Genetic variability in maple syrup urine disease: novel mutations and their pathogenicity in the Iranian population

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder caused by a deficiency in the branched-chain alpha-keto acid dehydrogenase complex, leading to the accumulation of branched-chain amino acids. This case series describes the clinical and genetic findings of ten Iranian patients with MSUD, focusing on novel mutations in the BCKDHA, BCKDHB, and DBT genes.

Ten unrelated patients, all from consanguineous marriages, were diagnosed with MSUD based on clinical presentations and metabolite levels. Whole exome sequencing (WES) and Sanger sequencing identified five novel mutations (c.776 C > T, IVS5-1G > C, c.1070 C > T, c.807-813del7nt, c.772-773insT) and two previously reported mutations in these patients. Pathogenicity was assessed using bioinformatics tools and confirmed by their absence in healthy controls.

This case series highlights the genetic heterogeneity of MSUD in the Iranian population, identifying novel mutations associated with severe clinical presentations. These findings emphasize the value of genetic testing for early diagnosis and genetic counseling in consanguineous populations, with implications for managing MSUD and preventing complications.