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