TY - JOUR
T1 - Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families
AU - Sass, Jörn Oliver
AU - Gemperle-Britschgi, Corinne
AU - Tarailo-Graovac, Maja
AU - Patel, Nisha
AU - Walter, Melanie
AU - Jordanova, Albena
AU - Alfadhel, Majid
AU - Barić, Ivo
AU - Çoker, Mahmut
AU - Damli-Huber, Aynur
AU - Faqeih, Eissa Ali
AU - García Segarra, Nuria
AU - Geraghty, Michael T.
AU - Jåtun, Bjørn Magne
AU - Kalkan Uçar, Sema
AU - Kriewitz, Merten
AU - Rauchenzauner, Markus
AU - Bilić, Karmen
AU - Tournev, Ivailo
AU - Till, Claudia
AU - Sayson, Bryan
AU - Beumer, Daniel
AU - Ye, Cynthia Xin
AU - Zhang, Lin-Hua
AU - Vallance, Hilary
AU - Alkuraya, Fowzan S.
AU - van Karnebeek, Clara D. M.
PY - 2016
Y1 - 2016
N2 - Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the gamma-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology. (C) 2016 Elsevier Inc. All rights reserved
AB - Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the gamma-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology. (C) 2016 Elsevier Inc. All rights reserved
U2 - https://doi.org/10.1016/j.ymgme.2016.07.008
DO - https://doi.org/10.1016/j.ymgme.2016.07.008
M3 - Article
C2 - 27477828
SN - 1096-7192
VL - 119
SP - 44
EP - 49
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1-2
ER -