Takehiko Matsumura

Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells

Abstract. We report a 62-year-old Japanese man with familial frontotemporal dementia and a novel missense mutation (N296H) in exon 10 of the tau gene. The patient presented with frontal signs followed by temporal signs and parkinsonism. The brain showed localized frontotemporal lobe atrophy including the precentral gyrus and discoloration of the substantia nigra, and revealed severe neuronal loss with proliferation of tau-positive protoplasmic astroglia in the affected cerebral cortex, tau-positive coiled bodies and threads in the subcortical white matter, and tau-positive pretangle neurons in the subcortical and brain stem nuclei. There were no tau-positive neurofibrillary tangles, Pick bodies, tuft-shaped astrocytes or astrocytic plaques in the cerebral cortex. Immunoelectron microscopically, phosphorylated tau accumulated in both neurons and glial cells in different modalities, such as glial filaments in protoplasmic astroglia, straight tubules in coiled bodies, and free ribosomes in pretangle neurons. These findings suggest that tau proteins are not always assembled in abnormal filaments such as twisted ribbons, paired helical filaments and straight tubules in neurons and glial cells, which have been shown in previous cases with frontotemporal dementia and parkinsonism linked to chromosome 17. Immunoblotting of sarkosyl-insoluble tau exhibited accumulation of four-repeat tau isoforms in the brain. The N296H mutation may interfere with the ability of mutated tau to bind with microtubules and lead to tau aggregation. Further study is necessary to determine whether this mutation can account for the characteristic tau pathology of this case.

Anxiety and prevalence of psychiatric disorders among patients awaiting surgery for suspected ovarian cancer

Aim:  The goal of the current study was to determine the anxiety level and prevalence of psychiatric disorders among patients awaiting surgery for ovarian tumors. Also analyzed were the predictive factors for psychiatric disorders and changes after surgical diagnosis.

Lack of association in Japanese patients between neuroleptic malignant syndrome and a debrisoquine 4-hydroxylase genotype with low enzyme activity.

Decreased activity of debrisoquine 4-hydroxylase (CYP2D6), which participates in hepatic metabolism of several frequently used neuroleptics and antidepressants, is inherited as an autosomal recessive trait through polymorphic CYP2D6 gene alleles. In eastern Orientals, a C --> T substitution at nucleotide 188 (Pro34Ser) is primarily responsible for decreased ability to metabolize CYP2D6 substrates. We therefore studied a possible association between neuroleptic malignant syndrome (NMS) and the C188T mutation. We examined the frequency of the C188T mutation by polymerase chain reaction and restriction fragment length polymorphism analysis in 36 Japanese patients previously diagnosed with NMS and 107 neuroleptic-treated schizophrenic patients with no NMS history. The C188T allele frequency was 0.417 in NMS patients and 0.463 in patients without NMS. No significant allele or genotype associations were observed. We cannot conclude that low CYP2D6 activity genotype causes susceptibility to NMS in Japanese patients.

Neuroleptic malignant syndrome and hydroxylase gene mutations: no association with CYP2D6A or CYP2D6B.

To examine a possible association between debrisoquine 4-hydroxylase gene mutations and neuroleptic malignant syndrome, we assessed frequencies of wild type and A and B mutant alleles of the CYP2D6 gene in 24 patients with a history of nuroleptic malignant syndrome, 50 patients with neuroleptic-treated schizophrenia but no history of neuroleptic malignant syndrome, and 50 healthy controls. Allele frequencies did not differ significantly between these groups. Homozygotes for CYP2D6A and for CYP2D6B, which indicate a poor-metabolizer phenotype for the CYP2D6 substrate, were not detected among the neuroleptic malignant syndrome cases. This result indicates no excess of poor CYP2D6 metabolizers in neuroleptic malignant syndrome. The aetiology of neuroleptic malignant syndrome is not explainable in terms of CYP2D6 gene mutations.

CYP2D6 gene deletion allele in patients with neuroleptic malignant syndrome: preliminary report.

