What Is Glutathione Synthetase Deficiency?

Introduction

Glutathione synthase deficiency (GSD) is a rare congenital disorder that affects the metabolism of an antioxidant called glutathione. GSD affects just over 80 individuals worldwide.¹ It is an autosomal recessive disorder, meaning the affected individual must have inherited two copies of a faulty gene, one from each parent. GSD is caused by mutations in the glutathione synthetase (GSS) gene.² GSD is extremely rare, and before 2007, only 50 families accounted for the 70 patients diagnosed globally at the time, meaning several families had multiple members affected by GSD.¹ The disease is usually characterised by the destruction of red blood cells (haemolytic anaemia), elevated acidity in the body (metabolic acidosis), progressive neurologic symptoms, and recurrent bacterial infections.²

What is glutathione?

Role of glutathione in the body

Glutathione (GSH) is a tripeptide (composed of the amino acids cysteine, glycine, and glutamic acid). GSH plays a key role in reducing oxidative stress, maintaining redox balance, enhancing metabolic detoxification, regulating the immune system, and reducing the toxin load in the body by promoting the breakdown and excretion of pollutants (such as mercury) by the liver. There is growing recognition that supporting the body's glutathione levels is important for maintaining health and helping to prevent disease. Various age-related chronic diseases, such as those associated with neurodegeneration, mitochondrial dysfunction, and even cancer, have been associated with deficient glutathione levels.¹

Glutathione has many functions, such as participating in amino acid transport, detoxifying foreign compounds, and supporting the function of several enzymes.⁴

Glutathione is one of the body's main antioxidants, helping to neutralise harmful molecules called free radicals and helping to protect cells from oxidative damage. Free radicals are molecules that can cause oxidative stress, which damages cells, DNA, and various parts of the cell.⁴ Glutathione also helps maintain redox balance inside the cell. The redox state is the equilibrium between oxidised molecules (electron deficient) and reduced molecules (electron-rich). Glutathione participates in the regulation of protein structure and function by regulating protein folding and protecting proteins from oxidative damage.⁵

How glutathione is made

Glutathione is produced mainly in a circular cycle called the gamma-glutamyl cycle. Glutathione is processed from glycine and y-glutamylcysteine by glutathione synthetase (GSS) in a reaction that uses ATP (the main source of energy in cells). Glutathione then helps to slow down the action of GSS, regulating its own production in a process known as feedback inhibition.^3,4

In GSD, a shortage of glutathione synthase means that less glutathione is made, which leads to overproduction of the precursor γ-glutamylcysteine. This results in excess amounts of a form of the amino acid proline in urine.⁴ Furthermore, red blood cells have one of the highest concentrations of glutathione in the body, so red blood cells in patients with GSD are more susceptible to oxidative stress. 

Cause of GSD

GSD is caused by a glutathione synthetase deficiency resulting from mutations in both copies of the GSS gene.

The human GSS enzyme is a homodimer, meaning it is formed from two identical units. Genetic studies have shown that GSS gene mutations affect enzyme stability, catalytic ability, and substrate affinity, meaning that the mutated enzyme is not as effective. The most damaging mutation was found to affect the structure of the enzyme, resulting in a severely reduced affinity for ATP.²

Clinical presentation and symptoms of GSD

The disorder is congenital, so clinical signs are usually present from birth.¹ Patients can be divided into mild, moderate, and severe phenotypes.

Mildly affected patients have mutations affecting enzyme stability, and haemolytic anaemia (having lower levels of red blood cells because they keep breaking down) is the only clinical symptom. Symptoms of haemolytic anaemia can include fatigue, shortness of breath and a higher heart rate.

Patients whose GSD is of moderate severity have haemolytic anaemia and metabolic acidosis (a buildup of acid in the body).³ As well as fatigue, weakness, and an abnormal heart rate, metabolic acidosis may also be associated with jaundice, confusion, dizziness, and nausea. 

Severely affected patients have neurologic manifestations, including dyskinesia and developmental delays, in addition to severe metabolic acidosis. Examples include central nervous system disorders manifesting as intellectual disability, seizures, spasticity, ataxia, and intention tremors, as well as poor response to light in the eye and retinal pigmentation.^2,3 A subset of patients also have an increased susceptibility to bacterial infection, which is thought to be due to defective granulocyte (a type of white blood cell involved in protection against bacteria) function.³

Diagnosis of GSD

Physical examination and medical history

To diagnose GSD, the medical practitioner will first examine the infant and take a family medical history. In many cases, parents and siblings of the affected individual may be healthy and completely unaffected by GSD. Unaffected parents will be heterozygotes (have one copy) for the faulty gene, and siblings may also be heterozygotes; these individuals will not suffer from GSD.⁶

