Original Paper

Acta Neuropathologica

, Volume 122, Issue 2, pp 223-229

First online:

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

  • Hidefumi ItoAffiliated withDepartment of Neurology, Kyoto University Graduate School of Medicine Email author 
  • , Masataka NakamuraAffiliated withDepartment of Neurology, Kansai Medical University
  • , Osamu KomureAffiliated withShin-ai Hospital
  • , Takashi AyakiAffiliated withDepartment of Neurology, Kyoto University Graduate School of Medicine
  • , Reika WateAffiliated withDepartment of Neurology, Kansai Medical University
  • , Hirofumi MaruyamaAffiliated withDepartment of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University
  • , Yoshimi NakamuraAffiliated withDepartment of Neurology, Kansai Medical University
  • , Kengo FujitaAffiliated withDepartment of Neurology, Kansai Medical University
  • , Satoshi KanekoAffiliated withDepartment of Neurology, Kansai Medical University
    • , Yoko OkamotoAffiliated withDepartment of Neurology, Kyoto University Graduate School of Medicine
    • , Masafumi IharaAffiliated withDepartment of Neurology, Kyoto University Graduate School of Medicine
    • , Tetsuro KonishiAffiliated withNational Hospital Organization Utano Hospital
    • , Kazumasa OgasawaraAffiliated withDepartment of Pathology, School of Medicine, Shiga University of Medical Science
    • , Asao HiranoAffiliated withDivision of Neuropathology, Department of Pathology, Montefiore Medical Center
    • , Hirofumi KusakaAffiliated withDepartment of Neurology, Kansai Medical University
    • , Ryuji KajiAffiliated withDepartment of Clinical Neuroscience, University of Tokushima Graduate School
    • , Ryosuke TakahashiAffiliated withDepartment of Neurology, Kyoto University Graduate School of Medicine
    • , Hideshi KawakamiAffiliated withDepartment of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University

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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 sclerosis Optineurin TDP-43 Golgi fragmentation