rhodanine and Metal-Metabolism--Inborn-Errors

This preliminary study summarizes the genotypes of 42 Labrador Retrievers and Labrador Retriever-Golden Retriever crosses and phenotypes a subset of ten of these dogs that are homozygous mutant, heterozygous, or homozygous normal for mutations in the ATP7A and ATP7B genes that have been associated with the development of copper toxicosis in Labrador Retrievers. The purpose of this study is to evaluate whether there is a correlation between ATP7A and ATP7B genotypes and clinical evidence of hepatic pathology in young, asymptomatic Labrador Retrievers. We evaluated serum ALT levels, hepatic copper concentrations, and hepatic histopathology from ten offspring where both parents had a least one copy of the ATP7B mutation. Five were homozygous mutant, four were heterozygous, and one was homozygous normal for comparison. None had increased serum ALT activity. All dogs homozygous for the ATP7B mutation had elevated hepatic copper concentrations compared to dogs heterozygous for the ATP7B mutation regardless of sex or presence of an ATP7A mutation with the mean hepatic copper concentration being 1464 ppm (reference range 100-330 ppm). Mean hepatic copper concentration in homozygous normal and heterozygous dogs was 328 ppm. In this preliminary analysis, we found that dogs that carry two copies of the ATP7B mutation have abnormally elevated hepatic copper levels despite having normal serum ALT activity. Our findings support the hypothesis that the ATP7B DNA test can predict defects in hepatic copper metabolism. Veterinarians can test for the ATP7B gene mutation to identify Labrador Retrievers at risk for copper toxicosis so that they can take steps to prevent development of copper-associated chronic hepatitis in their patients.

Topics: Alanine Transaminase; Animals; Copper; Copper-Transporting ATPases; Dog Diseases; Dogs; Female; Genetic Predisposition to Disease; Genotype; Hepatolenticular Degeneration; Humans; Liver Cirrhosis; Male; Metal Metabolism, Inborn Errors; Rhodanine

Sections of paraffin-embedded specimens of liver obtained from Bedlington terriers were stained with rhodanine for copper and examined and graded by two pathologists. Their results correlated well with each other, as well as with the results of quantitative determinations of hepatic copper content. Copper toxicosis was established by cytochemistry in 20 of 21 specimens, indicating a sensitivity of 95%. The method is highly specific--none of the 19 specimens obtained from unaffected dogs displayed copper-containing granules suggestive of copper toxicosis. Copper cytochemistry appears to be a satisfactory substitute for chemical analysis of hepatic copper content.

Topics: Age Factors; Animals; Copper; Cytoplasmic Granules; Dog Diseases; Dogs; Female; Histocytochemistry; Liver; Male; Metal Metabolism, Inborn Errors; Rhodanine