Biomedical subjects

K Sakoe

Publications and source records attributed to K Sakoe.

At least 19 recordsLinked to original sources

PubMed2006

16q-linked autosomal dominant cerebellar ataxia: a clinical and genetic study.

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.

Age of Onset↗

PubMed2006

Sacsin-related ataxia (ARSACS): expanding the genotype upstream from the gigantic exon.

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.

Adult↗

PubMed2005

A phenotype without spasticity in sacsin-related ataxia.

The authors describe two Japanese siblings with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) without spasticity, usually a core feature of this disorder. They had a novel homozygous missense mutation (T987C) of the SACS gene, which resulted in a phenylalanine-to-serine substitution at amino acid residue 304.

Adult↗

PubMed2004

Identification of a SACS gene missense mutation in ARSACS.

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).

Adult↗

PubMed2002

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Adult↗

PubMed2002

A Japanese SPG4 family with a novel missense mutation of the SPG4 gene: intrafamilial variability in age at onset and clinical severity.

OBJECTIVES: We report the results of clinical and genetic studies on a Japanese SPG4 family. MATERIAL AND METHODS: Family N included eight patients in four generations with autosomal dominant transmission. We performed neurological and molecular analyses on the SPG4 gene in the family members comprising three patients, 12 at-risk individuals, and three normal spouses. RESULTS: The three patients showed pure spastic paraplegia, two of them exhibiting a decrease in vibration sense. There was marked intrafamilial variability in age at onset and clinical severity in the present family. On molecular analysis, a novel missense mutation (nt1579 C-->T) in exon 12 of the SPG4 gene was found in the three patients, three probably affected, and an asymptomatic carrier. CONCLUSION: The present SPG4 family, which was shown to have a novel SPG4 mutation, exhibited marked variability in the clinical features, indicating the participation of additional factors in the phenotypic appearance of this family.

Adenosine Triphosphatases↗

PubMed2001

Choreiform movements in spinocerebellar ataxia type 1.

We describe the unusual case of a 51-year-old woman with spinocerebellar ataxia type 1 (SCA1) who showed choreiform movements in addition to cerebellar ataxia. To date, extrapyramidal signs including involuntary movements have been rarely reported in SCA1. Surface electromyogram in our patient revealed grouped discharges whose duration was longer than that of chorea observed in HD, indicating that the involuntary movements represented choreoathetosis rather than pure chorea. These choreiform movements have not been seen in non-hereditary spinocerebellar ataxia. Therefore, if "sporadic" cases of cerebellar ataxia show such movements, the possibility of genetic origin of the ataxia is high and a surveillance of various forms of hereditary spinocerebellar ataxia including SCA1 is required.

Cerebellum↗

PubMed2001

Meiotic instability of the CAG repeats in the SCA6/CACNA1A gene in two Japanese SCA6 families.

Intergenerational stability of the CAG repeat number has been considered to be a specific molecular feature of SCA6 compared with other CAG repeat diseases. Nevertheless, we showed meiotic instability of the CAG repeats in the SCA6/CACNL1A gene in two Japanese SCA6 families, including de novo expansion. In one family, the CAG20 allele expanded to the CAG26 one during paternal transmission, and in the other family, the CAG19 allele expanded to the CAG20 one during maternal transmission. Although it is controversial as to whether the CAG20 allele is pathological or not, this is the first case of haplotype analysis-proven de novo expansion in SCA6, confirming the derivation of an expanded allele from one normal allele. We should carefully follow up the individuals carrying the CAG20 allele in our family who show normal neurological and radiological findings at present.

Adult↗

PubMed2001

A large Japanese SPG4 family with a novel insertion mutation of the SPG4 gene: a clinical and genetic study.

We studied a large Japanese family with autosomal dominant pure hereditary spastic paraplegia (ADPHSP) clinically and genetically. To date, seven loci causing ADPHSP have been mapped to chromosomes 14q, 2p, 15q, 8q, 12q, 2q, and 19q. Among these loci, the SPG4 locus on chromosome 2p21--p22 has been shown to account for approximately 40% of all autosomal dominant hereditary spastic paraplegia (ADHSP) families. Very recently, Hazan et al. identified the SPG4 gene encoding a new member of the AAA (ATPases associated with diverse cellular activities) protein family, named spastin. We found a novel insertion mutation (nt1272--1273insA) in exon 8 of the SPG4 gene in the present family. Our study is the first to confirm the causative mutation of the SPG4 gene in Japanese. Clinically, it is noteworthy that the disease progression in the patients of this family was slow in spite of the late onset, and more than half of the patients showed severe constipation in addition to pure spastic paraplegia.

Adenosine Triphosphatases↗

PubMed2000

Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription.

At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.

Aged↗

PubMed2000

[A familial case of spinocerebellar ataxia type 8 (SCA 8)--its clinical findings and an issue about the genetic basis].

