Programmed axon degeneration gene variants in human disease.
Level 5 - mechanism / opinion, no new human data
Narrative review synthesizing mechanistic and genetic association literature without systematic review methodology.
PubMed 42341897 · doi:10.1016/j.expneurol.2026.115891
What was done
Narrative review synthesizing evidence on human pathogenic variants in the programmed axon degeneration (PAD / Wallerian degeneration) pathway. The review describes clinical phenotypes linked to variants in enzymes regulating nicotinamide adenine dinucleotide (NAD) homeostasis—specifically NAMPT, NMNAT1, NMNAT2, and SARM1—and outlines emerging therapeutic strategies targeting this pathway.
What was found
The abstract provides qualitative associations without quantitative effect estimates or patient counts: - NAMPT variants are linked to sensory and motor neuropathies with neurodevelopmental features. - NMNAT1 variants cause Leber Congenital Amaurosis type 9. - NMNAT2 variants cause childhood-onset peripheral neuropathies. - SARM1 gain-of-function variants resulting in constitutively active NADase activity are enriched in patients with amyotrophic lateral sclerosis (ALS). - Therapeutic interventions discussed include SARM1 inhibitors undergoing clinical evaluation, gene therapy, and NAD precursor supplementation.
Why it matters
Connecting genetic disruptions in NAD maintenance to distinct neurological conditions validates the programmed axon degeneration pathway in human disease and provides a rationale for developing SARM1 inhibitors and related neuroprotective agents.
Limits
The abstract describes a narrative review without systematic search criteria, quality appraisal, or pooled quantitative data. Genetic variants discussed are rare, and findings from monogenic disorders may not fully translate to common sporadic neurodegenerative diseases. Clinical efficacy of targeted therapies remains unproven in the abstract.
Cited by
- supports Heart failure, central and peripheral neurodegeneration, and UV sun exposure deplete or disturb NAD system levels in affected tissues.