TY - CHAP
T1 - A new approach for fast metabolic diagnostics in CMAMMA
AU - de Sain-van der Velden, Monique G.M.
AU - van der Ham, Maria
AU - Jans, Judith J.
AU - Visser, Gepke
AU - Prinsen, Hubertus C.M.T.
AU - Verhoeven-Duif, Nanda M.
AU - van Gassen, Koen L.I.
AU - van Hasselt, Peter M.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - 3MCC Deficiency
KW - Malonic Acid
KW - Methylmalonic Acid
KW - Methylmalonic Aciduria
KW - Organic Acid Analysis
UR - http://www.scopus.com/inward/record.url?scp=85050850406&partnerID=8YFLogxK
U2 - 10.1007/8904_2016_531
DO - 10.1007/8904_2016_531
M3 - Chapter
C2 - 26915364
VL - 30
T3 - JIMD Reports
SP - 15
EP - 22
BT - JIMD Reports
PB - Springer
ER -