Methylmalonic Acidemia
Pathogenesis (Organic Acid Disorder)
- Methylmalonyl CoA Mutase (a mitochondrial, B12 dependent enzyme) inactivity prevents the breakdown of key molecules and macromolecules. Normally, methylmalonyl CoA mutase works with Vitamin B12 (cobalamin) to breakdown methylmalonyl CoA to succinyl-CoA – this failure leads to toxic accumulation of these molecules and macromolecules.
- Molecules: Amino acids – Isoleucine, Threonine, Methionine, Valine
- Macromolecules: Odd-chain Fatty Acids, Cholesterol side chain.
- B12 (Cobalamin) Enzyme deficiency can also lead to methylmalonic academia in concert with homocysteinemia.
Clinical
- Onset: Infancy
- Presentation: Failure to Thrive
- Trigger: Catabolic stress due to acute illness.
- Neurological manifestations: Cognitive Delay
- Systemic manifestations: Kidney Failure, Pancreatitis
- Laboratory findings: Poor glucose utilization leads to – Hypoglycemia. Increased organic acids leads to – Metabolic acidosis w/increased anion gap, Ketosis, Hyperammonemia, and Hyperglycinemia.
- Treatment: Cease Protein Intake, Eliminate Metabolites (Dialysis), Hydrate & Correct Metabolic Abnormalities, Cofactor supplementation (B12 supplementation).
Genetics
- Multiple genes (including the MUT gene)
- Autosomal recessive
References
- Calvo, Sherri; Collins, Heather; Greenberg, Kathleen, et. al at US National Library of Medicine, Genetics Home Reference. https://ghr.nlm.nih.gov