Methylmalonic aciduria due to methylmalonyl-coa mutase deficiencyMMUT geneAlso known as: Methylmalonic academia due to methylmalonyl-coa mutase deficiency, Methylmalonic Aciduria Vitamin B12 non-responsive, MUT type; MUT or MUT0 OMIM#251000

Methylmalonic aciduria, cblA type – MMAA gene – Also known as: Methylmalonic acidemia, type cblA; Methylmalonic aciduria, Vitamin B12-responsive, due to defect in synthesis of Adenosylcobalamin, cblA type OMIM#251100

Methylmalonic aciduria, cblB type – MMAB gene – Also known as: Methylmalonic acidemia, type cblB; Methylmalonic aciduria, Vitamin B12-responsive, due to defect in synthesis of Adenosylcobalamin, cblB type OMIM#251110

Methylmalonic aciduria and Homocystinuria, cblD type – MMADHC geneAlso known as: cblD-isolated MMA; Disorders of intracellular cobalamin metabolism, cblD defectOMIM#277410

Methylmalonyl-CoA Epimerase Deficiency – MCEE gene – Also known as: Methylmalonyl-CoA racemase Deficiency; Methylmalonic Aciduria III, formelyOMIM#251120

1. The disease:

Isolated methylmalonic acidemia/aciduria (iMMA) is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. This group of diseases is complex with different classification and the information around it is still being built up, so talk to your metabolic doctor for up-to-date data and treatment.

2. The Symptoms:

Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. Lack of early signs or symptoms does not exclude the diagnosis.

  • In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life.
  • In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age if untreated.
  • An intermediate B12-responsive phenotype can occasionally be observed in neonates, but it is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake.
  • Atypical late-onset/ adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate.

3. Actions to take in case of early diagnosis:

  • Infants with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in one of the gene referred above) should continue breastfeeding, avoid fasting or high-protein baby formulas. Early treatment is essential in preventing chronic symptoms.
  • Biochemical correlation is essential for confirming diagnosis with analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Plasma homocysteine levels (Hcy) are important to exclude combined cobalamin defects with homocystinuria. Biochemical NBS with tandem mass spectrometry can also help (can show increased C3 and ratios).
  • iMMA is a group of lifelong diseases that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
  • Critically ill individuals must be stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output.
  • Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections.
  • Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy.
  • Gene therapy is under investigation with initial clinical trials.
  • For more details, read more about the specific gene or metabolic disease, which your baby was diagnosed with.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

 4. For more information



  • Baumgartner MR, Hörster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130. PMID: 25205257.