LITMIR.BIZ

Скачать книгу

X‐Linked Hereditary Nephropathy X‐Linked Myotubular Myopathy

The other big problem with relying on genotypic testing alone is that, at the present time at least, genetic testing is only available for a relatively small number of phenes (conditions, traits, etc.), representing perhaps 20–30% of heritable conditions. Some of the most common conditions with a heritable component, such as allergies or hip dysplasia, have more complex inheritance, often influenced by environmental factors. Such tests that get developed will likely not be entirely predictive, but may indicate whether risk is higher, lower or moderate for an individual, compared to the relevant population base.

      Because the body has so many redundancies built into the system, it is also possible that an individual might have a genotypically determined risk but never develop phenotypic disease. It is also possible that a pet has a genotypically determined risk but the phenotypic presentation does not really compromise the animal's health. For example, a Labrador retriever might have a determined risk for exercise‐induced collapse (EIC) but in its typical environment and with its typical exercise regimen, it never becomes problematic.

      For some conditions, even though they may be predicted with a genotypic test, phenotypic tests are needed to determine when the condition becomes clinically relevant and treatment is needed, and then for monitoring. For example, the risk for some forms of glaucoma can be predicted based on genotypic testing, but it is still necessary to use intraocular pressure to diagnose clinical disease and as a way of monitoring treatment.

      The best use of genotypic tests is as a health screen rather than a disease screen. Pets are typically first examined around 8 weeks of age, and during this period the veterinary healthcare team will search for evident congenital issues, such as malocclusion, umbilical hernia, and luxating patellas. On the basis of this initial physical evaluation, vaccination and parasite control typically begin, and this is also the optimal time for starting pet health insurance, before anything gets identified that would be considered a preexisting condition (see 10.16 Pet Health Insurance).

Then, at 12 weeks of age, genotypic testing is indicated. Since DNA variants and the tests that measure them don't change with age, this can provide a good indication of health, at least for the tests that can be performed at this early age. Similarly, most human infants get postnatal genetic testing, typically for a few dozen hereditary conditions (such as phenylketonuria, congenital hypothyroidism, cystic fibrosis, etc.) – not because the majority of children are expected to have these problems, but it provides peace of mind for the parents that some potential problems can be screened. Postnatal screening does not mean that there won't be any problems that develop later in life, but screening has been done for the things that can be evaluated at this young age.

      Phenotypic tests are more commonly done in practice, including blood tests, urinalysis, imaging, electrocardiography, etc. (Table 3.11.2). By 16 weeks of age, phenotypic testing regimens usually begin. This might involve early evaluation for hip dysplasia, urinalysis and tests looking for evidence of “stone” or “crystal formation” in the urine, or even following up on early suspicions of potential congenital heart disease. Further phenotypic testing will likely be predicated on the results of risk assessment (see 2.7 Risk Assessment), but might include definitive screening for hip dysplasia in the mature pet, glaucoma screening based on breed or genetic susceptibility, baseline evaluation of hemograms and biochemistries, and even specialist evaluation of breeding animals by ophthalmologists and/or cardiologists. All of this can be conducted seamlessly within a personalized care plan (see 1.3 Personalized Care Plans).

      Of course, phenotypic tests also have their limitations. In some cases, the disease process has to progress considerably before disease will be detected. For example, with diabetes mellitus, a diagnosis might not be confirmed until the patient is clinical and the blood glucose and urine glucose levels rise about a standard point. Prior to that, though, testing may indicate a trend toward that possible outcome. In other cases, such as with prepatent period, a pet may have a parasite, but it is not detectable until it reaches a life stage that is detectable on testing. In other situations, there may not be a single phenotypic test that can render a diagnostic result, so a panel of different tests might be needed to support a diagnosis.

      One other feature of some phenotypic tests is that a particular animal (or breed) may not reflect what is considered a “normal range” for the species. For example, there is a DNA test for congenital hypothyroidism with goiter in the toy fox terrier, but no such test for the adult‐onset hypothyroidism more commonly seen in practice. That requires testing with a panel of tests that might include free and total levels of thyroid hormones, thyroid‐stimulating hormone and even autoantibody levels to thyroid hormones. A diagnosis can sometimes still be elusive, especially in breeds that tend not to conform to the reference interval established by the testing laboratory (see 4.8 Pet‐Specific Relevance of Reference Intervals). In these cases, a better approach may be to establish a “normal range” for the individual, by assessing 3–5 tests of thyroid function in the young adult, and using that later in life to evaluate trends.

      One important distinction between genotypic and phenotypic testing is that genotypic test results do not change over time and so don't need to be repeated, whereas phenotypic results do change over time so need to be periodically reevaluated. For example, diabetes mellitus is a relatively common chronic disorder in both dogs and cats. In dogs, it is likely a complex genetic disorder in which several susceptibility genes affect overall genetic risk in a breed‐specific manner. Thus, some breeds might be considered at increased risk, including keeshonden, Australian terriers, golden retrievers, miniature schnauzers, pugs, Samoyeds, etc. It cannot currently be predicted with a DNA test, and phenotypic testing with blood glucose levels and urinalysis can either be used to confirm a diagnosis or, preferably, can be used proactively to screen animals at potential risk to identify the prediabetic animal and attempt to alter the course of the disease. To identify such trends regarding the slow progression of such chronic diseases (including glaucoma, hypothyroidism, etc.), veterinary teams need to determine trends by periodically reevaluating relevant phenotypic tests.

EXAMPLES

      Mrs Thompson presented her 2‐year‐old Doberman pinscher, Brutus, for routine evaluation and vaccination. Brutus had genetic testing as a puppy and was found to be “affected” on a DNA test for dilated cardiomyopathy. Initially Mrs Thompson was quite concerned and considered relinquishing Brutus to a shelter, but the veterinary team at ABC Animal Hospital helped put things in perspective.

      It was true that Brutus had the PDK4 (DCM1) mutation that was associated with an increased risk for dilated cardiomyopathy, but she now understood that the mutation did not cause the disease (it was just associated with increased risk in a certain cohort of Doberman pinschers), was not the only mutation associated with the disease, and that there were also other factors that could influence cardiomyopathy onset in a complex manner. In fact, she also read about some diets that could possibly be associated with the disease in a number of different breeds.

      The team at ABC Animal Hospital helped establish a sensible ongoing screening protocol with their local veterinary cardiologist, and Mrs Thompson felt quite relieved that they had identified a risk factor, but now had a sensible program in place to make sure Brutus would have the care he needed.

TAKE‐AWAYS

       In most pets, a combination of genotypic and phenotypic testing is needed for the early detection of disease conditions.

       Genotypic

Скачать книгу