Mildly affected patients have isolated hemolytic anemia, moderately affected patients also have metabolic acidosis, and the severely affected patients show all symptoms including progressive dysfunction of the central nervous system and a short life expectancy. In addition, affected patients typically display low enzyme activity and low levels of glutathione (1% -30% and 5%-20% of healthy controls, respectively).² Clinical severity cannot be predicted by enzyme activity level. Management of the disease is to correct the acidosis with sodium bicarbonate and supplement with vitamins C and E. Diagnosis is confirmed with the presence of a mutation in the Glutathione Synthetase (GSS) gene.^3,4

The gene GSS codes for the enzyme glutathione synthetase, which is part of the gamma glutamyl cycle to synthesize glutathione. Glutathione protects against cellular oxidative damage and toxins, facilitates nucleotide formation, and acts as a coenzyme for other pathways. Lower levels of glutathione will lead to acidosis and an increase in production of 5-oxoproline. Excretion of 5-oxoproline in the urine is observed in all but a minority of the mildly affected patients.² Thirty-one mutations have been identified to be causative (19 missense/nonsense, 8 splicing, 2 small deletions, 1 small insertion, and 1 gross dele- tion).⁵ Early identification allows treatment and supplementation and avoidance of medi- cations that may precipitate hemolytic crisis.³