Glutathione Synthetase Deficiency

A rare disorder characterised by hemolytic anemia, associated with metabolic acidosis and 5-oxoprolinuria in moderate forms, and with progressive neurological symptoms and recurrent bacterial infections in the most severe forms.

Epidemiology

This disease has been detected in at least 70 patients in more than 50 families worldwide.

Etiology

Several mutations have been identified in the gene encoding glutathione synthetase, localized to chromosome 20q11.2. Glutathione synthetase catalyses the last step in the synthesis of glutathione and a deficiency results in low levels of glutathione. Acidosis is due to reduced feedback inhibition of gamma-glutamyl cysteine synthetase in the gamma-glutamyl cycle, which ultimately leads to overproduction and accumulation of 5-oxoproline.

Diagnostic methods

The diagnosis usually involves the following: clinical findings, the finding of 5-oxoprolinuria, low levels of glutathione, low activity of glutathione synthetase, and mutation analysis of the glutathione synthetase gene.

Differential diagnosis

Other causes of 5-oxoprolinuria include 5-oxoprolinase deficiency (see this term), diet (certain infant formulas and tomato juice), severe burns, Stevens-Johnson syndrome (see this term), inborn errors of metabolism not involving the gamma-glutamyl cycle, e.g. X-linked ornithine trancarbamylase deficiency, urea cycle defects, tyrosinemia, as well as homocystinuria (see these terms), drug metabolism (paracetamol, vigabatrin, flucloxacillin, netimicin), prematurity, malnutrition, pregnancy and nephropatic cystinosis.

Antenatal diagnosis

Antenatal diagnosis is possible.

Genetic counseling

Transmission is autosomal recessive.

Management and treatment

Management includes correction of the acidosis, supplementation with antioxidants and avoidance of drugs known to precipitate hemolytic crises in patients with glucose-6-phosphate dehydrogenase deficiency, e.g. phenobarbital, acetylsalicylic acid and sulfonamides.

Prognosis

A long-term follow up study of 28 patients with glutathione synthetase deficiency has showed that the factors most predictive of survival and long-term outcome are early diagnosis, correction of acidosis and early supplementation with vitamin C and vitamin E.