Acta Neuropathologica

, Volume 119, Issue 3, pp 355–364 | Cite as

Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation

  • Takahisa Tateishi
  • Toshihiro Hokonohara
  • Ryo Yamasaki
  • Shiro Miura
  • Hitoshi Kikuchi
  • Akiko Iwaki
  • Hiroshi Tashiro
  • Hirokazu Furuya
  • Yuko Nagara
  • Yasumasa Ohyagi
  • Nobuyuki Nukina
  • Toru Iwaki
  • Yasuyuki Fukumaki
  • Jun-ichi KiraEmail author
Original Paper


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.


Familial amyotrophic lateral sclerosis Fused in sarcoma/translated in liposarcoma Basophilic inclusion Glial cytoplasmic inclusion 


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Takahisa Tateishi
    • 1
  • Toshihiro Hokonohara
    • 1
    • 3
  • Ryo Yamasaki
    • 1
  • Shiro Miura
    • 4
  • Hitoshi Kikuchi
    • 1
  • Akiko Iwaki
    • 3
  • Hiroshi Tashiro
    • 2
  • Hirokazu Furuya
    • 5
  • Yuko Nagara
    • 1
  • Yasumasa Ohyagi
    • 1
  • Nobuyuki Nukina
    • 6
  • Toru Iwaki
    • 2
  • Yasuyuki Fukumaki
    • 3
  • Jun-ichi Kira
    • 1
    Email author
  1. 1.Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Neuropathology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  3. 3.Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
  4. 4.Division of Respirology, Neurology and Rheumatology, Department of MedicineKurume University School of MedicineKurumeJapan
  5. 5.Department of Neurology, Neuro-Muscular CenterNational Omuta HospitalOmutaJapan
  6. 6.Laboratory for Structural NeuropathologyRIKEN Brain Science InstituteWakoJapan

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