3.1 Abstract
Objective: The objective of this study is to describe the prevalence and formation of primary non-congenital cataracts (CAT) in the German Pinscher population in Germany and to analyze the familial occurrence and the mode of inheritance in this dog breed.
Materials: Data included veterinary records for presumed inherited eye diseases of German Pinschers born between 1993 and 2008 that were examined between 1997 and 2009 by certified veterinary ophthalmologists which were provided by the German panel of the European Eye Scheme for diagnosis of inherited eye diseases in animals (DOK). A total of 443 eye examinations reports of 261 dogs were analyzed.
Results: CAT was diagnosed in 40 (15.33 %) of the examined dogs. The pedigree included 58 ophthalmologically examined dogs with 20 unaffected and 38 affected dogs. The coefficient of relationship as well as the coefficient of inbreeding was significantly higher in the group of CAT-affected dogs than in a contemporary group of German Pinschers. Simple segregation analysis revealed a recessive mode of inheritance.
Conclusions: A bilateral anterior cortical CAT was the most prevalent CAT form among close relatives in German Pinschers. The pedigrees supported a monogenic autosomal recessive inheritance pattern. In order to improve breeding strategy ophthalmologic examinations should be compulsory for all breeding animals. The molecular genetic basis should be unravelled to avoid breeding with affected animals and carriers so far.
Prevalence and formation of primary cataracts in the German Pinscher Population in Germany
3.2 Introduction
Primary non-congenital cataracts (CAT) are a leading cause of visual impairment and blindness in purebred dogs. More than 120 dog breeds world wide are affected by this eye disease, the reported prevalences range between 1.8 and 88.0%. Cataracts in adult dogs have been shown to be hereditary in several dog breeds including Leonbergers1, Entlebucher Mountain Dog2,3,4, Bichon Frise5,6, Tibetan Terriers7, Chow Chows8, Golden and Labrador Retrievers9,10,11,12, German Shepherds13, Standard Poodles14, Miniature Schnauzers15,16, West Highland White Terriers17, Welsh Springer Spaniels18, Chesapeake Bay Retrievers19, Boston Terriers20, Staffordshire Bull Terriers20, American Cocker Spaniels21,22, Cocker Spaniels23, Afghan Hounds24, Old English Sheep Dogs25 and Beagles26. In the majority of the dog breeds, a recessive mode of inheritance is assumed, but also dominant patterns are described. In the German Pinscher breed in Finland, an autosomal recessive or incomplete dominant inheritance pattern has been suspected27. CAT in German Pinschers is only reported in one study based on eye examinations of 122 dogs of the German Pinscher population in Finland27. The prevalence of CAT in this study was 7.4% (n = 9) and the median age of manifestation was 9 years; the youngest reported CAT case was a 4.7-year-old dog. Cataracts were posterior and subcapsular in four dogs and in the anterior part of the lens in five dogs.
Because the only effective therapy known yet is the surgical intervention, the containment of this inherited disease has large impact for animal welfare. In most dog breeding associations, regular ophthalmologic examinations, carried out by specialized ophthalmologists, are compulsory to achieve a breeding license in order to reduce the risk of transmission of the disease to the offspring through affected parents and to reduce the prevalence of the disease in the whole breed.
The fact that many inherited canine cataracts develop in the adolescence or the adulthood, often after the age of first breeding, decreases the effectiveness of this approach. In case of a recessive mode of inheritance, it is even more difficult to remove the defective allele from the population, because it can spread among the
population unnoticed over several generations. It can only be noticed if both parents pass it to their offspring. Inbreeding increases the risk for infesting with CAT.
As the German Pinscher is a breed predisposed to primary non-congenital cataracts it is assumed that these cataracts are hereditary. A study in Finland found that a recessive mode of inheritance seems to be more likely than a dominant mode27. A DNA test, showing if the dog is homozygous for a CAT-causing mutation or a heterozygous carrier or free from CAT-causing mutations would be very helpful.
Combined with an adequate breeding program, the prevalence of CAT could be faster and more effectively decreased in this breed. In addition, the risk of a selection-caused bottle-neck-phenomenon could be minimized.
The aim of this study was to characterize the prevalence and formation of CAT in the German Pinscher population in Germany and to analyze the mode of inheritance in this dog breed.
3.3 Material and Methods
The Pinscher-Schnauzer-Klub 1895 e.V. (PSK) and the German panel of the European Eye Scheme for diagnosis of inherited eye diseases in animals, the Dortmunder Kreis (DOK), provided the data for this analysis. The study is based on the veterinary records for presumed inherited eye diseases of 261 German Pinschers; the data were collected between January 1995 and October 2009. All dogs were born in 1993 - 2008. The mean number of German Pinscher puppies per year (1993 – 2008) was 382; consequently only 7% of all dogs born in this specified period were ophthalmologically examined until October 2009. The examinations were performed by specialized and DOK-certified ophthalmologists using slit-lamp biomicroscopy and indirect ophthalmoscopy. The DOK-members were approved for examination for presumed inherited eye diseases (PIED) after successful completion of a two-year training program and examination according to the rules of the European College of Veterinary Ophthalmologists (ECVO). For all dogs the results were recorded on official forms based on the standardized eye examination corresponding to the ECVO. The ECVO considers all bilateral or unilateral cataracts
Prevalence and formation of primary cataracts in the German Pinscher Population in Germany
and especially cortically cataracts to be hereditary. Exceptions include cases of obvious association with trauma, inflammation, metabolic disease or nutritional deficiencies, and minor, clearly circumscript cataracts located in the suture lines or the nucleus.
