Two novel CPS1 mutations in a case of carbamoyl phosphate synthetase 1 deficiency causing hyperammonemia and leukodystrophy

Abstract

This study described the specific clinical characteristics and the variations of physiological and biochemical indices in a Chinese neonatal patient with CPS1D, which facilitated the diagnosis and mechanism research of the disease. Two novel causative missense mutations were identified, which enriched the mutation spectrum of CPS1D in China and worldwide. Advice of prenatal diagnosis was given to the family for a new pregnancy.

Novel Neonatal Variants of the Carbamoyl Phosphate Synthetase 1 Deficiency: Two Case Reports and Review of Literature

“…Therefore, both patients were finally diagnosed as neonatal-onset CPS1D caused by CPS1 mutations. To our knowledge, this study is the fifth case report of CPS1D in China and the 262–264th novel mutations in CPS1 documented in the world (Chen et al, 2013; Yang et al, 2017; Chen et al, 2018; Zhang et al, 2018), which expands the mutation spectrum of CPS1 ( Supplementary Tables S1 to S4 ).…”

“…Of the variants, 81 (30.7%) were predicted to cause protein truncation, including 22 nonsense, 31 small deletions, 16 small insertions, 4 small indels, 6 splicing site changes, and 2 large deletions. Our reviewing data further clarified that most CPS1 variants (≥90%) were “private” with non-recurrence, and the few recurrent mutations tended to occur at CpG dinucleotides, which made the diagnosis more complicated ( Supplementary Tables S1 to S4 ) (Hoshide et al, 1993; Finckh et al, 1998; Summar et al, 1998; Ihara et al, 1999; Aoshima et al, 2001a; Aoshima et al, 2001b; Rapp et al, 2001; Wakutani et al, 2001; Häberle et al, 2003; Eeds et al, 2006; Kurokawa et al, 2007; Khayat, 2009; Ono et al, 2009; Pekkala et al, 2010; Häberle et al, 2011; Wang et al, 2011; Funghini et al, 2012; Kretz et al, 2012; Diez-Fernandez et al, 2014; Ali et al, 2016; Choi et al, 2017; Rokicki et al, 2017; Yang et al, 2017; Chen et al, 2018; Zhang et al, 2018).…”

“…However, this technology cannot differentiate CPS1D from N -acetylglutamate synthase deficiency (NAGSD) in UCDs due to their similar intermediate metabolites. Until recently, next-generation sequencing (NGS), a powerful DNA sequencing technology, has revolutionized genomic research with great utility in the molecular diagnosis of genetic disorders (Choi et al, 2017; Jia et al, 2017; Rokicki et al, 2017; Li et al, 2018; Zhang et al, 2018), and has been proven reliable and important to detect CPS1 mutation for early diagnosis of CPS1D, as the severity of clinical manifestations in CPS1D patients is determined by the extent of CPS1 deficiency (Choi et al, 2017; Chen et al, 2018; Zhang et al, 2018).…”

“…Strikingly, for the first time, we identified three novel pathogenic mutations of CPS1 . To our knowledge, there have been so far only three reports of using NGS to detect CPS1 mutations for CPS1D diagnosis (Choi et al, 2017; Chen et al, 2018; Zhang et al, 2018). Our novel findings further expanded the mutational spectrum of CPS1 and demonstrated additional evidences of using NGS for precise identification of CPS1 mutations in patients.…”

A hypomyelinating leukodystrophy in German Shepherd dogs

“…46 In humans, gene variants in CPS1 underlying carbamoyl phosphate synthetase 1 deficiency are associated with severe neonatal hyperammonemia and leukodystrophy. 47 We cannot exclude a similar underlying process in the cases described here. However, no conclusive findings were identified on neurometabolic screening.…”