Genetic Diseases And Development Disabilities: Aspects Of Detection And Prevention

Tamah L Sadick

• Publisher: Routledge
• Year: 2019
• eBook ISBN:
  9780429727085
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

Advances in medical genetics during the past two decades have made possible the detection and prevention of many genetic disorders and developmental disabilities. The emphasis of this book is on the application of these new developments to real-life situations. Covering homozygote newborn screening, heterozygote detection in the community, and pren

Part I
Prevention Through Screening and Carrier Detection

2
Genetic Screening

The Heterozygote Experience

Charles R. Scriver

Two quotations from Juvenal (1), the Roman satirist, introduce my contribution to this symposium.

What good are family trees?

(Satire VIII)

What a grossly ravening maw

That man must have who dines off whole roast boar - a beast Ordained for convivial feasting! But you'll pay the price All too too soon, my friend, when you undress and waddle Into the bath, your belly still swollen with undigested Peacock-meat - a lightning heart attack, with no time To make your final will.

(Satire I)

Juvenal wrote the Satires as a series of moral portraits for an age which - in some ways - was not unlike our own. By "family tree" in the first quotation, we presume he meant social lineage. But in our age the term refers also to biological lineage, and we do care about the family tree, because it may contain information we need to prevent inherited disease. In the second quotation the satirist paints a grotesque vignette to limn a general lesson on lifestyle. Yet even moral men have lightning, premature heart attacks - when they have special risks to their personal health. Their family tree - not their morality - can set those risks upon them.

Most of us are not likely to believe we have genetically - determined risks to our own health. Such risks tend to make ourselves "the enemy"; and we are not conditioned to enjoy that message.

Medical and Genetic Paradigms of Disease

We have been taught to wage war upon disease; and why not? Past crusades and campaigns against scourges have been very successful. Causes of disease (the enemy) have been identified; cures mobilized. Polio has been eradicated; smallpox vanquished; entrenched infections routed. We use the language of World War I to describe our victorious attacks on disease (Table 1). Past campaigns have changed the pattern of contemporary disease in developed countries. Degenerative diseases, malignancies, hereditary problems and birth defects now dominate the disease profiles of these nations, and now, we wage new wars on these stubborn ailments. But where is the cause of cancer? What agent causes the premature heart attack? How do we cure birth defects? How do we understand the enemy when it is partly ourselves. Our cherished medical paradigms fail us when we try to understand.

The traditional medical approach to disease fails us because we tend to ignore the fact that we are not all created equal - biologically. We need a new declaration of independence creating a state of awareness of our biological rights. The declaration might begin by recognizing that

Table 1
DISEASE as the ENEMY and MEDICINE as a WAR

The language we use:

... killer disease

... breakthrough discovery/treatment

... crush ...

... eradicate ...

... (cobalt) bomb

... war on (cancer/polio/ ...)

... entrenched infection ...

women are different from men. It would recognize that human beings are freighted with genetic variation; some of it advantageous under particular circumstances - as for example in the case of sickle cell trait in a falciparum malaria environment; most of it neutral under the general conditions of life; a bit of it responsible for actual or potential harm - such as the mutation causing abnormal membrane receptor activity for the LDL-cholesterol complex.

Rapid growth of knowledge about the inborn errors of metabolism in the past quarter century, and an initial modest success with screening and treatment of affected homozygotes for a few Mendelian diseases, has dramatized these rare examples of human biochemical variation. Although about 2500 other Mendelian traits and disorders have now been catalogued (2), we tend to view them all for what they are - an aggregate of outlier events at a remote end of the disease spectrum (Figure 1). In this spectrum, expression of rare mutant genes in the universal environment occupies one end while the effect of a particular environment upon individuals of universal genotype occupies the other. In the middle lie the common multifactorial diseases which fill our hospital beds. The underlying theme is that particular genes confer special risks for many of these common diseases. To put it another way, it is heterozygotes who tend to fill our hospital beds.

We have begun to act rather confidently on behalf of the homozygotes among us. We design programs for the screening, diagnosis, counseling and treatment of them - for example in the prevention of phenylketonuria. We even recognize that genetic heterogeneity is the rule rather than the exception among the inborn errors of metabolism (3). We know that the recognition of heterogeneity is important, because it guides us to titrate the environment precisely to the tolerance of the mutant individual in the process of treatment. Accordingly, we are relatively comfortable in this microcosm of extreme genetic variation because its significance is understood (4).

