Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity ofMCCA andMCCB mutations and impact on risk assessment

Abstract

New technology enables expansion of newborn screening (NBS) of inborn errors aimed to prevent adverse outcome. In conditions with a large share of asymptomatic phenotypes, the potential harm created by NBS must carefully be weighed against benefit. Policies vary throughout the United States, Australia, and Europe due to limited data on outcome and treatability of candidate screening conditions. We elaborated the rationale for decision making in 3-methylcrotonyl-coenzyme A (CoA) carboxylase deficiency (MCCD), which afflicts leucine catabolism, with reported outcomes ranging from asymptomatic to death. In Bavaria, we screened 677,852 neonates for 25 conditions, including MCCD, based on elevated concentrations of 3-hydroxyisovalerylcarnitine (3-HIVA-C). Genotypes of MCCA (MCCC1) and MCCB (MCCC2) were assessed in identified newborns, their relatives, and in individuals (n = 17) from other regions, and correlated to biochemical and clinical phenotypes. NBS revealed eight newborns and six relatives with MCCD, suggesting a higher frequency than previously assumed (1:84,700). We found a strikingly heterogeneous spectrum of 22 novel and eight reported mutations. Allelic variants were neither related to biochemical nor anamnestic data of our probands showing all asymptomatic or benign phenotypes. Comparative analysis of case reports with NBS data implied that only few individuals (< 10%) develop symptoms. In addition, none of the symptoms reported so far can clearly be attributed to MCCD. MCCD is a genetic condition with low clinical expressivity and penetrance. It largely represents as nondisease. So far, there are no genetic or biochemical markers that would identify the few individuals potentially at risk for harmful clinical expression. The low ratio of benefit to harm was pivotal to the decision to exclude MCCD from NBS in Germany. MCCD may be regarded as exemplary of the ongoing controversy arising from the inclusion of potentially asymptomatic conditions, which generates a psychological burden for afflicted families and a financial burden for health care systems.

Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency

“…Stadler et al recently reported that there was no correlation between phenotypes and genotypes in MCC deficiency (Stadler et al 2006). From these findings and our results, we conjecture that factors other than the genotype at the MCC loci, such as modifying genes and environmental factors, may have a major influence on the MCC deficiency phenotype.…”

“…Enzyme deficiency can result from mutations in either the MCCA or MCCB gene (MIM 210200 and MIM 210210, respectively). Investigators have so far reported 28 MCCA and 41 MCCB mutation alleles, including missense, nonsense, frameshift, and splice site mutations (Stadler et al 2006).…”

Is l-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?

“…diastolic, BP blood pressure, ECG electrocardiogram, TTE transthoracic echocardiography, LVMI left ventricle mass index (normal value ¼ <115 for males and <95 for females), LVEF left ventricular ejection fraction (normal value¼ > 55), Symp. symptoms, PE pulmonary embolism (Stadler et al 2006). The listed prevalences and incidences are conservative estimates, because we only report on carnitinedeficient 3-MCCd cases and not everyone in the Faroe Islands participated in the voluntary screening programme.…”

“…Increased renal excretion of 3-hydroxyisovalerylcarnitine is a natural way of excreting toxic intermediary metabolites that interfere with normal metabolism at the cost of low plasma carnitine levels (Roschinger et al 1995). Among organic acidurias, 3-MCCd is the most frequently diagnosed disorder at neonatal tandem mass spectrometry (MS/MS) screening (Koeberl et al 2003;Schulze et al 2003;Wilcken et al 2003;Stadler et al 2006;Lam et al 2013). The 3-MCC enzyme consists of two subunits, a and b, encoded by the MCCC1 and MCCC2 genes, located at 3q25-q27 and 5q12-q13, respectively (Baumgartner et al 2001;Gallardo et al 2001;Holzinger et al 2001).…”

“…The clinical picture may show extensive intrafamiliar variation (Visser et al 2000;Baumgartner et al 2004;Darin et al 2007;Dirik et al 2008;Eminoglu et al 2009;Grunert et al 2012). However, most children detected through newborn screening remain asymptomatic (Stadler et al 2006;Lam et al 2013;Koeberl et al 2003).…”