Motor Neuron Dysfunction in SORD Deficiency: Implications for Therapeutic Development in Peripheral Neuropathies

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as one of the most common causes of autosomal-recessive Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary neuropathy, collectively referred to as SORD deficiency. These mutations result in loss of sorbitol dehydrogenase activity, a key enzyme in the polyol pathway that metabolizes glucose, leading to marked accumulation of sorbitol in patient-derived fibroblasts. However, the mechanisms by which SORD dysfunction drives axonal degeneration remain poorly understood, and robust in vitro models of human SORD-deficient motor neurons (MNs) are still lacking. To address this gap, we established a human