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1 Human Genetics Concepts and Applications Tenth Edition RICKI LEWIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or.

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Presentation on theme: "1 Human Genetics Concepts and Applications Tenth Edition RICKI LEWIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or."— Presentation transcript:

1 1 Human Genetics Concepts and Applications Tenth Edition RICKI LEWIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display PowerPoint ® Lecture Outlines Prepared by Johnny El-Rady, University of South Florida 20 Genetic Testing and Treatment

2 2 Horses vs. Zebras Medical students are told early on, “When you hear hoofbeats, think horses, not zebras.” Single-gene disorders, however, are often zebras Medical geneticists are trained to see the big picture - Can solve a medical mystery by putting together the pieces

3 3 Genetic Counseling Addresses medical, psychological, sociological, and ethical issues A genetic counselor has medical, scientific, and communication skills Genetic counseling began in pediatrics, and prenatal care, and has become specialized The field has even infiltrated public policy as genetic testing has become widespread

4 4 Genetic Counselors The US only has about 3,000 Provide information to individuals, couples expecting children, and families about: - Modes of inheritance - Disease risks and symptoms - Available tests and treatments Interpret direct-to-consumer genetic tests and assist other health care professionals with genetic information in their practices

5 5 Genetic Counselors When genetic counseling began, it was “nondirective” - The practitioner did not offer an opinion or suggest a course of action, but presented options A more recent definition of the role of the genetic counselor is “shared deliberation and decision making between the counselor and client”

6 6 Figure 20.1

7 7 Genetic Testing Genetic tests diagnose and predict the course of a disease and predict and monitor response to treatment Using them widely must balance two traits 1) Genetic determinism: our tendency to blame all ills on our genes 2) Identifying ways to change our lifestyles to compensate for factors that we cannot control

8 8 Table 20.1

9 9 Newborn Screening Usually tests for inborn errors of metabolism Are not genetic tests, but instead they use tandem mass spectrometry to identify unusual metabolites or chemical imbalances that indicate a certain disease The American College of Medical Genetics recommends testing for 29 disorders - However, the actual number of tests varies by state

10 10 The field of newborn screening began in 1961 with the Guthrie test for phenylketonuria (PKU) - It detects phenylalanine, which builds up in affected individuals In 1963, a specialized diet became available The diet is difficult to follow, but does prevent mental retardation After diet’s success, genetic tests expanded Some states perform DNA tests on newborns as well as biochemical tests

11 11 Figure 20.2

12 12 Figure 20.3

13 13 Direct-To-Consumer Genetic Testing Companies market DNA-based tests for traits, susceptibilities, and genetic diseases to the general public The Clinical Laboratory Improvement Amendments (CLIA) control genetic testing DTC tests presented as information, not diagnoses, may not be regulated Unawareness of incomplete penetrance is one complication of DTC genetic testing

14 14

15 15 Nutrigenetics Testing Some DTC testing company websites offer genetic tests along with questionnaires about diet, exercise, and lifestyle habits The company then sends a “nutrigenetics” profile with dietary suggestions and pitches to purchase supplements However, many of these companies provide inaccurate information - Some suggestions are even dangerous

16 16 Matching Patient to Drug A pharmacogenetic test detects a variant of a single gene that affects drug metabolism A pharmacogenomic test detects variants of multiple genes or gene expression patterns that affect drug metabolism These are often considered together under the umbrella term “personalized medicine” - Help physicians to select the best drugs for individual patients

17 17 Treating Genetic Disease Treatments have evolved through stages 1) Removing an affected body part 2) Replacing an affected body part or biochemical with material from a donor 3) Delivering pure, human proteins derived from recombinant DNA technology to compensate for the effects of a mutation 4) Gene therapy, to replace mutant alleles

18 18 Treating The Phenotype Lysosomal storage diseases are a subclass of inborn errors of metabolism Treatments are based on understanding metabolic pathways - If any enzyme is deficient or its activity blocked, the substrate builds up and the product is deficient There are three general approaches for counteracting these diseases

19 19 Figure 20.4

20 20

21 21 Gene Therapy Altering genes theoretically can provide a longer-lasting effect than treating symptoms The first efforts focused on inherited disorders with a known mechanism, even though the conditions are rare Gene therapy now is targeting more common illnesses, such as heart disease and cancers

