Phosphofructokinase deficiency

The deficiency of the muscle phosphofructokinase belongs to the group of glycogenoses (Inherited Glycogen Storage Disease). The PFK-deficiency or glycogenose, type VII affects people and even other mammals, in particular dogs.

The enzyme phosphofructokinase plays a main role in the control of glycolyse (glucose splitting); it catalyzes the transfer of a phosphoryl group from ATP to fructose-6-phosphate (F6P) to yield fructose-1,6-biphosphate (FBP), which is then split in two triose sugars (sugars with 3 C-atoms). In the metabolic pathway of these triose sugars, 1,3-biphosphoglycerate (1,3-BFG) is formed that is then metabolised to pyruvate in the glycolyse chain, but also 2,3-biphosphoglycerate is formed on the by-way (2,3-BFG).
2,3-BFG affects the oxygen affinity of haemoglobin and therefore takes an essential part in the control of oxygen transfer by erythrocytes. The PFK-deficiency causes a deficit of 2,3-BFG and affects the function of erythrocytes (symptoms of haemolytic anemia may occur).
The deficiency of PFK-enzymes in muscles results in accumulation of glycolytic metabolites in form of glucose-6-phosphat (G6P) and F6P. The high concentration of G6P in muscle stimulates the glycogen synthesis, which accumulates.

With people, this PFK-deficiency is also known as Tarui-Layzer-syndrome. It is rare and is characterised by metabolic myopathy and well compensated hemalytic anemia. The main clinical features are especially muscle fatigue, weakness and exercise intolerance. The affected animal suffers from muscle cramps and pain during exercise.

The PFK-deficiency has been described in English Springer Spaniel and American Cocker Spaniel dog breeds (Ginger et al. 1985); the same mutation has been found in Wippet dogs (Gerber et al. 2009).
In PFK-deficient dogs, the activity of PFK in erythrocytes is 6-22 % only and the activity of PFK in muscles is 1-4% of the normal enzyme activity in healthy patients (Ginger et al. 1986). The clinical symptoms are in particular sporadic haemolytic crises with pigmentura, anemia and icterus. Exercises, hyperventilation and stress of the animal stimulate occurrence of these heamalytic crises.

The clinical symptoms may occur in the first months of the life; however, they may be relatively bad recognisable and some cases go unrecognised. The life quality of the affected animal can be improved, if you avoid exercises that stimulate the occurrence of hemalytic crisis.

The deficiency of PFK-enzyme is caused by point-substitution in the last but one exon of M-PFK-gen. Due to this mutation, the resulting enzyme is shortened and becomes instable and degradates quickly (Smith et al. 1996). As the molecular and genetic principles of PFK-deficiency have been identified, it is also possible to discover the disease vectors. The molecular-genetic test can detect the presence of the mutation c.2228G>A in exon of 21 PFK gene that is the cause of PFK-deficiency (Smith et al. 1996).

PFK is inherited autosomally recessively which means that the disease develops only in those dogs who inherit mutated allele from both parents. Carriers of mutated allele (heterozygotes) are clinically healthy but transmit the mutation on their descendants. In case of mating two heterozygous dogs there is a theoretical chance that 25% of descendants will be absolutely healthy, 50% will be carriers a 25% will inherit from both parents mutated allele and therefore will be PFK affected.

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References:

Smith BF, Stedman H, Rajpurohit Y, Henthorn PS, Wolfe JH, Patterson DF, Giger U (1996) Molecular basis of canine muscle type phosphofructokinase deficiency. The Journal of Biological Chemistry, 33, 20070-20074

Giger, U., Harvey, J. W., Yamaguchi, R. A., McNulty, P. K., Chiapella, A., Beutler, E. Inherited phosphofruktokinase deficiency in dogs with hyperventilation induced hemolysis:increased in vitro and in vivo alkaline fragility of erythrocytes. Blood 1985;65:435-351.

Giger, U., Reilly, M. P., Asakura, T., Baldwin, C. J., and Harvey, J. W. (1986) Autosomal recessive inherited phosphofructokinase deficiency in English springer spaniel dogs. Anim. Genet. 17, 15-23

Gerber K, John W. Harvey JW , D'Agorne S, Wood J, Giger U (2009) Hemolysis, myopathy, and cardiac disease associated with hereditary phosphofructokinase deficiency in two Whippets. Vet Clin Pathol. 38, 46-51