Glutathione synthetase (GSS) deficiency is an extremely rare autosomal recessive inborn error of metabolism. This metabolic disorder is caused by mutations in the GSS gene, which encodes GSS-an enzyme that catalyses the ATP-dependent conversion of γ-glutamyl-cysteine and glycine to glutathione. Low glutathione impairs the cellular antioxidant defence mechanism, leaving cells susceptible to oxidative stress and damage.

Glutathione synthetase deficiency (GSSD) is a rare, autosomal recessive disease that causes disruption in glutathione metabolism. According to clinical findings, it occurs in three forms: mild, moderate and severe. In severe forms, metabolic acidosis and hemolytic anemia are accompanied by neurological findings. Although there is no definitive treatment, early initiation of sodium bicarbonate, vitamin C, and vitamin E supplements is one of the most important factors affecting prognosis. Here we present a severe case of GSSD in a neonate with intrauterine periventricular cystic lesions, and postnatally developed severe hemolytic anemia, metabolic acidosis, and dilated cardiomyopathy. Exchange transfusion and peritoneal dialysis were performed because of refractory hyperbilirubinemia and acidosis despite sodium bicarbonate and vitamin supplementation. Early diagnosis and initiation of supportvive treatment with sodium bicarbonate, vitamin C, and vitamin E are esential for survival in severe GSSD. Dilated cardiomyopathy may represent a new complication of disease, highlighting the need for early cardiac monitoring.

Glutathione synthetase deficiency (GSSD) is a rare metabolic disorder manifesting in early newborn period, characterized by hemolytic anemia, metabolic acidosis, 5-oxoprolinuria. In severe cases, neurological impairment may occur as well. The diagnosis can be suspected clinically and confirmed by urine gas chromatography mass spectrometry (GCMS) and genetic analysis. The case reported here is of a newborn presenting with sepsis-like features at day 3 of life. The blood investigations revealed hemolysis and metabolic acidosis, and after ruling out other causes of the latter, the possibility of GSSD was considered, which was supported by elevated levels of 5-oxoproline in urine. He was managed with soda bicarbonate and antioxidants and is under follow-up with normal neurological status till writing of this report. The case highlights the importance of early recognition and diagnosis of metabolic disorders by being aware of the clinical presentation of these rare conditions, to prevent delay in initiation of treatment for better outcome.

Glutathione synthetase deficiency is a rare inborn metabolic disease usually caused by biallelic variants in GSS. Clinical severity varies from isolated hemolytic anemia, sometimes associated with chronic metabolic acidosis and 5-oxoprolinuria, to severe neurological phenotypes with neonatal lethality. Here we report on two fetal siblings from two pregnancies with glutathione synthetase deficiency exhibiting similar multiple congenital anomalies associating phocomelia, cleft palate, intra-uterine growth retardation, genito-urinary malformations, and congenital heart defect. Genome sequencing showed that both fetuses were compound heterozygous for two GSS variants: the previously reported pathogenic missense substitution NM_000178.4 c.800G>A p.(Arg267Gln), and a 2.4 kb intragenic deletion NC_000020.11:g.34944530_34946833del. RNA-seq on brain tissue revealed the out-of-frame deletion of the exon 3 and an almost monoallelic expression of the missense variant (88%), suggesting degradation of the deletion-harboring allele by nonsense-mediated mRNA decay. 5-oxoproline (pyroglutamic acid) levels in amniotic fluid were elevated, suggesting an alteration of the gamma-glutamyl cycle, and corroborating the pathogenicity of the two GSS variants. Only one case of glutathione synthetase deficiency with limb malformations has previously been reported, in a newborn homozygous for the c.800G>A variant. Thus, our data allow us to discuss a potential phenotypic extension of glutathione synthetase deficiency, with a possible involvement of the c.800G>A variant.