Inherited renal and cardiac disease in the bull terrier

O'Leary, Caroline Ann. (2002). Inherited renal and cardiac disease in the bull terrier , School of Veterinary Science, The University of Queensland.

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Author O'Leary, Caroline Ann.
Thesis Title Inherited renal and cardiac disease in the bull terrier
School, Centre or Institute School of Veterinary Science
Institution The University of Queensland
Publication date 2002
Supervisor Professor R. B. Atwell
Professor C. Huxtable
Total pages 471
Collection year 2002
Language eng
Subjects L
270299 Genetics not elsewhere classified
300501 Veterinary Medicine
300506 Pathology
Formatted abstract
This study in Bull Terriers was conducted following anecdotal reports of widespread familial renal and cardiac disease in this breed in Australia. Two familial renal diseases have been reported to occur in Bull Terriers in Australia; Bull Terrier polycystic kidney disease (BTPKD) and Bull Terrier hereditary nephritis (BTHN). Mitral valve disease (MVD) has also been reported to be familial in Bull Terriers, and left ventricular outflow tract obstruction (some forms also referred to as subaortic stenosis) is common in this breed. This study of BTPKD, MVD and LVOTO was undertaken in three parts; clinical and pathological description of BTPKD, clinical and pathological description of left ventricular outflow tract obstruction (LVOTO) and MVD, and molecular studies in BTPKD. 

BTPKD is an autosomal dominant disorder present in 26% of Bull Terriers tested from popular lines in Australia in 1997. Abnormal urine sediment and proteinuria are common in affected dogs. Diagnosis is based on detection of renal cysts by ultrasonography and family history of the disease. Equivocal cases are confirmed by gross renal examination at necropsy or histopathology on renal tissue. Renal cysts are usually bilateral, occur in cortex and medulla and vary in size from less than 1 mm to over 2.5 cm in diameter. Ultrastructural findings in five cases of BTPKD demonstrate that cysts are of nephron or collecting duct origin, and that a second inherited renal disease of Bull Terriers, hereditary nephritis, occurs concurrently in some animals.

The high prevalence of BTPKD in some lines of dogs and autosomal dominant inheritance makes control of this disease important. However renal ultrasonography may not detect early disease or animals with cysts only in the medulla, and renal cysts may not always be due to BTPKD, hence an investigation into the molecular defect responsible for the disease was performed with the aim of developing a molecular diagnostic test that could detect affected animals prior to breeding.

BTPKD is clinically and pathologically similar to autosomal dominant polycystic kidney disease (ADPKD) in humans. ADPKD is due to mutations in at least two genes, with 85-90% of cases having mutations in the gene polycystic kidney disease 1 (PKD1) and most of the remaining cases having mutations in the gene polycystic kidney disease 2 (PKD2). Consequently the coding region of the canine homologue of the PKD1 gene was sequenced to detect a possible disease-associated mutation. While 8 non-disease-associated polymorphisms were characterised, no disease-associated mutations were found. However this does not absolutely exclude a mutation in this gene from causing BTPKD, as mutations In noncoding regions such as promoter and intronic regions, may be involved.

A study of familial cardiac disease in Bull Terriers was also conducted. As echocardiographic parameters vary between breeds, echocardiographic parameters were determined in 14 apparently clinically normal Bull Terriers from several bloodlines. These dogs had greater left ventricular wall thickness and smaller aortic root diameters than those reported as normal for other breeds of comparable body size. They also had larger left atrial dimensions, however this may have been due to measurement methods. This baseline group also had aortic outflow tract velocities of 1.6-2.3m/s; values greater than those reported for other breeds. This may have been due to a smaller aortic root diameter or other abnormal anatomic substrate of the left ventricular outflow tract, lower systemic vascular resistance, or primary or secondary left ventricular hypertrophy.

