Genetic Test Information Fears Unfounded

San Francisco—The discovery of gene mutations linked to cancer or other serious illnesses has paved the way to genetic testing to determine if an individual, typically someone from a high-risk family, carries a flawed gene.

A positive genetic test may help patients by alerting them to the need for screening or preventive measures. But many people who are good candidates may be reluctant to undergo testing because they fear that insurers and employers will use genetic information to discriminate against them.

Despite such fears, however, genetic discrimination by health insurers has not been a problem, according to a study presented at the annual meeting of the American Society of Human Genetics. Like so-called urban legends that are built on rumor rather than fact, the perception of insurance company bias against patients who undergo predictive genetic testing seems to be largely unsubstantiated.

"Genetics just isn't on underwriters' radar screens," said Mark A. Hall, JD, of the public health sciences department at Wake Forest University School of Medicine.

In 1998, Hall and colleagues surveyed insurance underwriters, agents, actuaries, regulators, genetic counselors, and patient advocates in Colorado, Florida, Iowa, Minnesota, New Mexico, North Carolina, and Ohio. With the exception of Iowa, these states had laws protecting state residents against genetic discrimination regarding health insurance.

The investigators also conducted a direct market test, in which insurance agents were asked about obtaining individual and group health insurance based on such fictitious scenarios as a positive test for BRCA1 (a gene mutation found in some women with a family history of breast cancer) or a family history of Alzheimer disease.

"The view from geneticists is that discrimination is a serious problem, and is assumed to be widespread," said Hall. But he found little or no indication of discriminatory policies or practices by insurers based on genetic test information before or after the state laws were passed, he said.

Insurers appear to have little interest in whether potential policyholders have a genetic predisposition for a disease, perhaps because of the high turnover rate in health insurance policies, he suggested. Many people remain in a health plan for only a few years, and the likelihood that they will develop symptomatic disease during that period is relatively small.

It's possible that state laws restricting health insurers' use of genetic information have not reassured people who fear genetic discrimination, Hall noted. Based on interviews with genetic counselors, medical geneticists, and patient advocates, and a review of studies exploring factors affecting patients' decisions to be tested and their perceptions of the potential threat testing posed, the investigators concluded that people aren't convinced that such laws will prevent discrimination.

Such fears affect patient behavior. Worry over genetic discrimination is one of the most common reasons people don't obtain predictive genetic testing for hereditary cancer syndromes, and perceptions of genetic discrimination as a problem are found not only among patients but also among those who provide genetic counseling, according to another study, presented by researchers at Yale University School of Medicine, said Ellen T. Matloff, MS, who led the study.

Matloff, director of cancer genetic counseling, and colleagues surveyed 296 active members of the National Society of Genetic Counselors, received 163 responses, and found that the vast majority of responders would pursue genetic testing for inherited mutations linked to colorectal cancer or breast and/or ovarian cancer if they had a 50% chance they carried such a mutation.

"But they said they would do some things to protect themselves against the perceived risk of genetic discrimination," she said. Most said they would not submit the charges for testing to their insurance companies, and one in four said they would use an alias to ensure test results remained secret.

"We know there's a problem with maintaining insurance for people who [already] have a disease," noted Matloff. "But in our 4-year program, we've not had a documented case of genetic discrimination."

Mary-Claire King, PhD, a geneticist at University of Washington School of Medicine who has studied hundreds of women who carry genetic mutations that predispose them to breast and/or ovarian cancer, said that many participants in her studies are concerned about genetic discrimination.

"To my mind, the concerns are real, but I have yet to encounter a case where a woman has said to me ‘I had trouble with my insurance after I found out my genotype,'" said King. "But I have encountered a number of women who've said ‘I had terrible trouble with my insurance after my diagnosis of breast cancer.'"

Some health insurance professionals interviewed by the Wake Forest researchers said their current hands-off attitude with respect to using genetic test results to make decisions about insurance coverage may change in the future. But state laws restricting the use of genetic information have created a sense among insurers that the practice would invite social disapproval, suggested Hall. "That gives me some confidence that the laws have had some beneficial effect and that this attitude may not likely change any time soon," Hall said.

Seattle—Studies in the last decade have suggested that transplantation of human fetal brain tissue is effective in slowing progression of Parkinson disease (PD) in some patients. However, the limited supply of tissue—not to mention the moral objections and ethical questions raised by its use—have generated interest in finding alternative, nonhuman species to use for such transplants.

One promising source of fetal brain tissue is the pig. Among the benefits of using porcine cells are pigs' large litter size (10 to 15 fetuses) and short gestation period, said Samuel A. Ellias, MD, PhD, of Boston University Medical Center, at a conference on the Etiology, Pathogenesis, and Treatment of Parkinson Disease and Other Movement Disorders held here in October.