Abstract  Neuroleptic malignant syndrome (NMS) is a potentially fatal adverse reaction to psychopharmacologic treatment. Reported herein are two NMS patients with schizophrenia who were found to possess a CYP2D6 gene deletion allele (CYP2D6*5). The deletion results in decreased CYP2D6 activity, possibly leading to drug accumulation. Both patients with NMS had been treated with neuroleptics, including CYP2D6 substrates. Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analyses and long PCR were performed to detect CYP2D6 genotype. One patient was found to possess *5/*10; the other had a *1/*5 genotype. The present preliminary report suggests that pharmacokinetic factors cannot be excluded and the CYP2D6 polymorphism is possibly associated with the etiology of NMS.

A Novel Missense Mutation (G209R) in Exon 8 of the Presenilin 1 Gene in a Japanese Family with Presenile Familial Alzheimer's Disease

Over fifty missense mutations in the presenilin‐1 (PSEN1) gene have been reported in families with presenile familial Alzheimers disease (FAD). We describe a novel missense mutation (G209R) within the predicted fourth transmembrane domain of the PSEN1 in a Japanese family with presenile FAD. The affected cases showed similar disease histories with the mean age at onset of 49.6 ± 3.1 years and rapid progressive dementia characterized by memory impairment, amnestic aphasia, disorientation and personality change, but lacking parietal focal symptoms such as apraxia or agnosia. Compared with the previously reported cases of same Gly209 mutation (G209V), the clinical features of the G209R‐FAD cases appear to be less critical than those of G209V‐FAD cases, although the Gly to Arg mutation is considered to be less conservative than the Gly to Val mutation. These findings may suggest the possible existence of other genetic and/or environmental factors or the possibility that these two different Gly209 mutations may underlie different pathomechanisms in the development of presenile FAD. Hum Mutat 14:90, 1999.

A patient with treatment-resistant schizophrenia and cytochrome p4502d6 gene duplication

We describe a patient with treatment‐resistant schizophrenia who had a duplication in the cytochrome P450IID6 (CYP2D6) gene. This severely ill 71‐year‐old‐woman had responded poorly to several neuroleptics. Molecular genetic study revealed CYP2D6 gene duplication, which results in excessive activity of CYP2D6 that metabolizes various commonly used neuroleptics. The mutation may have contributed to treatment resistance in this case.

Novel acceptor splice site mutation in the invariant AG of intron 6 of α‐galactosidase A gene, causing Fabry disease

We found a novel acceptor splice site mutation in the invariant AG of intron 6 of α‐galactosidase A (α‐Gal A) gene (IVS6‐1G→A) in a patient with Fabry disease by sequencing of genomic DNA. Sequencing of RT‐PCR revealed the deletion of first base pair (c909del) of exon 7 in mRNA and a frameshift resulting in premature termination. This mutation gives rise to a rare aberrant splicing (Simultaneous 3′ destruction and 3′ creation). Hum Mutat 11:483, 1998.

A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease. Mutation in brief no. 254. Online.

Over fifty missense mutations in the presenilin‐1 (PSEN1) gene have been reported in families with presenile familial Alzheimers disease (FAD). We describe a novel missense mutation (G209R) within the predicted fourth transmembrane domain of the PSEN1 in a Japanese family with presenile FAD. The affected cases showed similar disease histories with the mean age at onset of 49.6 ± 3.1 years and rapid progressive dementia characterized by memory impairment, amnestic aphasia, disorientation and personality change, but lacking parietal focal symptoms such as apraxia or agnosia. Compared with the previously reported cases of same Gly209 mutation (G209V), the clinical features of the G209R‐FAD cases appear to be less critical than those of G209V‐FAD cases, although the Gly to Arg mutation is considered to be less conservative than the Gly to Val mutation. These findings may suggest the possible existence of other genetic and/or environmental factors or the possibility that these two different Gly209 mutations may underlie different pathomechanisms in the development of presenile FAD. Hum Mutat 14:90, 1999.

Novel acceptor splice site mutation in the invariant AG of intron 6 of alpha-galactosidase A gene, causing Fabry disease. Mutations in brief no. 146. Online.

Using DNA sequencing of the coding and exon flanking regions of the low density lipoprotein receptor (LDLR) gene we identified an Alw26 I site in exon 10 by a transition G1426A. The alleles are represented by one uncut fragment (A1 = 108 bp) or two fragments (A2 = 82 bp and 26 pb). Two other fragments (72 bp and 16 bp) were systematically found within the amplified product. The alleles were detected in 157 unrelated French Caucasians with A1 frequency = 0.58 and A2 = 0.42. The observed heterozygoty was 44.5%.