GSS – Glutathione Synthetase Deficiency with 5-Oxoprolinuria

Glutathione synthetase deficiency (GSSD; MONDO:0009947) is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants in GSS (HGNC:4624). Affected individuals present with elevated urinary 5-oxoproline, metabolic acidosis, hemolytic anemia, hyperbilirubinemia and, in severe cases, progressive encephalopathy and recurrent infections. The clinical spectrum ranges from isolated erythrocyte-restricted hemolysis to lethal neonatal multisystem disease. Early biochemical screening and genetic confirmation are critical for prompt management with acid correction, transfusion support and antioxidant therapy.

Genetic evidence is robust: initial reports described seven pathogenic alleles across three families and four probands, confirmed by yeast complementation and bacterial expression assays (PMID:8896573). Subsequent cohort studies encompassing 41 patients from 33 families, including 23 homozygous and 18 compound heterozygous cases, expanded the variant spectrum to 27 missense, nine splice, two deletions, one insertion and one nonsense mutation (PMID:15717202). More than 90 cases have been reported worldwide, demonstrating recurrent and private GSS alleles in diverse populations.

Inheritance is autosomal recessive. Segregation analyses in multiple families revealed affected sibships carrying biallelic loss-of-function or severe missense variants without phenotypic inconsistencies. The variant spectrum includes missense, splice-site, frameshift and intragenic deletions; no clear founder variants have been defined. A representative pathogenic allele is c.374G>A (p.Arg125His), identified in a neonate with hemolytic anemia, intractable acidosis and progressive encephalopathy (PMID:28267090).

Functional studies confirm a loss-of-function mechanism. Yeast complementation demonstrated inability of mutant cDNAs to rescue GSS activity (PMID:8896573). Kinetic analyses of seven missense enzymes revealed 2–27% residual activity and altered substrate cooperativity for variants such as p.Arg283Cys (PMID:15056072). RNA-seq of fetal brain tissue with an exon-3 deletion showed monoallelic expression and predicted nonsense-mediated decay, corroborating pathogenicity (PMID:39221916).

Phenotypic variability is influenced by residual enzyme activity and modifying factors. Severe neonatal cases manifest high anion-gap metabolic acidosis, 5-oxoprolinuria, hemolysis and neurodevelopmental impairment, whereas milder forms present primarily with anemia. Early diagnosis via expanded newborn screening (MS/MS) and timely initiation of alkalinization, transfusions and antioxidant supplementation significantly improve outcomes (PMID:19728142).

Integration of extensive genetic and experimental data yields a Definitive gene–disease association. The concordance of biallelic GSS variants with functional enzyme deficiency and consistent clinical phenotype across >90 patients establishes definitive clinical validity. Key Take-home: Molecular testing of GSS and prompt biochemical assessment in neonates with unexplained metabolic acidosis and hemolytic anemia guide early intervention and improve prognosis.

References

• Nature Genetics • 1996 • Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. PMID:8896573
• Human genetics • 2005 • Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. PMID:15717202
• The Biochemical journal • 2004 • Human hereditary glutathione synthetase deficiency: kinetic properties of mutant enzymes. PMID:15056072
• Journal of inherited metabolic disease • 2009 • Diagnosis of glutathione synthetase deficiency in newborn screening. PMID:19728142
• Journal of pediatric hematology/oncology • 2018 • A Rare Cause of Neonatal Hemolytic Anemia: Glutathione Synthetase Deficiency. PMID:28267090
• Clinical genetics • 2024 • Multiple congenital anomalies in two fetuses with glutathione-synthetase deficit. PMID:39221916

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