Novel Biallelic Variants in DLD Gene Cause a Reversible Sensory Neuropathy.

Abstract

Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare autosomal recessive disorder that typically affects the liver, brain, and muscle. Peripheral neuropathy has not been previously associated with this condition. We report a novel case of DLDD in a 20-year-old woman who presented with recurrent hepatic dysfunction and progressive sensory neuropathy. Clinical evaluation, electrophysiology, and nerve biopsy revealed a severe sensory axonal neuropathy with lipid accumulation. Genetic analysis identified compound heterozygous DLD variants (c.745G>T, p.G249C; c.1344_1347del, p.D448Efs*16), and Western blotting confirmed markedly reduced DLD protein in patient-derived fibroblasts. Treatment with a branched-chain amino acid (BCAA)-free formula, methylcobalamin, and thiamine led to complete resolution of vomiting and significant improvement in neuropathic symptoms, as confirmed by follow-up nerve conduction studies. This is the first report to link DLDD with a reversible sensory neuropathy, expanding the phenotypic spectrum of the disease. Our findings suggest a role for lipid dysregulation and metabolic imbalance in the pathogenesis of peripheral nerve involvement and support early targeted dietary therapy in patients with atypical DLDD presentations.