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Y Takiyama

Publications and source records attributed to Y Takiyama.

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↗
PubMed2006

Early onset insulin-dependent diabetes mellitus as an initial manifestation of aceruloplasminaemia.

BACKGROUND: Aceruloplasminaemia is an autosomal recessive disorder caused by specific mutations in the ceruloplasmin gene. Aceruloplasminaemia is clinically characterized by diabetes mellitus, pigment degeneration of the retina, and neurological abnormalities, such as cerebellar ataxia, extrapyramidal signs, and dementia. We present a patient with aceruloplasminaemia who, until progressive neurological abnormalities were noticed, had been treated for more than 30 years as having Type 1 diabetes mellitus requiring multiple insulin injection therapy. CASE REPORT: The patient was a 58-year-old man. At the age of 23 years, he developed diabetes that required multiple insulin injection therapy. At the age of 39 years, he was commenced on continuous subcutaneous insulin infusion (CSII) therapy. Despite CSII therapy, the patient's blood glucose levels were poorly controlled (HbA(1c), approximately 9.5%). He was diagnosed as having aceruloplasminaemia at 58 years of age when he presented with progressive cerebellar ataxia, extrapyramidal signs of recent onset and pigment degeneration of the retina. CONCLUSIONS: It is possible that some diabetic patients with aceruloplasminaemia are mistakenly diagnosed as having Type 1 diabetes mellitus, as they have reduced insulin secretion and develop diabetes at a younger age, before neurological abnormalities associated with aceruloplasminaemia are apparent. Therefore, aceruloplasminaemia should be considered in patients with insulin-dependent diabetes mellitus who develop progressive neurological abnormalities of unknown aetiology along with a microcytic hypochromic anaemia and retinal degeneration.

Blood Protein Disorders↗
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

Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome.

BACKGROUND: The pathogenesis of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) remains unknown. METHODS: Fourteen stroke-like episodes in six patients with MELAS were studied using clinical, neuroradiologic, and electrophysiologic approaches. In two patients postmortem examination was done. RESULTS: Headache and epileptic seizure were the most common presenting symptoms. In 13 of 14 episodes the cerebral cortex was primarily involved with variable subcortical edema particularly in the temporal, occipital, and parietal cortex. Repeated MRI performed in two episodes revealed progressive spread of the cortical lesion to the surrounding cortex for a few weeks after the onset of symptoms. In 6 of 11 episodes T1-weighted hyperintense cortical signal compatible with cortical laminar necrosis was seen during subacute stage of the episode. Fat-suppression MRI confirmed intracortical gyral hemorrhage in one episode. Petechial gyral microhemorrhages were also pathologically confirmed in the autopsy of another patient. In 9 of 11 episodes focal epileptiform discharges on EEG were noted in the acute brain lesion. In seven of nine episodes focal cortical hyperperfusion was seen in SPECT studies. CONCLUSION: The stroke-like episodes in MELAS may reflect neuronal hyperexcitability, which increases energy demand and creates energy imbalance between energy requirement and adequate availability of adenosine triphosphate due to oxidative phosphorylation defect particularly in the susceptible neuronal population, causing cortical necrosis. The episodic nature of stroke-like episodes is unexplained.

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↗
PubMed2001

Spinocerebellar ataxia type 1 in China: molecular analysis and genotype-phenotype correlation in 5 families.

