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Phosphofructokinase deficiency
Specialty	Endocrinology

Phosphofructokinase deficiency, also known as glycogen storage disease type VII or Tarui's disease, is a muscular metabolic disorder, with an autosomal recessive inheritance pattern.

It may affect humans as well as other mammals (especially dogs). In humans, it is the least common type of glycogen storage disease. It was named after the Japanese physician, Seiichiro Tarui (1927– ) who first observed the condition in 1965.

Risk factors

In humans

In order to get Tarui’s disease, both parents must be carriers of the genetic defect so that the child is born with the full form of the recessive trait. The best indicator of risk is a family member with PFK deficiency.

In dogs

Canine phosphofructokinase deficiency is found mostly in English Springer Spaniels and American Cocker Spaniels, but has also been reported in Whippets and Wachtelhunds. Mixed-breed dogs descended from any of these breeds are also at risk to inherit PFK deficiency.

Pathophysiology

Phosphofructokinase is a tetrameric enzyme that consists of three types of subunits: PFKL (liver), PFKM (muscle), and PFKP (platelet). The combination of these subunits varies depending on the tissue in question. In this condition, a deficiency of the M subunit (PFKM) of the phosphofructokinase enzyme impairs the ability of cells such as erythrocytes and rhabdomyocytes (skeletal muscle cells) to use carbohydrates (such as glucose) for energy. Unlike most other glycogen storage diseases, it directly affects glycolysis. The mutation impairs the ability of phosphofructokinase to phosphorylate fructose-6-phosphate prior to its cleavage into glyceraldehyde-3-phosphate which is the rate limiting step in the glycolysis pathway. Inhibition of this step prevents the formation of adenosine triphosphate (ATP) from adenosine diphosphate (ADP), which results in a lack of available energy for muscles during heavy exercise. This results in the muscle cramping and pain that are common symptoms of the disease.

In humans

Genetic mutation is the cause of phosphofructokinase deficiency. Several different mutations in the gene that encodes for PFKM have been reported in humans, but the result is production of PFKM subunits with little to no function. As a result, affected individuals display only about 50-65% of total normal phosphofructokinase enzyme function.

In dogs

PFK deficiency is believed to be the result of a nonsense mutation in the gene that encodes for PFKM. This results in an unstable, truncated protein that lacks normal function. This results in a near complete loss of PFKM activity in the skeletal muscle. Dogs with the mutation display 10-20% of normal PFK activity in their erythrocytes, due to a higher proportion of PFKM in those cells.

Diagnosis and treatment

Symptoms of phosphofructokinase deficiency can closely resemble those of other metabolic diseases, include deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, beta-enolase and aldolase A. Thus, proper diagnosis is important to determine a treatment plan.

In humans

A diagnosis can be made through a muscle biopsy that shows excess glycogen accumulation. Glycogen deposits in the muscle are a result of the interruption of normal glucose breakdown that regulates the breakdown of glycogen. Blood tests are conducted to measure the activity of phosphofructokinase, which would be lower in a patient with this condition. Patients also commonly display elevated levels of creatine kinase.

Treatment usually entails that the patient refrain from strenuous exercise to prevent muscle pain and cramping. Avoiding carbohydrates is also recommended.

A ketogenic diet also improved the symptoms of an infant with PFK deficiency. The logic behind this treatment is that the low-carb high fat diet forces the body to use fatty acids as a primary energy source instead of glucose. This bypasses the enzymatic defect in glycolysis, lessening the impact of the mutated PFKM enzymes. This has not been widely studied enough to prove if it is a viable treatment, but testing is continuing to explore this option.

Genetic testing to determine whether or not a person is a carrier of the mutated gene is also available.

In dogs

Diagnosis of canine phosphofructokinase deficiency is similar to the blood tests used in diagnosis of humans. Blood tests measuring the total erythrocyte PFK activity are used for definitive diagnosis in most cases. DNA testing for presence of the condition is also available.

Treatment mostly takes the form of supportive care. Owners are advised to keep their dogs out of stressful or exciting situations, avoid high temperature environments and strenuous exercise. It is also important for the owner to be alert for any signs of a hemolytic episode. Dogs carrying the mutated form of the gene should be removed from the breeding population, in order to reduce incidence of the condition.

References

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12. Raben, N; Sherman, JB (1995). "Mutations in muscle phosphofructokinase gene". Human Mutation. 6 (1): 1–6. doi:10.1002/humu.1380060102. PMID 7550225.
13. Vora, Shobhana; Giger, Urs; Turchen, Steven; Harvey, John (December 1985). "Characterization of the enzymatic lesion in inherited phosphofructokinase deficiency in the dog: an animal analogue of human glycogen storage disease type VII". Proceedings of the National Academy of Sciences of the United States of America. 82 (23): 8109–8113. doi:10.1073/pnas.82.23.8109. PMC 391452. PMID 2933748.
14. Harvey, J.W.; Smith, J.E. (June 1994). "Haematology and Clinical Chemistry of English Springer Spaniel Dogs with Phosphofructokinase Deficiency". Comparative Harmatology International. 4 (2): 70–75. doi:10.1007/BF00368272.
15. ^ Cite error: The named reference pmid18421897 was invoked but never defined (see the help page).
16. Malfatti, Edoardo; Birouk, Nazha; Romero, Norma B.; Piraud, Monique; Petit, François M.; Hogrel, Jean-Yves; Laforêt, Pascal (2012-05-15). "Juvenile-onset permanent weakness in muscle phosphofructokinase deficiency". Journal of the Neurological Sciences. 316 (1–2): 173–177. doi:10.1016/j.jns.2012.01.027.
17. Ronquist, Gunnar. "Tarui disease". The Swedish Information Center for Rare Diseases. University of Gothenburg.
18. "Glycogen Storage Disease Type VII". Rare Disease Database. National Organization for Rare Disorders.
19. Swoboda, Kathryn; Specht, Linda; Jones, Royden; Shapiro, Frederic; DiMauro, Salvatore; Korson, Mark (December 1997). "Infantile phosphofructokinase deficiency with arthrogryposis: Clinical benefit of a ketogenic diet". The Journal of Pediatrics. 131 (6): 932–934. doi:10.1016/s0022-3476(97)70048-9.
20. Gerber, Karen; Harvey, John; D'Agorne, Sara; Wood, Jonathan; Giger, Urs (March 2009). "Hemolysis, myopathy, and cardiac disease associated with hereditary phosphofructokinase deficiency in two Whippets". Veterinary Clinical Pathology. 38 (1): 46–51. doi:10.1111/j.1939-165X.2008.00089.x. PMC 2692053. PMID 19228357.
21. Giger, U; Kimmel, A; Overlery, D; Schwartz, B; Smith, B; Rajpurohit, Y. "Frequency of Phosphofructokinase (PFK) Deficiency in English Springer Spaniels: A Longitudinal and Randomized Study". English Springer Spaniel Field Trial Association.

External links

• Glycogen storage disease type 7; Muscle phosphofructokinase deficiency; Tarui disease at NIH's Office of Rare Diseases
• Asociación Española de Enfermos de Glucogenosis

• Inborn errors of carbohydrate metabolism
• Autosomal recessive disorders