Abstract
Methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (OMIM #251,000) is an autosomal recessive disorder of organic acid metabolism associated with life-threatening acute metabolic decompensations and significant neuropsychological deficits. “Isolated” MMA refers to the presence of excess methylmalonic acid without homocysteine elevation. Belonging to this class of disorders are those that involve complete deficiency (mut0) and partial deficiency (mut−) of the methylmalonyl-CoA mutase enzyme and other disorders causing excess methylmalonic acid excretion. These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions. Neuropsychological attributes associated with isolated MMA have become more relevant as survival rates increased following improved diagnostic and treatment strategies. Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning. Mean IQ for all types apart from cblA defect enzymatic subtype is rarely above 85 and much lower for mut0 enzymatic subtype. Identifying psychological domains responsive to improvements in biochemical status is important. This review suggests that processing speed, working memory, language, attention, and quality of life may be sensitive to fluctuations in metabolite levels while IQ and motor skills may be less amenable to change. Due to slower developmental trajectories, Growth Scale Values, Projected Retained Ability Scores and other indices of change need to be incorporated into clinical trial study protocols. Neuropsychologists are uniquely qualified to provide a differentiated picture of cognitive, behavioral and emotional consequences of MMA and analyze benefits or shortcomings of novel treatments.
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Abbreviations
- MMA:
-
Methylmalonic acidemia
- mut0:
-
Methylmalonyl CoA mutase enzyme, complete deficiency
- mut − :
-
Methylmalonyl CoA mutase enzyme, partial deficiency
- cblA:
-
Cobalamin A defect
- cblB:
-
Cobalamin B defect
- B12:
-
Vitamin B12 (adenosyl cobalamin)
- IQ:
-
Intelligence quotient
- μmol/L:
-
Micromoles/liter
- MRI:
-
Magnetic resonance imaging
- T2:
-
Time constant for the decay of transverse magnetization
- WPPSI-IV:
-
Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition
- WASI-II:
-
Wechsler Abbreviated Scale of Intelligence, Second Edition
- WISC-V:
-
Wechsler Intelligence Scale for Children, Fifth Edition
- WAIS-IV:
-
Wechsler Adult Intelligence Scale, Fourth Edition
- NIH:
-
National Institutes of Health
- CANTAB:
-
Cambridge Automated Neuropsychological Test Battery
- PROMIS:
-
Patient Reported Outcomes Measurement Information System
- BASC-3:
-
Behavior Assessment System for Children, Third Edition
- GSV:
-
Growth Scale Values
- PAS:
-
Personal Ability Scores
- PRAS:
-
Projected Retained Ability Score
- MDRI:
-
Multi-Domain Responder Index
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The author thanks Harvey Levy, MD and Kimberly Chapman, MD for their helpful comments on an earlier draft of this manuscript and Stephanie Sacharow, MD for her careful editing of the final version.
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S. Waisbren reviewed the literature, analyzed the accumulated information, and wrote the manuscript.
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S. Waisbren consults to Hemoshear Therapeutics.
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Waisbren, S.E. Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments. Metab Brain Dis 37, 1317–1335 (2022). https://doi.org/10.1007/s11011-022-00954-1
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DOI: https://doi.org/10.1007/s11011-022-00954-1