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Genetics and the Congenital Glaucomas*
AMERICAN J O U R N A L OF OPHTHALMOLOGY DECEMBER, 1965
VOLUME 60
NUMBER 6
GENETICS AND T H E CONGENITAL GLAUCOMAS* XXI
EDWARD JACKSON MEMORIAL LECTURE ROBERT N.
SHAFFER,
M.D.
San Francisco, California
Dr. Edward Jackson was born in 1856 and died in 1942. Although ophthalmic literature has been enriched by hundreds of his contributions, his consuming interest was in promotion of the education of the American ophthalmologist. He founded the AMERICAN JOURNAL OF OPHTHALMOLOGY, whose parent organization, the Ophthalmic Publishing Company, sponsors this lecture. He was president of our American Academy and of the American Ophthalmological Society, and was elected the first president of the American Board of Ophthalmology in honor of his efforts in founding this first examining board of a specialty group in the United States. Most of us in this meeting never had the opportunity to know this giant of American ophthalmology, but all of us are deeply in his debt. To find a subject worthy of Dr. Jackson and of this Academy is a challenging task. The title "Genetics and the congenital glaucomas" has been chosen because of my longterm interest in the subject and because of the. recent amazing developments in the knowledge of genetics and of the congenital anomalies. Environmental factors have held center stage for a century. During this time we have seen great advances in physical diagnosis and knowledge of disease processes, culminating in the largely successful victory * From the Department of Ophthalmology, University of California Medical Center. Presented at the 69th annual session of the American Academy of Ophthalmology and Otolaryngology, Chicago, October 18-23, 1964. 981
over most of the micro-organisms in the past 25 years. It now seems obvious that this generation and the next are to be plagued by embryonic, metabolic and degenerative conditions of genetic origin. Until recently it seemed futile to speculate about such diseases because it had been generally understood that only environmental factors are amenable to control. Discoveries in the biochemical field make new insight into genetic processes a certainty, and actual control of some of those processes an intriguing possibility. The importance of these genetic concepts in the future practice of medicine cannot be overemphasized. Except for those recently out of training, we tend to become a bit vague about the terminology and even the principles. It is the underlying purpose of this paper to review these principles in brief. It is the specific purpose to emphasize that all the primary glaucomas are of genetic origin ; to consider what eye physicians can do to prevent blindness in these glaucomas ; and, hopefully, to kindle interest in the entire area of genetically determined disease. INTRODUCTION TO GENETICS
Since the days of Mendel and Darwin, the science of genetics has trod a path lined by freaks and family pedigrees. Another offshoot of biology, biochemistry, has followed a divergent trail of analysis and synthesis of organic matter. Events of the last 20 years have brought these separate paths together into the exciting new highway of molecular genetics.
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ROBERT N. SHAFFER
The first event was the discovery that mutations within the organism can alter the chemical composition of the enzyme proteins, resulting in their inactivation. The second event was the demonstration by Avery, MacLeod and McCarty 3 that the mysterious substance which induced colonies of pneumococci to alter their appearance and properties was the nucleoprotein desoxyribonucleic acid, or DNA. Confirmation came from Hershey and Chase15 in the third event, when they showed that the nucleoprotein of bacteria which was responsible for their characteristic inheritance was also desoxyribonucleic acid. The unification of the two fields came in the fourth event, which was the deduction of the chemical structure of this genetic material by Watson and Crick,24 who inferred from its structure the mechanism of DNA replication and of spontaneous mutation. Finally, Grunberg and her colleagues14 and Kornberg 18 brought about the synthesis of DNA in a cell-free system containing the four nucleotides, the enzyme polymerase and a small amount of DNA to "prime" the reaction. Both DNA and ribonucleic acid (RNA) have been synthesized in vitro and self-duplication has been realized. Lack of both time and talent prevents more than a cursory description of the wonders of the DNA duplicating machinery. We know that each cell is endowed with the potentialities of its parent and passes on to its offspring those potentialities, unaged and undiluted—essentially immortal. NATURE OF THE GENETIC CODE
