2. Academic Validation
  3. A sensory and motor neuropathy caused by a genetic variant of NAMPT

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

  • Sci Adv. 2025 Sep 26;11(39):eadx2407. doi: 10.1126/sciadv.adx2407.
Zhe Zhang 1,  Jacek Pilch 2,  Samuel Lundt 2,  Nannan Zhang 2,  Yongchang Chang 2,  Tracey Singer 2,  Dariusz Śladowski 3,  Xiao-Ling Hu 4,  Lijun Zheng 4,  Woo-Ping Ge 4,  Hua Zhang 5,  De-Pei Li 5,  Xianlin Han 6,  Rafal Ploski 7,  Shinghua Ding 1 8
Affiliations

Affiliations

  • 1 Dalton Cardiovascular Research Center (DCRC), University of Missouri, Columbia, MO, USA.
  • 2 Department of Pediatric Neurology, Faculty of Medical Science, Medical University of Silesia, Katowice, Poland.
  • 3 Department of Transplantology and Central Tissue Bank, Medical University of Warsaw, Warsaw, Poland.
  • 4 Chinese Institute for Brain Research, Beijing, China.
  • 5 Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, USA.
  • 6 Barshop Institute for Longevity and Aging Studies and Department of Medicine, University of Texas Health Center at San Antonio, San Antonio, TX, USA.
  • 7 Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
  • 8 Department of Chemical and Biomedical Engineering (ChBME), University of Missouri, Columbia, MO, USA.
PMID: 41004591 DOI: 10.1126/sciadv.adx2407
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 the NAMPT gene. 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.

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