A case of severe glutathione synthetase deficiency with novel GSS mutations

Abstract

Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.

5-Oxoprolinemia in a Patient With Severe Hypothyroidism and Chronic Acetaminophen Use

“…Multiple factors such as acetaminophen use, malnutrition, and hypothyroidism could have led to alterations in the enzymatic processes of the gamma-glutamyl pathway leading this patient to develop a 5-oxoprolinemia elevated anion gap metabolic acidosis. However, the incidence of 5-oxoprolinemia is frequently described in the literature in pediatric populations rather than adults [ 1 ]. An autosomal recessive form of glutathione synthetase deficiency that predisposes pediatric populations to develop elevated anion gap metabolic acidoses with 5-oxoprolinemia typically begins in the neonatal period and has devastating outcomes [ 1 ].…”

“…5-oxoprolinemia, also known as pyroglutamic acidosis, is caused by a lack of glutathione produced by the gamma-glutamyl cycle [ 1 , 2 ]. The predilection to this process is related to transient polymorphisms of multiple enzymes in the cycle occurring throughout the patient's life as well as toxic metabolic insult in the adult population [ 1 - 3 ].…”

“…5-oxoprolinemia, also known as pyroglutamic acidosis, is caused by a lack of glutathione produced by the gamma-glutamyl cycle [ 1 , 2 ]. The predilection to this process is related to transient polymorphisms of multiple enzymes in the cycle occurring throughout the patient's life as well as toxic metabolic insult in the adult population [ 1 - 3 ]. The presenting symptoms usually include altered mental status and hyperventilation in the setting of elevated anion gap metabolic acidosis, but patients may also be neurologically intact if presenting early [ 1 - 2 ].…”

“…The predilection to this process is related to transient polymorphisms of multiple enzymes in the cycle occurring throughout the patient's life as well as toxic metabolic insult in the adult population [ 1 - 3 ]. The presenting symptoms usually include altered mental status and hyperventilation in the setting of elevated anion gap metabolic acidosis, but patients may also be neurologically intact if presenting early [ 1 - 2 ]. Risk factors for 5-oxoprolinemia include malnourishment, ingestion of certain medications such as acetaminophen, flucloxacillin, netilmicin, vigabatrin, and risk factors like diabetes, liver disease, and pregnancy [ 1 - 2 ].…”

Polymorphisms of Genes Related to Phase-II Metabolism and the Resistance of Clopidogrel

“…Glutathione synthase (GSS) gene is the source of glutathione synthase enzyme, which is an essential enzyme in the biosynthesis of glutathione that acts as a cofactor for antioxidant enzymes (see figure .4). [23]…”