Two brothers, aged 16 and 11 years, had recurrent episodes of
vomiting, diarrhoea and
abdominal pain, starting in infancy. In spite of extensive investigations no cause of their
enterocolitis could be established. After several years symptomatic treatment was discontinued without any recurrence of symptoms. Their father and several paternal relatives have had
kidney stones. Both boys developed
urolithiasis and an
oxalate-containing stone was removed from the elder brother's kidney. He had no
hypercalciuria. His glomerular and tubular function tests were normal. Gas chromatography of urine from both brothers revealed massive excretion of L-5-oxoproline (
pyroglutamic acid).
Glutathione levels in erythrocytes of both patients were normal. The activities of
enzymes of the gamma-glutamyl cycle were analysed in erythrocytes, leukocytes and cultured skin fibroblasts. The level of
glutathione synthetase was normal, as was the affinity of this
enzyme for its substrate gamma-glutamyl-
cysteine. Feedback inhibition of
gamma-glutamyl-cysteine synthetase by
glutathione was also normal. Both patients had a specific deficiency of
5-oxoprolinase, the activity of which was 2-4% of that of control subjects. Their parents had intermediate
5-oxoprolinase activities in fibroblasts, indicating a recessive mode of inheritance. Thus,
5-oxoprolinuria in these two patients was due to a lack of
5-oxoprolinase, i.e., a new inborn error in the gamma-glutamyl cycle.