title: A New Approach for Fast Metabolic Diagnostics in CMAMMA.
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.
authors.affiliation: Department of Medical Genetics, UMC Utrecht, 85090, 3508AB, Utrecht, The Netherlands. m.g.desain@umcutrecht.nl.
authors.forename: Monique G M
authors.initials: MG
authors.lastname: de Sain-van der Velden
authors.affiliation: Department of Medical Genetics, UMC Utrecht, 85090, 3508AB, Utrecht, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: van der Ham
authors.affiliation: Department of Medical Genetics, UMC Utrecht, 85090, 3508AB, Utrecht, The Netherlands.
authors.forename: Judith J
authors.initials: JJ
authors.lastname: Jans
authors.affiliation: Department of Pediatric Gastroenterology and Metabolic Diseases, University Medical Centre (UMC) Utrecht, Utrecht, The Netherlands.
authors.forename: Gepke
authors.initials: G
authors.lastname: Visser
authors.affiliation: Department of Medical Genetics, UMC Utrecht, 85090, 3508AB, Utrecht, The Netherlands.
authors.forename: Hubertus C M T
authors.initials: HC
authors.lastname: Prinsen
authors.affiliation: Department of Medical Genetics, UMC Utrecht, 85090, 3508AB, Utrecht, The Netherlands.
authors.forename: Nanda M
authors.initials: NM
authors.lastname: Verhoeven-Duif
authors.affiliation: Department of Medical Genetics, UMC Utrecht, 85090, 3508AB, Utrecht, The Netherlands.
authors.forename: Koen L I
authors.initials: KL
authors.lastname: van Gassen
authors.affiliation: Department of Pediatric Gastroenterology and Metabolic Diseases, University Medical Centre (UMC) Utrecht, Utrecht, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt