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

<b>Background/Objectives</b>: 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-<i>MMUT</i>, <i>MMAA</i>, <i>MMAB</i>, <i>MMADHC</i>, and <i>MCEE</i>-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. <b>Material and Methods</b>: 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 <i>MMUT</i>, <i>MMAA</i>, <i>MMAB</i>, <i>MMADHC</i>, or <i>MCEE</i> genes. <b>Results</b>: The cohort consisted predominantly of Iban patients (<i>n</i> = 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 <i>MMUT</i> variants (c.246_250delinsGA and c.1358G>C), four known <i>MMUT</i> variants (c.560C>G, c.693C>G, c.982C>T, c.1106G>A), and one known <i>MMAB</i> variant (c.644+1G>A). Clinical presentation and disease severity varied across cases, reflecting underlying genotypic heterogeneity. <b>Conclusions</b>: 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.