Pyroglutamic Aciduria — a New Inborn Error of Metabolism

Jellum, Egil; Kluge, T; Börresen, Hans Chr.; Stokke, Oddvar; Eldjarn, L.

doi:10.3109/00365517009046241

Cited by 140 publications

(37 citation statements)

References 7 publications

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“…After administration of [14C]5-oxoproline, the patient expired very little 14CO2 in this breath (in contrast to extensive 14CO2 expiration in a normal control). Although this finding is consistent with a block at the 5-oxoprolinase step of the 7y-glutamyl cycle, it would be expected that the administered [I4C I-oxoproline would be greatly diluted by the very high blood plasma concentration of 5-oxoproline (50 mg/100 ml (8), initially reported erroneously to be 5 mg/100 nil (5,7,9)). It is notable also that the cultured skin fibroblasts from this patient exhibited substantial 5-oxoprolinase activity (10).…”

Section: Discussionsupporting

confidence: 51%

“…The patients studied here exhibited (AminoAcid) 7-glutomyl (5,(7)(8)(9)(10), it seems probable that this patient may also have glutathione synthetase deficiency. It is notable that this patient was jaundiced during the early neonatal period and was very ill for 2 weeks after birth (22).…”

Section: Discussionmentioning

confidence: 99%

“…The patient was at first thought to have a defect in the urea cycle (5), but subsequent studies (7)(8)(9)(10) have indicated a lesion in the y-glutamyl cycle, although the exact location was not determined.…”

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confidence: 99%

“…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)(8)(9)(10) have indicated a lesion in the y-glutamyl cycle, although the exact location was not determined.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…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%