title: Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation.
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.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Japan. itohid@kuhp.kyoto-u.ac.jp.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Osamu
authors.initials: O
authors.lastname: Komure
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.forename: Reika
authors.initials: R
authors.lastname: Wate
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kengo
authors.initials: K
authors.lastname: Fujita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Konishi
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogasawara
authors.forename: Asao
authors.initials: A
authors.lastname: Hirano
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kusaka
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
mesh_terms: D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D035582:Transcription Factor TFIIIA / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA