Combined Methylmalonic Aciduria and Homocystinuria Presenting as Pulmonary Hypertension

Abstract

Combined methylmalonic aciduria and homocystinuria, cblC type, (MAHCC) is a rare autosomal recessive metabolic disorder of remethylation caused due to mutations in the MMACHC (metabolism of cobalamin associated C) gene with predominant neurological involvement. Microvascular, renal, and cardiovascular complications are also known to occur. However, the disease presenting primarily with a cardiovascular phenotype without any neurological involvement is a rare entity. We report a case of developmentally normal 23-mo-old female child, who presented with pulmonary arterial hypertension (PAH) and succumbed to cardiac failure. Extensive workup for PAH was inconclusive. Posthumous trio whole-exome sequencing revealed pathogenic compound heterozygous variants in the MMACHC. Diagnosis of MAHCC should be considered as a differential diagnosis for unexplained PAH in children. An elevated plasma homocysteine level can serve as a simple screening modality for this disorder. Accurate diagnosis has paramount therapeutic implications, as management with hydroxocobalamin and betaine may lead to partial or complete remission of PAH in these patients.

Keywords: Cobalamin C; Homocystinuria; MMACHC; Methylmalonic aciduria; Pulmonary arterial hypertension.