Acta Neuropathologica

, Volume 122, Issue 2, pp 223–229

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

  • Hidefumi Ito
  • Masataka Nakamura
  • Osamu Komure
  • Takashi Ayaki
  • Reika Wate
  • Hirofumi Maruyama
  • Yoshimi Nakamura
  • Kengo Fujita
  • Satoshi Kaneko
  • Yoko Okamoto
  • Masafumi Ihara
  • Tetsuro Konishi
  • Kazumasa Ogasawara
  • Asao Hirano
  • Hirofumi Kusaka
  • Ryuji Kaji
  • Ryosuke Takahashi
  • Hideshi Kawakami
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

Authors and Affiliations

  • Hidefumi Ito
    • 1
  • Masataka Nakamura
    • 2
  • Osamu Komure
    • 3
  • Takashi Ayaki
    • 1
  • Reika Wate
    • 2
  • Hirofumi Maruyama
    • 4
  • Yoshimi Nakamura
    • 2
  • Kengo Fujita
    • 2
  • Satoshi Kaneko
    • 2
  • Yoko Okamoto
    • 1
  • Masafumi Ihara
    • 1
  • Tetsuro Konishi
    • 5
  • Kazumasa Ogasawara
    • 6
  • Asao Hirano
    • 7
  • Hirofumi Kusaka
    • 2
  • Ryuji Kaji
    • 8
  • Ryosuke Takahashi
    • 1
  • Hideshi Kawakami
    • 4
  1. 1.Department of NeurologyKyoto University Graduate School of MedicineKyotoJapan
  2. 2.Department of NeurologyKansai Medical UniversityOsakaJapan
  3. 3.Shin-ai HospitalOsakaJapan
  4. 4.Department of EpidemiologyResearch Institute for Radiation Biology and Medicine, Hiroshima UniversityHiroshimaJapan
  5. 5.National Hospital Organization Utano HospitalKyotoJapan
  6. 6.Department of Pathology, School of MedicineShiga University of Medical ScienceShigaJapan
  7. 7.Division of Neuropathology, Department of PathologyMontefiore Medical CenterNew YorkUSA
  8. 8.Department of Clinical NeuroscienceUniversity of Tokushima Graduate SchoolTokushimaJapan