Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency

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Abstract
Pyroglutamic aciduria (5‐oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5‐oxoprolinase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT‐PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141‐bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491→A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847→T [ARG283→CYS] mutation in exon 9.