Correlation between toxic organic acid fluctuations and neurodevelopment in patients with methylmalonic acidemia

Abstract

Abstract Background Methylmalonic acidemia (MMA) is a rare autosomal recessive disorder, that causes multisystem damage by accumulating toxic metabolites. These metabolites, particularly affecting nerve cells, contribute to suboptimal neurodevelopment in MMA patients. While fluctuations in these toxic metabolites are common in MMA patients, their precise impact on neurodevelopment remains unclear. Results This study enrolled 20 MMA patients, comprising 14 methylmalonyl-CoA mutase (MMUT) type and 6 cobalamin (cbl) type. Diverse parameters were assessed, including methylmalonic acid (MA), methylcitric acid (MCA), propionylcarnitine (C3), acylcarnitine (C2), ammonia, glycine, and lactate. Cognitive function was evaluated using the Bayley-III and Wechsler intelligence scale, and brain imaging was conducted through magnetic resonance spectroscopy (MRS). The frequency and extent of fluctuations in toxic organic acids were computed based on blood test results. MMUT-type patients exhibited elevated levels of MA, MCA, C3, C3/C2 ratio and lactate, with more frequent and significant MA and C3 fluctuations than cbl-type patients. Brain imaging revealed central nervous system (CNS) demyelination in MMUT-type patients, while cbl-type patients displayed normal MRS results. Cbl-type patients exhibited significantly better neurocognitive outcomes, with higher scores in cognitive, motor, language, and social-emotional domains. A negative correlation was identified between the frequency of MA fluctuations and the developmental status of MMA patients. Conclusion Variances between MMUT-type and cbl-type MMA patients extend to neurocognitive outcomes, along with differences in frequency and magnitude of toxic organic acid fluctuations. MMA, particularly in MMUT-type patients, is associated with developmental delays and cognitive deficits, contrasting with more favorable outcomes in cbl-type patients due to treatment efficacy. Furthermore, a negative correlation was identified between the frequency of widely fluctuating MA and developmental conditions in MMA patients.