Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations

Abstract

Methylcrotonylglycinuria (MCG) is an inborn error of leucine catabolism and results from the deficiency of 3-methylcrotonyl-CoA carboxylase. Patients with MCG show a highly variable clinical phenotype, ranging from asymptomatic to severe. With the introduction of newborn screening using tandem mass spectrometry, most patients with MCG are identified in their asymptomatic neonatal periods. Owing to their fair clinical outcomes, there exists a controversy over the need for aggressive medical intervention or even for newborn screening for MCG. Our study, reporting 11 Korean MCG patients from nine unrelated families, who were identified by newborn screening or family member testing and normally developed without experiencing an metabolic crisis during the follow-up period of 2.6±1.96 years (range, 1-10 years), indicates that the aggressive medical intervention might not be needed at least for the MCG patients identified by screening program in asymptomatic period. A total of six MCCC2 mutations, but no MCCC1 mutation, were identified in 17 of 18 alleles (94.4%). p.D280Y was identified in the 12/18 alleles (66.7%), indicating a founder effect. Moreover, the rest five variants, p.S342K, p.Q496H, p.P552S, p.T556A and p.P459S, were all previously unreported. The results of our study indicate that the distinct molecular genetic characteristics exist in Korean MCG patients.

Structure and function of biotin-dependent carboxylases

“…Deficiencies in MCC activity in humans are linked to 3-methylcrotonylglycinuria (MCG), which constitute one of the most frequently observed inborn errors of metabolism [217–226]. The clinical manifestations of MCG are highly variable, from asymptomatic individuals to neonatal onset, severe cases that can result in death.…”

3-methylcrotonyl Coenzyme A (CoA) carboxylase complex is involved in the Xanthomonas citri subsp. citri lifestyle during citrus infection

“…In most of the organisms, the carboxylation of 3-methylcrotonyl-CoA to generate 3-methylglutaconyl-CoA, catalyzed by the enzyme 3-methylcrotonyl-CoA carboxylase (MCC), is an essential step for the catabolism of leucine and isovalerate [ 15 , 21 , 22 – 25 ]. The final products of this pathway are acetyl- and acetoacetyl-CoA, which can be reintroduced into different metabolic pathways in situations of nutritional stress or amino acid excess.…”

“…The final products of this pathway are acetyl- and acetoacetyl-CoA, which can be reintroduced into different metabolic pathways in situations of nutritional stress or amino acid excess. Deficiency in the MCC activity of is linked to serious diseases in humans [ 22 – 25 ]. The role of these enzymes in Gram-negative bacteria was only studied in Pseudomonas , where MCC is involved in the metabolism of acyclic terpenoids [ 26 – 31 ].…”

Novel heterozygous MCCC1 mutations identified in a patient with 3-methylcrotonyl-coenzyme A carboxylase deficiency

“…MCCC2 mutations were reported to be 1.7 times more common than MCCC1 mutations, as found in a cohort study of 53 newborns [3]. Of the genetic mutations reported in Korean patients, 75% have been found within MCCC2 [4,5]. Infants carrying a mutation identified by neonatal screening usually appear to be asymptomatic and remain healthy.…”