Ninety-nine Bull Terriers, which were regarded as normal by their owners, were examined for BTPKD, BTHN and cardiac disease. Nineteen animals were diagnosed with BTPKD. Eight (42%) of the dogs with BTPKD had cardiac murmurs or arrhythmias auscultated, and when examined using echocardiography, eleven of 16 (69%) had valvular disease. The remaining 80 Bull Terriers were assessed as free of BTPKD, but 22 (28%) of these had a murmur or arrhythmia detected. Seventy of these 80 dogs underwent echocardiographic examination, with 45 (62%) found to have valvular disease. Murmurs were more common in dogs with BTPKD than those without (42% versus 28%), and MVD was significantly associated with BTPKD (P=0.006), as was the severity of LVOTO (P=0.009). In addition, Bull Terriers free of BTPKD but descended from a recent ancestor with BTPKD, had an increased risk of having LVOTO and MVD, and a greater severity of LVOTO compared with Bull Terriers not descended from an ancestor with BTPKD.

Progression of cardiac disease and age at first diagnosis were investigated using auscultation and echocardiography in 52 Bull Terriers that were examined twice, one year apart. Sixty-nine percent of animals with MVD were diagnosed by six years of age. Eighty-two percent of animals with LVOTO were diagnosed by five years of age, however 44% were diagnosed by two years of age. Doppler echocardiography allowed earlier diagnosis of LVOTO than did auscultation. Dynamic LVOTO was observed in a nine of 27 Bull Terriers with LVOTO, however systolic anterior motion of the mitral valve was only present in two dogs. Pedigree analysis in Bull Terriers suggests LVOTO may be inherited in an autosomal dominant manner, as occurs in other dog breeds and humans. Ninety percent of dogs with aortic valve disease (AoVD) were diagnosed by five years, with AoVD likely to be secondary to fast or turbulent blood flow in the left ventricular outflow tract due to LVOTO.

Familial cardiac disease was also assessed using pathological and histopathological methods in 30 Bull Terriers with varying levels of clinical heart disease and results were compared with those in six dogs of mixed breed that did not resemble the Bull Terrier phenotype. Mitral and aortic valvular disease occurred in 93% and 70% of Bull Teniers respectively, and aortic stenosis and subvalvular LVOTO (consisting of fibrous nodules or a muscular ridge below the aortic valve in the LVOT) was observed in 13% and 37% respectively. Histopathology in Bull Terriers with clinical cardiac disease revealed severe subintimal fibromuscular proliferation of the intramural small and medium sized coronary arterioles in 87% of cases, evidence of myocardial ischaemia (20%), myocardial inflammation and fibrosis (27%), and inflammation and infiltrative fibrosis in the cardiac conduction tissue or nearby areas (47%). Bull Terriers with subclinical cardiac disease also showed these changes, though to a lesser degree. All dogs with BTPKD had various combinations of mitral, tricuspid and aortic valve disease, aortic stenosis, and subvalvular LVOTO. Six of seven dogs with BTPKD also had subintimal fibromuscular proliferation and muscular hypertrophy affecting intramural coronary arterioles. Four of these seven cases also showed myocarditis and myocardial fibrosis primarily affecting the left ventricle, and five of seven inflammation and fibrosis in cardiac conduction tissue.

Necropsy examination of the heart showed that murmurs were present in only 41% of Bull Terriers with gross valvular disease at necropsy. Similarly echocardiography detected abnormalities in 62% of grossly abnormal valves at necropsy. The clinical significance of valvular and histologic lesions in Bull Terriers is unknown, however severe lesions were found more often in dogs with clinical signs of cardiac disease. Interestingly four dogs with murmurs, echocardiographic signs of abnormal blood flow in the LVOT or dynamic LVOTO, did not have explanatory gross or histopathologic lesions at post mortem, suggesting dynamic LVOTO may not be obvious at routine necropsy.

The high prevalence of familial cardiac disease in Bull Terriers in Australia, and the evidence for autosomal dominant inheritance, are strong indications for controlled breeding. Initially selection should be based on yearly auscultation by an experienced veterinarian. Animals with murmurs, animals younger than 2.5 years of age and animals from parents with murmurs prior to five years of age should be excluded from breeding. While this should reduce disease prevalence within the breed, it is possible those with late onset disease may not be diagnosed prior to breeding. Once disease prevalence is reduced using these measures, subsequent screening prior to breeding using Doppler echocardiography may further reduce prevalence. In future the further development of molecular diagnostic techniques will aid in disease control. 
Keyword Dogs -- Diseases

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Fri, 24 Aug 2007, 17:57:33 EST