5-Oxoprolinuria can be caused by genetic defects in either of 2 enzymes involved in the gamma-glutamyl cycle of glutathione metabolism: glutathione synthetase (GSS; 601002) or 5-oxoprolinase (OPLAH; 614243). GSS deficiency (266130) is best characterized as an inborn error ... 5-Oxoprolinuria can be caused by genetic defects in either of 2 enzymes involved in the gamma-glutamyl cycle of glutathione metabolism: glutathione synthetase (GSS; 601002) or 5-oxoprolinase (OPLAH; 614243). GSS deficiency (266130) is best characterized as an inborn error of glutathione metabolism, but there is debate as to whether OPLAH deficiency represents a disorder or simply a biochemical condition with no adverse clinical effects because patients lack a consistent clinical picture apart from 5-oxoprolinuria (summary by Calpena et al., 2013).
Larsson et al. (1981) reported the cases of 2 brothers, aged 16 and 11, who had enterocolitis and urolithiasis and exhibited excessive excretion of 5-oxo-L-proline. They had had recurrent episodes of vomiting, diarrhea, and abdominal pain, starting in ... Larsson et al. (1981) reported the cases of 2 brothers, aged 16 and 11, who had enterocolitis and urolithiasis and exhibited excessive excretion of 5-oxo-L-proline. They had had recurrent episodes of vomiting, diarrhea, and abdominal pain, starting in infancy. Urinary stones in 1 of the brothers contained calcium oxalate and carbonate. One patient had a plasma 5-oxoproline level of about 0.18 mM. They had normal erythrocyte glutathione levels and did not show acidosis, neurologic symptoms, or hemolysis. The glutathione synthetase activities of erythrocytes, leukocytes, and cultured skin fibroblasts were within normal limits (see 266130), as was also the activity of erythrocyte gamma-glutamylcysteine synthetase (see 601176). The cultured skin fibroblasts of both brothers and the leukocytes of one of them exhibited very low levels of 5-oxoprolinase. The activity in the cells of the parents had a level intermediate between those of the brothers and controls. Roesel et al. (1981) found 5-oxoprolinase deficiency in a woman who was found to excrete large quantities of 5-oxoproline when she was studied in connection with her child who had prolinemia and birth defects. The father and the child had daily urinary 5-oxoproline excretion that was less than 1 mM/day. The mother's plasma 5-oxoproline level was 9 times greater than that in controls. Cultured skin fibroblasts had about 2% of control values of 5-oxoprolinase. Although the urinary excretion of 5-oxoproline and the level of depression of 5-oxoprolinase activity was about the same in all 3 patients, the clinical findings were different. See Meister and Larsson (1989). Henderson et al. (1993) described a 2-year-old boy who developed transient hypoglycemia 8 hours after birth and was found on subsequent evaluation to have markedly elevated urinary concentrations of 5-oxoproline. Hematologic investigation revealed no abnormality, and he had normal levels of glutathione synthetase (GSS; 601002) and normal activities of gamma-glutamyl cyclotransferase (GGCT; 137170) and gamma-glutamylcysteine synthetase. However, the leukocyte level of 5-oxoprolinase activity was markedly reduced. The boy remained in good health and exhibited normal growth and psychomotor development, with no evidence of acidosis, hypoglycemia, or other metabolic disturbance. Family studies revealed that his clinically unaffected 6-year-old brother also excreted large amounts of 5-oxoproline. Almaghlouth et al. (2012) reported a 10-month-old Indian boy, born of first-cousin parents, who had transient hypoglycemia at birth and was also found to have indirect hyperbilirubinemia and mild metabolic acidemia. Extended newborn screening revealed moderately elevated 5-oxoproline in the urine. Repeated blood gas measurements were normal, but he continued to have elevated 5-oxoproline levels in the urine. Motor, social, and cognitive development were normal for age. He had an 8-year-old sister with no known medical problems. Calpena et al. (2013) studied a 1-year-old Indian girl, born of nonconsanguineous parents, who presented at 1.5 months of age with repeated episodes of respiratory difficulties with perioral cyanosis while breastfeeding, accompanied by generalized tonic-clonic seizures. Evaluation revealed vitamin D deficiency with hypocalcemia, increased phosphate levels, elevated PTH (168450), and metabolic acidosis. General and neurologic examinations were normal between episodes, and EEG and brain ultrasound were normal. Vitamin D and B12 supplementation was provided with normalization of all altered biochemical parameters and normal development at 1 year of age. Urinary organic acids were analyzed 3 times, showing increased pyroglutamic acid excretion twice during decompensation, with normalization at 1 year of age. Calpena et al. (2013) also studied an 8-year-old boy with Duchenne muscular dystrophy (310200) and a known deletion in the dystrophin gene (300377), who was incidentally found to have massive urinary excretion of pyroglutamic acid. Blood glutathione levels were normal in both children, and no causes of secondary increased excretion of pyroglutamate were detected.
In a 10-month-old Indian boy with 5-oxoprolinase deficiency, Almaghlouth et al. (2012) analyzed the candidate genes GSS and OPLAH and identified homozygosity for a 1-bp insertion in the OPLAH gene (614243.0001). His clinically unaffected sister was also homozygous ... In a 10-month-old Indian boy with 5-oxoprolinase deficiency, Almaghlouth et al. (2012) analyzed the candidate genes GSS and OPLAH and identified homozygosity for a 1-bp insertion in the OPLAH gene (614243.0001). His clinically unaffected sister was also homozygous for the mutation and was subsequently found to have increased 5-oxoproline excretion in the urine. Their first-cousin parents were heterozygous for the mutation. Given the largely benign course of these sibs despite persistent 5-oxoprolinuria, Almaghlouth et al. (2012) noted that it would be important to establish the molecular basis in the few cases with abnormal neurologic outcomes, to exclude potentially overlapping biochemical defects and explore potential genotype/phenotype correlations. In a 1-year-old Indian girl and an unrelated 8-year-old boy who both manifested massive excretion of 5-oxoproline in urine, but who had no symptoms related to glutathione cycle defects and were negative for mutation in the GSS gene, Calpena et al. (2013) identified heterozygosity for missense mutations in the OPLAH gene (614243.0002 and 614243.0003, respectively).