ABSTRACT. Inherited selective intestinal malabsorption of cobalamin (Cbl) was observed in a family of giant schnauzer dogs. Family studies and breeding experiments demonstrated simple autosomal recessive inheritance of this disease. Affected puppies exhibited chronic inappetence and failure to thrive beginning between 6 and 12 wk of age. Neutropenia with hypersegmentation, anemia with anisocytosis and poikilocytosis, and megaloblastic changes of the bone marrow were present. Serum Cbl concentrations were low, and methylmalonic aciduria and homocysteinemia were present. Parenteral, but not oral, cyanocobalamin administration rapidly eliminated all signs of Cbl deficiency except for low serum Cbl concentrations. Cbl malabsorption in affected dogs was documented by oral administration of [57Co]cyanocobalamin with or without simultaneous oral administration of intrinsic factor or normal dog gastric juice. Quantitation and function studies of intrinsic factor and transcobalamin-I1 from affected dogs revealed no abnormality. Other gastrointestinal functions and ileal morphology were normal, indicating a selective defect of Cbl absorption at the level of the ileal enterocyte. Immunoelectron microscopy of ileal biopsies showed that the receptor for intrinsic factor-Cbl complex was absent from the apical brush border microvillus pits of affected dogs. This canine disorder resembles inherited selective intestinal Cbl malabsorption (Imerslund-Grasbeck syndrome)
SummaryThis report describes a third mucopolysaccharidosis in animals: canine mucopolysaccharidosis VII. The affected dog was the offspring of a father-daughter mating. Weakness in the rear legs was evident at 8 weeks of age and became progressively worse. He had a large head, a shortened maxilla, and corneal granularities. Most joints were extremely lax, easily subluxated, with joint capsules that were swollen and fluctuant.The dog was alert and had apparently normal pain perception. At 13 months of age, there was radiographic evidence of extensive skeletal disease including bilateral femoral head luxation. abnormalities in the shape and density of the carpal and tarsal bones, radiolucent lesions of the epiphyseal regions of most long bones, and cervical vertebral dysplasia and platyspondylia. The electrophoretic pattern of precipitated glycosaminoglycans indicated a predominance of chondroitin sulfate.The animal died suddenly from gastric dilatation. There was generalized hepatomegaly, thickening of the atrioventricular heart valves, and generalized polyarthropathy. Vacuolated cytoplasm was observed in hepatocytes, keratocytes, fibroblasts, chondrocytes and cells of the synovial membrane, retinal pigment epithelium, and cardiac valves. Neurons had cytoplasmic vacuoles. Electron microscopy demonstrated membrane-bound cytoplasmic inclusions in polymorphonuclear leukocytes, hepatocytes, synovium, heart valves and spleen.The activities of 12 lysosomal hydrolases were determined in liver from the affected and control dogs: 8-glucuronidase (EC 3.2. The MPS are a group of genetic diseases resulting from defective degradation of GAG (1 2). Each syndrome has a characteristic combination of clinical signs, urinary GAG excretion, and a specific lysosomal enzyme deficiency. The general clinical characteristics include dysostosis multiplex, facial dysmorphia, h e p atosplenomegaly, mental retardation, lysosomal accumulation and urinary excretion of GAG, and metachromatic granules in blood leukocytes. Animal models of MPS I [domestic cat (7), plott hound dog (1 7)], and VI [Siamese cat (lo)] have been described. This report describes a third mucopolysaccharidosis in animals: canine mucopolysaccharidosis VII. MATERIALS AND METHODSFour animals were studied: The affected animal (referred to us by Dr. Niels Pederson, University of California, Davis) its parents, and a newborn half-sibling of the affected animal ( Fig. 1 ).Urinary G1.vcosaminoglycans. Urine spot tests for GAG were performed (1). Urine was mixed with 10% cetylpyridinium chloride, the precipitate was treated as previously described (4), and the residue was dissolved in 2 ml of distilled water. Aliquots were used for microelectrophoresis on a 0.7% agarose gel in 0.05 M 1,3diaminopropane:acetate buffer, pH 9.0. Digestion of the crude urinary GAG with chondroitinase AC (EC 4.2.2.5) and ABC (EC 4.2.2.4) (Sigma Chemical Co.) was performed as previously described ( 14).Pathology. Blood samples were collected in EDTA for light microscopy or in heparin for EM. Leukocyte...
A male German shepherd pup had symmetrical areas of hairlessness as well as missing and misshapen teeth. There was no family history of a similar phenotype. In biopsies of the hairless skin and foot pads there were no hair follicles, adnexal structures, or eccrine glands. These findings resemble those in ectodermal dysplasia in the Tabby mouse and anhidrotic/hypohidrotic ectodermal dysplasia (HED) in man, which are both X-linked recessive disorders and thought to be homologous gene defects. While similar cases of ectodermal dysplasia have been reported in the dog and some genetic studies carried out, definitive confirmation of X-linked inheritance of canine ectodermal dysplasia is lacking. Family studies and experimental matings using the propositus gave results that confirm X-linked recessive inheritance. On statistical grounds, it is concluded that ED in the propositus is due to a new mutation. A colony of dogs with this mutation is maintained for further study.
A Siamese cat that presented clinical signs similar to those seen in humans with mucopolysaccharidoses was studied. The animal excreted increased amounts of polymeric glycosaminoglycans in the urine, consisting almost entirely of dermatan sulfate. Electron microscopy of circulating polymorphonuclear leukocytes revealed the presence of many membrane-bound lamellar inclusion bodies. Sulfate incorporation studies with cultured skin fibroblasts indicated defective glycosaminoglycan degradation. These cells showed a deficiency in arylsulfatase B activity. The disorder appears similar or identical to the Maroteaux-Lamy syndrome described in humans.
Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A, McKusick 25290) was diagnosed in two adult wire-haired Dachshund littermates. Clinical and pathologic features paralleled the human disorder; both dogs exhibited progressive neurologic disease without apparent somatic involvement. Pelvic limb ataxia was observed when the dogs were 3 y old and progressed gradually within 1-2 y to severe generalized spinocerebellar ataxia. Mentation remained normal throughout the course of the disease. A mucopolysaccharide storage disorder was indicated in both dogs by positive toluidine blue spot tests of urine. The diagnosis of MPS IIIA was confirmed by documentation of urinary excretion and tissue accumulation of heparan sulfate and decreased sulfamidase activity in fibroblasts and hepatic tissue. Mild cerebral cortical atrophy and dilation of the lateral ventricles were grossly evident in both dogs. Light microscopically, fibroblasts, hepatocytes, and renal tubular epithelial cells were vacuolated. Within the nervous system, cerebellar Purkinje cells, neurons of brainstem nuclei, ventral and dorsal horns, and dorsal ganglia were distended with brightly autofluorescent, periodic acid-Schiff-positive, sudanophilic material. Ultrastructurally, visceral storage presented as membrane-bound vacuoles with finely granular, variably electron-lucent contents. Neuronal storage appeared as membranous concentric whorls, lamellated parallel membrane stacks, or electron-dense lipid-like globules. This represents the first reported animal disease homolog of the human Sanfilippo A syndrome.
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