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.