Phosphoglycerate kinase deficiency

Other Names: PGK deficiency; Phosphoglycerate kinase 1 deficiency; PGK1 deficiency

Phosphoglycerate kinase deficiency is a genetic disorder that affects the body's ability to break down the simple sugar glucose, which is the primary energy source for most cells.

Epidemiology

Phosphoglycerate kinase deficiency appears to be a rare disorder. About 30 families with affected members have been reported in the scientific literature.

Cause

Phosphoglycerate kinase deficiency is caused by mutations in the PGK1 gene. This gene provides instructions for making an enzyme called phosphoglycerate kinase, which is involved in a critical energy-producing process in cells known as glycolysis. During glycolysis, the simple sugar glucose is broken down to produce energy.

Mutations in the PGK1 gene reduce the activity of phosphoglycerate kinase, which disrupts energy production and leads to cell damage or cell death. It is unclear why this abnormality preferentially affects red blood cells and brain cells in some people and muscle cells in others. Researchers speculate that different PGK1 gene mutations may have varying effects on the activity of phosphoglycerate kinase in different types of cells.

Inheritance

X-linked recessive inheritance

This condition is inherited in an X-linked recessive pattern. The PGK1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Females with one altered PGK1 gene, however, may have some features of phosphoglycerate kinase deficiency, such as anemia. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Types

Researchers have described two major forms of the condition. The most common form is sometimes called the hemolytic form. It is characterized by a condition known as chronic hemolytic anemia, in which red blood cells are broken down (undergo hemolysis) prematurely. Chronic hemolytic anemia can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), fatigue, shortness of breath, and a rapid heart rate. Some people with the hemolytic form also have symptoms related to abnormal brain function, including intellectual disability, seizures, and stroke.

The other form of phosphoglycerate kinase deficiency is often called the myopathic form. It primarily affects muscles, causing progressive weakness, pain, and cramping, particularly with exercise. During exercise, muscle tissue can be broken down, releasing a protein called myoglobin. This protein is processed by the kidneys and released in the urine (myoglobinuria). If untreated, myoglobinuria can lead to kidney failure.

Most people with phosphoglycerate kinase deficiency have either the hemolytic form or the myopathic form. However, other combinations of signs and symptoms (such as muscle weakness with neurologic symptoms) have also been reported.

Signs and symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms

• Ataxia
• Decreased hemoglobin concentration
• Delayed speech and language development(Deficiency of speech development)
• Exercise-induced muscle fatigue
• Exercise-induced myalgia(Exercise-induced muscle pain)
• Global developmental delay
• Hemolytic anemia
• Hyperbilirubinemia(High blood bilirubin levels)
• Intellectual disability(Mental deficiency)
• Migraine(Intermittent migraine headaches)
• Muscle spasm
• Muscle weakness(Muscular weakness)
• Myoglobinuria
• Myopathy(Muscle tissue disease)
• Reticulocytosis(Increased immature red blood cells)
• Rhabdomyolysis(Breakdown of skeletal muscle)
• Tremor

5%-29% of people have these symptoms

• Renal insufficiency(Renal failure)
• Retinal dystrophy(Breakdown of light-sensitive cells in back of eye)
• Visual loss(Loss of vision)

1%-4% of people have these symptoms

• Blindness

Diagnosis

Diagnosis is made on the basis of the clinical picture, together with biochemical studies revealing low erythrocyte and muscle PGK enzyme activity (below 23% and 25% of normal respectively), and identification of PGK1 gene mutations by molecular analysis.

Differential diagnosis The differential diagnosis should include other causes of hereditary non-spherocytic hemolytic anemia.

Antenatal diagnosis Molecular prenatal diagnosis is feasible for families of an index case.

Treatment

In patients with severe chronic anemia, regular blood transfusions are required. Splenectomy has been shown to be beneficial in some cases.

Prognosis

The prognosis is variable, depending on the severity of the anemia and on the presence of the other manifestations.

class="navbox mw-collapsible autocollapse"

Glycolysis metabolic pathway

Glucose Hexokinase ATP ADP Glucose 6-phosphate Glucose-6-phosphate isomerase Fructose 6-phosphate Phosphofructokinase-1 ATP ADP Fructose 1,6-bisphosphate Fructose-bisphosphate aldolase Dihydroxyacetone phosphate + + Glyceraldehyde 3-phosphate Triosephosphate isomerase 2 × Glyceraldehyde 3-phosphate 2 ×  Glyceraldehyde-3-phosphate dehydrogenase NAD++ Pi NADH + H+ NAD++ Pi NADH + H+ 2 × 1,3-Bisphosphoglycerate 2 ×  Phosphoglycerate kinase ADP ATP ADP ATP 2 × 3-Phosphoglycerate 2 ×  Phosphoglycerate mutase 2 × 2-Phosphoglycerate 2 ×  Phosphopyruvate hydratase (enolase)   H2O   H2O 2 × Phosphoenolpyruvate 2 ×  Pyruvate kinase ADP ATP 2 × Pyruvate 2 ×

NIH genetic and rare disease info

• NIH info on Phosphoglycerate kinase deficiency

Phosphoglycerate kinase deficiency is a rare disease.

Phosphoglycerate kinase deficiency Resources
Latest articles Most recent articles Ongoing trials	Wikipedia