Tay-Sachs Disease: Genetic Testing, Ethics, and Counseling

Introduction

Genetic testing is becoming a much more common practice in medicine today. This presents a unique set of challenges for medical professionals in virtually all specialties. The practical aspects of determining which test to order and interpreting results accurately in the context of family history can be difficult.

The Interdisciplinary Team

Additionally, the ethical conundrums that frequently arise when genetic risk assessment or genetic testing is being considered can be daunting. These challenges present real concerns for both medical professionals and patients alike. This paper reviews some of the practical and ethical complexities associated with genetic testing, and emphasizes pretest and posttest genetic counseling as an important and essential process in today's medical practice.

The interdisciplinary team members should include an obstetrician, a genetic counselor, a psychologist or psychiatrist, a geneticist, and a neurologist. Each of these team members would play an essential role in the Trosacks' care. The obstetrician would attend to Rita Trosack's pregnancy; the genetic counselor would advise on prenatal genetic testing; the psychologist would address the psychosocial concerns of testing; the geneticist would inform the Trosacks of the social, ethical, and legal implications of their choices for themselves and the baby; and the pediatric neurologist would assist with the baby's care after birth.

Each team member was chosen for the contribution they would provide in helping the Trosacks understand the implications of genetic testing for themselves and their baby. The burden on the Trosacks is quite large in this case and would extend to other family members who are feeling the psychological effects of a positive prenatal test for Tay-Sachs disease.

Teaching Plan: Diagnosis, Carrier Frequency, and Prognosis

Due to the complexities involved in genetic testing—and the far-reaching effects of a genetic test result for both the patient and their family—genetic counseling is an integral part of the genetic testing process. Genetic counseling is defined as a communication process that deals with human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family. The genetic counseling process includes information gathering, establishing or verifying a diagnosis, risk assessment, information giving, and psychosocial counseling.

In the case of the Trosacks, with Peter's paternal grandparents having had one daughter and one son die of unknown causes, the probability that the Tay-Sachs gene is present in his family is high. Rita also has paternal grandparents who had a son die of unknown causes. The genetic diagnosis is that both Peter and Rita carry the recessive allele for the Tay-Sachs gene, and both alleles appeared in the fetus.

Tay-Sachs disease is an autosomal recessive lysosomal storage disorder characterized by progressive neuronal accumulation of GM2 ganglioside. It is caused by mutations in the HEXA gene, resulting in a defect of hexosaminidase A (Hex A). There are three clinical types: infantile (acute), juvenile (subacute), and adult-onset (chronic).

The geneticist would disclose the following information about the carrier frequency of Tay-Sachs disease in Irish-American and Polish-American populations. From data collected in a North American Tay-Sachs disease (TSD) heterozygote screening program, the TSD carrier frequency among 46,304 Jewish individuals was found to be 0.0324 (1 in 31 individuals). This frequency is consistent with earlier estimates based on TSD incidence data. TSD carrier frequencies were then examined by country and region of origin in 28,029 Jews within this sample for whom such data were available. Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a TSD carrier frequency of 0.0327. No TSD carriers were observed among the 166 Jews of Near Eastern origins. Relative to Jews of Polish and Russian origins, there was at least a twofold increase in the TSD carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins (Petersen et al., 1983).

Previous reports have also found that non-Jewish Americans with ancestry from Ireland have an increased frequency of heterozygosity for Tay-Sachs disease, although frequency estimates vary substantially. In a recently published study, the frequency of heterozygosity for TSD among Irish Americans was determined in subjects referred for heterozygosity testing who had no known family history of Tay-Sachs disease. Of 610 nonpregnant subjects with Irish background, 24 TSD heterozygotes were identified by biochemical testing, corresponding to a heterozygote frequency of 1 in 25 (4%; 95% CI, 1/39–1/17). Samples from 21 Irish heterozygotes were analyzed for HEXA gene mutations. Two (9.5%) had the lethal IVS-9+1 G→A mutation, whereas 9 (42.8%) had a benign pseudodeficiency mutation. No mutation was found in 10 (47.6%) heterozygotes (Branda, 2004).

Once a genetic test result is obtained, the psychosocial implications of that result should be further explored during posttest genetic counseling. It is important to keep in mind that the actual patient reaction may differ from what is expected. For example, one might assume that a positive test (indicating increased risk) represents a "bad" outcome, while a negative test is a "good" outcome. In clinical practice, this is not always the case. Many patients who have strong family histories of potentially hereditary conditions feel relieved and empowered by a positive genetic test: it provides answers for why there is a high frequency of disease in the family and can serve as a tool for at-risk family members to determine their own level of risk. Conversely, in families where a known disease-causing mutation has previously been identified, patients who do not carry the familial mutation may experience survivor guilt. As part of posttest genetic counseling, the patient should be encouraged to discuss their reaction to the test result. The disclosure of genetic test results to family members and their reactions should also be discussed, since the disclosure process can be distressing for many individuals. Throughout this process, the patient should feel supported, and referrals to a support group, psychologist, or psychiatrist should be offered as indicated (Ensenauer, 2005).

Hex A is composed of one alpha subunit and one beta subunit. Mutations in the HEXA gene encoding the alpha subunit cause TSD. In the absence of Hex A activity, the glycolipid GM2 ganglioside accumulates in cells of the central nervous system, leading to cellular dysfunction and death, paralleled clinically by a progressive loss of neurological function. An infant with TSD typically develops normally for several months before beginning to decline and losing developmental milestones; paralysis and death between the ages of 2 and 6 years ultimately result (Gravel et al., 2001).