Pathogenic mutations in the gene for methylmalonyl-CoA mutase involved in the intracellular metabolism of cobalamin can induce isolated methylmalonic aciduria. Some of these mutations may be sensitive to cobalamin. The examples presented emphasized the necessity of genetic testing in methylmalonic aciduria instances and the need for standardization of in vivo cobalamin-responsiveness assessments. 

The authors described two patients who developed fast neurological deterioration in the first week of birth due to metabolic acidosis and acute hyperammonemia, necessitating extracorporeal elimination in addition to protein restriction, energy support, carnitine, and vitamin B12 treatment. Both patients had isolated methylmalonic aciduria due to the severity of their clinical symptoms and high methylmalonic acid concentrations in their urine (>30,000 mol/mmol creatinine) without hyperhomocysteinemia. They presumed the cobalamin non-responsive type based on the neonatal manifestation and the high methylmalonic acid urine levels. Both individuals underwent an in vivo test of cobalamin response. Patients 1 and 2 both have bi-allelic mutations in the MMAB and MMAA genes, according to genetic studies. Based on these findings, they began extensive hydroxocobalamin treatment in both patients. Patient 1 had no acute crisis necessitating hospitalization therapy intensification, while Patient 2’s urine methylmalonic acid levels reduced even more.

Despite conducting in vivo cobalamin responsiveness tests in both patients, only the results of molecular genetic studies led to the proper diagnosis and enabled rigorous hydroxocobalamin treatment. For reliable diagnosis and treatment of isolated methylmalonic aciduria, a combination of standardized in vivo cobalamin responsiveness and genetic testing is required.