Genetic Testing In Neurology


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Genetic Testing In Neurology

  1. 1. Genetic testing in Neurology
  2. 2. Introduction <ul><li>Genetic testing is rapidly permeating various subspecialities of neurology. </li></ul><ul><li>Offers potential for confirmation of diagnosis and prognostication. </li></ul><ul><li>Need for the neurologist to be aware of: </li></ul><ul><li>Indications </li></ul><ul><li>Current standards of clinical genetic practice </li></ul><ul><li>Risks, potential for inappropriate use. </li></ul><ul><li>Pharmacogenomics. </li></ul>
  3. 3. Definition of a Genetic Test <ul><li>‘‘ the analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes’’ </li></ul><ul><li>----(Holtzman and Watson 1997). The US Task Force on Genetic Testing. </li></ul>
  4. 4. m Indications for Genetic Testing
  5. 5. Introduction <ul><li>----The unit of care is the family--- </li></ul><ul><li>Patients diagnosed with a genetic condition will have immediate concerns beyond their own health- they will be concerned about the implications on other family members. </li></ul><ul><li>This presents tensions and ethical dilemmas that are beyond the scope of the usual neurology practice. </li></ul>
  6. 6. 1. Diagnostic testing <ul><li>Establishing the diagnosis enables: </li></ul><ul><li>Medical management </li></ul><ul><li>Accurate prognosis </li></ul><ul><li>Peace of mind for the patient </li></ul><ul><li>Genetic counseling for the patient and other family members. </li></ul><ul><li>Eg: SCA 1, 2, 3, 6, 7, 8 </li></ul><ul><li>FRDA </li></ul><ul><li>Angelman syndrome </li></ul>
  7. 7. Disclosing a Positive Diagnostic Gene Test Result <ul><li>Know the facts. </li></ul><ul><li>Make sure the results make sense. </li></ul><ul><li>Know how the gene relates to the disease. </li></ul><ul><li>Discuss uncertainties with laboratory before disclosing results to the patient. </li></ul><ul><li>Present results in person. </li></ul><ul><li>Discuss medical implications of results. </li></ul><ul><li>Discuss genetic implications of result. </li></ul>
  8. 8. Negative gene test Results: Probable Explanations
  9. 9. 2. Prenatal Testing <ul><li>This is generally provided by genetics professionals in collaboration with obstetricians. </li></ul><ul><li>The neurologist who diagnoses a genetic condition should know that the patient, parent, or other family members will want information about prenatal testing and should be in a position to provide appropriate information or referrals. </li></ul>
  10. 10. 3. Predictive Testing <ul><li>Gene test in an asymptomatic person to identify the presence or absence of a disease-causing gene mutation. </li></ul><ul><li>For family members at risk for adult-onset dominantly inherited diseases: myotonic dystrophy, HD, SCAs. </li></ul><ul><li>Major benefits and risks are psychosocial. So the health professional should ensure adequate psychosocial preparation and support for the patient during the testing process. </li></ul>
  11. 11. Predictive Testing Guidelines <ul><li>Pretest genetic counseling: </li></ul><ul><li>Review of the clinical genetics of the particular disease. </li></ul><ul><li>Nature of disease-causing mutations. </li></ul><ul><li>Accuracy and predictive value of the test. </li></ul><ul><li>Potential impact of test results on the individual, the family, employability, and insurability. </li></ul><ul><li>Psychological assessment: </li></ul><ul><li>Evaluate the patient’s current psychological state. </li></ul><ul><li>Discuss the potential psychological impact of the results. </li></ul><ul><li>Identify professional and family support systems and services. </li></ul>
  12. 12. Predictive Testing Guidelines <ul><li>Neurologic examination: if the patient has any concerns about disease symptoms, recognizing that the genetic test does not address the etiology of current symptoms. </li></ul><ul><li>Time for consideration. </li></ul><ul><li>Test results given in person in the context of support and explanation of their implications for the patient and family. </li></ul><ul><li>Availability of psychosocial support on an ongoing basis as needed after the test is complete. </li></ul>
  13. 13. Predictive Testing <ul><li>Benefits: </li></ul><ul><li>Relief of anxiety in those found to be free of the gene </li></ul><ul><li>Relief of uncertainty in those found to carry it. </li></ul><ul><li>Family, career, financial, and personal planning can be modified. </li></ul><ul><li>Disease preventing or disease-slowing treatments. </li></ul><ul><li>Risks. </li></ul><ul><li>Psychological and social. </li></ul><ul><li>Risk of severe psychiatric distress after testing for HD is low with pretest genetic and psychological counseling. </li></ul><ul><li>Mild psychological distress is common. </li></ul>
