Genotype and clinical phenotype in four patients with glutathione synthetase deficiency

Background and aims: Glutathione synthetase deficiency (GSSD) is an autosomal recessive disorder described in the literature in roughly 80 patients. Currently, there is little known about genotype-phenotype correlations in GSSD though severity can be predicted to a limited extent via mutation analysis. Here, we describe four patients with GSSD and assess their genotypes and phenotypes. Additionally, we have provided an updated review of the literature. Methods: We retrospectively reviewed all medical charts for patients with GSSD in the last ten years at AlMakassed Hospital in Jerusalem, Palestine. We reviewed the literature for medical management and latest research in treatment and discussed the phenotype-genotype correlations. Results: We describe four patients with confirmed GSSD. Clinical presentation varied in severity, but patients typically presented with hemolytic anemia and lactic acidosis. Urine organic acid analysis demonstrated massive excretion of lactic acid and pyroglutamic acid. All patients were treated with N-acetylcysteine, vitamin E, vitamin C, and sodium hydrogen carbonate. All improved significantly following treatment, apart from one patient who died at two months of age. Conclusion: GSSD presents similarly to many other diseases, at times causing a delay in diagnosis. Early initiation of treatment can improve clinical outcomes and overall development. If there is a high suspicion for GSSD, it is important to consider mRNA sequencing in an effort to prevent a delay in diagnosis when a splice site mutation is present