title: Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation.
abstract: We performed clinicopathological analyses of two amyotrophic lateral sclerosis (ALS) patients with homozygous Q398X optineurin (OPTN) mutation. Clinically, both patients presented signs of upper and lower motor neuron degeneration, but only Patient 1 showed gradual frontal dysfunction and extrapyramidal signs, and temporal lobe and motor cortex atrophy. Neuropathological examination of Patient 1 revealed extensive cortical and spinal motor neuron degeneration and widespread degeneration of the basal ganglia. Bilateral corticospinal tracts exhibited degeneration. Loss of spinal anterior horn cells (AHCs) and gliosis were observed, whereas posterior columns, Clarke's columns, intermediate lateral columns, and the Onuf's nucleus were spared. In the brainstem, moderate neuronal loss and gliosis were noted in the hypoglossal and facial motor nuclei. No Bunina bodies were found in the surviving spinal and brainstem motor neurons. Transactivation response (TAR) DNA-binding protein 43 (TDP-43)-positive neuronal and glial cytoplasmic inclusions were observed throughout the central nervous system. The Golgi apparatus in motor neurons of the brainstem and spinal cord was often fragmented. Immunoreactivity for OPTN was not observed in the brain and spinal cord, consistent with nonsense-mediated mRNA decay of OPTN. The TDP-43 pathology of Q398X was similar to that of an autosomal dominant E478G mutation. This result suggests that the loss-of-function, but not the proteinopathy itself, of OPTN results in TDP-43 deposits in neuronal and glial cytoplasm and Golgi apparatus fragmentation, leading to multisystem neurodegeneration.
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Department of Neurological Intractable Disease Research, Kagawa University School of Medicine, Kagawa, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kamada
authors.forename: Yuishin
authors.initials: Y
authors.lastname: Izumi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Seiko
authors.initials: S
authors.lastname: Kagawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Kudo
authors.forename: Wataru
authors.initials: W
authors.lastname: Sako
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishida
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D018797:Cell Cycle Proteins; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation; D035582:Transcription Factor TFIIIA / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA
keywords: ALS-Plus syndrome; TDP-43; amyotrophic lateral sclerosis; autosomal recessive; optineurin