Author:
Grünert Sarah C,Stucki Martin,Morscher Raphael J,Suormala Terttu,Bürer Celine,Burda Patricie,Christensen Ernst,Ficicioglu Can,Herwig Jürgen,Kölker Stefan,Möslinger Dorothea,Pasquini Elisabetta,Santer René,Schwab K Otfried,Wilcken Bridget,Fowler Brian,Yue Wyatt W,Baumgartner Matthias R
Abstract
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Genetics (clinical),General Medicine
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