A sensory and motor neuropathy caused by a genetic variant of.

Abstract

Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway for nicotinamide adenine dinucleotide (NAD) biosynthesis in mammalian cells and is essential for survival. Here, we report on a previously unidentified axonal sensory and motor neuropathy likely caused by a homozygous genetic variant of missense mutation (c.472G>C, p.P158A) in thegene. Two affected siblings presented with a range of clinical features including impaired motor coordination, muscle atrophy, foot deformities, and positive Babinski sign. Using different preparations including recombinant human and mouse NAMPT proteins, patient fibroblasts, and mouse model, we showed that the p.P158A mutation decreased NAMPT enzyme activity, leading to disrupted cellular bioenergetics, metabolic derangements, and increased oxidative stress. Moreover, the p.P158A mutation could cause synaptic dysfunction and motor neuron degeneration in the mouse model. This Mutation in NAMPT Axonopathy (MINA) syndrome is the first human hereditary neurological disease linking to an NAMPT variant. Our study has substantial clinical implications.