PDP1 Deficiency – Pyruvate Dehydrogenase Phosphatase 1 Deficiency
Pyruvate Dehydrogenase Phosphatase 1 deficiency, or PDP1 Deficiency, is an inherited disorder affecting the Clumber and Sussex Spaniels, and it is a form of exercise intolerance syndrome. The exercise intolerance syndromes are well known to be associated with inborn errors of metabolism affecting glycolysis and fatty acid oxidation.
The Clumber and Sussex Spaniels are an old breed, originating from 18th and early 19th century. PDP 1 deficiency was first described in a population of Clumber spaniels during late 1970’s. The disorder is characterized by lack of pyruvate dehydrogenase phosphatase 1, resulting in dog’s extreme exhaustion.
Pyruvate dehydrogenase, as well as pyruvate kinase, is just some of the enzymes involved in carbohydrate metabolism. Understanding pathways and regulation of this metabolism is of crucial importance for understanding metabolism disorders as diabetes and obesity. Pyruvate dehydrogenase (E1) is part of the large protein complex known as pyruvate dehydrogenase complex (PDHc). The complex consists of two other components, E2 and E3. Pyruvate dehydrogenase phosphatase reverses the action of pyruvate dehydrogenase kinase. Pyruvate dehydrogenase kinase catalyzes phosphorylation of E1 component, which inhibits the PDHc, while pyruvate dehydrogenase phosphatase catalyzes the dephosphorylation and activates the PDHc. Mutations within gene encoding for results in metabolic disorder known as Pyruvate Dehydrogenase Phosphatase 1 deficiency. Due to inactive PDHc, resting plasma lactate and pyruvate concentrations are high among affected dogs. Glycolysis increases to compensate for lack of oxidative energy, and less of ATP is being produced, resulting in exercise intolerance in dogs.
Characteristics and Symptoms
Affected dogs at first appear normal as their littermates, and first clinical signs appear around 1 year of age. The dog would, after short exercise, need to slow down and eventually sit. After few minutes of resting, dog can continue with the exercise but only for short time. Physical and neurological examinations give results within normal range. Cardiovascular examination shows mild mitral insufficiency, a disorder of the heart in which the mitral valve does not close properly when the heart pumps out the blood. Death onset varies in age among affected dogs. An affected dog that passed away at three years of age has been reported with hypertrophic cardiomyopathy found on necropsy.
PDP1 Deficiency is caused by mutation in PDP 1 gene. The disorder is inherited in an autosomal recessive pattern. Dog carrying one copy of the mutated gene is heterozygous and will not show the PDP1 deficiency, or exercise intolerance syndrome symptoms. When mating two carriers (heterozygotes) at conception each cub has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. A research conducted on 100 randomly selected Clumber and Sussex Spaniels, revealed high carrier rate of 20%.