Pyroglutamic Aciduria (5-Oxoprolinuria), an Inborn Error in Glutathione Metabolism

Abstract

Extractscribed by Jellum e t al. (7) in an adult male who suffered from metabolic acidosis and neurologic symptoms such as mental Two sisters, One a neonate and the other years of age, retardation, spastic tetraparesis, ataxia, and intentional tremor. were found to suffer from pyroglutamic aciduria (5-oxoproWe have recently described a young girl who also had linuria). They had a chronic metabolic acidosis and required pyroglutamic aciduria and chronic metabolic acidosis but no with their parents, both excreted detectable neurologic damage (6). This patient was studied at large quantites of L-pyroglutamate in the urine.the age of 14 months, when her daily excretion of No ~~r o g l u t a m a t e could be demonstrated in aurine sample ~-~~~~~l~t~~~t in urine amounted to 50 mmol and her blood obtained from the pregnant mother at 30 weeks of gestation. plasma concentration was 4.5 mM. Pyroglutamate turnover Pyroglutamate was, however, detected in amniotic fluid and cord blood plasma as well as in urine from the neonate studies under steady state conditions showed that approxicollected during the first few hours after birth. Metabolic mately 75% of the amount synthesized was metabolized by acidosis developed during the 1st day of life and bicarbonate the patient. The level of 5-oxoprolinase in the patient's therapy was started. The patient also showed a moderate leukocytes was be hyperbilirubinemia but no further c o m p~~c a t~o n s were enIndependent studies by Eldjarn and coworkers (2)(3)(4)(5)7,16) countered in the neonatal period. on their adult patient have also failed to reveal the primary ~h~ 3-year-old girl had a daily excretion of pyroglutamate in defect in pyroglutamic aciduria. The daily excretion of urine corresponding to 195 mmo1/1.73 rn2, i.e., identical with pyr0glutamate in urine was 270 mmol (4, 7)that found at 14 months of age. ~h~ excretion showed no and was not affected significantly by variations in the dietary correlation with feeding or physical activity. The concentra-Protein intake (2). After an intravenous dose of (14 c )~~r o~l utions of pyroglutamate in plasma and cerebrospinal fluid were tamate the patient expired considerably less 14c02 than a 2.2 m~ and 1.3 m~, respectively. she had no evidence of a normal control subject, and this was taken as evidence of a disturbed renal transport of a-amino acids. Her psychologic block in the patient's capacity to metabolize ~~r o~l u t a m a t e and somatic development was normal, and she had no signs of (2). However, the patient had a normal level of 5-Oxoprolinase neurologic damage. in cultured fibroblasts (16) and subsequent studies have Both patients presented evidence of increased hemolysis and revealed evidence of an increased production of ~~r o~l u t a m a t e their levels of glutathione in erythrocytes were markedly ( 3 3 4). decreased, which indicated a defect in glutathione metabolism.The metabolic role of pyroglutamate has not been settled. Its involvement in the metabolism of glutathione has been Speculation proposed (14). A model for...

Glutathione Synthetase Deficiency, an Inborn Error of Metabolism Involving the γ-Glutamyl Cycle in Patients with 5-Oxoprolinuria (Pyroglutamic Aciduria)

“…Since 1 year of age she is known to have excreted in the urine more than 6 g of 5-oxoproline per day, and her plasma concentration of 5-oxoproline has been 2-5 mM (11,12). Studies in which this patient was given [14C]5-oxoproline are consistent with the conclusion that about 25% of the amount of 5-oxoproline formed by this patient is excreted and that the rernainder is metabolized (11); a similar conclusion may now be drawn from the studies done on the first patient (8).…”

“…A (12). Since 1 year of age she is known to have excreted in the urine more than 6 g of 5-oxoproline per day, and her plasma concentration of 5-oxoproline has been 2-5 mM (11,12).…”

“…This patient is a young girl, now about 3 years of age, who developed metabolic acidosis in the neonatal period and has required therapy with bicarbonate since then. Her mental development has so far been normal and she has no neurological symptoms (12). Since 1 year of age she is known to have excreted in the urine more than 6 g of 5-oxoproline per day, and her plasma concentration of 5-oxoproline has been 2-5 mM (11,12).…”

“…SUBJECTS The two sisters with 5-oxoprolinuria studied here are the second and third cases of this disease to be reported; their histories and clinical findings have been published elsewhere (11,12). Common features of their disease, in addition to matkedly increased concentrations of 5-oxoproline in their body fluids, are development of metabolic acidosis in the neonatal period, requirement for bicarbonate therapy, decreased concentration of glutathione in erythrocytes, and increased rate of hemolysis.…”

“…The young girl with 5-oxoprolinuria has recently acquired a sister who suffers from the same inborn error of metabclism (12). 13oth patients, in addition to increased concentrations of 5-oxoproline in their body fluids and metabolic acidosis, were found to have markedly decreased concentrations of glutathione in their erythrocytes and signs of increased rate of hemolysis (12). In the present work we have examined the activities of the y-glutamyl cycle enzymes in erythrocytes, cultured fibroblasts, and placental tissue in patients with 5-oxoprolinuria.…”