Phosphoglycerate Kinase 1 Deficiency

Synonyms: Phosphoglycerokinase deficiency, PGK deficiency, PGK1 deficiency, Haemolytic anaemia with PGK Deficiency,

Phosphoglycerate kinase deficiency is a hereditary metabolic disease. Phosphoglycerate kinase (PGK1) is a ubiquitous glycolytic enzyme that catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate generating one molecule of ATP. Its gene lies on the X-chromosome (locus Xq13) and there are related pseudogenes on the X-chromosome and chromosome 19.^[1]

It is a complex enzyme: several subtypes of deficiency have been identified,^[2] based on the tissues in which the enzyme deficiency occurs and the type of inheritance. Clinically, there are two distinct syndromes:

• A pure muscle syndrome characterized by recurrent cramps and muscle breakdown in response to intense exercise.^[3]
• A "muscle plus" syndrome which may feature mental retardation and/or haemolytic anaemia.

Different mutations of the erythrocyte enzyme PGK1 gene have been identified but the reason for the multifarious clinical manifestations of mutations of the same gene remains unknown.^[4]

Epidemiology

• It is extremely rare.
• The gene encoding the erythrocyte enzyme PGK1 is X-linked and PGK is transmitted as an X-linked recessive disorder in nearly 75%. Females are carriers and have a 50% chance of transmitting the gene to an affected son or a carrier daughter. Affected males produce carrier daughters and unaffected sons.
• It is inherited as an autosomal recessive in about 25%.^[5]

Presentation

• Presentation is variable but occurs between infancy and adolescence.
• Clinical findings include:
  • Muscle pain and weakness
  • Rust-coloured urine after vigorous exercise due to myoglobinuria
• Other features are rare and highly variable but may include:
  • Nausea after exercise
  • Variable degrees of mental retardation
  • Seizures
  • Haemolytic anaemia
• Some patients may have a purely myopathic syndrome with progressive proximal muscle weakness and episodes of myoglobinuria, exercise intolerance and easy fatigue.
• There can be emotional lability, aphasia with impaired ability to comprehend speech or writing and hemiplegia.
• Female carriers may have haemolytic anaemia.

Differential diagnosis

There are a number of enzyme defects that can cause myoglobinuria^[6] as well as other causes to remember:

• Biochemical abnormalities (eg hypokalaemia, hypophosphataemia)
• Myopathies
• McArdle's disease (Glycogen storage disorder V) and Tarui's disease (Glycogen storage disorder VII)
• Acetyl-CoA dehydrogenase deficiency and lactate dehydrogenase deficiency
• Polymyositis and dermatomyositis
• Malignant hyperthermia
• Neuroleptic malignant syndrome
• Crush syndrome
• Muscle ischaemia secondary to arterial occlusion or insufficiency
• Septicaemia
• Drug abuse

Investigations

• Diagnostic testing is available for the absence of the enzyme phosphoglycerate kinase.
• There is recurrent myoglobinuria, especially after exercise.
• Serum CK levels are high or normal.
• Anaerobic exercise produces no rise in lactate.
• Gene mutation identification within family groups.

Management

Non-Drug

Strenuous exercise should be avoided.

Drugs

None are of proven value.

Surgery

Splenectomy can reduce the haemolytic anaemia and the need for transfusion.^[7]

Complications

Myoglobinuria from prolonged exercise can produce renal damage.

Prognosis

Severity varies but the myopathic syndrome is usually slowly progressive. In one study of a large family, many sufferers died before reaching adulthood.^[8]

Prevention

Identification of the gene^[9] may permit prenatal diagnosis with a view to termination of pregnancy.