJD1), we analyzed the CAG repeat sizes of 1036 single sperm from six individuals with Machado-Joseph disease (MJD). The segregation ratio between single sperm with an expanded allele and those with a normal allele is significantly different (P <0.0001) from the expected 1:1 segregation ratio, which demonstrates segregation distortion of expanded alleles in male meiosis. In single sperm from individuals with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] genotype, significantly greater instability of the CAG repeat was observed compared with single sperm from individuals with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] genotype (F-test, P <0.001). These findings in single sperm confirm non-Mendelian transmission of the MJD1 gene and the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability of the CAG repeats in the MJD1 gene, which have been observed in clinical and genetic studies. Our results indicate similarities and dissimilarities between MJD and Huntington's disease or myotonic dystrophy in terms of the inter-allelic interaction, segregation distortions and size distribution of trinucleotide repeats in mutant alleles. Further study is required to determine whether there is a common mechanism underlying the instability of the triplet repeats in 'triplet repeat diseases'.
Human Molecular Genetics 08/1997; 6(7):1063-8. · 7.64 Impact Factor
