Naoya Sugiyama

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.

Pelizaeus-Merzbacher disease: three novel mutations and implication for locus heterogeneity.

We report a mutational and polymorphic analysis of the proteolipid protein gene in members of 27 Japanese families with Pelizaeus‐Merzbacher disease. We found causative mutations in 6 members of 27 families (22.2%); 5 of the 6 mutations, including two novel mutations, Leu45Arg and 231 + 2T → G, resulted in the typically severe clinical symptoms. Paradoxically, the Cys219Tyr mutation, presumed to disrupt the tertiary structure of proteolipid protein by removing the disulfide bond between Cys200 and Cys219, was associated with a mild clinical presentation wherein the patient could walk with assistance and speak. It was inferred that the structural change prevented the toxicity associated with a gain of function mutation. Moreover, in one family 3 patients exhibited a intragenic polymorphism that did not segregate with the disease, suggesting a locus heterogeneity for Pelizaeus‐Merzbacher disease. Ann Neurol 1999;45:59–64

JAPANESE CREUTZFELDT-JAKOB DISEASE PATIENTS EXHIBITING HIGH INCIDENCE OF THE E200K PRNP MUTATION AND LOCATED IN THE BASIN OF A RIVER

Seven cases with Creutzfeldt-Jakob disease (CJD) located in the basin of the Fuji river (Fuji area) in Japan were examined genetically and clinicopathologically. The onset of the disease was between 1989 and 1995. All cases were from different families, although 3 cases were family members of previously reported CJD patients. They had clinical and/or neuropathological features, corresponding to subacute spongiform encephalopathy. Five of the 7 cases, including the 3 familial cases, had the E200K mutation in the gene encoding prion protein (PRNP). It is suggested that there is a small cluster of CJD patients with a founder effect of the E200K mutation in the Fuji area, because the incidence of CJD with the E200K mutation appears to be much higher in this area than other areas in Japan. The disease penetrance of the 5 cases with the E200K mutation seems to be low, and they may have an age-related incidence in the Fuji area. These findings support the hypothesis that the phenotypes of CJD patients with the PRNP mutations are linked to the position of the mutation, but not related to ethnic or environmental factors.

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.

Mutation involving cytochrome P450IID6 in two Japanese patients with neuroleptic malignant syndrome

Cytochrome P450IID6 (CYP2D6) plays an important role in the hepatic metabolism of various psychotropic drugs. We detected a mutation of the CYP2D6 gene in two patients who previously had episodes of neuroleptic malignant syndrome (NMS). They were homozygous for a mutated CYP2D6J allele conferring a poor-metabolizer phenotype. Possession of this trait may contribute to susceptibility to NMS.

Efficacy of shared decision making on treatment satisfaction for patients with first-admission schizophrenia: study protocol for a randomised controlled trial

BackgroundShared decision making is a promising model for patient-centred medicine, resulting in better clinical outcomes overall. In the mental health field, interventions that consider the patient-centred perspective—such as patient quality of life, involvement in the treatment, treatment satisfaction, and working alliance—have increased and better clinical outcomes discovered for patients with schizophrenia. However, few studies have examined the efficacy of shared decision making for schizophrenia treatment. The objective of this study is to evaluate the effect of a shared decision making intervention compared to treatment as usual on patient satisfaction at discharge for first-admission patients with schizophrenia.Methods/DesignThis is a randomised, parallel-group, two-arm, open-label, single-centre study currently being conducted in an acute psychiatric ward of Numazu Chuo Hospital, Japan. We are recruiting patients between 16 and 65 years old who are admitted to the ward with a diagnosis of schizophrenia without prior experience of psychiatric admission. Fifty-eight participants are being randomised into a shared decision making intervention group or a treatment as usual control group in a 1:1 ratio. The intervention program was developed based on a shared decision making model and is presented as a weekly course lasting the duration of the patients’ acute psychiatric ward stay. The primary outcome measure is patient satisfaction at discharge as assessed by the Client Satisfaction Questionnaire. Due to the study’s nature, neither the patient nor staff can be blinded.DiscussionThis is the first randomised controlled trial to evaluate the efficacy of shared decision making for patients with early-treatment-stage schizophrenia. The intervention program in this study is innovative in that it includes both of the patient and staff who are involved in the treatment.Trial registrationThe study has been registered with ClinicalTrials.gov as NCT01869660.

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.

Mval polymorphism in the proteolipid protein (PLP) gene

We report a rare polymorphism in the human proteolipid protein (PLP) gene. A synonymous mutation, 168 A→G, was detected in exon 2 of the PLP gene. Mutations in this gene have been reported in some cases of Pelizaeus-Merzbacher disease.

A randomized, double-blind, placebo-controlled study of rapid-acting intramuscular olanzapine in Japanese patients for schizophrenia with acute agitation

No abstract

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.