During cell division, the genetic material is inert, being packaged into the stubby, compact bodies known as chromosomes. These are only a few micra in length. After cell division, the condensed DNA of the chromosomes unravels into a loose form which may be 10 million microns or a meter in length when fully extended. This forms the blueprint, the code of instruction for the manufacture of any living thing, from a
virus to an ophthalmologist. The differentiated cell loses its mantle of immortality to serve the total organism in a specialized capacity. Cells which are likely to be injured, such as the epithelial cells, retain their capacity for regeneration. With aging, this ability slows down. In the highly specialized cells of the nervous system, all replacement capacity is lost. Natural death occurs only in multicellular organisms. Strehler21 states, "Senescence is the price the organism pays for the luxury of differentiation." The molecule, desoxyribonucleic acid, which contains the essential genetic information, is formed of a double-stranded helix of desoxyribose and phosphate. The two long fibers coil about each other and are held together by links resembling the rungs of a long spiral ladder. The rungs of the ladder consist of two of the four purine or pyrimidine bases, guanine, adenine, cytosine and thymine. Each pair fits together to form one rung. The sequence of these bases along the two long ribbons acts like areas of altered magnetism along a tape recorder ribbon to carry the instructions for the manufacture of thousands of protein-buildingblocks. These four bases are like a four-letter alphabet which must be translated into the 20-letter alphabet representing the 20 amino acids. It has been calculated that a simple 100-unit chain of a coded repeat of four components would introduce 10" variants. This is a number vastly in excess of the total living organisms of earth, air and ocean.9 The DNA of a mammalian cell may carry as many as 500 million base pairs, so we can see that the DNA replicating tape is infinite in detail, but of relatively simple construction. During the process of replication, the double spiral of the DNA molecule unwinds at the incredible speed of 10,000 revolutions per second. The base pairs are now split and available to pick up their complementary base from the nucleotides of the cytoplasm of the cell. A duplicate of the original
GENETICS AND THE CONGENITAL GLAUCOMAS
DNA helix will be formed if the cell is a parent cell, or some part of the organism will be formed if it is a differentiated cell. The DNA of the cells does not directly participate in protein synthesis. The long unwound ribbon serves as a template for the formation of smaller molecules, called RNA or ribonucleic acid, which are implanted with the information. The DNA in the nucleus is like a master template kept in the front office of a factory. It is used to stamp out a die of ribonucleic acid, "messenger RNA," which in small segments carries information to the ribosomes within the cytoplasm of cells where the individual protein is to be manufactured (figs. 1, 2 and 3). Many of these proteins are enzymes. From a chemical point of view, in any physical system there is a certain probability that any possible reaction will occur. Living systems use catalysts to increase the probability that certain reactions will predominate. In this way the enzymes serve as directors of the course of chemical reaction in the body.
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Fig. 2 (Shaffer). Model of DNA molecule as new base pairs fit into the exposed code. (Life Magazine, © Time, Inc., 1963. All rights reserved ) MUTATIONS AND THE MOLECULAR DISEASES
Fig. 1 (Shaffer). Model of DNA molecules. The two strands begin to separate. (Life Magazine, © Time Inc., 1963. All rights reserved.)
