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Correlation between toxic organic acid fluctuations and neurodevelopment in patients with methylmalonic acidemia
I-Chih Ling1,2, Dau-Ming Niu1,3, Chia-Feng Yang1,3
1Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
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 vitamin B12 non-responsive (B12-NR) type and 6 vitamin B12 responsive (B12-R) type. Diverse parameters were assessed, including methylmalonic acid (MA), methylcitric acid (MCA), propionylcarnitine (C3), acetylcarnitine (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. B12-NR type patients exhibited elevated levels of MA, MCA, C3, C3/C2 ratio and lactate, with more frequent and significant MA, MCA and C3 fluctuation than B12-R type patients. Brain imaging revealed central nervous system demyelination in B12-NR type patients, while B12-R type patients displayed normal MRS results. B12-R type patients exhibited significantly better neurocognitive outcomes, with higher scores in all domains.
Conclusion:
Patients with B12-NR type MMA exhibit worse neurodevelopmental outcomes and more pronounced biochemical imbalances compared to those with B12-R type. Significant correlations were observed between higher fluctuation frequencies of toxic metabolites and lower developmental and IQ scores. These findings emphasize the importance of targeted strategies to manage organic acid fluctuations for improving neurodevelopmental outcomes in MMA.
Insights
Methylmalonic acidemia (MMA) impacts neurodevelopment, especially in vitamin B12 non-responsive types. Managing toxic metabolite fluctuations is key to improving developmental outcomes in MMA patients.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Methylmalonic acidemia (MMA) is a rare genetic disorder causing toxic metabolite accumulation and multisystem damage.
- These toxic metabolites negatively affect nerve cells, leading to suboptimal neurodevelopment in MMA patients.
- The exact impact of toxic metabolite fluctuations on neurodevelopment in MMA remains unclear.
Purpose of the Study:
- To investigate the relationship between toxic metabolite fluctuations and neurodevelopmental outcomes in patients with Methylmalonic acidemia (MMA).
- To compare biochemical and neuroimaging findings between vitamin B12-responsive (B12-R) and non-responsive (B12-NR) MMA subtypes.
- To identify potential therapeutic targets for improving neurodevelopmental outcomes in MMA.
Main Methods:
- Enrolled 20 MMA patients (14 B12-NR, 6 B12-R).
- Assessed biochemical markers (MA, MCA, C3, C2, ammonia, glycine, lactate) and calculated fluctuation frequencies.
- Evaluated cognitive function (Bayley-III, Wechsler) and performed brain imaging (MRS).
Main Results:
- B12-NR patients showed elevated toxic metabolites and more frequent fluctuations than B12-R patients.
- B12-NR patients exhibited central nervous system demyelination on MRS, unlike B12-R patients.
- B12-R patients demonstrated significantly better neurocognitive outcomes across all assessed domains.
Conclusions:
- Vitamin B12 non-responsive MMA is associated with poorer neurodevelopmental outcomes and greater biochemical imbalances.
- Increased fluctuation frequency of toxic metabolites correlates with lower developmental and IQ scores.
- Targeted management of organic acid fluctuations is crucial for enhancing neurodevelopmental outcomes in MMA.
