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 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. A diagnosis can be made through a muscle biopsy that shows excess glycogen accumulation.