22 22 Gene Therapy Germline gene therapy - Gamete or zygote alteration; heritable; not done in humans; creates transgenic organisms Somatic gene therapy - Corrects only the cells that a disease affects; not heritable

23 23 Table 20.7

24 24 Table 20.8

25 25 Ex vivo gene therapy is applied to cells outside of body that are then returned In situ gene therapy occurs directly on accessible body parts In vivo gene therapy is applied directly to an interior body part - The most invasive Invasiveness of Gene Therapy

26 26 Figure 20.5

27 27 Figure 20.6

28 28 Gene Delivery Physical methods - Electroporation, microinjection, and particle bombardment Chemical methods - Liposomes and other types of lipids Biological approaches - A vector (modified viral genomes)

29 29 Somatic Gene Therapy Targets Endothelium  can secrete needed proteins directly into bloodstream Skin  skin grafts can secrete therapeutic proteins Muscle – accessible, comprises ½ body mass and has a good blood supply Liver  many functions and can regenerate Lungs  are easily accessed with aerosol spray Nervous tissue  many illnesses and injuries affect nervous system, hard to change neurons Cancer  about ½ of current trials target cancer

30 30 Gene Therapy: ADA, Adenosine Deaminase Deficiency Severe combined immune deficiency (SCID) can be caused by ADA deficiency Lack of ADA blocks the breakdown of metabolic toxins to uric acid Toxins destroy T cells, thereby causing susceptibility to infections and cancer Replacement of ADA in individuals genetically deficient was attempted

31 31 Injections of PEG-ADA given to first child in 1986 - Increased ADA levels and T cell survival - Improved immune function White blood cells from a patient receive a functional copy of ADA and the cells are returned - Increased T cells present with normal ADA gene Stem cells from umbilical cord blood are isolated Cells are treated to replace mutated ADA allele with normal allele and returned T cells with normal allele accumulate in patient Gene Therapy for ADA Deficiency

32 32 First Gene Therapy Patient Ashanthi DeSilva Ashanthi is doing well after she was part of a clinical trial of gene therapy that patched her own white blood cells with functional ADA genes. By 2005,thirty youngsters had been treated, successfully, with a new version of the gene therapy. Figure 20.7

33 33 Deficiency of OTC is inherited as an X- linked recessive mutation OTC normally breaks down amino acids present in protein Lack of OTC allows buildup of ammonia, which damages brain function Low-protein diets and ammonia-binding drugs are used to treat OTC deficiency Gene Therapy: OTC, Ornithine Transcarbamylase

34 34 Gene Therapy: OTC, Ornithine Transcarbamylase Clinical trials to treat OTC deficiency were established using adenovirus as a vector for the normal OTC gene Jesse Gelsinger had a mild OTC deficiency, volunteered for the OTC gene therapy trial and was accepted Four days after gene therapy Jesse died from an overwhelming immune reaction and associated complications

35 35 OTC Gene Therapy Figure 20.8

36 36 Gene Therapy: Canavan Disease Causes brain degeneration in children Good gene therapy candidate because: 1. Gene and protein are well known 2. Window of time exists for treatment 3. Only the brain is affected 4. Brain scans can be used to monitor treatment 5. No existing treatment

37 37 Gene Therapy: Canavan Disease An aspartoacylase enzyme deficiency Neurons release N-acetylaspartate (NAA) NAA is normally broken down by the enzyme aspartoacylase to harmless components Enzyme deficiency creates NAA buildup, which destroys oligodendrocytes Lack of oligodendrocytes prevents myelin formation and neurons cease functioning

38 38 Figure 20.9

39 39 Gene Therapy: Leber’s Congenital Amaurosis II Most severe form of blindness Inherited as autosomal recessive disease Mutation is in a gene called RPE64 Gene therapy first tried on Briard dogs, who have the same mutation as humans - It was then tried on four young adults, and later on 8-year old Corey Haas - So far it is working!

40 40 Gene Therapy: Leber’s Congenital Amaurosis II Figure 20.10

41 41 Perspective on Gene Therapy Great promise, but slower than expected More complex than expected - Gene interactions - Appropriate vectors - Adequately targeting and sustaining therapeutic effects - Safety issues

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