Chapter 064. The Practice of Genetics in Clinical Medicine (Part 7)

Therapeutic Interventions Based on Genetic Risk for Disease Specific treatments are now available for an increasing number of genetic disorders, whether identified through population-based screening or directed testing (Table 64-2). Although the strategies for therapeutic interventions are best developed for childhood hereditary metabolic diseases, these principles are making their way into the diagnosis and management of adult-onset disorders. Hereditary hemochromatosis illustrates many of the issues raised by the availability of genetic screening in the adult population. For instance, it is relatively common (approximately 1 in 200 individuals of northern European descent are homozygous), and its complications are potentially preventable...
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Chapter 064. The Practice of Genetics in Clinical Medicine (Part 7) Chapter 064. The Practice of Genetics in Clinical Medicine (Part 7) Therapeutic Interventions Based on Genetic Risk for Disease Specific treatments are now available for an increasing number of geneticdisorders, whether identified through population-based screening or directedtesting (Table 64-2). Although the strategies for therapeutic interventions are bestdeveloped for childhood hereditary metabolic diseases, these principles aremaking their way into the diagnosis and management of adult-onset disorders.Hereditary hemochromatosis illustrates many of the issues raised by theavailability of genetic screening in the adult population. For instance, it isrelatively common (approximately 1 in 200 individuals of northern Europeandescent are homozygous), and its complications are potentially preventablethrough phlebotomy (Chap. 351). The identification of the HFE gene, mutations ofwhich are associated with this syndrome, has sparked interest in the use of DNA-based testing for presymptomatic diagnosis of the disorder. However, up to one-third of individuals who are homozygous for the HFE mutation do not haveevidence of iron overload. Consequently, in the absence of a positive familyhistory, current recommendations include phenotypic screening for evidence ofiron overload followed by genetic testing. Whether genetic screening forhemochromatosis will someday be coupled to assessment of phenotypicexpression awaits further studies. In contrast to the issue of population screening,it is important to test and counsel other family members when the diagnosis ofhemochromatosis has been made in a proband. Testing allows the physician toexclude family members who are not at risk. It also permits presymptomaticdetection of iron overload and the institution of treatment (phlebotomy) before thedevelopment of organ damage. Table 64-2 Examples of Genetic Testing and Possible Interventions Genetic Disorder Inherita Genes Interventions nce Oncologic Hereditary AD MSH2, Early endoscopicnonpolyposis colon MLH1, MSH6,cancer PMS1, PMS2, screening TGFBR2 Familial AD APC Early endoscopicadenomatous polyposis screening Nonsteroidal anti-inflammatory drugs Colectomy Familial breast and AD BRCA1 Estrogenovarian cancer , BRCA2 receptor antagonists Early screening by exams and mammography Consideration of prophylactic surgery Familial AD CDKN Avoidance ofmelanoma 2A UV light Screening and biopsies Basal cell nevus AD PTCH Avoidance ofsyndrome UV light Screening and biopsies Hematologic Factor V Leiden AD F5 Avoidance of thrombogenic risk factors and oral contraceptives Hemophilia A XL F8C Factor VIII replacement Hemophilia B XL F9 Factor IX replacement Possible gene therapy Glucose 6-PO4 XL G6PD Avoidance ofdehydrogenase deficiency oxidant drugs Cardiovascular Hypertrophic AD MYH7, Echocardiographcardiomyopathy MYBPC3, ic screening TMSA, Early ...