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

Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis in mammalian cells and is essential for survival. Here, we report on a novel axonal sensory and motor neuropathy likely caused by a homozygous genetic variant of missense mutation (c.472G>C, p.P158A) in NAMPT. The 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 NAMPT proteins, patient fibroblasts (FBs), and mouse model, we showed that the p.P158A mutation decreased NAMPT enzyme activity, caused mitochondrial dysfunction, disrupted cellular bioenergetic and metabolic homeostasis, and increased oxidative stress. Moreover, the p.P158A mutation caused impairments of excitability and synaptic function and motor neuron degeneration in the mouse model. This Mutation in NAMPT Axonopathy (MINA) syndrome is the first human hereditary neurological disease linking to a NAMPT variant and has significant clinical implications.