Objectives Charcot-Marie-Tooth disease is an inherited peripheral neuropathy marked by progressive loss of motor and sensory function. GDAP1 mutations are implicated in Charcot-Marie-Tooth disease, but the precise mechanism is not fully understood. This study aims to decipher the underlying genetic variant and its functional consequences in a consanguineous Indian family. Methods Clinical and electrophysiological examination was carried out in proband and family members. Whole-exome sequencing was done in proband and the identified variant validated among family members and healthy controls. Skin fibroblasts, derived from patient, family members, and controls were used to analyse mitochondrial structural and functional integrity using transmission electron microscopy, mitochondrial membrane potential measurements, reactive oxygen species quantification, and Seahorse-based extracellular flux assays. Results An 8-year-old boy born to consanguineous parents and affected younger sister presented with progressive motor and sensory limb involvement secondary to progressive severe distal axonal neuropathy. Whole-exome sequencing identified a novel homozygous frameshift variant (c.503_504delAG) in GDAP1 in proband that was segregated among the family members. Patient-derived fibroblasts demonstrated complete loss of protein expression and swollen mitochondria with disrupted cristae in the cultured fibroblasts of affected individuals. Altered mitochondrial membrane potential with elevated reactive oxygen species levels, and significantly reduced ATP production and oxygen consumption rate in affected individuals compared to unaffected parents and controls, indicated impaired mitochondrial bioenergetics. Conclusions We report a novel GDAP1 frameshift variant that disrupts mitochondrial structure and bioenergetics, underscoring GDAP1’s role in mitochondrial quality control. However, the other downstream mechanisms implicated in axonal degeneration remains to be elucidated.
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