With the infinite complexities of the master template, DNA, it would be surprising if copying errors did not appear. It is now becoming obvious that many so-called "metabolic" or "abiotrophic" diseases arc inherited because during the replicating process in some ancestor the pattern slipped and a malpositioning of a base pair resulted —called a mutation. For example, the code of three base pairs, ATT, results in the manufacture of tyrosinase. If the die were incorrectly stamped ATA, no tyrosine could be produced ; the child could not form melanin and would have albinism. Since biochemistry is now proving the chemical characteristics of these metabolic disorders, they should probably be called "molecular diseases." Most mutations are lethal because of the widespread defects in the development of various systems. Some may be of little importance to the health of the organism and escape notice. Of others it has been
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ROBERT N. SHAFFER
Fig. 3 (Shaffer). Model of the formation of two new DNA molecules in the completion of replication. (Life Magazine, © Time Inc., 1963. All rights reserved.) said, "Mistakes are made in the reproduction of cells; evolution turns such mistakes —mutations—into history." 21 It should be pointed out that there has been a basic change in Mendel's concept of dominant and recessive inheritance. It has been thought that a recessive gene was completely subservient to its companion dominant gene in the hétérozygote and could become clinically apparent only when a pair of recessive genes was present in the homozygous individual. It now seems definite that a mild, but clinically detectable, form of a recessively inherited disease can sometimes be caused by one recessive gene in the hétérozygote. Sickle-cell anemia in Negroes is a good example of a condition with both homozygous and heterozygous expression. The defect of the red blood corpuscles which causes sickling is the result of a defective copying mechanism. Ingram 16 demonstrated by the fragmentation of the molecule of hemoglobin with its complex chain
of about 300 amino acids, that the abnormality was due to a small difference in its chemical constitution—the substitution of valine for the glutamic acid found in normal hemoglobin in an identifiable position. The inheritance of this recessive gene from both parents (homozygosity) expresses itself in childhood as a profound and often fatal anemia. When only one such gene is inherited (heterozygosity), the red blood cell abnormality does not become manifest until adulthood, and then in the relatively benign form of ischémie necrosis of the femur or a kind of Eales' disease of the peripheral retina. Infants with galactosemia are known to be unable to convert galactose to glucose, and they develop cataracts, mental deficiency and hepatosplenomegaly. This is caused by an inherited defect in the enzyme galactose1-phosphate uridyl transferase. The heterozygous parents of such patients have a partial deficiency of transferase, but do not have the disease. Thus, in many diseases the carrier state of a single recessive gene may be demonstrable by extremely careful examination, by enzymatic assays, or by various provocative tests. It is quite probable that such a situation has been discovered in the elevated intraocular pressures which have been caused by the prolonged local or systemic use of corticosteroids. DOMINANT AND RECESSIVE INHERITANCE OF THE GLAUCOMAS
The molecular defect responsible for the congenital glaucomas is completely unknown, but there is general agreement on the usual mode of inheritance. The term congenital glaucoma has been reserved for those inherited conditions in which the anomaly is demonstrable at birth. Infantile glaucoma is the most prevalent, but all are quite rare. Symptoms of infantile glaucoma usually appear during the first year of life, with the great majority occurring before six months. Infantile glaucoma is recessively inherited, which means that both the parents are heter-
GENETICS AND THE CONGENITAL GLAUCOMAS
985
Fig. 4 (Shaffer). Goniophotograph of aniridia, showing short stub of peripheral iris.
ozygous, carrying the abnormal gene and passing it on to 25 percent of their children (gN X gN = gg + gN + gN + N N ) . Fifty percent of the children are heterozygous and will be carriers of the recessive glaucoma gene ( g N ) . These form the reservoir in the general population which produces the sporadic cases of infantile glaucoma when they crossmate. The pool of pathologic genes is much smaller than in open-angle glaucoma, being estimated by Delmarcelle8 to have a prevalence of 0.028 in the population. It is for this reason that an ophthalmologist will seldom see more than a half-dozen cases of infantile glaucoma in a lifetime of practice. Most of the other glaucoma-associated anomalies tend to be dominantly inherited. These include aniridia, neurofibromatosis, Sturge-Weber's syndrome, and Axenfeld's syndrome or iridocorneal mesodermal dysplasia. Often increased pressure does not become manifest in the first years of life and may be delayed into adulthood (figs. 4, 5, 6 and 7).
Now what contributions can genetics make to the understanding of the so-called primary glaucomas? It is quite certain that the configuration of the anterior chamber which results eventually in angle-closure glaucoma is genetically determined. Törnquist22 measured the anterior chambers of 398 persons with normal eyes in various age
Fig. S (Shaffer). Bilateral Sturge-Weber syndrome
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R O B E R T N. S H A F F E R
Fig. 6 (Shaffer). Axenf eld's syndrome with microcornea and glaucoma.
