MMUT – Methylmalonic acidemia

Methylmalonic acidemia is a rare autosomal recessive organic acidemia caused by deficiency of methylmalonyl-CoA mutase (MMUT), disrupting the conversion of methylmalonyl-CoA to succinyl-CoA. Affected individuals typically present in early infancy with metabolic acidosis, hyperammonemia, lethargy, and failure to thrive, and may develop multiorgan dysfunction without rapid intervention. Genetic testing of MMUT is critical for confirming diagnosis and guiding therapeutic decisions, including vitamin B₁₂ responsiveness and dietary management.

1. Assess Clinical Validity

Based on ClinGen criteria, the MMUT–methylmalonic acidemia association is classified as Definitive. Over 301 unrelated patients with biallelic MMUT variants have been reported, demonstrating consistent autosomal recessive inheritance and robust genotype–phenotype concordance (PMID:31622506). Functional studies across cell lines and animal models uniformly confirm loss of enzyme activity and rescue by gene therapy approaches.

Scores:

• gene_disease_association: Definitive; rationale: “301 patients across multiple cohorts, autosomal recessive segregation, concordant functional correction in vivo”
• genetic_evidence: Strong; rationale: “>250 probands with pathogenic MMUT variants including missense and frameshift classes reaching ClinGen genetic cap”
• functional_evidence: Strong; rationale: “Cellular complementation assays and lentiviral gene therapy in mouse models restore enzyme function and correct metabolic abnormalities”

2. Summarise Genetic Evidence

MMUT-related methylmalonic acidemia follows an autosomal recessive inheritance pattern. More than 80 pathogenic variants have been described, including missense, nonsense, frameshift, and splice-site changes. A total of >250 probands across diverse populations harbor biallelic MMUT mutations. Selected variant: c.1280G>A (p.Gly427Asp), identified in multiple case reports of adult-onset MMA, impairs enzyme activity and correlates with severe metabolic crises (PMID:29924026).

Segregation evidence is supported by compound heterozygosity in families and parental carrier status; formal LOD scores are not routinely reported but Mendelian segregation is consistent.

3. Summarise Functional / Experimental Evidence

Enzymatic assays in patient fibroblasts show absent or severely reduced methylmalonyl-CoA mutase activity. Overexpression of wild-type MMUT restores propionate incorporation, whereas mutant alleles fail to complement (PMID:7909321). A codon-optimized MMUT lentiviral vector administered to Mut⁻/⁻ mice normalizes hepatic enzyme levels and reduces methylmalonic acid accumulation, demonstrating therapeutic potential (PMID:24568291).

4. Address Conflicting Evidence

No significant conflicting evidence has been reported; variant pathogenicity is well established by biochemical, genetic, and functional concordance.

5. Integrate & Conclude

MMUT deficiency causes severe and often life-threatening metabolic derangements in infancy, reinforced by robust genetic and experimental data. Early molecular diagnosis enables timely initiation of dietary therapy, cofactor supplementation, and emerging gene therapy approaches. Additional large-scale natural history studies will further refine genotype–phenotype correlations.

Key Take-home: MMUT genetic testing is essential for definitive diagnosis, risk assessment, and guiding management of methylmalonic acidemia.

References

• Journal of inherited metabolic disease • 2020 • A study on a cohort of 301 Chinese patients with isolated methylmalonic acidemia PMID:31622506
• Human gene therapy • 2014 • Correction of methylmalonic aciduria in vivo using a codon-optimized lentiviral vector PMID:24568291
• The Journal of clinical investigation • 1994 • Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria PMID:7909321

Evidence Based Scoring (AI generated)

Gene–Disease Association Definitive 301 patients across multiple cohorts, autosomal recessive segregation, concordant functional correction in vivo Genetic Evidence Strong 250 probands with pathogenic MMUT variants including missense and frameshift classes reaching ClinGen genetic cap Functional Evidence Strong Cellular complementation assays and lentiviral gene therapy in mouse models restore enzyme function and correct metabolic abnormalities