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Glutathione Synthetase Deficiency: An Inborn Error of the Gamma-Glutamyl Cycle

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Glutathione (GSH) is a tripetptide consisting of the amino acids glutamate, cysteine and glycine. It is ubiquitous in the eukaryotic organism and plays a role in many fundamental cellular processes. GSH is metabolized in the gamma-glutamyl cycle in which six enzymes take part in its synthesis and turnover. The most common disorder of the gamma-glutamyl cycle is glutathione synthetase (GSS) deficiency. About 70 patients have been described worldwide. GSS deficiency is inherited in an autosomal recessive manner resulting in decreased levels of cellular glutathione and subsequent overproduction of 5-oxoproline which accumulates in body fluids and is excreted in urine. GSS deficiency is a heterogeneous condition with varying clinical severity. Based on the severity of the clinical symptoms it is classified into three groups. The most severe form is mainly associated with metabolic acidosis, usually present in the neonatal period, haemolytic anemia, 5-oxoprolinuria and central nervous system (CNS) damage. Diagnosis is established by measurement of enzyme activity and mutation analysis. Antenatal diagnosis is possible. Treatment is symptomatic and aims at correction of metabolic acidosis, prevention of haemolysis and support of endogenous defence against reactive oxygen species (ROS). The prognosis is difficult to predict, as the number of patients is limited and the clinical condition varies widely.


gamma-glutamyl cycle, glutathione, haemolytic anemia, metabolic acidosis, 5-oxoprolinuria

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