Dual molecular genetic diagnosis with combined malonic and methylmalonic aciduria (CMAMMA): implications of coexisting genetic disorders on clinical presentation

Abstract Objectives Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited metabolic disorder caused by ACSF3 variants leading to malonyl-CoA synthetase (MCS) deficiency. Despite its well-defined genetic basis, the clinical spectrum of CMAMMA remains highly variable. Case presentation This study reports six patients from three unrelated families, aged 12 days to 30 years, presenting with heterogeneous clinical manifestations. Exome sequencing (ES) identified a homozygous ACSF3 variant, c.1470G>C [p.(Glu490Asp)], in five patients, and a novel variant, c.1145T>C [p.(Leu382Pro)], in one patient. Notably, in each family’s index case, ES revealed additional pathogenic variants consistent with a dual molecular diagnosis: a homozygous CHRNG variant in one patient; compound heterozygous BTD variants in two siblings, confirming biotinidase deficiency; and a novel CDK10 frameshift variant, c.520_521del [p.(Lys174Glyfs*34)], in another patient. Half of the patients with CMAMMA demonstrated mild to moderate developmental delay. Notably, the sibling with both CMAMMA and biotinidase deficiency exhibited developmental delay, whereas the sibling with isolated CMAMMA had normal development. Symptomatic individuals showed clinical improvement following dietary protein restriction and carnitine supplementation. Conclusions These findings highlight that CMAMMA may cause developmental delay, emphasizing the importance of early diagnosis and treatment. Furthermore, in patients with atypical features, high-throughput sequencing technologies offer a comprehensive approach to identifying additional pathogenic variants in genes beyond ACSF3.