And yet we are uneasy with the broader, but equivalent, concept of prevalent heterozygosity - or polymorphism - in the apparently healthy population. For example, Harris and colleagues found extensive polymorphism at the gene loci responsible for normal acid phosphatase activity in red blood cells (5). With an electrophoretic method they demonstrated six different patterns of acid phosphatase to account for the frequency distribution of enzyme activity among individuals in a British Caucasian population. These investigators went on to show comparable genetic variation

Figure 1. Spectrum of human diseases to emphasise those of primarily intrinsic origin (top left) or extrinsic origin (bottom right) and those of multifactorial origin (middle).

at one third of the gene loci they examined (6,7). They calculated an average heterozygosity per gene locus of at least 6.7%. After taking into account the limitation of electrophoretic methods to detect Mendelian variation in proteins, they predicted the average heterozygosity per human gene locus is close to 20 percent.

We are not yet in a position to interpret the biological significance of most of this heterozygosity. But we can't ignore it. We are due to learn about it, as we have learned about the meaning of genetic heterogeneity in our party pieces - the inborn errors of metabolism.

Heterozygotes for autosomal recessive diseases such as phenylketonuria, Tay-Sachs disease and sickle cell anemia constitute between two and ten percent of the community in which the disease is found; the medical significance of that fact has only recently been perceived. Now we must extend the concept of heterozygosity to include virtually everyone in the population and to realize that heterozygosity in relation to a particular environment may influence the health of the individual.

The traditional view of how disease occurs is in transition. The medical paradigm of cause does not explain many common ailments and it offers no option for cure. The genetic paradigm of special inherited risks for particular Individuals is often a more useful interpretation and it can sometimes provide the option for prevention.

The genetic paradigm views health as an equilibrium between the genome-or our "nature", and the environment-or our "nurture". Disease is disequilibrium, sometimes caused by an excess of the environment, at other times the result of a change in the fulcrum controlling equilibrium. In the paradigm, the gene product is the fulcrum; it determines the equilibrium between the biological function and the environmental force acting upon the organism.

Consider three Mendelian examples of the genetic paradigm.

1. Porphyria variegata is associated with life-threatening neurologic crisis. Exposure to barbiturates precipitates the crises. The aberrant function is a step in the biosynthesis of porphyrin.
2. Hemolytic anemia is provoked by exposure to the antimalarial primaqutn or other oxidant agents. The aberrant function is an enzyme in the pentose pathway of red blood cells.
3. Emphysema is probably more prevalent in smokers with ou antitrypsin deficiency; aberrant protease inhibitor activity in the presence of a chronic irritant environment permits lung damage.

In each case the health of a heterozygous person is at risk because of the specific inherited genotype; an environmental event, harmless to most persons, provokes disease in the person at risk. It follows that knowledge of genotype allows one to prescribe a specific course of action or lifestyle that can prevent disease.

So far so good, as long as these examples are confined to the teaching of genetics and don't get in the way of the real business at hand - the practice of medicine. But that attitude just won't do for a world view of human health. The barbiturate risk is pertinent to one-in 400 Afrikaaners and a South African physician is liable to a malpractice suit if his patients receive barbiturates without being screened for porphyria variegata. The primaquin example is relevant to thousands of men living in malarial regions of the world. The smoking risk is still being evaluated and because it could be pertinent to hundreds of thousands, it has earned a place of its own, in this volume.

The larger issues revealed in these examples of genetic variation are important for two reasons. First they suggest that heterozygote screening may become a major medical activity in defining special medical risks for particular individuals. Second they imply that prevalent heterozygosity could be the basis of much disease.

Most citizens are unfamiliar with their own genetic diversity. Therefore we can anticipate a denial of programs designed to reveal it - as we have seen for example in the case of sickle cell screening (8). And most physicians are equally unfamiliar with these concepts; therefore they do not want to know about their patients' genotypes.

How we classify a person as a carrier of a variant gene is a delicate process. It threatens self-image; and it challenges traditional medical practices. Accordingly, the basic principles of screening and classification merit our attention. It is also prudent to know why citizens know so little about their own heterozygosity. If genetics were an item on our personal and national agendas and if screening practices were ideal, I believe we could alleviate the disease burden of modern society rather considerably.

Accordingly, the remainder of this paper is addressed to problems of classification in screening and public education in genetics.

Genetic Screening

Genetic screening is a process whose aim is to identify genetic variation among individuals in populatio...

Table of contents

• Cover
• Half Title
• Series Page
• Title
• Copyright
• Contents
• List of Figures
• List of Tables
• About the Editors and Authors
• Introduction
• PART I: PREVENTION THROUGH SCREENING AND CARRIER DETECTION
• PART II: RECENT ADVANCES AND EXPERIENCE IN PRENATAL DIAGNOSIS
• PART III: BRIDGING THE GAP BETWEEN RESEARCH AND PRACTICE: EDUCATIONAL IMPLICATIONS