5-Oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione metabolism: the glutathione synthetase and the 5-oxoprolinase. 5-Oxoprolinase deficiency is a sporadic autosomal recessive disorder of the gamma-glutamyl cycle, primarily caused by pathogenic variants in the OPLAH gene. Low levels of 5-oxoproline can normally be detected in urine, although high levels are a clue for diagnosing 5-oxoprolinase deficiency. The clinical picture is not well defined due to the limited number of cases. Some authors questioned whether it is a real inherited metabolic disorder or only a nonspecific biochemical finding. Nephrolithiasis, enterocolitis, PMR, and microcytic anemia are the well-known clinical symptoms and signs of 5-oxoprolinuria (pyroglutamic aciduria). We present 4 patients who were diagnosed with 5-oxoprolinuria that had different clinical symptoms and 3 out of 4 patients were siblings. In this study, 2 female and 2 male patients with 5-oxoprolinase deficiency were included. There were different clinical findings in the same family. Patients had unreported clinical symptoms such as growth retardation and drug-resistant epilepsy. OPLAH gene mutations have been observed to cause different clinical findings in the same family. A correlation was found between urine 5-oxoproline levels and the severity of clinical findings.

Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.

Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the γ-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.

5-Oxoprolinuria is a rare inherited metabolic disorder caused by a defective gamma-glutamyl cycle resulting from mutations in the genes encoding 5-oxoprolinase (OPLAH) and glutathione synthetase (GSS). No inherited 5-oxoprolinuria case has been reported in mainland China until now. In this study, clinical, biochemical, and genetic aspects of five Chinese 5-oxoprolinuria patients with OPLAH or GSS gene mutations were investigated. Three boys and two girls from five unrelated Chinese families with symptomatic 5-oxoprolinuria were identified within the past 3years in Peking University First Hospital. OPLAH and GSS genes were analyzed. Patients were hospitalized between the age of 13days to 1year and 3months for hypersomnia, developmental retardation, feeding deficiency, vomiting, icterus and recurrent pneumonia. All patients had significantly elevated urine 5-oxoproline. Three novel mutations (c.1904G>A and c.2813_2815delGGG in Patient 1, c.2978G>T in Patient 2) on OPLAH, on GSS, one novel mutation (c.1252C>T in Patient 3) and a reported mutation (c.491G>A in Patients 3-5) were detected. Patient 4 has homozygous mutation c.491G>A, the others are heterozygous. After treatment by l-carnitine, vitamin E, B1, B2 and coenzyme Q10, three patients with GSS deficiency improved, but the two 5-oxoprolinase-deficient patients did not respond to treatment. 5-Oxoprolinase deficiency and GSS deficiency share some clinical and biochemical features. Genetic analysis is important for the deferential diagnosis. In this study, five Chinese patients had severe central nervous system damage. Antioxidant treatments were proved effective for the three patients with GSS deficiency but not for the two patients with 5-oxoprolinase deficiency.