BACKGROUND: Twelve genetic types of autosomal dominant hereditary ataxia have been recently identified and the genes responsible for most of them cloned. Molecular identification of the type of ataxia is important to determine the disease prevalence and its natural history in various populations. OBJECTIVES: To perform molecular analysis of 75 Chinese families affected with spinocerebellar ataxia (SCA) and to evaluate the spectrum of mutations in these genes and the correlation between genotypes and phenotypes in Chinese patients. SETTING: Neurogenetics Unit, China-Japan Friendship Hospital, Beijing, China. METHODS: One hundred nine patients from 75 kindreds diagnosed as having autosomal dominant SCA, 16 patients with sporadic SCA or spastic paraplegia, 280 control chromosomes of the Chinese population, and 120 control chromosomes of the Sakha population were selected for this study. We conducted detailed mutational analysis by direct sequencing of polymerase chain reaction products amplified from genomic DNA. RESULTS: Spinocerebellar ataxia type 1 (SCA1) was identified in 5 families with 12 studied patients. All affected family members were heterozygous for a CAG repeat expansion in the SCA1 gene containing 51 to 64 trinucleotide repeats. Normal alleles had 26 to 35 repeats. Spinocerebellar ataxia type 1 accounted for 7% of the studied Chinese families with ataxia. In addition, we determined the frequency of a single vs double CAT interruption in 120 control chromosomes of the Siberian Sakha population, which has the highest known prevalence of SCA1, and compared this with 280 control chromosomes from the Chinese populations. The results show that 64.7% of the Siberian normal alleles contain a single CAT interruption, whereas 92% of the Chinese had more than 1 interruption. CONCLUSIONS: Spinocerebellar ataxia type 1 is responsible for 7% of affected families in the Chinese population. A correlation between the prevalence of SCA1 and the number of CAT interruptions in the trinucleotide chain suggests that a CAT-to-CAG substitution may have been the initial event contributing to the generation of expanded alleles and influencing relative prevalence of SCA1.

Adult↗
PubMed2001

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

Amino Acid Sequence↗
PubMed2000

The role of the DAP12 signal in mouse myeloid differentiation.

DAP12 is a recently cloned, immunoreceptor tyrosine-based activation motif-bearing transmembrane adapter molecule that is associated with the NK-activating receptors. Previous reports showed that the DAP12 message could be detected not only in NK cells but also in granulocytes, monocytes, dendritic cells, and macrophages. In this study we found a significant level of DAP12 protein expression in macrophage-related cell lines and organs. Additionally, we observed increased expression of DAP12 after LPS-induced differentiation of M1 cells into macrophages. To examine the role of DAP12 in the myeloid cell lineage, we established M1 FLAG-DAP12 transfectants (FDAP-M1) and demonstrated the marked morphological changes in FDAP-M1 cells caused by signaling through DAP12. Cell surface phenotypic analysis showed up-regulation of macrophage markers CD11b, 2.4G2, and adhesion molecule B7-2. Additionally, after stimulation through DAP12, phosphorylated FLAG -DAP12 could be immunoprecipitated using anti-phosphotyrosine mAbs. Collectively, these findings indicate that direct DAP12 signaling has an important role in macrophage differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed2000

A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter.

Dominantly inherited, late-onset pure cerebellar ataxia is a group of genetically heterogeneous neurodegenerative disorders. Approximately half of these disorders in the Japanese population are caused by moderate expansion of a CAG repeat in the coding region of the CACNA1A gene on chromosome 19p13 (SCA6). However, neither the loci nor the specific mutations for the remaining disorders have been determined. We performed systematic linkage analysis in a three-generation Japanese family with a locus or mutation that differed from those of known spinocerebellar ataxias. The family members with a late onset (> or =39 years old) exhibited pure cerebellar ataxia, whereas those with an early onset (< or =27 years old) first showed intermittent axial myoclonus followed by ataxia. Other neurological signs were sparse, and neuroimaging studies revealed that atrophy was confined to the cerebellum. Multipoint analysis and haplotype reconstruction ultimately traced this novel spinocerebellar ataxia locus (SCA14) to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter (Zmax = 4.08, corrected for age-dependent penetrance).

Adolescent↗
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

[An unusual case of epilepsy exhibiting gelastic seizure, simple visual hallucination, and transient swelling of the left parieto-occipital region].

We report a 74-year-old man with gelastic seizure, simple visual hallucination, and adversive seizure. The patient described his visual hallucinations as "rotating light like a firefly" and "mimicking a stream". Brain CT scan showed a transient swelling as well as low density of a left parieto-occipital region. Electroencephalographic study revealed spikes and fast waves beginning at left occipital region. Although temporal lobe and hypothalamic lesions (especially hypothalamic hamartomas) are well known as origins of gelastic seizures, we could not find any report that described a series of occurrence of gelastic seizure and simple visual hallucination. Usually, simple visual hallucination is thought to occur in occipital lesion. In our case, it is possible that gelastic seizure and simple visual hallucination are related to the epileptic discharge from occipital lesion directly or indirectly. The reversible brain swelling with low density seen in the present case might be caused by cytotoxic edema due to status epilepticus.

Aged↗