Biochemical investigations of biopsied brain tissue and autopsied organs from a patient with pyroglutamic acidemia (5-oxoprolinemia)

Biochemical investigations have been carried out in autopsied tissues from a patient with pyroglutamic acidemia who died recently from thrombo-embolism. Very low activities of glutathione synthetase and a high content of pyroglutamate were found in all tissues examined. Especially high levels of pyroglutamate were found in tissues possessing high activity of γ-glutamyl cyclotransferase, namely the kidney and the brain. In addition to reduced feed-back inhibition by glutathione on γ-glutamyl-cysteine synthetase, we suggest that an increased availability of free cysteine also may be an important factor in the overproduction of pyroglutamate in these patients. The glutathione content was markedly reduced in all regions of the patient's brain, being especially low in the cerebellar cortex, which was the region showing the most prominent pathological changes. The low content of glutamate, γ-aminobutyric acid and taurine in this region probably reflects neuronal losses. A frontal cortical biopsy from the patient obtained some weeks before his death contained markedly reduced amounts of glutathione (32% of the normal mean), but most other amino compounds were present in normal concentrations. The cerebral lesions found in our patient closely resembled those found in patients with chronic organic mercury intoxication (Minamata disease). It is likely that the cerebral damage occurring in our patient was caused by lack of the normal protection against oxidative damage. If progressive neurological damage appears in these patients, attempts at treatment with some thiol compound or other antioxidant capable of crossing the blood-brain barrier should be considered.