MCCC1 – 3-Methylcrotonyl-CoA Carboxylase Deficiency

Isolated partial 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder characterized by failure to thrive and hypotonia in infancy. The first reported patient presented with feeding difficulties and muscular hypotonia at birth, progressed to diaphragmatic paresis and respiratory failure, and died at 6.5 months; enzyme assays showed residual MCC activity of 25% in lymphocytes and 3.8% in fibroblasts, with 28% residual incorporation of 14C-isovalerate into macromolecules in intact fibroblasts (PMID:9537490).

A second infant with isolated MCC deficiency developed hypoglycemia, focal-onset seizures, respiratory failure and hemiparesis during a febrile illness at 16 months and stabilized on protein restriction and carnitine; this highlights metabolic stroke as a rare presentation (PMID:10485305).

In a family study, a 15-month-old index case had atonic seizures, his brother delayed speech and their uncle adult-onset epilepsy; all three harbored a large homozygous 2,264 bp deletion in MCCC1, confirming segregation in two additional affected relatives (PMID:19339287).

A mutation screen of 28 MCC-deficient probands (9 symptomatic, 19 identified by newborn screening) uncovered 10 novel MCCC1 alleles, including missense, nonsense, frameshift and splice site changes, with no clear genotype–phenotype correlation; this cohort forms the largest genetic series to date in MCC deficiency (PMID:16010683).

Functional assays of five MCCC1 missense mutations expressed in MCC-deficient cell lines demonstrated null or severely diminished MCC activity, confirming loss-of-function as the predominant pathogenic mechanism; heterologous expression validated that these variants abolish enzyme function (PMID:11181649).

Taken together, autosomal recessive variants in MCCC1 across multiple unrelated families, segregation in affected relatives and concordant functional data establish a definitive gene–disease relationship for 3-Methylcrotonyl-CoA Carboxylase Deficiency. Key take-home: early diagnosis via newborn screening and biochemical confirmation enables timely dietary and carnitine therapy to prevent metabolic decompensation.

References

• European journal of pediatrics • 1998 • Partial 3-methylcrotonyl-CoA carboxylase deficiency in an infant with fatal outcome due to progressive respiratory failure. PMID:9537490
• European journal of pediatrics • 1999 • Metabolic stroke in isolated 3-methylcrotonyl-CoA carboxylase deficiency. PMID:10485305
• Journal of child neurology • 2009 • 3-Methylcrotonyl-CoA carboxylase deficiency: phenotypic variability in a family. PMID:19339287
• Human mutation • 2005 • 3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening. PMID:16010683
• The Journal of clinical investigation • 2001 • The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. PMID:11181649

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