MCCC2 – 3-Methylcrotonyl-CoA Carboxylase Deficiency

MCCC2 encodes the β-subunit of 3-methylcrotonyl-CoA carboxylase (MCCB), a biotin-dependent mitochondrial enzyme in the leucine catabolic pathway. Pathogenic variants in MCCC2 cause isolated 3-methylcrotonyl-CoA carboxylase deficiency, an autosomal recessive organic aciduria (OMIM 210200).

Clinical presentations are highly variable, ranging from fatal neonatal respiratory failure and failure to thrive at 6.5 months ([PMID:9537490]) to metabolic stroke with hypoglycemia, seizures, hemiparesis in infancy ([PMID:10485305]), intracranial calcifications and intractable seizures in early childhood ([PMID:34899149]), and asymptomatic adults identified via newborn screening ([PMID:22642865]). Core features include failure to thrive (HP:0001508), hypotonia (HP:0001252), respiratory failure (HP:0002878), global developmental delay (HP:0001263), and seizures (HP:0001250).

Genetic evidence is definitive: bi-allelic MCCC2 variants have been reported in >43 unrelated individuals across multiple cohorts, including 18 of 28 probands in a mutation analysis study ([PMID:16010683]) and 25 of 88 individuals in a large natural history series ([PMID:22642865]). Variants span missense (e.g., c.803G>C (p.Arg268Thr)), nonsense, frameshift, splice-site, and cryptic exon activation alleles, with recurrent population-specific and founder mutations identified.

Inheritance is autosomal recessive, with enzymatic confirmation in lymphocytes and fibroblasts demonstrating reduced MCC activity. Although segregation data are limited, multiple unrelated families show concordant bi-allelic genotypes and clinical phenotypes.

Functional studies provide moderate experimental support: minigene assays of the exon-11 splice enhancer mutation c.1054G>A (p.Gly352Arg) reveal activation of a cryptic exon with complete loss of MCC activity in vitro ([PMID:19706617]). Additional in vitro expression of missense alleles demonstrates severely diminished enzymatic function.

No significant conflicting evidence has been reported. The robust genetic and functional concordance over >20 years of study establishes MCCC2 as definitively implicated in 3-methylcrotonyl-CoA carboxylase deficiency. Newborn screening and enzymatic testing enable early diagnosis, and carnitine supplementation may prevent life-threatening metabolic crises.

Key Take-home: Bi-allelic MCCC2 variants cause a clinically heterogeneous, autosomal recessive organic aciduria; genetic testing and enzyme assays are critical for early diagnosis and management.

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
• 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 Biological Chemistry • 2009 • Cryptic exon activation by disruption of exon splice enhancer: novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency. PMID:19706617
• Orphanet Journal of Rare Diseases • 2012 • 3-Methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. PMID:22642865

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