But among the concerns raised by xenotransplantation, Ellias reminded listeners, is cross-species infection (JAMA. 1995:274;285–288). Although most potential pathogens can be eliminated from fetal pigs before transplantation, Ellias said it is important when using porcine tissue in transplantation to test for porcine endogenous retrovirus (PoERV), which is resistant to eradication because it permanently integrates into the pig genome. Therefore, further animal and clinical research is needed before brain grafting with fetal pig cells can be contemplated as a treatment for PD.

Ellias and his colleagues have been evaluating the safety and efficacy of using fetal pig brain tissue transplantation. Results from a phase 1 study sponsored by Diacrin Inc and Genzyme Tissue showed a favorable safety profile and provided preliminary evidence of efficacy of this approach, he said.

The average age of the 12 patients in the study was 60.8 years, with a range of 37 to 70 years. All patients had moderate to severe PD, with the mean Hoehn-Yahr stage (a 1-to-5 staging scale for PD) being 3.7 OFF. All of the patients had had the disease for about 14 years, and in none of them was medication useful in alleviating symptoms.

The patients received unilateral transplantation of porcine ventral mesencephalic cells from day 25 to 28, with a total of 12 million cells being distributed in three tracks—one in the caudate and two in the putamen—with 4 million cells per track. After surgery they were randomized into two groups, with one group of six patients receiving cyclosporine and the other group of 6 treated with an F(ab′²) antibody fragment directed against major histocompatibility complex (MHC) class 1.

The patients' ability to perform a variety of movements was assessed postoperatively every 3 months for 2 years using a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Of the 12 patients, two patients, both in the group receiving cyclosporine, were not fully evaluable over the full duration of the study, said Ellias. One was excluded from the group analysis because his condition was so poor at the time of baseline testing that all measurements could not be taken. Ellias noted however that after surgery this patient has shown remarkable improvement. The other patient died 7 months after transplantation from a pulmonary embolism, a cause believed to be unrelated to the treatment.

A member of the audience remarked that a small number of other transplant recipients had also succumbed to pulmonary emboli, raising the issue of whether there might be a causal relationship. In spite of the fact that pulmonary emboli are more likely to occur in these patients simply because of their age, Ellias said he has had similar concerns about a possible connection and thinks it should be investigated.

Ellias said no serious adverse effects were noted that were directly related to the porcine cells, and safety testing for PoERV with a polymerase chain reaction–based assay detected no sequences of the virus. He added that further evidence for the safety of using this material in humans appeared in an article published in August on the longitudinal expression of PoERV in humans who have been exposed to living porcine tissue (Science. 1999:285;1236-1241).

In addition, Ellias said no worsening of dyskinesia or dystonia was seen, no spontaneous dyskinesias developed, and a number of patients showed improvements in dyskinesia. At 2-year follow-up, an 18% improvement (P<.05) was seen in the total UPDRS (OFF) score, 22% for the group receiving cyclosporine and 15% for those receiving the antibody. Statistically significant improvement was gained from treatment in activities of daily living, postural instability, and complications of treatment.

One patient who had been in the cyclosporine group showed 45% improvement at 12 months and maintained this change at 24 months. A patient in the antibody group showed 51% improvement at 12 months, which was maintained through the next year. Both patients showed bilateral responses in arm speed and sustained improvement in walking speed, despite the fact that the graft was unilateral. Ellias said these results warrant further trials.

Eighteen volunteer patients have been enrolled in a double-blind controlled trial involving bilateral implantation of twice the number of fetal porcine brain cells used in the phase 1 study. Patients will be randomized into a group that receives the transplants and a control group that undergoes a surgical procedure but does not receive these cells. "We believe it's necessary to do this in a placebo/sham surgery trial to make sure some of these effects are not placebo effects," said Ellias. Results from this study should be in by next August, he said.

Atlanta—A renewed effort is being made to increase lagging rates of immunization against influenza and pneumococcal disease. At its October meeting here, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) unanimously adopted a recommendation that standing orders be introduced into a variety of settings to increase immunization coverage rates for these diseases among persons 65 years and older and other high-risk groups.

The recommendation says: "Health care delivery organizations, health care providers, and certain social service agencies including, but not limited to inpatient and outpatient facilities, managed care organizations, assisted living facilities, long-term care facilities, skilled nursing facilities, home health care agencies, and correctional facilities, may utilize standing orders programs to improve immunization rates in their patient, client, or resident populations."

"We're doing a fairly lousy job immunizing adults under 65 with high-risk conditions," said Richard Zimmerman, MD, of the University of Pittsburgh School of Medicine, one of several speakers who urged approval of the recommendation. Zimmerman, the American Academy of Family Physicians liaison representative on the ACIP, noted that 24% of the US population between ages 50 and 65 years has a high-risk condition but only 38% is being vaccinated.