Laboratory tests for glutathione levels

Laboratory tests for metabolic acidosis and haemolysis will be performed to assess whether GSD is present.¹ Glutathione levels can be assessed with a blood test, and an enzyme assay can check the activity levels of glutathione synthase. If the patient has the disorder, blood metabolic screening and plasma amino acid profile may reveal elevated levels of glutamate.¹ Additionally, urine analysis may show massive excretion of 5-hydroxyproline.¹

Genetic testing and mutation analysis

The patient’s DNA can be sequenced to detect the specific mutation causing GSD.¹ Further, DNA samples of the parents of the affected child may be analysed to explore the source of the mutation. In families with a history of GSD, a genetic test may be able to diagnose the condition before birth. In some US states, GSD can be picked up during standard newborn screening procedures.

Treatment and management of GSD

Supportive care

GSD is a metabolic disease requiring lifelong treatment, and treatment varies depending on the patient’s symptoms. Among them, oxidative stress should be monitored very closely, as increased oxidative stress may hinder the developmental progression of the child.

If the patient has increased susceptibility to oxidative stress, patients can start treatment with antioxidants such as vitamins E, C, and n-acetylcysteine to relieve symptoms.¹ After the newborn is stable, it can be discharged from the hospital and followed up in the metabolic clinic.³

Symptom-specific interventions

During the neonatal (newborn) period, it is especially important to prevent hyperbilirubinemia to protect the brain from kernicterus (newborn jaundice). Anaemia resulting from GSD is usually treated with blood transfusions. Also, it is important to avoid certain drugs that may cause haemolysis.

Patients with moderate and severe GSD may require treatment for metabolic acidosis. In extreme cases, intravenous sodium bicarbonate can be given to reduce metabolic acidosis. After stabilisation, long-term management can be maintained using citrate or tromethamine (THAM).³ Alternatively, a combination of citrate, potassium citrate, and sodium citrate can be used to treat patients with metabolic acidosis. It has also been reported that sodium bicarbonate may be effective in the treatment of chronic metabolic acidosis caused by GS deficiency.³

Prognosis and long-term outlook in GSD

Impact of early diagnosis and intervention

Early diagnosis and treatment are associated with a better long-term prognosis. Advanced diagnostic techniques such as prenatal diagnosis can be performed by measuring 5-hydroxyproline in amniotic fluid or after birth by detecting 5-hydroxyproline in newborn screening blood spots.³

Factors influencing disease progression

Prognosis depends on the type of mutation, the severity of acidosis, both the frequency and severity of any bacterial infections and the quality of supportive care. In terms of treatment methods, long-term follow-up studies of GSD patients have shown that early diagnosis and early vitamin C and vitamin E supplementation are the most influential factors in survival and positive long-term outcomes.³

FAQs

Who is at risk of GSD?

The disease is an autosomal genetic disease, so those whose parents are heterozygous (carriers) for a faulty GSS gene are at higher risk of the disease. 

How common is GSD?

Glutathione synthetase deficiency (GSD) is an extremely rare genetic disorder, affecting only 80 people worldwide.

How can I prevent GSD？

Unfortunately, as of now, there is no known way to prevent the genetic mutations that cause GSD. However, understanding the severity and symptoms of the disease can help in reducing the impact of GSD.

When should I see a doctor?

GSD is a congenital disease, and symptoms will likely be apparent from birth, so there is no risk of developing the disease later in life. However, even if you do not suffer from GSD, there is a very rare possibility of being a carrier for the faulty gene that causes the disease. If you have a family history of the disease, it may be wise to seek genetic testing in order to stay informed. If you are worried about your baby, seek advice from a medical professional and if you are expecting, it is recommended to carry out relevant genetic testing before birth.

Summary

Glutathione synthase deficiency (GSD) is a rare congenital disorder affecting glutathione metabolism. GSD is an autosomal recessive disorder caused by mutations in the GSS gene that impair the synthesis of glutathione. 

Glutathione is a tripeptide composed of three amino acids: glutamate, cysteine, and glycine. It plays a crucial role in various cellular processes, including detoxification, antioxidant defence, and the maintenance of cellular redox balance.

Patients with GSD may present with hemolytic anaemia, metabolic acidosis and neurological symptoms, depending on the severity of the condition. Currently, there are known to be over 80 patients worldwide. 

Long-term treatment includes regular supplementation of antioxidants such as vitamins C and E. Related drugs may also be needed to treat acidosis and haemolysis. Prenatal genetic testing can be used to diagnose the condition before the affected child is born, which can ensure the best treatment plan and result in an improved prognosis.