Abstract
Background: The presence of increased urinary concentrations of both methylmalonic acid (MMA) and malonic acid (MA) is assumed to differentiate combined malonic and methylmalonic aciduria (CMAMMA), due to mutations in the ACSF3 gene, from other causes of methylmalonic aciduria (classic MMAemia). Detection of MA in urine, however, is challenging since excretion of MA can be easily missed. The objective of the study was to develop a method for quantification of MA in plasma to allow differentiation between CMAMMA and classic MMAemia.
Methods: Compound heterozygosity for mutations in the ACSF3 gene was detected in two female siblings using diagnostic exome sequencing. Urine (MMA and MA) was analyzed with GC/MS, while plasma was analyzed with UPLC-MS/MS. MA/MMA ratios were calculated.
Results: Both patients had a severe psychiatric presentation (at the age of 6 years and 5.5 years, respectively) after a viral infection. MA excretion in the patients was only just above the highest control value in several samples. MA concentrations in plasma from the two patients were clearly above the highest value observed in control subjects. However, MA concentrations in plasma from patients with classic MMAemia were also elevated. Additional, calculation of MA/MMA ratio in plasma allowed to fully differentiate between CMAMMA and classic MMAemia.
Conclusions: Calculating the MA/MMA ratio in plasma allows differentiation between CMAMMA and classic MMAemia. The full clinical spectrum of CMAMMA remains to be delineated.
Competing interests: None declared
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We like to thank Martina de Barse and Karen van Baal.
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Communicated by: Ivo Barić, M.D., PhD, Professor of Pediatrics
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Take-Home Message
Childhood psychiatric presentation can be added to the clinical spectrum of CMAMMA, a disorder which can easily be diagnosed by calculation the MA/MMA ratio in plasma.
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Monique G.M. de Sain-van der Velden, Maria van der Ham, Judith J. Jans, Gepke Visser, Hubertus C.M.T. Prinsen, Nanda M. Verhoeven-Duif, Koen L. I. van Gassen, and Peter M. van Hasselt declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
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This article does not contain any studies with animal subjects.
Details of the Contributions of Individual Authors
Monique G.M. de Sain-van der Velden and Peter M. van Hasselt were involved in conception and design, analysis and interpretation of data, and drafting the article.
Maria van der Ham was involved in conception and design, analysis and interpretation of data, and revising it critically for important intellectual content.
Koen L. I. van Gassen was involved in analysis and interpretation of data and revising it critically for important intellectual content.
Judith J. Jans, Gepke Visser, Hubertus C.M.T. Prinsen, and Nanda M. Verhoeven-Duif were involved in interpretation of data and revising it critically for important intellectual content.
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de Sain-van der Velden, M.G.M. et al. (2016). A New Approach for Fast Metabolic Diagnostics in CMAMMA. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 30. JIMD Reports, vol 30. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_531
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DOI: https://doi.org/10.1007/8904_2016_531
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