MCCC1 – 3-Methylcrotonyl-CoA Carboxylase 1 Deficiency

3-Methylcrotonyl-CoA carboxylase 1 deficiency is an autosomal recessive disorder of leucine catabolism caused by loss-of-function variants in the MCCC1 gene, which encodes the biotin-dependent α subunit of the mitochondrial enzyme complex. Affected individuals accumulate 3-methylcrotonylglycine and 3-hydroxyisovaleric acid, detected by tandem mass spectrometry–based newborn screening. Clinical presentation ranges from severe neonatal metabolic crises with encephalopathy to asymptomatic adults, including maternal carriers identified only via abnormal neonatal screening in their offspring (PMID:9296536; PMID:25114694).

Genetic studies have confirmed an autosomal recessive inheritance pattern with at least 24 unrelated MCCC1-deficient probands reported: 14 in early molecular characterization cohorts (PMID:11170888) and 10 in targeted mutation screening of newborn-screening–identified cases (PMID:16010683). Segregation analysis in nine families, including asymptomatic mothers with biallelic pathogenic alleles, supports cosegregation with biochemical deficiency (PMID:25114694).

The variant spectrum in MCCC1 includes missense, nonsense, splice-site, and frameshift mutations. A recurrent missense variant, c.1153A>G (p.Arg385Gly), has been detected in multiple unrelated patients and shown to abolish enzyme activity in vitro (PMID:11170888). Other pathogenic alleles include splice-disrupting intronic changes and early truncating mutations, cumulatively exceeding the ClinGen genetic evidence threshold for a strong classification.

Functional assays in patient fibroblasts and heterologous expression systems demonstrate marked loss of MCC α-subunit activity for MCCC1 missense alleles (PMID:14680978). A fungal mccA knockout model recapitulates the block in leucine catabolism and confirms enzyme essentiality (PMID:11170888). Dominant-negative effects of certain alleles, such as p.Arg385Ser, further elucidate pathogenic mechanisms and biotin responsiveness in vivo (PMID:15868465).

Despite extensive variant discovery, genotype–phenotype correlations remain poor; penetrance is low and many individuals remain asymptomatic or display mild fatigue (HP:0012378) and myopathy (HP:0003198) even with confirmed bi-allelic mutations (PMID:25114694). This variability underscores the need for biochemical confirmation and long-term follow-up of newborn-screened cases.

In summary, biallelic pathogenic variants in MCCC1 definitively cause 3-methylcrotonyl-CoA carboxylase 1 deficiency. Genetic screening and enzymatic assays enable early diagnosis, inform prognosis, and guide management, including biotin therapy trials. Key take-home: Clinicians should include MCCC1 variant analysis in newborn screening follow-up to prevent metabolic decompensation.

References

• Korean journal of pediatrics • 2014 • Asymptomatic maternal 3-methylcrotonylglycinuria detected by her unaffected baby's neonatal screening test. PMID:25114694
• European journal of pediatrics • 1997 • An asymptomatic infant with isolated 3-methylcrotonyl-coenzyme: a carboxylase deficiency detected by newborn screening for maple syrup urine disease. PMID:9296536
• American journal of human genetics • 2001 • The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism. PMID:11170888
• Human mutation • 2005 • 3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening. PMID:16010683
• Orphanet journal of rare diseases • 2012 • 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. PMID:22642865
• Molecular genetics and metabolism • 2003 • Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria. PMID:14680978
• Journal of inherited metabolic disease • 2005 • Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency. PMID:15868465

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