Research
3-methylcrotonyl-CoA carboxylase deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals
1 Division of Metabolism and Children’s Research Center (CRC), University Children’s Hospital Zurich, Steinwiesstraße 75, 8032, Zurich, Switzerland
2 Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
3 Zürich Center for Integrative Human Physiology (ZHIP), University of Zürich, Zürich, Switzerland
4 Metabolic Unit, University Children's Hospital, Basel, Switzerland
5 Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
6 Children’s Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Section of Biochemical Genetics, Philadelphia, Pennsylvania, USA
7 University Children’s Hospital Frankfurt, Frankfurt, Germany
8 Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany
9 Department of Pediatric and Adolescent Medicine, University Hospital Vienna, Vienna, Austria
10 Metabolic and Muscular Unit, Clinic of Pediatric Neurology, Meyer Children's Hospital, Florence, Italy
11 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
12 Department of Biochemical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
13 Structural Genomics Consortium, University of Oxford, Oxford, UK
Orphanet Journal of Rare Diseases 2012, 7:31 doi:10.1186/1750-1172-7-31
Published: 29 May 2012Abstract
Background
Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 encoding the α and β subunit of MCC, respectively. The phenotype is highly variable ranging from acute neonatal onset with fatal outcome to asymptomatic adults.
Methods
We report clinical, biochemical, enzymatic and mutation data of 88 MCC deficient individuals, 53 identified by newborn screening, 26 diagnosed due to clinical symptoms or positive family history and 9 mothers, identified following the positive newborn screening result of their baby.
Results
Fifty-seven percent of patients were asymptomatic while 43% showed clinical symptoms, many of which were probably not related to MCC deficiency but due to ascertainment bias. However, 12 patients (5 of 53 identified by newborn screening) presented with acute metabolic decompensations. We identified 15 novel MCCC1 and 16 novel MCCC2 mutant alleles. Additionally, we report expression studies on 3 MCCC1 and 8 MCCC2 mutations and show an overview of all 132 MCCC1 and MCCC2 variants known to date.
Conclusions
Our data confirm that MCC deficiency, despite low penetrance, may lead to a severe clinical phenotype resembling classical organic acidurias. However, neither the genotype nor the biochemical phenotype is helpful in predicting the clinical course.