  14. 14. 4. Carrier testing <ul><li>Indicated for family members of individuals with autosomal recessive or X-linked genetic disorders. </li></ul><ul><li>Families of an affected individual are tested. </li></ul><ul><li>Autosomal recessive: The biological parents of the patient must both be carriers of the abnormal gene, and other relatives being potential carriers may request testing. </li></ul><ul><li>X-linked condition: depending on the age of onset for the particular disease, unaffected males can be assumed to be noncarriers, but unaffected female relatives need testing. </li></ul>
  15. 15. Carrier testing <ul><li>Benefits. </li></ul><ul><li>Accurate definition of a person’s reproductive risks. </li></ul><ul><li>Has no medical implications for the person tested. </li></ul><ul><li>Risks. </li></ul><ul><li>Misinterpretation of a positive carrier test, equating the presence of an abnormal gene to the diagnosis of a disease. </li></ul><ul><li>Eg: The sickle cell anemia program in 1970. </li></ul><ul><li>Accurate individualized genetic counseling before and after the test is the best way to avoid this problem. </li></ul>
  16. 16. Carrier testing <ul><li>Recessive disease genes can be enriched in ethnically, geographically, or religiously isolated groups, or in inbred families or populations. </li></ul><ul><li>Attempts to provide systematic genetic screening of ethnic or religious groups may be ethically intolerable. </li></ul><ul><li>A number of laboratories offer Ashkenazi Jewish carrier testing panels that include 10 to 20 genetic conditions. </li></ul>
  17. 17. 5. Disease Risk Testing <ul><li>Increasing focus on identifying genetic variants associated with common diseases. </li></ul><ul><li>This will enable delineation of genetic variants that increase the risk or susceptibility for a disease. </li></ul><ul><li>Genetic counseling will be much more complicated than in genetic variants that directly cause a disease. </li></ul><ul><li>Eg: APOE as a neurogenetic risk factor. </li></ul><ul><li>The APOE4 allele has shown a robust association with Alzheimer disease but is neither necessary nor sufficient to cause the disease. </li></ul>
  18. 18. 5. Disease Risk Testing <ul><li>Benefits. </li></ul><ul><li>Relief of anxiety for those found to be at low risk. </li></ul><ul><li>Relief of uncertainty for those found to be at high risk. </li></ul><ul><li>Potential for risk modification. </li></ul><ul><li>Risks. </li></ul><ul><li>No absolute relationship between genetic variant and disease. </li></ul><ul><li>Possibility of unknown ethnic, racial, or gender variations in the relationship. </li></ul><ul><li>Patient, family, community, employers, or insurers may incorrectly equate an increased risk for a disease with the actual presence of the disease. </li></ul>
  19. 19. 6. Pharmacogenetic Testing <ul><li>A genetic variant of cytochrome P 450 2C9 gene (CYP2C9), seen in 10% to 35% of individuals, results in slow metabolism of warfarin. </li></ul><ul><li>Some individuals have a less active genetic variant of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1), the enzyme inhibited by warfarin. </li></ul><ul><li>These variants results in reduced warfarin requirement. </li></ul><ul><li>CYP2C9 is important in metabolizing other drugs, such as ibuprofen, naproxen, amitriptyline, and phenytoin. </li></ul><ul><li>Other cytochrome P450 complex genetic variants are also being developed for clinical testing. </li></ul>
  20. 20. Conclusion <ul><li>The availability of gene tests has enhanced our ability to diagnose disorders with genetic basis. </li></ul><ul><li>Understanding genotype- phenotype correlation in various neurologic diseases. </li></ul><ul><li>Current focus is on identifying genetic factors underlying common diseases and drug metabolism. </li></ul><ul><li>While genetic susceptibility testing is yet to have a significant impact on clinical practice, pharmacogenetic testing has. </li></ul>
  21. 21. Conclusion <ul><li>Clinicians must be able use information from a gene test in clinical practice. </li></ul><ul><li>They should remember that the unit of care is the family rather than the individual patient. </li></ul><ul><li>The neurologist can work together with geneticists to provide appropriate genetic counseling and testing for patients with neurogenetic disorders and their families. </li></ul>