Long-term clinical outcome in patients with glutathione synthetase deficiency

Ristoff, Ellinor; Mayatepek, Ertan; Larsson, Agne

doi:10.1067/mpd.2001.114480

Cited by 83 publications

(77 citation statements)

References 14 publications

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“…However, after skeletal muscle surgery, GS activity is selectively reduced, thus becoming limitant (Luo et al, 1998). Deficiency of GS in humans is associated with 25% of lethality in the neonatal period (Ristoff et al, 2001). Depending on the clinical manifestations, patients may suffer a mild condition, with alterations in enzyme stability (Spielberg et al, 1978) leading to hemolytic anemia.…”

Section: +mentioning

confidence: 99%

S-glutathionylation: relevance in diabetes and potential role as a biomarker

Sánchez‐Gómez

Espinosa‐Díez

Dubey

et al. 2013

Biological Chemistry

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Glutathione is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying deleterious molecules. The oxidative stress induced as a result of a variety of stimuli promotes protein oxidation, usually at cysteine residues, leading to changes in their activity. Mild oxidative stress, which may take place in physiological conditions, induces the reversible oxidation of cysteines to sulfenic acid form, while pathological conditions are associated with higher rates of reactive oxygen species production, inducing the irreversible oxidation of cysteines. Among these, neurodegenerative disorders, cardiovascular diseases and diabetes have been proposed to be pathogenetically linked to this state. In diabetes-associated vascular complications, lower levels of glutathione and increased oxidative stress have been reported. S-glutathionylation has been proposed as a posttranslational modification able to protect proteins from over-oxidizing environments. S-glutathionylation has been identified in proteins involved in diabetic models both in vitro and in vivo. In all of them, S-glutathionylation represents a mechanism that regulates the response to diabetic conditions, and has been described to occur in erythrocytes and neutrophils from diabetic patients. However, additional studies are necessary to discern whether this modification represents a biomarker for the early onset of diabetic vascular complications.

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Section: +mentioning

confidence: 99%

S-glutathionylation: relevance in diabetes and potential role as a biomarker

Sánchez‐Gómez

Espinosa‐Díez

Dubey

et al. 2013

Biological Chemistry

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“…GSD can be divided into 3 clinical forms: a mild form, presenting with HA and variable 5-oxoprolinuria; a moderate form, associated with HA, constant 5-oxoprolinuria, and metabolic acidosis; and the severe form, associated with HA, constant 5-oxoprolinuria, metabolic acidosis, and neurologic defects. 4,7,8 Pathophysiology is explained by a decreased concentration of GSH due to the mutated GSS enzyme, which is unable to fulfill its role in the γ-glutamyl cycle. 4 GSH exerts negative feedback on γ-glutamyl cysteine synthetase, thus regulating its own formation (Fig 2A).…”

Section: Discussionmentioning

confidence: 99%

“…and central nervous system impairment. 7,8 This case report describes the discovery of GSD in a newborn who had presented with recurrent isolated HA since birth. Diagnosis was made fortuitously, at 6.5 months of age, by identification of 5-oxoproline in urine organic acid chromatography (UOAC) initially conducted to screen for causes of hypoglycemia.…”

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confidence: 99%

Recurrent Isolated Neonatal Hemolytic Anemia: Think About Glutathione Synthetase Deficiency

et al. 2016

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Hemolytic anemia (HA) of the newborn should be considered in cases of rapidly developing, severe, or persistent hyperbilirubinemia. Several causes of corpuscular hemolysis have been described, among which red blood cell enzyme defects are of particular concern. We report a rare case of red blood cell enzyme defect in a male infant, who presented during his first months of life with recurrent and isolated neonatal hemolysis. All main causes were ruled out. At 6.5 months of age, the patient presented with gastroenteritis requiring hospitalization; fortuitously, urine organic acid chromatography revealed a large peak of 5-oxoproline. Before the association between HA and 5-oxoprolinuria was noted, glutathione synthetase deficiency was suspected and confirmed by a low glutathione synthetase concentration and a collapse of glutathione synthetase activity in erythrocytes. Moreover, molecular diagnosis revealed 2 mutations in the glutathione synthetase gene: a previously reported missense mutation (c.[656A>G]; p.[Asp219Gly]) and a mutation not yet described in the binding site of the enzyme (c.[902T>C]; p.[Leu301Pro]). However, 15 days later, a control sample revealed no signs of 5-oxoprolinuria and the clinical history discovered administration of acetaminophen in the 48 hours before hospitalization. Thus, in this patient, acetaminophen exposure allowed the diagnosis of a mild form of glutathione synthetase deficiency, characterized by isolated HA. Early diagnosis is important because treatment with bicarbonate, vitamins C and E, and elimination of trigger factors are recommended to improve long-term outcomes. Glutathione synthetase deficiency should be screened for in cases of unexplained newborn HA.

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“…The clinical descriptions of patients GS 23 and GS 33 have been reported elsewhere (Ristoff et al, 2001). All seven patients were unrelated as far as known by the investigators and presented with hemolytic anemia, metabolic acidosis, and 5-oxoprolinuria in the neonatal period (Ristoff et al, 2001). The study was approved by the Ethical Committees of Karolinska Institutet and the Animal Care and Ethics Committee, Uppsala University.…”

Section: Subjectsmentioning

confidence: 99%

Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene

et al. 2003

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The synthesis of the ubiquitous tripeptide glutathione is impaired in patients with glutathione synthetase deficiency. The defect is inherited in an autosomal recessive manner, and the diagnosis is based on clinical, biochemical, and genetic criteria. In seven of our 30 index cases, however, no disease causing mutations could be identified in the coding exons or exon-intron boundaries of the glutathione synthetase gene GSS. These patients had severely decreased glutathione synthetase activities in lysates of cultured fibroblasts, and the levels of the enzyme were undetectable using a polyclonal antibody raised against human glutathione synthetase. RT-PCR mediated sequence analysis revealed previously not reported splice mutations in all patients. Thus, we conclude that in the investigation of patients with glutathione synthetase deficiency, and probably other genetic diseases as well, it might be time saving to initiate mutation analysis with sequencing of mRNA.

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Long-term clinical outcome in patients with glutathione synthetase deficiency

Cited by 83 publications

References 14 publications

S-glutathionylation: relevance in diabetes and potential role as a biomarker

S-glutathionylation: relevance in diabetes and potential role as a biomarker

Recurrent Isolated Neonatal Hemolytic Anemia: Think About Glutathione Synthetase Deficiency

Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene

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