Isolated methylmalonic acidemia in Mexico: Genotypic spectrum, report of two novel MMUT variants and a possible synergistic heterozygosity effect.

Isolated methylmalonic acidemia (iMMA) is a group of monogenic metabolic disorders affecting methylmalonate and cobalamin metabolism. Five iMMA-responsible genes have been described to date: (MIM *609058), (MIM *607481, (MIM *607568), (MIM *611935), and (MIM 608419). Although iMMA is the most common form of organic acidemia reported in Mexico, its genotypic spectrum is still largely unknown. We performed a clinical exome analysis on 42 unrelated Mexican patients with iMMA. deficiency accounted for 73.8 % of all cases, followed by (14.2 %), (7.2 %), and (2.4 %) deficiencies. One patient presented and double heterozygosity, which should be further experimentally confirmed to prove that synergistic heterozygosity could be another inheritance mechanism in iMMA. The most frequent genotype involved the Hispanic variant NM_000255.4:c. [322C > T];[322C > T] or p.[Arg108Cys];[Arg108Cys] (14.3 %). Two novel variants, NM_000255.4:c.589G > A or p.(Ala197Thr) and c.1476C > A or p.(Tyr492), were identified in a deceased newborn presenting the neonatal-onset severe form of the disease. protein modeling of the p.(Arg108Cys) and novel p.(Ala197Thr) variants suggested disruption of the substrate-binding and catalytic domains of the protein, respectively. This study expands the current knowledge on the molecular spectrum of iMMA in the Mexican population and reinforces the importance of genetic analysis in guiding clinical management.