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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.
It is a complex enzyme: several subtypes of deficiency have been identified, 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.
- 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.
- 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%.
- 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
- 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.
There are a number of enzyme defects that can cause myoglobinuria as well as other causes to remember:
- Biochemical abnormalities (eg hypokalaemia, hypophosphataemia)
- 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
- Drug abuse
- 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.
Strenuous exercise should be avoided.
None are of proven value.
Splenectomy can reduce the haemolytic anaemia and the need for transfusion.
Myoglobinuria from prolonged exercise can produce renal damage.
Severity varies but the myopathic syndrome is usually slowly progressive. In one study of a large family, many sufferers died before reaching adulthood.
Identification of the gene may permit prenatal diagnosis with a view to termination of pregnancy.
Further reading & references
- CLIMB, Children Living with Inherited Metabolic Diseases
- Phosphoglycerate Kinase-1 Deficiency, Online Mendelian Inheritance in Man (OMIM)
- Tsujino S, Shanske S, DiMauro S; Molecular genetic heterogeneity of phosphoglycerate kinase (PGK) deficiency. Muscle Nerve. 1995;3:S45-9.
- Spiegel R, Gomez EA, Akman HO, et al; Myopathic form of phosphoglycerate kinase (PGK) deficiency: A new case and pathogenic considerations. Neuromuscul Disord. 2009 Jan 19.
- Beutler E; PGK deficiency. Br J Haematol. 2007 Jan;136(1):3-11.
- Phosphoglycerate Kinase (PGK) 1 Deficiency, Online Mendelian Inheritance in Man (OMIM)
- Tonin P, Lewis P, Servidei S, et al; Metabolic causes of myoglobinuria. Ann Neurol. 1990 Feb;27(2):181-5.
- Fujii H, Miwa S; Other erythrocyte enzyme deficiencies associated with non-haematological symptoms: phosphoglycerate kinase and phosphofructokinase deficiency. Baillieres Best Pract Res Clin Haematol. 2000 Mar;13(1):141-8.
- Turner G, Fletcher J, Elber J, et al; Molecular defect of a phosphoglycerate kinase variant associated with haemolytic anaemia and neurological disorders in a large kindred. Br J Haematol. 1995 Sep;91(1):60-5.
- Flanagan JM, Rhodes M, Wilson M, et al; The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA. Br J Haematol. 2006 Jul;134(2):233-7. Epub 2006 Jun 1.
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Dr Chloe Borton
Dr Chloe Borton