METABLIC DISORDERS INTRODUCTION

Metabolic diseases may be inherited or acquired, the latter being more common and significant. Metabolic diseases are clinically important because they affect energy production or damage tissues critical for survival.

Metabolic Storage Disorders and Inborn Errors of Metabolism Storage diseases and inborn errors of metabolism are classified as either genetic or acquired. These diseases are characterized by the accumulation or storage of specific lysosomal enzyme substrates or byproducts within cells because of partial or complete deficiency of those enzymes. Although lysosomal storage diseases are often widespread throughout the body, the majority of clinical signs are due to the effects on the CNS.

Genetic storage diseases are named according to the specific metabolic byproduct that accumulates in the lysosomes. Animals are typically normal at birth, then manifest clinical signs within the first weeks to months of life. These diseases are progressive and usually fatal, as specific treatments do not exist. In small animals the gangliosidoses (GM1 and GM2) are seen in Siamese, Korat, and domestic cats, and in Beagle crosses, German Shorthaired Pointers, and Japanese Spaniels. Sphingomyelinosis is seen in German Shepherds and Poodles, and in Siamese and domestic shorthaired cats. Glucocerebrosidosis is seen in Australian Silky Terriers and Dalmatians. Ceroid lipofuscinosis is seen in English Setters, Cocker Spaniels, Dachshunds, Chihuahuas, Salukis, Border Collies, and domestic cats. Mannosidosis is seen in Persian and domestic cats. Glycogenosis is seen in Silky Terriers, and in domestic shorthaired and Norwegian forest cats. Globoid cell leukodystrophy (Krabbe’s disease) is seen in Cairn Terriers, West Highland White Terriers, Beagles, Bluetick Hounds, Poodles, and domestic shorthaired cats. Mucopolysaccharidosis type I is seen in Siamese, Korat, and domestic shorthaired cats; type IV is seen in Siamese cats. In dogs, mucopolysaccharidosis is seen in Miniature Pinschers, Plott Hounds, and mixed-breed dogs and is associated with lameness. Diseases associated with decreased RBC survival and anemia include pyruvate kinase deficiency in Basenjis, Beagles, and West Highland White and Cairn Terriers; phosphofructokinase deficiency in English Springer and American Cocker Spaniels; and porphyria in Siamese and domestic shorthaired cats.

In large animals, α-mannosidosis occurs in Angus, Murray Grey, Simmental, Galloway, and Holstein cattle. β-mannosidos is seen in Saler cattle and Nubian and Nubian-cross goats. Generalized glycogenosis (GM1) is seen in Holstein cattle and Suffolk sheep. Generalized glycogenosis (GM2) is seen in Shorthorn and Brahman cattle, and in pigs. Globoid cell leukodystrophy is seen in polled Dorset sheep. Other identified diseases that are manifest by neurologic signs and appear to be inherited include neuronal lipodystrophy in Angus and Beefmaster cattle, shaker calf syndrome of horned Hereford cattle, maple syrup urine disease of Hereford and polled Shorthorn cattle, and hereditary neuraxial edema of polled and horned Hereford and Hereford-Friesian cross cattle. There have been no reports of lysosomal storage diseases in horses; however, inherited diseases manifest by neurologic signs include inherited myoclonus of Peruvian Paso foals and congenital encephalomyelopathy in Quarter Horses.

Other inherited diseases that involve basic errors of metabolism in various tissues include goiter of sheep and goats, inherited parakeratosis (edema disease) of cattle, osteogenesis imperfecta of sheep and cattle, and possibly cardiomyopathy of cattle, the hypotrichoses, baldy calves, photosensitization of sheep ( Photosensitization: Introduction), dermatosis vegetans and porcine stress syndrome ( Malignant Hyperthermia : Introduction) of pigs, dermatosparaxia and Ehlers-Danlos syndrome of cattle, hemochromatosis of cattle ( Hemochromatosis), and Marfan syndrome in cattle. Many other inherited defects, especially those based on abnormal growth of collagen, cartilage, and bone, also are likely to have basic errors of metabolism of structural tissues. Many disorders of metabolism have been described involving dysfunctions of the immune system.

Acquired storage diseases are caused by the ingestion of plants that contain inhibitors of specific lysosomal catabolic enzymes. Chronic ingestion of locoweed plants ( Astragalus or Oxytropis spp ) results in an acquired neurologic storage disease. Several toxic components including locoine, swainsonine n-oxide, and indolizidine alkaloids interfere with α-mannosidase activity. Horses are most susceptible to intoxication; however, cattle, sheep, and goats can also be affected. Production-related Metabolic Disorders While the development of the following diseases is largely related to production or management factors, the pathogenesis of each disease is primarily related to alterations in metabolism. In most cases the basis of disease is not a congenital or inherited error in metabolism, but rather an increased demand for a specific nutrient that has become deficient under certain conditions. Diseases such as hypocalcemia, hypomagnesemia, and hypoglycemia are augmented by management practices that are directed toward improving and increasing production. They are therefore correctly considered production diseases. However, they are also metabolic diseases because management of the animal is directed at production, which at its peak, is beyond the capacity of that animal’s metabolic reserves to sustain a particular nutrient at physiologic concentrations. For example, parturient paresis of cows ( Parturient Paresis in Cows) occurs when the mass of calcium in the mammary secretion is greater than the cow’s diet or its skeletal reserves can supply. Comparable situations occur with magnesium and glucose metabolism, and with phosphorus in relation to postparturient hemoglobinuria (Disorders of Phosphorus Metabolism). Most production-induced metabolic diseases result from a negative balance of a particular nutrient. In some cases, dietary intake of the nutrient is rapidly reduced because of an ongoing, high metabolic requirement for that nutrient. Examples include pregnancy toxemia of ewes ( Pregnancy Toxemia in Ewes), protein-energy malnutrition in beef cattle (Nutritional Requirements), fat cow syndrome in dairy cattle ( Fatty Liver Disease of Cattle), and hyperlipemia in ponies (Hyperlipemia and Hepatic Lipidosis in Horses, Donkeys, and Camelids). Furthermore, some diseases may be precipitated when producers, primarily due to economic concerns, are compelled to not supplement animals that already have a substandard nutritional plane. Exertional rhabdomyolysis of horses ( Exertional Myopathies in Horses: Overview) is another production-induced metabolic disease. In this case, the production activity (draft or racing) is maintained by and matched to a level of caloric intake. Management decisions not to work or race these horses without a concomitant decrease in caloric intake may result in accumulation of muscle glycogen to dangerous levels. Disease results when work is resumed and the production of lactate exceeds its metabolism. The difference between production-related metabolic diseases and nutritional deficiencies is often subtle. Typically, nutritional deficiencies are longterm, steady state conditions that can be corrected through dietary supplementation. Metabolic diseases are generally acute states that dramatically respond to the systemic administration of the deficient nutrient or metabolite, although affected animals may require subsequent dietary supplementation to avoid recurrence. An important aspect of dealing with production-induced metabolic diseases is accurate and rapid diagnosis. Ideally, diagnostic tests can be used to predict the occurrence of disease before its clinical onset.