title: Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB 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.
authors.affiliation: Research Center, Department of Biochemical Genetics and Molecular Biology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Stadler
authors.forename: Roman
authors.initials: R
authors.lastname: Polanetz
authors.forename: Esther M
authors.initials: EM
authors.lastname: Maier
authors.forename: Sylvia C
authors.initials: SC
authors.lastname: Heidenreich
authors.forename: Birgit
authors.initials: B
authors.lastname: Niederer
authors.forename: Peter U
authors.initials: PU
authors.lastname: Mayerhofer
authors.forename: Florian
authors.initials: F
authors.lastname: Lagler
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Koch
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.forename: Janice M
authors.initials: JM
authors.lastname: Fletcher
authors.forename: Enzo
authors.initials: E
authors.lastname: Ranieri
authors.forename: Anibh M
authors.initials: AM
authors.lastname: Das
authors.forename: Ute
authors.initials: U
authors.lastname: Spiekerkötter
authors.forename: Karl O
authors.initials: KO
authors.lastname: Schwab
authors.forename: Simone
authors.initials: S
authors.lastname: Pötzsch
authors.forename: Iris
authors.initials: I
authors.lastname: Marquardt
authors.forename: Julia B
authors.initials: JB
authors.lastname: Hennermann
authors.forename: Ina
authors.initials: I
authors.lastname: Knerr
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.forename: Nicolai
authors.initials: N
authors.lastname: Kohlschmidt
authors.forename: Bernhard
authors.initials: B
authors.lastname: Liebl
authors.forename: Ralph
authors.initials: R
authors.lastname: Fingerhut
authors.forename: Bernhard
authors.initials: B
authors.lastname: Olgemöller
authors.forename: Ania C
authors.initials: AC
authors.lastname: Muntau
authors.forename: Adelbert A
authors.initials: AA
authors.lastname: Roscher
authors.forename: Wulf
authors.initials: W
authors.lastname: Röschinger
mesh_terms: D000483:Alleles; D019735:Carbon-Carbon Ligases / Q000172:deficiency* / Q000235:genetics; D015331:Cohort Studies; D003677:Deficiency Diseases / Q000175:diagnosis / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D005858:Germany; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening / Q000331:legislation & jurisprudence*; D019683:Penetrance; D018570:Risk Assessment
chemical_list: D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase