title: Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation.
abstract: Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2+/-8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C>T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Tateishi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hokonohara
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamasaki
authors.forename: Shiro
authors.initials: S
authors.lastname: Miura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tashiro
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nagara
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Toru
authors.initials: T
authors.lastname: Iwaki
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fukumaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
mesh_terms: D000328:Adult; D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D001706:Biopsy; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D016373:DNA, Antisense / Q000235:genetics; D018450:Disease Progression; D004576:Electromyography; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005838:Genotype; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000209:etiology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology*; D009460:Neurologic Examination; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D015899:Tomography, Emission-Computed, Single-Photon; D055815:Young Adult
chemical_list: D016373:DNA, Antisense; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D034702:RNA-Binding Protein FUS