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

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disor der caused by either glutathione synthetase deficiency (GSSD) or 5-oxoproli nase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic acid uria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic a ciduria were studied. All presented with hemolytic anemia and metabolic aci dosis. Two (brothers) also had Fanconi nephropathy, which is not seen in py roglutamic 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 firs t patient showed a 141-bp deletion corresponding to the entire exon 4, whil st the corresponding genomic DNA showed a G(491) --> A homozygous splice si te mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients s howed a C-847 --> T [ARG(283) --> CYS] mutation in exon 9.