Electrodiagnostic testing and histopathologic changes confirm peripheral nervous system myelin abnormalities in the feline model of niemann-pick disease type C

Abstract

Niemann-Pick disease type C (NPC disease) is an incurable, neurodegenerative, autosomal recessive disease caused by mutations in either the NPC1 or the NPC2 gene. These mutations affect the intracellular trafficking of lipids and cholesterol, resulting in the intralysosomal accumulation of unesterified cholesterol and glycosphingolipids. These abnormalities are associated with clinical ataxia and impaired motor and intellectual development, and death frequently occurs in adolescence. The incidence of peripheral neuropathy in NPC patients is not known. We investigated peripheral nerves in the naturally occurring feline model of NPC disease, which has proven to be critical for understanding both disease pathogenesis and for evaluating experimental therapies. Electrodiagnostic studies revealed significantly slowed motor and sensory nerve conduction velocities in affected cats in the absence of altered M-wave amplitude. Histologic and ultrastructural analyses showed thin myelin sheaths, membranous debris, myelin figures, lipid vacuolization of Schwann cell cytoplasm, and expanded paranodal areas. Axonal degeneration was not identified. There was a shift to small myelinated fibers in affected cats, and there were significant decreases in fiber diameter, axon diameter, and myelin thickness. These changes were similar to those described in the murine NPC disease model and in rare patients in whom nerve biopsy has been performed. Characterization of the demyelinating neuropathy is necessary for evaluating clinical trials that target only the CNS aspects of NPC. © 2013 American Association of Neuropathologists, Inc.