variants in cause sporadic early-onset progressive sensorimotor neuropathy.

Park J, Flores BR, Scherer K, Kuepper H, Rossi M, Rupprich K, Rautenberg M, Deininger N, Weichselbaum A, Grimm A, Sturm M, Grasshoff U, Delpire E, Haack TB
J Med Genet. 2020 57 (4): 283-288

PMID: 31439721 · DOI:10.1136/jmedgenet-2019-106273

BACKGROUND - Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in in three unrelated patients with intermediate CMT.

METHODS - We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in oocytes.

RESULTS - We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in oocytes showed a significant reduction in potassium influx for both changes.

CONCLUSION - Our findings expand the genotypic and phenotypic spectrum associated with variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

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MeSH Terms (17)

Adolescent Agenesis of Corpus Callosum Age of Onset Charcot-Marie-Tooth Disease Child Female Genotype Hereditary Sensory and Autonomic Neuropathies Humans Infant Magnetic Resonance Imaging Male Mutation Pedigree Peripheral Nervous System Diseases Phenotype Symporters

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