Clinical and Genetic Characterization of Isolated Methylmalonic Acidemia in Malaysian Children: Identification of Two Novel MMUT Variants

Background/Objectives: Isolated methylmalonic acidemia (iMMA) is a rare autosomal recessive metabolic disorder caused by defects in methylmalonyl-CoA mutase (MCM) activity or in the biosynthesis of its cofactor, adenosylcobalamin. Mutations in five genes—MMUT, MMAA, MMAB, MMADHC, and MCEE—are known to underlie this condition. This study aimed to characterize the clinical features and molecular spectrum of iMMA in Malaysian patients of diverse ethnic backgrounds. Material and Methods: Patients with biochemical evidence suggestive of iMMA, including elevated propionylcarnitine (C3), increased C3/C2 ratio, and raised urine methylmalonic acid levels in the absence of hyperhomocysteinemia, were selected for genetic testing. Sanger sequencing was performed to identify pathogenic variants in the MMUT, MMAA, MMAB, MMADHC, or MCEE genes. Results: The cohort consisted predominantly of Iban patients (n = 5), with the remaining cases comprising one Malay and one Thai–Malay individual. Age at diagnosis ranged from Day 1 of life to 6 years. All 7 patients were confirmed to have iMMA through molecular analysis. A total of seven pathogenic or likely pathogenic variants were identified, including two novel MMUT variants (c.246_250delinsGA and c.1358G>C), four known MMUT variants (c.560C>G, c.693C>G, c.982C>T, c.1106G>A), and one known MMAB variant (c.644+1G>A). Clinical presentation and disease severity varied across cases, reflecting underlying genotypic heterogeneity. Conclusions: This study highlights the molecular diversity and clinical variability of iMMA in Malaysia. Our findings reinforce the importance of integrating metabolic screening with molecular diagnostics to identify disease-causing variants and guide patient management strategies effectively.