Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late-onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 mutations. We screened 7 reported nonsynonymous missense variants of VPS35, including p.D620N, known as potentially disease-associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high-resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no controls. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor-predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N substitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, especially autosomal dominant PD or tremor-predominant PD.
An update of the endemic parkinsonism-dementia complex (PDC) frequently associated with amyotrophic lateral sclerosis (ALS) in the high prevalence ALS focus of the Kii peninsula of Japan is presented. The initial symptom was parkinsonian gait or hypobulia/amnesia, which was followed by akinesia, rigidity, occasional tremor, bradyphrenia, abulia and amnesia, and finally by akinetic mutism. In several years, most of the patients developed ALS symptoms such as muscle atrophy, bulbar palsy, and upper motor neuron signs. Magnetic resonance imaging and computed tomography of the brain showed marked atrophy of the temporal and frontal lobes and the cerebral blood flow reduction on single-photon emission computed tomography. Marked loss of nerve cells associated with abundant neurofibrillar tangles (NFTs) in the entire central nervous system, most predominantly in the brainstem and temporal lobe was characteristic. Concomitant ALS pathology involving the upper and lower motor neurons was common, and senile plaques were absent in most cases. NFTs consisted of twisted tubules on electron microscopy. Western blot of tau protein showed three bands consisting of six tau isoforms, similar to those of Alzheimer's disease. A family history of ALS/PDC was recorded in more than 70% of patients, but no abnormal mutation or polymorphism was found in the genes of SOD1, tau, and apolipoprotein E. Familial nature and continuing morbidity of Kii ALS/PDC suggest that genetic factors may be more likely in its pathogenesis.
We report the first case of neuropathologically verified parkinsonism-dementia complex of the Kii peninsula, together with the patient's brother, who had amyotrophic lateral sclerosis. The propositus woman developed parkinsonism and dementia at 63 years of age and died at 70 without displaying clinical features of amyotrophic lateral sclerosis. The brain exhibited marked atrophy of the frontal and temporal lobes. Microscopically, there were many neurofibrillary tangles in the central nervous system, most markedly in the mesial temporal lobe and deep nuclei, as well as changes of amyotrophic lateral sclerosis but no senile plaques or Lewy bodies. Neurofibrillary tangles exhibited twisted tubule structures on electon microscopic examination, and an analysis of insoluble tau protein extracted from the fresh brain revealed a 60-, 64-, 68-kD triplet. The tau gene exhibited no mutations. Her brother developed progressive bulbar palsy-type amyotrophic lateral sclerosis at 45 years of age and died at 49 without presenting with dementia or parkinsonism. Neuropathological examination revealed not only pathologic features of amyotrophic lateral sclerosis but also a moderate number of neurofibrillary tangles in the temporal cortex and deep nuclei. The siblings were neuropathologically similar despite their different clinical manifestations. These findings suggest that amyotrophic lateral sclerosis and parkinsonism-dementia complex of this family may be phenotypic variants of a tauopathy caused by genetic abnormalities.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.