The
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The
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Courtesy of Dr. Richard R. Sharp, National Institute for Environmental Health Sciences Genetic Profiles The purpose of this feature of our journal is to connect information on genetic determinants of disease usually seen and researched separately, and thus the domain of three separate communities: disease genes, susceptibility genes and sensitivity genes. With the help of Contributing Editor Robert Sandhaus and others, this section of Genes, Ethics & Environment! begins the process of profiling populations in each of the three categories.Robert
A Sandhaus*
Alpha-1-Antitrypsin Deficiency (also known as Alpha-1) is a hereditary
condition predisposing affected individuals to lung and liver damage that
can be life threatening. Alpha-1-Antitrypsin is a circulating
protein that blocks the activity of inflammatory proteases
(protein-degrading enzymes). Alpha-1 can lead to destructive lung
disease (pulmonary emphysema) in young adults and the liver failure caused
by Alpha-1 can affect individuals of all ages, and is particularly severe
in newborns. Although virtually unknown by the general public and under
diagnosed by the medical community, approximately 100,000 individuals in
the US have the severe form of the deficiency and an additional 5 million
individuals carry at least one abnormal gene. There are a
similar number of affected individuals in Europe. Demonstrating
co-dominant allelic expression, Alpha-1 carriers have approximately 50% of
the normal circulating levels of this protein. There is some
evidence of increased risks of liver and lung disease even in carriers.
The most common abnormal gene appears to have originated in Scandinavia.
The distribution of this gene matches the area of Viking conquests
at the start of the last millennium.
Thus it is fitting that the association between familial precocious
pulmonary emphysema and the deficiency of Alpha-1-Antrypsin was first
described in 1963 by investigators at Malmo General Hospital in Sweden.
It appears that in the absence of additional risk factors, individuals
with the severe deficiency of Alpha-1-Antitrypsin may lead healthy
lives. While some individuals without identified risk factors do
develop liver or lung injury, the majority of individuals who develop lung
disease have one of four identified environmental risk factors: personal
smoking history, parental smoking history, frequent lung infections,
significant occupational exposures to dust and/or fumes.
The risk factors that lead to the liver disease of Alpha-1 are
currently unknown.
Neonatal liver disease often leads to liver transplantation with its
attendant risks and lifelong morbidity. The lung disease of Alpha-1
leads to premature death in most individuals. The only specific
therapy currently available to individuals with Alpha-1 lung disease is
intravenous augmentation therapy with pooled human plasma-derived
Alpha-1-Antitrypsin, an expensive therapy with poorly documented efficacy. * Robert A. Sandhaus, MD, PhD, FCCP, is Executive Vice President and Medical Director of the Alpha One Foundation. Shirley
B. Webb* Ever since I can remember, I have had a hand tremor and have been poorly coordinated. I recall the children in grammar school yelling, “Oh, you run funny”. I could not jump or ride a bike either, and I needed a banister to climb the stairs. Over the years, my hand tremor worsened, making eating and drinking very difficult tasks for me. I quit teaching elementary school because I couldn’t stop my hand from falling off the chalkboard. My leg muscles gradually deteriorated until, in my fifties, I began to need to use a wheelchair. I had 44 years of misdiagnosis as Kugelberg-Welander Syndrome, a rare form of Muscular Dystrophy, and Amyotrophic Lateral Sclerosis (ALS). Then, in 1982, I was confirmed to have the rare neuromuscular disorder, Late Onset Tay-Sachs (LOTS). At the time of my diagnosis, only about a dozen cases of LOTS had been found since the late 1970s, when the disease itself was first recognized. At present, that number has markedly jumped to more than 100 known cases. Like myself, most LOTS carriers and the affected come from East European Ashkenazi Jewish ancestry. But non-Jewish groups are also known to have the condition. French Canadians are second most frequently affected. LOTS is caused by a deficiency of the enzyme, Hexosaminidase A (Hex A). In healthy people, Hex A breaks down lipids, fatty substances in the nerve cells of the brain. Those affected with LOTS have small amounts of Hex A, not enough for normal function. Very slowly, the lipids accumulate, gradually breaking down certain functions of the central nervous system. LOTS is a rare variant of better known infantile Tay-Sachs, with both diseases caused by a deficiency of the same HEX A enzyme. Because infants have essentially no Hex A activity, their central nervous system is totally destroyed. Normal motor life functions like breathing and swallowing are soon impaired, leading to death in early childhood. LOTS is a genetic disease. Both parents must be carriers of the Tay-Sachs gene in order to pass the disease on to their children. At least one parent must have the late onset mutation in order for the child to have LOTS. The second parent may have either the late onset mutation or the infantile mutation. When both parents are carriers, they have 1 chance in 4 in every pregnancy of having a child who will develop LOTS . They have 2 chances in 4 of having a child who is a LOTS carrier, and they have 1 chance in 4 of having a totally unaffected, non-carrier child. Symptoms of LOTS vary. They may include different degrees of clumsiness, hand tremors, muscle weakness, speech impediment, swallowing difficulties, problems with gait and balance, and seizures. Some LOTS patients suffer memory loss and have comprehension difficulties. Psychiatric problems, such as severe depression or mood disturbances, occur in 40 percent of LOTS cases. There is presently no treatment for LOTS, but patients use various ways of controlling it. Regular physical exercise and therapy programs have been found helpful. A cure may be found soon. In recent neural stem cells experiments , Dr. Evan Snyder, a neurologist at Children’s Hospital, Harvard Medical School, has succeeded in supplying a missing gene to the brains of Tay-Sachs affected mice, and was able to halt the disease in them. His research holds much promise to reversing Tay-Sachs and related diseases in humans. The LOTS Foundation was organized 6 years ago to offer outreach to the affected, to educate the general and medical communities about our disorder, and to support research to find a cure. The affected and our families are cautiously optimistic about the prospects for a cure. Meanwhile, we deal with our symptoms the best way we can. The marked increase in affected membership, from 6 to 55, in the 6 years since the LOTS Foundation was formed, indicates that the disease is more common than previously thought. For more information, contact the Philadelphia, Pennsylvania-based LOTS Foundation at (800)-672-2022 or at (215)-836-2368 (local), or log onto its Web site: www.lotsf.org. *Mrs. Webb is Vice President of the Late Onset Tay-Sachs Foundation Morris
