title: Clinicopathologic report of ocular involvement in ALS patients with C9orf72 mutation.
abstract: Our objective was to present clinicopathologic evidence of anterior visual pathway involvement in patients with amyotrophic lateral sclerosis (ALS) secondary to a C9orf72 mutation. Two related patients from an extended pedigree with ALS and GGGGCC hexanucleotide repeat expansion in the C9orf72 gene (C9-ALS) underwent neuro-ophthalmologic examination. Following death and tissue donation of the younger ALS patient, histopathologic examination of the retina, optic nerve and central nervous system (CNS) was performed. Ophthalmologic examination revealed contrast sensitivity impairment in the younger C9-ALS patient. Immunohistochemistry performed on this patient's donor tissue demonstrated p62-positive, pTDP43-negative perinuclear inclusions in the inner nuclear layer of the retina and CNS. Further colocalization with GLT-1 and recoverin suggested that the majority of retinal p62-positive inclusions are found within cone bipolar cells as well as some amacrine and horizontal cells. In conclusion, this is the first report that identifies disease-specific pathologic inclusions in the anterior visual pathway of a patient with a C9orf72 mutation. Cone bipolar cell involvement within the inner nuclear layer of the retina may explain the observed subtle visual function deficiencies in this patient. Further clinical and histopathologic studies are needed to fully characterize a larger population of C9-ALS patients and explore these findings in other forms of ALS.
authors.affiliation: Department of Ophthalmology.
authors.forename: Amani A
authors.initials: AA
authors.lastname: Fawzi
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Simonett
authors.forename: Patryk
authors.initials: P
authors.lastname: Purta
authors.forename: Heather E
authors.initials: HE
authors.lastname: Moss
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Lowry
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Nailah
authors.initials: N
authors.lastname: Siddique
authors.forename: Robert
authors.initials: R
authors.lastname: Sufit
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Volpe
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics*; D000073885:C9orf72 Protein; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D003941:Diagnostic Techniques, Ophthalmological; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D004676:Myelin Basic Protein / Q000378:metabolism; D009460:Neurologic Examination; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014786:Vision Disorders / Q000209:etiology* / Q000473:pathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D004676:Myelin Basic Protein; D011506:Proteins; C493397:SLC1A2 protein, human; C000598624:TARDBP protein, human; D025801:Ubiquitin
keywords: Pathology; amyotrophic lateral sclerosis; c9orf72; midget bipolar cells; neuropathology; retina; ubiquitin