For this study all German Pinschers officially diagnosed as affected by or suspicious for CAT were classified as affected by CAT. All other German Pinschers were classified as not affected by CAT. The data consisted of a total of 443 examination reports of 261 dogs. These examinations were performed by 61 ophthalmologists, each of them carried out from one to 62 examinations (average: 7.26 ± 9.35 examinations). The information from the recording forms was linked with the pedigree data provided by the PSK.
The pedigree was used for simple segregation analysis to test whether the data were compatible with the respective simple Mendelian model, a recessive mode of inheritance. The Singles method is a very straightforward method of simple segregation analysis28. The test involves a statistical comparison of the estimated segregation frequency p (probability that an offspring is affected by the respective disease) with the hypothesized value (p0) arising from the particular model of inheritance being tested. If a recessive mode of inheritance is assumed, and both parents in each of a set of full sib families are unaffected, the null hypothesis is that the true value of p0 = 0.25. The most straightforward use of the Singles method can be made when the investigator is certain that all families with affected offspring are included in the data. Then the segregation frequency can be estimated as p = (A - A1) / (T - A1) and its estimated variance is given by Est. Var. (p) = (T - A) / (T - A1)3 [A - A1 + 2A2 (T - A) / (T - A1)] where A is the total number of affected offspring in the available data, T is the total number of all examined offspring in the available data, A1
is the total number of families with just one affected offspring, and A2 is the total number of families with two affected offspring. Then the null hypothesis is tested using: Z2 = (p - p0)2 / Est. Var. (p). If the calculated value Z2 is not significant for p0 = 0.25 at α = 0.05, the data are consistent with a simple recessive mode of inheritance.
The mean coefficient of relationship was calculated using OPTI-MATE29 for the group of German Pinschers with CAT-affected offspring (n = 59) and a contemporary group
of dogs born in 2008 (n = 555). The mean coefficient of inbreeding was compared among CAT-affected dogs and the same contemporary group of dogs. Pedigree information over eight generations was considered, the completeness of pedigrees was larger then 95% in all eight generations. P values were calculated using t tests.
3.4 Results
Prevalence of CAT
The diagnosis CAT was made in 50 examinations (11.29% of all examinations) of 40 different dogs (15.33% of all dogs). Seven of these 40 dogs were examined one or two more times after the first diagnosis of CAT was made. Out of the affected German Pinschers, 67% were diagnosed as affected by CAT in the course of their first registered ophthalmologic examination.
CAT appeared unilaterally in 9 (22.5%) and bilaterally in 25 (62.50%) cases. CAT was specified as anterior cortical CAT (55%), posterior polar CAT (15%), nuclear CAT (2.5%), anterior cortical and posterior polar CAT (10%) or anterior cortical and posterior polar and nuclear CAT (7.5%). Specification of CAT was missing for four dogs.
The mean age of onset of CAT was 3.8 ± 1.6 years; the median age of onset was 3.9 years. The youngest reported CAT case was 0.34 years old; the oldest reported CAT case was 7.44 years old when the first diagnosis of CAT was made. Figure 1 shows the cumulative distribution of age at diagnosis of CAT in all examined German Pinschers. Almost 60% of the CAT-affected dogs were diagnosed as affected by primary CAT up to an age of 4 years. Only 5% were diagnosed as affected by primary CAT over an age of 6.8 years. CAT was diagnosed in 16/116 (13.68%) of all males and 24/145 (16.67%) of all females.
The majority of the dogs were examined only once (159/261; 60.92%), 54/261 (20.69%) were examined twice, 28/261 (10.73%) were examined three times and 20/261 (7.66%) were examined four times or more. Age at examination varied between 0.34 and 13.77 years. Most of the dogs were presented at an age of two to five years. The first examination for PIED took place on average at 3.0 ± 2.0 years of
Prevalence and formation of primary cataracts in the German Pinscher Population in Germany
age; when dogs were examined more than once the last registered examination took place at 4.0 ± 2.3 years of age. About 25% of all dogs were examined at least once when they were over five years of age. The number of examined males (44.4%) and females (55.56%) was not significantly different. Dogs originated from 83 kennels.
Pedigree analysis
Investigation of the pedigrees showed close relationships among the dogs affected by CAT (Fig. 2). There were 58 ophthalmologically examined dogs included in this pedigree with 20 unaffected and 38 CAT-affected dogs. Of all affected dogs, only two individuals were not included in this pedigree because of a more distant relationship.
The phenotype of the other 67 dogs was unknown, or they were examined < 4 years of age. Both males and females had been diagnosed with CAT, which gives reason to rule out sex linkage. CAT was not found in every generation, which suggests recessive inheritance for the disease.
