3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.
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.
Division of Metabolism and Children's Research Center (CRC), University Children's Hospital Zurich, and Zürich Center for Integrative Human Physiology (ZHIP), University of Zürich, Steinwiesstraße 75, 8032, Zürich, Switzerland.
Sarah C
SC
Grünert
Martin
M
Stucki
Raphael J
RJ
Morscher
Terttu
T
Suormala
Celine
C
Bürer
Patricie
P
Burda
Ernst
E
Christensen
Can
C
Ficicioglu
Jürgen
J
Herwig
Stefan
S
Kölker
Dorothea
D
Möslinger
Elisabetta
E
Pasquini
René
R
Santer
K Otfried
KO
Schwab
Bridget
B
Wilcken
Brian
B
Fowler
Wyatt W
WW
Yue
Matthias R
MR
Baumgartner
D019735:Carbon-Carbon Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D016133:Polymerase Chain Reaction; D011795:Surveys and Questionnaires; D056806:Urea Cycle Disorders, Inborn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
D019735:Carbon-Carbon Ligases