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.

Water Homeostasis and Cell Volume Maintenance and Regulation

“…Loss of function mutations in the gene are found in a few sporadic families throughout the world (Uyanik, et al, 2006) as well as in many Canadian families living in two regions around Quebec City (Howard, et al, 2002). Axonal swelling was found in KCC3-deficient patients (Auer, et al, 2016; Dupré, et al, 2003), consistent with this cotransporter isoform playing a role in regulatory volume decrease. Analysis of peripheral nerves in a knockout mouse model also found significant swelling of peripheral nerve fibers (Byun & Delpire, 2007).…”

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

“…Muscle biopsies show signs of denervation such as mildly atrophic and angulated fibers. 22,[24][25] Most causal variants associated with ACCPN are randomly distributed truncating variants, due to premature stop codons caused by INDEL, nonsense or splice site variants (recessive; homozygous or compound heterozygous). [16][17][18]20,26 Contrary to what would be expected, SLC12A6 mRNAs harboring premature termination codons are not degraded by nonsense-mediated mRNA decay, but are translated as truncated proteins.…”

“…The marked phenotypic differences between the human and canine phenotype of 25 As this is a chronic, progressive disease, an evolution in type of lesions and distribution pattern can be expected.…”

“…variants are striking, but quite pronounced phenotypic variations have already been reported between human patients, as well as with mice 17. Interestingly, as in humans where patients with ACCPN have extremely low body weights and heights25 , affected dogs weighted about 25% less than age-matched littermates at the time of euthanasia.The histopathologic findings show a strong correlation with the human ACCPN, as both display a severe axonopathy with striking unnoted neuronal damage, inflammation or gliosis. The dogs developed lesions in both central (mainly spinal cord and brain stem) and peripheral nervous system (mainly nerve roots), broadly consistent with the localization pattern in humans and mouse 25.…”

“…Interestingly, as in humans where patients with ACCPN have extremely low body weights and heights25 , affected dogs weighted about 25% less than age-matched littermates at the time of euthanasia.The histopathologic findings show a strong correlation with the human ACCPN, as both display a severe axonopathy with striking unnoted neuronal damage, inflammation or gliosis. The dogs developed lesions in both central (mainly spinal cord and brain stem) and peripheral nervous system (mainly nerve roots), broadly consistent with the localization pattern in humans and mouse 25. An important difference in dogs is the severe, bilateral symmetrical vacuolation of the spinal cord white matter, a feature not well described in humans.…”