groups. With increasing age there was a decrease in depth, but truly shallow chambers were very rare. When he studied relatives of 49 patients who had had typical attacks of acute angle-closure glaucoma, he found that their anterior chambers were significantly shallower than were normal values for the corresponding age. Investigation of 45 pairs of identical twins confirmed the genetic determination. The discovery that local corticosteroid
therapy could cause an increase in intraocular pressure resembling chronic open-angle glaucoma came as a shocking surprise to ophthalmologists.7·10'13 In the investigations which followed, it became apparent that only predisposed persons responded to corticosteroids by pronounced increases in pressure. The nature of this predisposition has been the subject of a great deal of investigation, particularly by Becker4"7 and Armaly. 1 ' 2 It is now apparent that most patients who have proven primary openangle glaucoma will respond to the use of corticosteroid eyedrops by a decreased facility of outflow and a rise in pressure. A similar response can be produced in most children of known open-angle glaucoma patients. An unexpected finding is that the pronounced response occurs in 35 percent of normal volunteers of all ages (tables 1 and 2). These findings cast doubt on the currently held belief in the dominant inheritance of primary open-angle glaucoma. Dominant inheritance can be easily proved, because 50 percent of the offspring will manifest the disease. The careful testing of families of known open-angle
Fig. 7 (Shaffer). Goniophotograph of Axenf eld's syndrome with many iris processes.
GENETICS AND T H E CONGENITAL GLAUCOMAS
987
TABLE 1 COMPARISON OF PRESSURE RESPONSES TO CORTICOSTEROID EYEDROPS (BETAMETHASONE) OF GLAUCOMA, GLAUCOMA SUSPECTS, VOLUNTEERS AND GLAUCOMA OFFSPRING (ALL AGES)*
Diagnosis Glaucoma Suspects Volunteers Offspring
No. Patients
%—Water Provocative Po/C>100
Po/C>100
C<0.18
A>6
50 50 50 75
100 100 0 47
100 100 30 97
98 96 32 96
92 80 32 73
%—Topical Betamethasone (3--6 wk)
A=Applanation pressure. C =Outflow facility.
Po = Schi0tz pressure. * Adapted from Becker and Hahn."
glaucoma patients by water-provocative tests and tonography will bring out significant deviations from the normal in nearly 50% (fig. 8). If open-angle glaucoma is of dominant inheritance, 50% of these subjects will have the dominant gene, but the other 50% should be completely normal (Gn X nn = Gn + Gn + nn + nn). It then becomes hard to explain the tension rise produced by corticosteroid drops in 90 to 100% of such family members. However, it has been pointed out by François 11 and Waardenburg 23 that apparent dominance can be simulated by recessive inheritance if there is a large reservoir of the recessive gene in the general population. The attempt to reconcile these facts has led Dr. Bernard Becker to his hypothesis of the recessive inheritance of primary open-angle glaucoma. He has calculated that the presently known incidence of open-angle glaucoma could be produced by a prevalence of a recessive gene amounting to 0.20 in the general population. According to the HardyWeinberg law, random matings would then
GLAUCOMA RELATIVES : 5 0 9 EYiS
% 60 r
MEAN+20( PREVALENCE 2.5% IN NORMAL EYES )
49%
50
42%
38%
40
30%
30 21%
20 12% Î0
P„>2I
M
CX0.I8
P./OIOO
Fig. 8 (Shaffer). Abnormal responses in the eyes of relatives of known open-angle glaucoma patients before and after water-provocative test.*
* U S P H S grant No. N B 02415. The Collaborative Glaucoma Study, The Johns Hopkins University, Washington University, University of California, The State University of Iowa and New York University.
TABLE 2 COMPARISON OF PRESSURE RESPONSES TO CORTICOSTEROID EYEDROPS (BETAMETHASONE) OF VOLUNTEERS AND GLAUCOMA OFFSPRING 4 0 YEARS OF AGE OR YOUNGER*
Diagnosis Volunteers
Offspring
No. Patients
%—Water Provocative P o / C > 100
Po/C>100
C<0.18
A>6
0 35
25 100
25 95
25 80
20 10
See key for Table 1. * Adapted from Becker and Hahn."