Greenberg* Editor’s note: This article mentions carriers of Sickle Cell Trait,, referring to those who carry a gene for Sickle Cell Anemia, but do not have the disease. Those who have the disease or the trait are often [but not exclusively] of African or Mediterranean ancestry. There is some evidence that under high altitude conditions some of those with only the trait develop the disease. G6PD [Glucose-6-Phosphate Dehydrogenase Deficiency is also mentioned. For half a century, it has been recognized that workers with this deficiency may suffer from severe anemia because of the destruction of red blood cells induced by exposure to certain foods , drugs, and oxidants in the work environment. The scientific literature points to possible links to copper, naphthalene, TNT and lead exposure. The disease was found among people in Mediterranean countries who ate fava beans. In pre-genome days, the classical strategy for worker protection against a hazardous agent followed the following cascade: # 1 Substitution to a less hazardous agent. As it was reasonably foreseeable that with the state of technology obtaining all these procedures could fail for any number of reasons, special conditions were applied to the employment of certain classes of individual according to perceived added risk or special aptitude. Thus, certain occupations were proscribed for young persons, either because of a belief in the susceptibility of the immature organism to the agent involved [e.g., lead and carcinogens generally], or because the immature could not be relied on when health and safety depended on strict adherence to safe practice. For thermally stressing or noxious work, it was convenient to believe that certain ethnic minorities were more adapted to discomfort or more resistant to disease. In a number of jobs, the employment of philoprogenitive women was controlled on grounds of fetal susceptibility [e.g., ionizing radiation, lead], social considerations [e.g., night work - except for nursing and similar occupations], and sentiment. The popular understanding was that adult males were not at special risk, or if they were it was accepted that in any job where diseases or death are involved, women and children were to be spared. With the observation that cigarette smokers were at added risk of lung cancer when working with asbestos, the small proportion of non-smokers available for work militated against eliminating these high risk persons from the workplace. Concern that atopic persons with their susceptibility to develop allergic responses to common agents would also sensitize more rapidly than the non-atopic to occupational allergens, led to the suggestion that persons responding to common allergens on skin testing should not be employed in certain jobs, which also ran across the arithmetic of ¼ to 1/3 of groups tested proving atopic. [ The preferred pathway for the metabolism of carcinogens and hence susceptibility to developing cancer has a genetic basis, much as atopics tend to have a familial history , but that was not dwelt on.] Proposals for screening workers for genetic-based disorders, including those that lead to Sickle Cell Trait and to Glucose-6-Phosphate-Dehydrogenase Deficiency [G6PD] , have been around for a long time, and when practiced have been controversial. For example, at one stage it was proposed that pilots with the trait for sickling should not be considered as fit for flying. In the American context this would have borne particularly hard on the Black population. Wiser heads prevailed and the proposal was discarded on scientific grounds. The transdermal uptake of aromatic amino- and nitro-compounds by workers in chemical plants leads to the production of methemoglobin, which persons with G6PD have difficulty in converting back to hemoglobin. When a do-it-yourself G6PD measurement kit was marketed, this led to an outbreak of screening and a policy of exclusion, and though the trait is shared with people of Middle Eastern and Mediterranean origin, blacks, some ten percent of whom have the deficiency, would have been predominantly affected. Exclusion of the susceptible from toxic exposure, at first sight appears to be a compassionate policy. However, in practice it has led to difficulties. When susceptibility is widely shared by the workforce, blind eye is turned to it, and when it occurs in an ethnic minority, their exclusion from employment has been perceived as discriminatory. If reliance cannot be placed on the four classic engineering measures, then a strong case would surely be required to justify the product or process. A safety policy that depends on a program of screening that discriminates against the employment of one genetic/ethnic minority in order to protect them, while selecting another genetic/ethnic group for exposure to a risk, even if it is believed to be a lesser one, at this stage of technology and the economy can surely be no substitute for efficient engineering. *Having retired from a distinguished private sector and government career in occupational and environmental medicine, the author prefers to be identified simply as Dr. Morris Greenberg of London. Dr. Greenberg welcomes comments and questions via TheEditors@RamazziniUSA.org. Future Profiles Genetic profiles will be amplified to create a catalog of "ecological" profiles. I.e., they will include social, economic, demographic, psychological, biomedical, and environmental data. Each of the affected populations face special problems, but share common research, legislative, employment, insurance, and health care needs. There may also be unexplored environmental questions that need to be highlighted, not only in terms of causation, but also in terms of protection as a population especially vulnerable to contaminated environments. Some members of each population are likely to have “membership” in other populations, creating an overlap of biomedical and environmental research and protection needs. |
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