3-methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father.
ABSTRACT Three affected members of one family, each with a different clinical presentation of isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase (MCC) deficiency are described. The index patient presented at 7 weeks of age with feeding difficulties, sweating and tachypnoea. Echocardiography showed a severely dilated left ventricle with minimal contractility. MCC deficiency was suspected on the basis of elevated urinary excretion of 3-hydroxyisovalerate and 3-methylcrotonylglycine. Deficiency of MCC activity was found in lymphocytes and fibroblasts (ca. 2% of mean normal). Serum carnitine was low (free 10 micromol/l). Some other possible causes of cardiomyopathy were excluded. Cardiomyopathy was not improved by carnitine therapy. The healthy father and a developmentally delayed brother also had MCC deficiency. Both also had decreased serum carnitine concentrations, but without cardiac involvement. Dilatative cardiomyopathy as predominant symptom in isolated MCC deficiency has not been described before, although severe carnitine deficiency is a common finding in MCC deficiency. It is not clear whether this is a coincidental association. CONCLUSION: In order to understand the phenotypic spectrum of this rare disorder, cardiac evaluation should be made in patients with 3-methylcrotonyl-CoA carboxylase deficiency. Biochemical and clinical investigations have also to be performed in their parents and siblings. In addition, 3-methylcrotonyl-CoA carboxylase deficiency should be included in the differential diagnosis of dilatative cardiomyopathy.
Article: 3-Methylcrotonyl-CoA Carboxylase Deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals.[show abstract] [hide 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 alpha and beta 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.Orphanet Journal of Rare Diseases 05/2012; 7(1):31. · 5.83 Impact Factor