Glutathione is the master antioxidant that is responsible for eliminating toxins in the body. Most people are able to generate glutathione naturally in their bodies, but there are instances where the body’s production may be insufficient to satisfy the body’s antioxidant requirements. The tripeptide glutathione typically consists of glutamate, cysteine, and glycine. It is found in in varying amounts in all cells present in the human body and performs a number of crucial biological functions. These functions are such as scavenging for free radical, detoxifying xenobiotics and carcinogens, biosynthesis of DNA, proteins, and leukotrienes and redox reactions and neurotransmission/neuromodulation.

Three-Dimensional Landscape of Genome.
HIPMap (high-throughput imaging position mapping) accurately determines the position of a gene in the three-dimensional (3D) space of the cell nucleus. In this illustration, images of genes (red, green, and blue spots within the nuclei of HeLa cells) are artificially superimposed on images of multi-well plates.
Creator:	Tom Misteli, Sigal Shachar, Murali Palangat.
Photo by National Cancer Institute / Unsplash

What is glutathione deficiency?

This antioxidant glutathione is synthesized through the gamma-glutamyl cycle, a process catalyzed by six enzymes. However, genetic deficiencies relating to glutathione have been found in five of these enzymes in human beings. If your stores of glutathione are depleted, you may have a medical condition referred to as glutathione deficiency. Glutathione deficiency develops when the body is unable to generate sufficient glutathione to cover all the functions for which it is intended.

According to the National Library of Medicine, the condition is rare and affects an estimated 70 people in the world. Reduced levels of glutathione may affect your child’s ability to produce red blood cells. This reduced capacity to produce red blood cells may cause hemolytic anemia. According to Medline Plus, hemolytic anemia may cause fatigue pale or yellow skin, chills, and fever, and dark urine, difficulties in breathing, heart rate irregularities or spleen enlargement.

The most common, genetic disorder that negatively affects glutathione and when it is severe, it may lead to hemolytic anemia, 5-oxoprolinuria, metabolic acidosis, damage of the central nervous system and recurrent bacterial infections is glutathione synthetase deficiency. According to available scientific research, Gamma-glutamylcysteine synthetase deficiency is also known to cause hemolytic anemia, and some patients with this disorder have demonstrated problems with neuromuscular function and generalized aminoaciduria. Gamma-glutamyl transpeptidase deficiency has been observed in patients with central nervous system involvement and glutathionuria. 5-Oxoprolinase deficiency is associated with 5-oxoprolinuria but without a clear association with other symptoms. Dipeptidase deficiency has been described in one patient. All these genetic disorders that negatively affect glutathione are uncommon and are passed on in an autosomal recessive manner.

GENETIC FACTORS THAT NEGATIVELY AFFECT GLUTATHIONE

(a). Gamma-glutamylcysteine synthetase deficiency

As the name suggests, this condition is due to insufficient levels of the enzyme gamma-glutamylcysteine synthetase. .Gamma-glutamylcysteine synthetase deficiency is very rare. Nine patients in seven families have been reported worldwide (USA, Germany, Japan, The Netherlands, Poland, and Spain). It is characterized by hemolytic anemia, and sometimes by neurological symptoms. The other symptoms include:

  • Low activity of gamma-glutamylcysteine synthetase in red blood cells, leukocytes and/or cultured skin fibroblasts.
  • The presence of mutation(s) in the gamma-glutamylcysteine synthetase genes. The patients whose results have been published have had homozygous mutations in the gene encoding the heavy subunit of the enzyme.
  • Low levels of glutathione and gamma-glutamylcysteine in red blood cells and/or cultured skin fibroblasts.

