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Treating Genetic Diseases: Lessons from Three Children

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Treating Genetic Diseases: Lessons from Three Children 003 1-3998/90/2706-OS 10$02.00/0 PEDIATRIC RESEARCH Vol. 27, No. 6 (Suppl), 1990 Copyright O 1990 International Pediatric Research Foundation, Inc Printed in U. S.A. Treating Genetic Diseases: Lessons from Three Children LEON E. ROSENBERG Yule University School of Medicine, Department of Human Genetics, New Haven, Connecticut 06510 This presentation has two goals. The first, to review in a general ment of a disease. Ordinarily, however, we use the word cure to way the therapeutic strategies employed for human genetic dis- refer to those situations in which a single course of treatment eases and the efficacy of these strategies. The second, to share results in elimination of the disease, that is, in situations in which my reflections of three particular children with genetic diseases treatment can be discontinued without relapse as in the cure of whom I've cared for, and whose lives (and, in some cases, deaths) pneumococcal pneumonia by penicillin or of acute appendicitis are important signposts along my own career journey in pediatric by appendectomy. research. As an "adopted son" of pediatrics, I feel particularly Central principle of gene action. Let me remind you of the privileged to share this part of the program with such bona fide organizing principle implicit in the treatment of genetic diseases. pediatricians as Barton Childs and Charles Scriver. I believe that all of us would agree that among the most funda- mental scientific truths revealed in the 100 years since the American Pediatric Society was founded is that which may be TERMS AND PRINCIPLES denoted the central principle of gene action. This principle states Genetic disease. Before I can reach either of these goals, I must that a gene acts by encoding a protein; that a protein (whether it define three terms and articulate a single organizing principle. be a structural protein, a circulating protein, or an intracellular The terms are as follows. I will use the generally accepted enzyme) functions by controlling a metabolic process; that dys- definition of genetic disease as a disorder resulting in impairment, function of such a metabolic process will ultimately give rise to disability, or handicap for which a variant DNA sequence is a a detectable phenotype. major etiologic determinant. Those of us who treat patients with genetic diseases are guided We recognize three major categories of genetic diseases (Table by this principle. For some years, we have intervened at the level 1). The first category consists of multifactorial traits such as of the phenotype, as when we correct a congenital heart defect congenital heart defects, neural tube abnormalities, pyloric ste- surgically. For some years, as well, we have directed our treat- nosis, cleft liplpalate, or juvenile diabetes. These conditions ment at the substrate or the product of the metabolic reaction, result from complex and poorly defined interactions between as when we restrict dietary phenylalanine in a patient with PKU. one or more genes and the environment. They cluster in families In an impressively expanding list of situations, our therapeutic but are not inherited in a simple mendelian fashion. They are target is the functional protein, as when we administer factor very common, occurring in 3 to 4% of live-born babies, and are VIII to patients with hemophilia or insulin to diabetics. Ulti- collectively very serious, accounting in North America and Eu- mately, I believe, we will intervene at the level of the gene itself- rose for 20% of uediatric insatient admissions and 30% of not as soon as some of us hope, but sooner than others fear. chfildhood deaths ( i-3). In the second category are the single-gene defects, such as PHENOTYPIC MODIFICATION cystic fibrosis, PKU, and muscular dystrophy. These are inher- ited as autosomal dominant, autosomal recessive, or x-linked Having established the goals and surveyed the terminologic traits depending on the location of the particular gene locus and terrain of this paper, let me move into a discussion of therapeutic the nature of the gene product. Although most of these conditions strategies and results. The subject of treatment of genetic diseases are individually rare, nearly 2000 of them are now known. Their generally calls forth statements like this one from a major recent overall incidence is about one per 100 live births (1 %). They are book: "There are very few genetic diseases that can be cured" responsible for 10% of pediatric inpatient admissions and 15% (4). Although this statement is true, it is quite misleading because of childhood deaths. it fails to consider that most patients with genetic diseases have In the third category are chromosomal abnormalities such as one of the multifactorial traits, and that it is just these conditions Down, Turner, and Fragile X syndromes. These are characterized where we can talk about cure using phenotypic modification by a microscopically detectable increase or decrease in the total (Table 2). mass of