Acta Neuropathologica

, Volume 122, Issue 2, pp 223–229

Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation

Authors

    • Department of NeurologyKyoto University Graduate School of Medicine
  • Masataka Nakamura
    • Department of NeurologyKansai Medical University
  • Osamu Komure
    • Shin-ai Hospital
  • Takashi Ayaki
    • Department of NeurologyKyoto University Graduate School of Medicine
  • Reika Wate
    • Department of NeurologyKansai Medical University
  • Hirofumi Maruyama
    • Department of EpidemiologyResearch Institute for Radiation Biology and Medicine, Hiroshima University
  • Yoshimi Nakamura
    • Department of NeurologyKansai Medical University
  • Kengo Fujita
    • Department of NeurologyKansai Medical University
  • Satoshi Kaneko
    • Department of NeurologyKansai Medical University
  • Yoko Okamoto
    • Department of NeurologyKyoto University Graduate School of Medicine
  • Masafumi Ihara
    • Department of NeurologyKyoto University Graduate School of Medicine
  • Tetsuro Konishi
    • National Hospital Organization Utano Hospital
  • Kazumasa Ogasawara
    • Department of Pathology, School of MedicineShiga University of Medical Science
  • Asao Hirano
    • Division of Neuropathology, Department of PathologyMontefiore Medical Center
  • Hirofumi Kusaka
    • Department of NeurologyKansai Medical University
  • Ryuji Kaji
    • Department of Clinical NeuroscienceUniversity of Tokushima Graduate School
  • Ryosuke Takahashi
    • Department of NeurologyKyoto University Graduate School of Medicine
  • Hideshi Kawakami
    • Department of EpidemiologyResearch Institute for Radiation Biology and Medicine, Hiroshima University
Original Paper

DOI: 10.1007/s00401-011-0842-y

Cite this article as:
Ito, H., Nakamura, M., Komure, O. et al. Acta Neuropathol (2011) 122: 223. doi:10.1007/s00401-011-0842-y

Abstract

We investigated a family manifesting amyotrophic lateral sclerosis (ALS) with a heterozygous E478G mutation in the optineurin (OPTN) gene. Clinically, slow deterioration of motor function, mood and personality changes, temporal lobe atrophy on neuroimaging, and bizarre finger deformity were noted. Neuropathologically, TAR DNA-binding protein 43 (TDP-43)-positive neuronal intracytoplasmic inclusions were observed in the spinal and medullary motor neurons. In these cells, the immunoreactivity of nuclear TDP-43 was reduced. Consecutive sections revealed that the inclusions were also reactive with anti-ubiquitin and anti-p62 antibodies, but noticeably negative for OPTN. In addition, TDP-43/p62-positive glial cytoplasmic inclusions (GCIs) were scattered throughout the spinal cord and the medullary motor nuclei. Furthermore, Golgi fragmentation was identified in 70% of the anterior horn cells (AHCs). The presence of AHCs with preserved nuclear TDP-43 and a fragmented Golgi apparatus, which are unrecognizable in sporadic ALS, indicates that patients with the E4787G OPTN mutation would manifest Golgi fragmentation before loss of nuclear TDP-43. In the neocortex, GCIs were sparsely scattered among the primary motor and temporal cortices, but no neuronal TDP-43-positive inclusions were detected. In the amygdala and the ambient gyrus, argyrophilic grains and ballooned neurons were seen. The thorough neuropathologic investigations performed in this work demonstrated that OPTN-positive inclusion bodies, if any, were not prominent. We postulate that optineurinopathy is closely linked with TDP-proteinopathy and speculate that this heterozygous E478G mutation would cause ALS by acting through a dominant-negative mechanism.

Keywords

Amyotrophic lateral sclerosisOptineurinTDP-43Golgi fragmentation

Supplementary material

401_2011_842_MOESM1_ESM.pdf (210 kb)
ESM1 (PDF 211 kb)

Copyright information

© Springer-Verlag 2011