(b). Glutathione synthetase deficiency

This is a very uncommon disorder characterized by very low levels of the glutathione synthetase enzyme in the body system. The enzyme glutathione synthetase is involved in the chemical process through which glutathione is produced endogenously in the body. Glutathione synthetase deficiency can be divided into mild, moderate or severe. The exact symptoms and seriousness sometimes vary in different individuals. The mild form of Glutathione synthetase does not affect any other body cells, but only red blood cells whereas severe forms are widespread throughout the body and affect various kinds of cells of present in the body. Moderate glutathione synthetase deficiency is a blend of the mild and severe forms. Glutathione synthetase deficiency usually results from an alteration of the GSS gene. It is inherited through an autosomal recessive process. The generalized form of glutathione synthetase deficiency may otherwise be referred to as pyroglutamic aciduria or 5-oxoprolinuria due to the fact that very high quantities of 5-oxoproline, which is an amino acid derivative, may be identified in the urine of patients with this syndrome. However, 5-oxoprolinuria may take place as part of various errors or as a consequence of various environmental factors.

When the condition is hereditary, it is regarded as an extremely rare autosomal recessive illness characterized by hemolytic anemia, metabolic acidosis, 5-oxoprolinuria, progressive neurological symptoms and recurring bacterial infections. The diagnosis of glutathione syntethase deficiency usually involves the following: clinical findings, the finding of 5-oxoprolinuria, low levels of glutathione, low activity of glutathione synthetase, and mutation analysis of the glutathione synthetase gene. Its diagnosis is established by:

  • Low activity of glutathione synthetase in cultured skin fibroblasts and/or red blood cells.
  • Low levels of glutathione in red blood cells and/or cultured skin fibroblasts.
  • Urinary 5-oxoproline (up to 1 g/kg/day).
  • Mutation(s) in the glutathione synthetase (GSS) gene.

(c). Gamma-glutamyl transpeptidase deficiency

Gamma-glutamyl transpeptidase deficiency is a very rare autosomal recessive disease characterized by increased glutathione concentration in plasma and urine. Central nervous system involvement is usually present in some cases. The diagnosis is established by the following:

  • Low activity of γ -glutamyl transpeptidase in nucleated cells like leukocytes or cultured skin fibroblasts. Erythrocyte also misses γ -glutamyl transpeptidase under normal conditions.
  • High levels of glutathione in plasma and urine (up to 1 g/day in urine; controls < 10 mg). Cellular levels of glutathione are normal.

(d). 5-Oxoprolinase deficiency

5-Oxoprolinase deficiency is a very rare autosomal recessive disease characterized by 5-oxoprolinuria and very heterogeneous clinical presentation (renal stone formation, enterocolitis, mental retardation, neonatal hypoglycemia, microcytic anemia, and microcephaly).

The diagnosis of 5-oxoprolinase deficiency is often established as shown below:

  • Low activity of 5-oxoprolinase in nucleated cells such as leukocytes or cultured skin fibroblasts (5-oxoprolinase is not present in erythrocytes).
  • Elevated levels of 5-oxoproline in body fluids.
  • Urinary 5-oxoproline.

Other known inborn errors of metabolism

Besides the above mentioned deficiencies, there are other inborn errors that may be seen. The inborn inaccuracy of metabolism not involving the gamma-glutamyl cycle, e.g. X-linked ornithine transcarbamylase deficiency, urea cycle defects, tyrosinemia. In vital organs (e.g. liver, kidney), lack of ATP, which is required for conversion of 5-oxoproline into glutamate, may result to 5-oxoprolinuria. These errors include;

  • Homocystinuria

Patients with Homocystinuria may perhaps have extreme formation of 5-oxoproline.

  • Drug metabolism

Paracetamol, vigabatrin, and antibiotics (flucloxacillin, netilmicin) probably interrelate with the gamma-glutamyl cycle.

  • Prematurity

Transient 5-oxoprolinuria has been observed in very preterm infants. The cause is not known.

  • Undernourishment, pregnancy.
  • Inadequate availability of glycine.
  • Nephropathic cystinosis.

Nephropathic cystinosis patients might suffer from 5-oxoprolinuria deficiency most likely because of reduced availability of free cysteine, resulting in a secondary impairment of the γ -glutamyl cycle.

Glutathione has been shown to provide health benefits and be supportive in relation to a large number of conditions. In order to maintain optimal glutathione levels, consider supplementing with Nano Glutathione.