MCCC1

MCCC1 is a protein-coding gene that encodes the alpha subunit of mitochondrial 3-methylcrotonyl-CoA carboxylase (MCC). The MCC enzyme participates in leucine catabolism as part of a biotin-dependent carboxylase system. In humans, MCC consists of alpha and beta subunits, with the alpha subunit encoded by MCCC1 and the beta subunit by MCCC2. The enzyme catalyzes the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, using CO2 and biotin as a cofactor, permitting further steps in leucine degradation.

Genetic defects in MCCC1 cause 3-methylcrotonyl-CoA carboxylase deficiency (MCCD), an autosomal recessive metabolic disorder. The clinical presentation is variable, ranging from asymptomatic individuals detected by newborn screening to patients experiencing metabolic crises, hypotonia, vomiting, lethargy, hypoglycemia, or developmental delay, particularly during illness or fasting. Biochemical hallmarks include elevated 3-hydroxyisovalerylcarnitine (C5OH) in plasma and elevated 3-methylcrotonylglycine in urine; some cases respond to biotin treatment, reflecting the biotin-dependency of MCC and related carboxylases.

Diagnosis is typically made by genetic testing confirming pathogenic variants in MCCC1, supported by metabolic testing and, in some centers, enzyme activity assays in lymphocytes or fibroblasts. Newborn screening can detect MCCD by elevated C5OH on acylcarnitine profiling, but confirmation requires molecular testing. Management focuses on avoiding catabolic stress, with dietary adjustments as needed and biotin supplementation in responsive individuals. Regular monitoring for metabolic decompensation and developmental assessment is advised.

Variants in MCCC1 have been described in diverse populations. The condition illustrates the broader spectrum of biotin-responsive multiple carboxylase deficiencies. Research continues to define variant-specific outcomes and optimize treatment strategies.