From the Research
Neuropsychiatric symptoms in methylmalonic acidemia can occur at serum methylmalonic acid levels above 0.4-0.7 μmol/L, though individual susceptibility varies. These symptoms typically manifest when methylmalonic acid accumulates due to vitamin B12 deficiency or inherited enzymatic defects in the methylmalonyl-CoA mutase pathway. Patients may experience a range of neuropsychiatric manifestations including depression, anxiety, cognitive impairment, psychosis, and behavioral changes even at moderately elevated levels. The mechanism involves neurotoxicity from accumulated organic acids, disruption of energy metabolism in neurons, and potential interference with neurotransmitter function.
According to the most recent and highest quality study available, 1, early-onset patients with methylmalonic acidemia manifested the most severe neurocognitive impairments, with a mean full-scale IQ of 71.1. The study also found that hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower full-scale IQ.
Some key points to consider:
- The neurocognitive outcomes seen in isolated methylmalonic acidemia are highly variable, with earlier age of disease onset and presence of hyperammonemia at diagnosis associated with more severe impairment 1.
- Selective deficits in processing speed were present in all patient subtypes, regardless of the severity of the disease 1.
- Early assessment and diagnosis have an important role in the prevention of disease progression and clinical signs, with patients diagnosed early having a more favorable clinical response in growth index, refractory seizure, anorexia, and neurodevelopmental delay 2.
- Regular monitoring of methylmalonic acid levels is essential for patients with known methylmalonic acidemia or risk factors for vitamin B12 deficiency, as early intervention with appropriate vitamin B12 supplementation or dietary protein restriction can prevent or reverse these neuropsychiatric manifestations before they become severe or permanent.
In terms of management, vitamin B12 supplementation, typically hydroxocobalamin or methylcobalamin, or dietary protein restriction can prevent or reverse neuropsychiatric manifestations. The choice of treatment should be individualized based on the patient's specific needs and circumstances.