Glutathione Synthetase Deficiency Clinical Presentation

Updated: May 18, 2017
  • Author: Reem Saadeh-Haddad, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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The phenotypic manifestations that have been described in association with glutathione synthetase (GS) deficiency include hemolytic anemia, which occurs in mild glutathione synthetase deficiency, and 5-oxoprolinuria (pyroglutamicaciduria) and variable degrees of secondary neurological involvement (occurring in systemic glutathione synthetase deficiency). As stated in Mortality/Morbidity, authors have suggested glutathione synthetase deficiency be described as mild, moderate, or severe. These categories represent a continuum of disease severity that depends on the degree of enzyme function; therefore, patients can have manifestations anywhere along the continuum of mild to severe glutathione synthetase deficiency.

The severe phenotypic manifestation, 5-oxoprolinuria (pyroglutamicaciduria), resulting from systemic glutathione synthetase deficiency, is an autosomal recessive disorder. It is characterized by very large peaks of 5-oxoproline on urine organic acid analysis findings, metabolic acidosis, hemolytic anemia, and eventual CNS damage. Because of deficient enzyme activity, a decreased quantity of glutathione results, which likely causes promoter activation of the GSS gene. The large amounts of gamma-glutamylcysteine synthetase that are produced increase the pool of gamma-glutamylcysteine, which is then converted to 5-oxproline because of the inability of the defective GSS gene to produce glutathione.

In moderate glutathione synthetase deficiency, neonatal acidosis and hemolytic anemia are present, but neurological involvement is not. The prognosis for the moderate form is intermediate.

In mild glutathione synthetase deficiency, hemolytic anemia is the primary finding with apparently no effects outside of erythrocytes. Individuals with this form do well clinically. Individuals with hemolytic anemia can present with fatigue, pallor, irregular heartbeats, lightheadedness, and shortness of breath.

Hemolytic anemia is found in all forms.



Patients with glutathione synthetase deficiency appear healthy and do not have unusual dysmorphic features.

In severe glutathione synthetase deficiency, neurological findings are the most prevalent and may include the following:

  • Spasticity (spastic tetraparesis)
  • Ataxia and other cerebellar findings
  • Intention tremors
  • Dysarthria
  • Intellectual disabilities
  • Psychomotor retardation
  • Psychosis
  • Seizure disorders
  • Eye abnormalities, which tend to be peripheral retinal pigmentation abnormalities

Individuals with moderate glutathione synthetase deficiency may have apparent respiratory distress as their bodies try to correct metabolic acidosis; however, other signs are not usually present.

In mild glutathione synthetase deficiency, physical findings are not present other than possible pallor, orthostatic hypotension, and/or irregular heartbeats associated with hemolytic anemia.

Splenomegaly may be present in some individuals with glutathione synthetase deficiency, even the mild form.



Pathogenic mutations in the GSS gene cause glutathione synthetase deficiency, which is inherited in an autosomal-recessive pattern. Carriers of one abnormal allele do not have symptoms of the condition. Two mutations are required for the condition to exist, one on each copy of the gene. Parents of an affected child are obligate carriers of glutathione synthetase deficiency. The likelihood that they will have another child with the condition is 25%.

The GSS gene is located at 20q11.2.