title: KCC3 axonopathy: neuropathological features in the central and peripheral nervous system.
abstract: Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.
authors.affiliation: Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Roland N
authors.initials: RN
authors.lastname: Auer
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Laganière
authors.affiliation: Department of Pathology, Hôpital Ste-Justine, Faculty of Medicine, University of Montréal, Montréal, Québec, Canada.
authors.forename: Yves O
authors.initials: YO
authors.lastname: Robitaille
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Richardson
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
authors.forename: Masoud
authors.initials: M
authors.lastname: Shekarabi
mesh_terms: D000328:Adult; D061085:Agenesis of Corpus Callosum / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001344:Autopsy; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009410:Nerve Degeneration; D017933:Peripheral Nervous System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010641:Phenotype; D011379:Prognosis; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000096922:K Cl- Cotransporters
chemical_list: D027981:Symporters; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters