Glutathione Synthetase Deficiency as a Cause of Hereditary Hemolytic Disease

Mohler, Daniel N.; Majerus, Philip W.; Minnich, Virginia; Hess, Charles E.; Garrick, Michael D.

doi:10.1056/nejm197012032832304

Cited by 91 publications

(15 citation statements)

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“…If the samples were analyzed immediately after withdrawal, the concentration of reduced glutathione was found to be 1.85 (SD 0.15) and oxidized glutathione 0.18 (SD 0.04) mmol/liter erythrocytes. These values are in good agreement with published data (12). After storage of the deproteinized samples at -20' for 2 days, the level of reduced glutathione was found to be 1.18 (SD 0.28) and oxidized glutathione 0.30 (SD 0.07) mmol/liter erythrocytes.…”

Section: Glutathione Levels In Erythrocytessupporting

confidence: 92%

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

et al. 1974

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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...

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Section: Glutathione Levels In Erythrocytessupporting

confidence: 92%

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

et al. 1974

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“…It is of interest that a number of patients have been reported to have erythrocyte glutathione synthetase deficiency associated with decreased erythrocyte glutathione concentrations and compensated hemolytic disease (23)(24)(25)(26)(27). The published information does not indicate the occurrence of serious neonatal morbidity, nor are there published data relating to the presence of acidosis or 5-oxoprolinuria.…”

Section: Discussionmentioning

confidence: 99%

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

Wellner

Sekura

Meister

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

135

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Enzyme studies on placenta, cultured skin fibroblasts, and erythrocytes from two sisters with the inborn error 5-oxoprolinuria (pyroglutamic aciduria) indicate that the metabolic lesion in this disease is at the glutathione syntbetase (EC 6.3.2.3) step of the 7y-glutamyl cycle. Excessive urinary excretion of 5-oxoproline by these patients appears to be associated with increased synthesis of -y-glutamyl-cysteine and formation of 5-oxoproline from this dipeptide. Thus, 5-oxoproline is produced in amounts that exceed the normal capacity of 5-oxoprolinase to convert it to glutamate. The data indicate that it may be possible to identify individuals who are heterozygous for this trait by determinations of erythrocyte glutathione synthetase.Previous studies on glutathione have indicated that its synthesis and utilization are integrated in a series of enzymecatalyzed reactions, which have been termed the y-glutamyl cycle. The y-glutamyl cycle consists of six enzyme-catalyzed reactions ( Fig. 1): amino acid-dependent breakdown of glutathione to yield y-glutamyl amino acid and cysteinyl-glycine catalyzed by -y-glutamyl transpeptidase (EC 2.3.2.2) conversion of -y-glutamyl amino acid to 5-oxoproline4 and the corresponding free amino acid catalyzed by 'y-glutamyl cyclotransferase (EC 2.3.2.4), enzymatic hydrolysis of cysteinylglycine to cysteine and glycine, conversion of 5-oxoproline to glutamate catalyzed by 5-oxoprolinase, and the two-step synthesis of glutathione from glutamate, cysteine, and glycine catalyzed by -y-glutamyl-cysteine synthetase (EC 6.3.2.2) and glutathione (GSH) synthetase (EC 6.3.2.3). The evidence for the existence of the cycle and for its involvement in amino-acid transport has been reviewed recently (1-3). §In 1970 Jellum et al. (5) reported on an interesting patient who had a massive urinary excretion of 5-oxoproline (about 30 g/day compared to less than a few mg/day in normal individuals).f This patient was a 19-year-old male with metabolic acidosis and multiple neurological symptoms such as mental retardation, spastic tetraparesis, and ataxia. The patient was at first thought to have a defect in the urea cycle (5), but subsequent studies (7-10) have indicated a lesion in the y-glutamyl cycle, although the exact location was not determined.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). 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).Studies on the peripheral leukocytes of the second patient have indicated the presence of 5-oxoprolinase (11). 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 co...

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“…Two different human syndromes are associated with decreased activity of erythrocyte glutathione synthetase (EC 6.3.2.3), one presenting in the newborn period with massive 5-oxoprolinuria (pyroglutamic aciduria), metabolic acidosis, and hemolytic anemia (1)(2)(3)(4)(5)(6), and the other at varying ages with isolated hemolytic anemia (7)(8)(9). In oxoprolinuria, erythrocytes, leukocytes, and cultured skin fibroblasts all have been shown to 27 December 1977. glutathione content (4,6).…”

Section: Introductionmentioning

confidence: 99%

“…Y.). Cells were obtained from an oxoprolinuric patient reported by Spielberg et al (6) and from a nonoxoprolinuric patient studied by Mohler et al (9). Assays were performed on confluent cells.…”

Section: Introductionmentioning

confidence: 99%