Case 19

Published on 18/02/2015 by admin

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Last modified 18/02/2015

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CASE 19

A married couple in your practice is planning their first pregnancy. They are both asthmatics, on regular inhalant therapy. They have both been hospitalized twice and one of them was intubated once for exacerbations. They are concerned to know the likelihood of a genetic predisposition, environmental factors, and so on, that might affect development of asthma in their child. You discuss these issues and the classic presentation and diagnosis of asthma.

QUESTIONS FOR GROUP DISCUSSION

1. In very general terms, what are the two main causes of airway obstruction in asthma (see Etiology).

2. Recent studies have attempted to unravel the complexities underlying genetic association and susceptibility to asthma using positional cloning. What is chromosomal linkage? What is the assumption in this approach?

3. Discuss the criteria that have been used to identify atopic individuals. List various gene clusters that are linked to polymorphic genes whose allelic expression is, in turn, associated with atopy in individuals.

4. What is a FEV₁? Explain its role in the diagnosis of asthma.

5. Describe the test used to measure airway hyperresponsiveness to confirm a diagnosis of asthma.

6. Explain the rationale for speculation that the presence of a dog in a family or a rural lifestyle is protective for allergic diseases.

7. Under what circumstances do high levels of IgE correlate with a particular allelic form of FcεR1-β in some Australian aborigines parasitized with helminths?

8. Explain why recent studies are focusing on the role of polymorphisms in the interleukin [IL]-4Rα component of the receptors for IL-4 and IL-13 as a contributory factor in the genetics of asthmatic disorders.

9. Inhaled glucocorticoids and or leukotriene receptor blockade is the presently accepted therapy for asthma. What are leukotrienes? How are they generated? What are the roles of phospholipase A₂ and phospholipase C in leukotriene production?

10. Explain why chemokine receptor antagonists are under investigation as possible therapeutic agents for the treatment of asthma.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Given the fact that both husband and wife are chronic asthmatics, their offspring would be at high risk for developing asthma. Although there is a major genetic component to the underlying cause of asthma, the inherited pattern cannot be classed as autosomal, X-linked, or recessive.

Recent studies using positional cloning have attempted to address the issue of genetic associations. Positional cloning is a technique that attempts to identify polymorphic genes located close to known positions (markers) on chromosomes. The assumption is that the allelic forms of polymorphic genes, relevant for developing allergies, will be common to atopic individuals. Various criteria have been used to identify atopic individuals, including levels of IgE antibodies, a diagnosis of asthma, atopic dermatitis, and so on. On the basis of these studies, common allelic forms of polymorphic genes have been identified because of their link to known gene clusters (markers) on chromosome 2 (close to the interleukin [IL]-1 cluster), chromosome 5 (cytokine gene cluster), chromosome 6 (major histocompatibility complex genes), chromosome 11 (FcεR1-β receptor for IgE), chromosome 12 (near the interferon gamma [IFNγ] gene cluster), and chromosome 13 (cysteinyl leukotriene 2 receptor), as well as several other chromosomes. Nevertheless there are still hundreds of genes encoded within the clusters of interest. Several cytokines encoded within the cytokine gene cluster on chromosome 5 have been implicated in allergic responses (e.g., IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor).

Implications/Analysis of Clinical History

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