The mean coefficient of inbreeding of CAT affected German Pinschers was 7.65 % which is significantly higher than the mean coefficient of inbreeding of the contemporary group (3.56 %, Table 1). The mean coefficient of relationship among parents with at least one CAT affected progeny was with a value of 12.97 % significantly higher than the mean coefficient of relationship of the contemporary group (7.44 %). The result of the simple segregation analysis using the Singles method revealed a Z2 of 0.282 which was not significant at α = 0.05. Accordingly, the observed distribution of CAT was consistent with a simple recessive mode of inheritance and a segregation frequency of p = 0.303.
Persistent hyperplastic tunica vasculosa lentis (PHTVL), the ocular disease which was found most frequently in the Finnish study27 (9% of all examined dogs), was found in only 4.2% of the German Pinschers examined in the present study. Two dogs were affected by both diseases. Two other dogs affected by PHTVL were full sibs of CAT-affected dogs (Fig. 2); the 7 remaining PHTVL-affected individuals were not included in this pedigree because of a distant relationship to the CAT-affected dogs and among each other.
3.5 Discussion
Compared to a large number of dogs of other breeds in Germany, the prevalence of CAT in German Pinschers in Germany was significantly higher, thus suggesting that CAT is hereditary in this dog breed. In the present study, the determined prevalence was higher and the age of onset for CAT lower than in a Finnish study about cataracts in German Pinschers in Finland27. In the German population the age of onset was nearly halved compared to the Finnish study. Moreover, it may be suspected that the true age of onset for CAT in German Pinschers may even be lower than in the present study because most of the dogs had signs of CAT in their first ophthalmological examination. Furthermore, in the German population an anterior cortical CAT was most prevalent whereas in the Finnish study posterior subcapsular and anterior CATs were found. So we may conclude that there are two different types of cataracts segregating: German Pinschers with different age of onset and different prevalences in different populations.
The prevalence of PHTVL in the present study was halved compared to the prevalence of PHTVL in the Finnish study27. Coherence of all PHTVL-affected individuals could not be shown in one pedigree because of a more distant relationship among the individuals.
Inbreeding coefficient was found to have a significant effect on the prevalence of CAT. In single colored English Cocker Spaniels CAT-affected dogs also had higher inbreeding coefficients due to matings among carriers and affected dogs30. Particularly in the presence of a recessive inheritance of CAT, inbreeding among unaffected carrier animals may lead to an accumulation of alleles identical by descent. Inbred individuals tend to be homozygous at more loci than no inbred individuals and in addition, are more likely to be homozygous at the CAT locus.
Comparison of coefficients of relationship revealed a significantly higher mean relationship coefficient among affected dogs than among a contemporary group of unaffected dogs. The general high inbreeding level in the whole population of German Pinschers studied here may be assumed to have significantly contributed to the increase of CAT-affected dogs because a high number of carriers and in some
Prevalence and formation of primary cataracts in the German Pinscher Population in Germany
instances CAT-affected dogs were mated. Furthermore, inbreeding decreases genetic diversity and due to an accumulation of detrimental or defective alleles in an increasing number of breeding animals, inherited diseases become evident in even more animals in fewer generations.
The problem of most genetic studies for evaluation of the mode of inheritance for CAT in dogs is the limited numbers of mating and affected offspring19. Most CATs do not become manifest until adulthood and may therefore necessitate several years of observations. However, in many cases assumptions on the mode of inheritance were based on visual inspection of available pedigrees. In this study, distribution of information on ophthalmologic examinations allowed simple segregation analyses.
However, the results of this simple segregation analysis do not preclude other more complex modes of inheritance.
Most congenital cataracts in dog breeds are believed to be inherited as autosomal monogenic recessive traits, for example in the Welsh Springer Spaniel18, Boston Terrier20, Miniature Schnauzer20, single colored English Cocker Spaniel30, Staffordshire bull terrier31, Boston terrier31 and French bulldog31, on the other hand, an autosomal monogenic incomplete dominant inheritance has been reported in the Norwegian Buhund17. Furthermore, a dominant mode of inheritance is suspected in the German Shepherd Dog20 and the Australian Shepherd31 and a polygenic inheritance of congenital cataracts has been proposed in the Cocker Spaniel23.
The late onset of cataract signs in some of the affected dogs is a big problem for breeders, as many dogs were used for breeding before CAT was diagnosed.
Regular ophthalmologic examinations, carried out by specialized ophthalmologists, should be made compulsatory for the assignation of the breeding allowance to reduce the risk of transmission and the prevalence of the disease in the whole breed and should be repeated annually as long as the dog is used for breeding. No dogs with CAT should be used for breeding any more, and breeders should preferably breed with animals that are old enough to enable positive CAT findings.
3.6 Acknowledgements
This study was supported by the Pinscher-Schnauzer-Klub e.V. (PSK) and the Association for Diagnosis of Inherited Eye Diseases in Animals (DOK).
Prevalence and formation of primary cataracts in the German Pinscher Population in Germany
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Prevalence and formation of primary cataracts in the German Pinscher Population in Germany
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