We report a 28-year-old woman with spinocerebellar ataxia type 8 (SCA 8). This patient began to exhibit dysarthria at the age of 19. At the age of 25, she fell and hit her head while drunk and then a neurosurgeon found that her cerebellum was atrophic on cranial CT and MRI. Neurological examination on admission to our hospital revealed ataxic speech, limb ataxia and mild hyperreflexia without Babinski's sign. Cranial MRI showed only mild atrophy of the cerebellar hemispheres and vermis. Based on the results of genetic analysis, which showed expanded CTG repeats[(CTA) 13 (CTG) 5 (CCG) 4 (CTG) 124] on the SCA 8 locus at 13q21, she was diagnosed as having SCA 8. As clinical signs of SCA 8, Koob et al. reported limb spasticity and diminished vibration perception including cerebellar ataxia. Furthermore, Hirose et al. and Satoh et al. reported cases showing involuntary movements such as myoclonus or chorea including cerebellar ataxia. Our case and Ikeda's cases presented a pure cerebellar phenotype. We think that SCA 8 exhibits clinical heterogeneity. On the other hand, Stevanin et al. and Worth et al. expressed doubt as to whether the SCA 8 locus at 13q21 is the gene actually responsible for autosomal dominant cerebellar ataxia (ADCA). We conclude that it is necessary to accumulate additional case reports, and to further investigate the relationship between the clinical findings and the results of genetic analysis in order to determine whether or not the SCA 8 locus at 13q21 is the genetic basis for ADCA.

Adult↗

PubMed1999

A case of McLeod syndrome with unusually severe myopathy.

A 51-year-old man developed weakness and muscle atrophy in the legs at the age of 41, later followed by choreiform involuntary movements. Neurological and laboratory examinations revealed severe muscle weakness and atrophy, and areflexia in all the extremities, acanthocytosis and an elevated serum creatine kinase level. Together with these findings, the weak expression of Kell blood group antigens and the absence of the Kx antigen led to a definite diagnosis of McLeod syndrome for his condition. Brain magnetic resonance imaging revealed marked atrophy of the head of the caudate nuclei. Although immunocytochemical analysis of dystrophin in muscle specimens from our patient revealed normal staining, we found prominent fiber size variability, central nuclei, and connective tissue proliferation as well as necrotic and regenerating fibers, which are as a whole compatible with the myopathology of muscular dystrophy. Moreover, muscle computerized tomography of the lower extremities revealed the 'selectivity pattern' characteristically reported in muscular dystrophies including Duchenne type muscular dystrophy. The muscular symptoms and pathology in McLeod syndrome have been reported to be mild, but the present case clearly shows that the muscular features in this condition may be much more severe than previously thought.

Acanthocytes↗

PubMed1999

Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy (DRPLA): the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases.

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.

Alleles↗

PubMed1998

Expression cloning and functional characterization of human cDNA for ganglioside GM3 synthase.

Ganglioside GM3 is a major glycosphingolipid in the plasma membrane and is widely distributed in vertebrates. We describe here the isolation of a human cDNA whose protein product is responsible for the synthesis of GM3. The cloned cDNA spanned 2,359 base pairs, with an open reading frame encoding a protein of 362 amino acids with a predicted molecular mass of 41.7 kDa. The deduced primary structure shows features characteristic of the sialyltransferase family, including a type II transmembrane topology and the sialylmotifs L at the center and S at the C-terminal region. An amino acid substitution from aspartic acid to histidine was demonstrated at a position invariant in sialylmotif L of all the other sialyltransferases so far cloned. The best acceptor substrate for the gene product was lactosylceramide, and cells transfected with the cloned cDNA clearly exhibited de novo synthesis of GM3, with a measurable decrease in the precursor lactosylceramide. Despite the ubiquitous distribution of ganglioside GM3 in human tissues, a major 2.4-kilobase transcript of the gene was found in a tissue-specific manner, with predominant expression in brain, skeletal muscle, and testis, and very low expression in liver.

Amino Acid Sequence↗

PubMed1998

A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene.

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.

Aged↗

PubMed1998

Maternal anticipation in Machado-Joseph disease (MJD): some maternal factors independent of the number of CAG repeat units may play a role in genetic anticipation in a Japanese MJD family.

We studied the relationship between the number of CAG repeat units in the MJD1 gene and clinical features of Machado-Joseph disease (MJD) in eight patients from two generations of a Japanese MJD family. Because of lack of characteristic clinical signs of MJD such as dystonia, bulging eyes or facial myokymia, clinical diagnosis of MJD in this family was difficult to make prior to molecular testing for the CAG repeat expansion in the MJD1 gene. All the patients exhibited maternal transmission of MJD, and the intergenerational change in the number of CAG repeat units in the MJD1 gene was very small (+0.5+/-0.3, mean+/-S.E.M., n=4) in spite of marked genetic anticipation (-17.0 years/generation). In the present family, the degree of anticipation per repeat unit in maternal transmissions was much larger than that in maternal transmissions in the other six MJD families. This indicates that some maternal factors other than the increase of the number of CAG repeat units, which is known to be the basis of anticipation, may play a role in genetic anticipation in this MJD family.

Adult↗

PubMed1997

Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability.

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'.

Alleles↗

PubMed1997

Machado-Joseph disease: cerebellar ataxia and autonomic dysfunction in a patient with the shortest known expanded allele (56 CAG repeat units) of the MJD1 gene.

We describe an unusual case of a patient with Machado-Joseph disease (MJD) who showed autonomic dysfunctions in addition to cerebellar ataxia. The number of CAG repeat units in the expanded allele of the MJD1 gene of the patient is smaller (56 CAG repeat units) than all previously reported numbers of CAG repeat units in expanded alleles. Thus, the findings in this patient indicate that the clinical features of MJD cover a wider spectrum than previously thought.

Alleles↗