chromosomal DNA. Whereas chromosomal abnormal- We now have three general therapeutic strategies under the ities occur in about 0.5% of live births, they account for almost heading of phenotypic modification: correction, excision, and half of first trimester abortions and 6% of stillbirths. They are transplantation. They are the province of our surgical colleagues. responsible for as much as 1 % of pediatric admissions and 3% I wish to focus on the strategy of correction and the following of childhood deaths. Collectively, then, the burden of genetic disease targets: congenital heart defects, cleft lip and palate, and diseases in the population is huge: a 5% incidence in all live pyloric stenosis. Because these three disease entities affect nearly births; 30% of pediatric inpatient admissions; and nearly half of 1.5% of all live-born babies (that is, -30% of all children with childhood deaths (1-3). genetic diseases) and because at least half of such children are Treatment and cure. The second term requiring definition is cured by a single surgical procedure, it is apparent that we now treatment, which refers simply to the management and care of a cure between 10 and 15% of children with genetic disease. This patient with the purpose of combating disease and effecting a is a much larger fraction than most doctors and patients realize. cure. The third term, cure, is slightly harder to define. To cure The strategies of excision and transplantation, too, yield cures, is often defined broadly as to restore health by successful treat- but in a far smaller number of children and adults. They affect s 10 TREATING GENETIC DISEASE: LESSONS FROM THREE CHILDREN s11 Table 1. Human genetic diseases* Impact Incidence Pediatric (per 100 inpatient Childhood live admissions deaths Category births) (%) (%I Prominent examples Multifactorial traits 3-4 20 30 Congenital heart defects Neural tube abnormalities Pyloric stenosis Cleft lip/palate Juvenile diabetes Single-gene defects Cystic fibrosis Sickle cell anemia Phenylketonuria Muscular dystrophy Chromosomal abnormalities 3 Down syndrome Fragile X syndrome Turner syndrome * Data extracted from references 1-3. Table 2. Treatment of genetic diseases: uhenotvuic modification excess in the urine, but the pattern was not specific and all other Prominent disease indices ofglomerular or tubular function were normal. He finally succumbed to progressive cardiorespiratory insufficiency at age Strategy targets 12. Significantly, an older sister and brother had died with a Correction Congenital heart disease virtually identical clinical picture at ages 8 and 7, respectively Cleft lip/palate (6). The remainder of the family history was unremarkable, save Pyloric stenosis the secret of a half-sib sister born out of wedlock (Fig. 1C). Neural tube abnormalities Let me emphasize the two lessons I derived from working with Steven. First, he taught me the power of the single clinical Excision Retinoblastoma scientific experience. He contributed enormously to my aca- Wilm's tumor demic development by personally attracting me to clinical re- Colonic polyposis search, to the field of genetics, to the area of amino acid metab- Polydactyly olism, and to the care and study of children. He helped me much more than I helped him. Second, because we did not know what Transplantation Dilated cardiomyopathy kind of disease he had and because there were no reports of Polycystic kidney disease similar patients in the literature, our therapeutic efforts were Osteopetrosis symptomatic and ultimately unsuccessful. His pedigree certainly suggested an autosomal recessive trait, but that was all we knew. the net fractional cure figure only in a small way because of the Parenthetically, I have not encountered nor have I noted in the infrequency of the conditions for which these modalities are literature another example of this familial disorder despite 30 employed. years of looking. Given the very efficacious results of such phenotypic modifi- cation, it is a bit hard to understand why successful treatment of EFFICACY OF TREATING SINGLE-GENE DEFECTS genetic disease is generally perceived to be such a rare event. The explanation, I believe, is that we ordinarily restrict our thinking Although our limited capacity to intervene successfully on about genetic diseases to the single gene defects and chromosomal behalf of children with single-gene defects has long been talked abnormalities, where, as you shall see, our therapeutic triumphs about, it was documented convincingly in 1985 in an important are relatively few in number. paper by Charles Scriver, Barton Childs, and their colleagues, Ailish Hayes and Teresa Costa (7). CHILD 1: STEVEN These investigators reviewed the eficacy of treatment of 35 1 diseases due to single-gene defects chosen randomly from Mc- It is in this vein that I wish to comment on the first of the Kusick's catalog of mendelian inheritance in man (8). Signifi- three children mentioned earlier. The patient, Steven, was a cantly, the gene product or involved locus was identified in only white male whose early growth and development was entirely 15% of these conditions.
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