Therefore, the recommendation includes lowering the age for receiving influenza vaccine from 65 years to 50 years, in part because morbidity and mortality from influenza start to rise at age 50. "It's higher at age 65 than it is at 50, of course, but it doesn't start at 65," said Zimmerman. He cited a study showing that vaccination of healthy working adults under age 65 (that is, those between 18 and 64 years of age) reduces morbidity and along with it absenteeism, and so is cost saving (N Engl J Med. 1995;333:889-893). "This benefits employers and society in general," he said.

Dixie Snider, MD, the CDC's associate director for science, said the new recommendationwill be published as a supplement to the Morbidity and Mortality Weekly Report. It will be the first statement recommending adult immunizations to appear since 1991.

The recommendation requires that elements of the service delivery components of standing orders programs should be described in written protocols, including procedures for (1) identifying persons eligible for vaccination because of vaccination status (eg, previously unvaccinated or due for vaccination per recommended schedule), and age or high-risk medical condition; (2) providing adequate information to patients or their guardians of the risks and benefits of the vaccine and documenting the delivery of that information; (3) regarding patient refusals or medical contraindications; and (4) recording postvaccination adverse events.

The ACIP move was hailed by Peggy Webster, MD, director of the National Coalition for Adult Immunization. She noted that physicians taking care of adults don't think of immunizations the way pediatricians do. "Immunizations have to be worked into their schedules, and this is another effort in that direction. I think this will be a push for providers to incorporate routine immunization into their practice, and will also help to raise awareness on the part of the public so [adult] immunizations will become a more and more accepted part of medical care."

Seattle—Researchers are developing new animal models of pathogenesis to gain greater insight into the underlying mechanisms of chronic neurodegeneration and to test new drug treatments for Parkinson disease (PD).

One such model, presented by J. Timothy Greenamyre, MD, PhD, of Emory University, at a conference on the Etiology, Pathogenesis, and Treatment of Parkinson's Disease and Other Movement Disorders, held here in October, appears to reproduce the neurochemical, neuropathological, and behavioral features of the disease through chronically exposing laboratory rats to the pesticide rotenone.

While the cause of PD remains elusive, said Greenamyre, it is known that the disorder seems to be associated with a systemic defect in complex I. Reports show that complex I, an enzyme in the mitochondrial electron transport chain that provides energy for the cell to make adenosine triphosphate, is reduced in the brain cells and platelets of patients with the disorder.

Greenamyre explained that complex I is also the site of inhibition of MPP+, a metabolite of the drug MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), and of rotenone. In the 1980s, MPTP was found to give rise to a form of PD. The recognition that MPTP chemically resembles pesticides such as rotenone prompted inquiry into whether pesticide exposure might be a risk factor for PD, an association that has been supported by epidemiological studies, he said.

Greenamyre and colleagues theorized that by inducing chronic systemic inhibition of complex I with rotenone they could cause selective degeneration of the nigrostriatal dopamine neurons involved in PD and produce the features of the disease in an animal model.

He pointed out that MPTP-induced PD does not test this hypothesis because although MPTP and rotenone both inhibit complex I, MPTP is toxic only to dopamine neurons. Rotenone, which is not selective in this manner, kills neurons whether or not they carry a dopamine transporter and, therefore, was used to investigate whether systemic inhibition of complex I would cause selective neurodegeneration.

Rotenone is a common insecticide, said Greenamyre, that is perceived in many quarters as relatively innocuous. "On the Internet it is touted as an organic or natural alternative to synthetic pesticides because it is a natural product. It's often used in reservoirs in the United States and to kill nuisance fish."

The protocol was simple, said Greenamyre, the goal being to use low dosages for long periods of time. Male rats were given rotenone by continuous infusion via minipumps for anywhere from 2 days to 3 months.

The animals became progressively bradykinetic and rigid. At various points, the animals were killed and rotenone infusion was found to inhibit complex I uniformly throughout the brain without affecting other electron transport complexes, such as II or IV.

Various staining techniques revealed that rotenone produced highly selective damage to the nigrostriatal dopaminergic terminals, and later the cell bodies, while sparing other transmitter systems, said Greenamyre. The nigrostriatal neurons appeared to die by apoptosis, at least in these preliminary experiments, and the researchers noted cytoplasmic inclusions reminiscent of early Lewy bodies—the hallmarks of PD.

Greenamyre said the results of his team's investigation indicate that systemic administration of rotenone brings about selective retrograde degeneration of the nigrostriatal system and mimics the slowly progressive course of PD.

The implications of these results, he said, "are that the nigrostriatal dopamine system has an intrinsic sensitivity to complex I inhibition, and that environmental toxins that impair complex I—including pesticides—may contribute to the pathogenesis of PD. Systemic rotenone infusion may provide an accurate model for the continuously progressive, chronic degeneration that characterizes the disease and may provide a novel and more accurate model to study neuroprotective drugs."

Editor's Note: Miscellanea Medica appears in the Medical News & Perspectives section occasionally. Items submitted for consideration should be directed to the attention of Marsha F. Goldsmith, Editor, Medical News & Perspectives.