Newborn screening and genetic diagnosis of 3-methylcrotonyl-CoA carboxylase deficiency in Quanzhou,China.

BACKGROUND AND AIMS: 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is an autosomal recessive leucine catabolism condition caused by 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency due to MCCC1/MCCC2 variants. We investigated its incidence and features in Quanzhou, China.

MATERIALS AND

METHODS

We screened 643,606 newborns (January 2014 to December 2022) for elevated 3-hydroxyisovalerylcarnitine (C5OH) levels using tandem mass spectrometry (MS/MS). Molecular analyses identified MCCC1/MCCC2 variants in suspected 3-MCCD cases.

RESULTS

Seventeen neonates, two maternal patients, and one paternal patient had 3-MCCD. Its incidence in the Quanzhou study population was 1/37,859 newborns. All patients and neonates with 3-MCCD exhibited increased C5OH concentrations. Most patients [76.5%(13/17)] had increased urinary 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA) levels. Eight neonates and all adults with 3-MCCD had secondary carnitine deficiency. We identified seventeen variants, including 6 novel ones.MCCC1and MCCC2 variants were found in 47.1% and 52.9% of patients,with c.1331G > A (31.3%) and c.351_353delTGG (50.0%) being the most prevalent, respectively. Clinical symptoms were observed in 11.8% of patients.

CONCLUSION

We identified six new MCCC1/MCCC2 variants, enhancing our understanding of the 3-MCCD molecular profile. Secondary carnitine deficiency occurred in eight neonates and all adult patients. Although clinical symptoms were observed in 11.8% of patients, whether they were related to 3-MCCD remain unclear. Therefore, further studies are required to decide whether 3-MCCD and C5OH indicators should continue to be used.