Diagnosis of glutathione synthetase deficiency in newborn screening

Abstract

Glutathione synthetase (GSS) deficiency is a rare disorder of glutathione metabolism with varying clinical severity. Patients may present with haemolytic anaemia alone or together with acidosis and central nervous system impairment. Diagnosis is made by clinical presentation and detection of elevated concentrations of 5-oxoproline in urine and low GSS activity in erythrocytes or cultured skin fibroblasts. Diagnosis can be confirmed by mutational analysis. Treatment consists of the correction of acidosis, blood transfusion, and supplementation with antioxidants. The most important determinants for outcome and survival in patients with GSS deficiency are early diagnosis and early initiation of treatment. The case of a newborn with GSS deficiency diagnosed by tandem mass spectrometry (MS/MS)-based newborn screening is described. After onset of clinical symptoms on the 2nd day of life, expanded newborn screening revealed normal results for all disorders included in the German screening programme; however, selective MS/MS screening revealed a >10-fold elevation of 5-oxoproline in dried blood, leading to the presumptive diagnosis of GSS deficiency by the 5th day of life. Diagnosis was later confirmed by detection of markedly reduced glutathione concentration in erythrocytes and mutational analysis of the GSS gene. Presently, GSS deficiency is not included in newborn screening programmes in Europe. As outcome depends significantly on early start of treatment, routine inclusion of this disorder in newborn screening panels should be considered.

A case of severe glutathione synthetase deficiency with novel GSS mutations

“…However, the case in this study had different mutation of GSS gene. In certain states in the USA, pyroglutamic aciduria is included in the neonatal screening programs ( 4 ).…”

“…Prior to 2007, only 70 patients were reported in more than 50 families worldwide ( 2 ). Due to increased awareness, several cases were reported in recent years, totaling more than 80 patients worldwide ( 3 – 8 ). Here, we report the case of a newborn infant with generalized GSSD.…”

Nineteen-year follow-up of a patient with severe glutathione synthetase deficiency

“…If a neonate presents with hemolytic anemia and metabolic acidosis, it is important to consider GSSD 14 , as rapidly fatal GSSD in newborns has been described 15 . Advanced diagnostic techniques such as antenatal diagnosis can be made by measuring 5-oxoproline in amniotic fluid 16 , 17 or a presumptive diagnosis can be made by detecting elevation of 5-oxoproline in newborn screen blood spots using tandem mass-spectrometry 18 . .…”

Efficacy of screening immune system function in at-risk newborns

“…72 The idea of newborn screening for depleted levels of glutathione was originally proposed in 1981 by Garrick et al where a simple and straightforward procedure was outlined to detect glutathione synthetase deficiency. 73 Further recommendations for screening glutathione as a disease marker have also been suggested for 5oxoprolinuria, 74 lung inflammation, 75 and to detect retinopathy disorders in premature infants. 76 A number of precise and validated tests exist for both plasma and blood.…”