OBTAINING THE FAMILY HISTORY
A review of family history and drawing of a pedigree are the essential first steps for determining the likelihood of a neurogenetic disease. A carefully constructed pedigree can guide the differential diagnosis by indicating whether any family history exists and, if it does, the possible mode of inheritance. At least a three-generation family history should be obtained, which includes ethnicity, age of onset of symptoms, age and cause of death, diagnoses determined by genetic testing, and known history of consanguinity. Specific family history questions can help to narrow the differential diagnosis. As an example, consider the patient with ataxia: a family history that includes mental retardation or premature ovarian failure would suggest a diagnosis of fragile X-associated tremor ataxia syndrome. Similarly, for a patient with amyotrophic lateral sclerosis (ALS) and a family history of dementia, a likely cause is a hexanucleotide expansion in
C9orf72. An Ashkenazi Jewish background in the presence of Parkinson disease could indicate a
LRRK2 or
GBA mutation and, in the presence of dystonia, a
Tor1A deletion (
Table 34.1).
A lack of family history, however, does not rule out a genetic diagnosis. A negative family history may be due to lack of information, early death, autosomal recessive inheritance, undisclosed adoption, false paternity, or de novo mutations (mutations that first appeared in the patient).
THE GENETIC COUNSELING DISCUSSION
The process of genetic counseling and testing differs, depending on whether the patient is being seen prior to diagnostic testing of a symptomatic patient or for predictive testing of an at-risk family member. Regardless, enough time should be given to genetic counseling to provide the patient/family with the understanding of the implications of testing. Clinicians may refer to the National Society of Genetic Counselors (http://www.nsgc.org) if they wish to locate a genetic counselor in their area. In general, patients should be encouraged to attend all counseling sessions with a support person who can help them interpret the information and support them through the process.
Even when testing is being performed to assist in diagnosis, the nature and genetics of the disorder; the implications of a positive result for other family members; the benefits, risks, and limitations of testing; and an emotional impact of testing should be discussed (
Table 34.2).
Pretest counseling for predictive genetic testing is an opportunity for anticipatory guidance. Patients should be asked how they would feel both over the short term and long term upon receiving a positive or negative result. They should consider how a positive or negative result would impact their life decisions including relationships, school or work choices, financial decisions, and reproductive choices. Many patients may need referrals for psychological counseling to help them work through the decision to test. In fact, the Huntington disease genetic testing protocol, which is used by many centers for predictive testing for fatal, untreatable neurogenetic conditions, advocates for a psychiatric assessment of all patients prior to predictive testing (
Table 34.3).
As with counseling for diagnostic genetic testing, the benefits, risks, and limitations of testing should be covered. In general, predictive testing should not be performed without confirmation of a genetic diagnosis (and known mutation) in another family member. Without a known mutation in the family, a negative result may falsely reassure the individual, or a discovery of a variant of unknown significance will be inconclusive without other informative cases in the family.
Genetic results should be given in person, especially when they are predictive. While delivering the results, the clinician should review the meaning of the test result for the patient and family members, assess the psychological state of the patient and refer for psychological counseling as necessary, determine a plan of action, and give information about appropriate disease associations and support groups. When a positive result has been given, the clinician should check in with the patient/family following the posttest session.
