**3.1 The breed**

An interesting story describing the breeding of desirable traits in animals is that of the Clumber spaniel. This breed of canine is of particular fascination to the authors of this chapter as our work in the Robinson lab in 2005 on a human autosomal recessive disorder affecting pyruvate metabolism, led to the diagnosis of the same metabolic disorder in the Clumber spaniel [3, 4]. There are a few theories regarding the origin of this breed, and each is entwined in romantic, historical folklore. The most common, and rather intriguing theory begins with the aristocracy of eighteenth century France and the Noailles family. Due to the French Revolution, most of the Noailles family documents were destroyed along with many family members. Any papers that survived the Revolution were destroyed in a fire at the Louvre in May 1871 [2]. The lore suggests that in the early 1760s, Louis de Noailles (the future 4th Duc de Noailles), invited his good friend Henry Pelham-Clinton (the future 2nd Duke of Newcastle), to go hunting on his estate in France. Henry Pelham-Clinton was extremely impressed with Louis de Noailles' hunting spaniels, particularly for their prowess in flushing game. Louis de Noailles gifted his breeding stock of Clumbers to Henry Pelham-Clinton, who brought the dogs to his Clumber Park estate in Sherwood Forest, Nottinghamshire, England in 1764. Together with the assistance of William Mansell, his gamekeeper, they further developed this breed for the "retired gentleman" or "elderly gentlemen's hunting companion." This breed of dog would have likely been lost forever in the chaos of the French Revolution as the French stock was wiped out [18]. The first record of Clumbers in England is seen in the 1788 painting by Sir Francis Wheatly as shown in **Figure 1**.

#### **Figure 1.**

*Sir Francis Wheatley's painting titled "The Return from Shooting" depicts the Duke of Newcastle on the hunt with Colonel Litchfield, his gamekeeper William Mansell, and four white with orange/lemon marked Clumber spaniels, confirming that the breed was likely in England before the of the French revolution which began on or about 1789 and ended in 1799. This picture is in the public domain and the original is in the possession of the Sheffield gallery in Sheffield, England. https://commons.wikimedia.org/w/index.php?curid=8708898*

The Clumber spaniel began as a small kennel of pure-bred dogs. No genetic diversity was introduced for approximately 30 years after the breed was brought to Clumber Park and under the direction of William Mansell [18]. True to the initial selection criteria of traits, the breed is not as energetic as other hunting spaniels. The Clumbers seem to require only about an hour of activity daily. The Clumber physique is long and low, typically heavier than other Spaniels, with a white coat that can be easily seen by hunters. They continue to be developed in the United Kingdom as working gun dogs, where modest size, lack of exaggeration, good eyes, good hips, good temperament, responsiveness, athleticism, and working aptitudes are the important qualities [2]. Their personality has been described by the American Kennel Club as mellow, gentlemanly, amiable, dignified but always amusing [19]. Selective breeding of this low-energy dog has resulted in approximately 20% of current live-born Clumber spaniels being carriers for a metabolic deficiency, which results in severe exercise intolerance with lactic acidosis [4]. The metabolic deficiency in the Clumber spaniel was first reported in 1979 by Herrtage and Houlton, who described a dog that collapsed and showed extreme lactic acidosis after moderate exercise [20]. Järvinen and Sankari reported that a 3-year-old Clumber spaniel had a history of exercise intolerance since puppyhood. During exercise, the dog would quickly tire, lay down, and could not rise until resting for up to 1 hour. Post-exercise blood lactate levels were very elevated. The dog died suddenly while investigations were being performed and a defect in pyruvate dehydrogenase activity was suspected [21].

#### **3.2 Etiology of lactic acidosis**

Lactic acid is a normal product of metabolism and is utilized mainly in the liver and kidney, which express the requisite enzymes for processing, in a pathway called gluconeogenesis. During exercise, skeletal muscle produces circulating lactate which typically normalizes in time. Lactic acidosis is also a common finding in disease states when there is an increased production accompanied by decreased clearance. Metabolic lactic acidosis occurs when there is a defect in the aerobic metabolism of pyruvate. Pyruvate is naturally generated as the final product of glycolysis. Pyruvate is then used, through a series of enzymatic steps, to generate ATP. ATP is the primary energy molecule that is used by the cell for activities such as muscle contraction, synthesis of macromolecules, and maintenance of the cellular membrane. The normal fate of pyruvate is first to enter the mitochondria where it is converted to acetyl CoA by the pyruvate dehydrogenase complex. Second, acetyl CoA feeds into the citric acid cycle which generates products that drive a series of reactions of the electron transport chain to finally produce ATP. Deficits in any of the enzyme systems of these pathways will result in the accumulation of pyruvate, which in turn is reduced to lactate, thus causing lactic acidosis. The clinical features of lactic acidosis include muscle weakness, confusion, increased heart rate, metabolic acidosis with an elevated anion gap, compensatory hyperventilation due to metabolic acidosis, and in extreme cases may result in coma.