%—Topical Betamethasone (3--6 wk)
ROBERT N. SHAFFER
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result in 4 % homozygotes with glaucoma ( g g ) ; ° 4 % normal homozygotes ( N N ) ; and 3 2 % heterozygous ( N g ) carriers. T h e offspring of any open-angle glaucoma patient (gg) would be certain to carry the recessive gene ( g ) whatever the genetic makeup of the mate. This would then account for the 100% responsiveness to corticosteroids of such offspring. T h e following are the possible offspring combinations which can occur when a known glaucoma patient (gg) mates: gg X gg = 100% gg (all with glaucoma) gg X NN (normal) = 100% Ng (all carriers; none with glaucoma) Kg X Ng (carriers) = 50% gg (glaucoma), 50% Ng (carriers) Finally, sporadic cases of open-angle glaucoma appear by the mating of two apparent normals who are carriers ( N g ) : Ng X Ng (2 carriers) = 25% NN (normal), 50% Ng (carriers) and 25% gg (glaucoma) W h e n normal volunteers are tested and found to be 35 percent responsive to steroids, this is easily explained by the presence of 32 percent carriers of the recessive gene ( N g ) in the general population. Dr. Becker's hypothesis is well documented and fits the facts surprisingly well. C L I N I C A L APPLICATIONS OF GENETIC CONCEPTS
It has been customary to classify the glaucomas into primary, secondary, and congenital. The definition of the primary glaucomas usually states that these are bilateral glaucomas of unknown etiology; the secondary glaucomas have a known cause; and the congenital glaucomas are caused by anomalies of the anterior chamber present at birth. It now seems obvious that a change in classification is required. T h e genetic glaucomas still include those present at birth, but they must also include the primary glaucomas, angle-closure and open-angle, which must be considered as examples of genetically determined defects whose manifestations appear later in life. Obviously no
one gene can be responsible for the various glaucoma entities, but the acceptance of a genetic origin for all the primary glaucomas removes them from the "unknown or idiopathic" category. It should re-orient the research ophthalmologist in his search for etiology and therapy of the primary glaucomas. It forces the ophthalmologist to face up to his responsibility in understanding genetic concepts and genetic counseling. P R E V E N T I O N OF BLINDNESS I N T H E CONGENITAL GLAUCOMAS
W e are well aware of the importance of early diagnosis and treatment of infantile glaucoma. I n 1954, the Symposium on Congenital Glaucoma given at the annual session of the Academy presented the statistics that the intraocular pressure of nearly 8 0 % of infants with infantile glaucoma can be controlled. 20 A note of caution should be sounded here. At the time of examination under anesthesia one must find a tension of more than 24 to 30 mm H g to justify goniotomy. Some of the other stigmas, such as actual corneal haze, corneal enlargement, tears in Descemet's membrane and the usual symptoms of photophobia and epiphora, should also be present. In a series of 30 patients with unilateral infantile glaucoma, the second, essentially normal eye was never operated upon, yet the initial tension in the second eye in all but three cases was between 20 and 29. T h e final tensions in subsequent examinations were almost all between 15 and 20. These eyes could have been unnecessarily subjected to the risk of surgery. Most of the children were still too young in 1954 for an analysis to be made of the outcome of the disease in terms of central visual acuity. Dr. Joseph H a a s at that time pointed out the danger of the development of amblyopia ex anopsia in unilateral cases. A recent study at the University of California by Dr. Kenneth Richardson has shown that the danger of amblyopia is far more prevalent than was realized and that
GENETICS AND THE CONGENITAL GLAUCOMAS 88
TENSION CONTROL <24mmHq
EYES
|
20/2020/50
VISUAL
> 20/5 0 CONTROL
Fig. 9 (Shaffer). Analysis of visual results of successful operation on eyes with infantile glaucoma. both unilateral and bilateral cases are involved, The combined patients of Drs. Barkan, Ferguson and Shaffer were used. When last tabulated, 54 patients whose ages ranged from five to 26 years had been traced. Thirtyfour of these cases were bilateral and 20 were unilateral. Complete results will be published in the future. Of the 88 eyes included in the study at this time, 92% had maintained satisfactory tension control (24 mm Hg or less). Since the goal of glaucoma therapy is control of the intraocular pressure, the ophthalmologist is tempted to be pleased with these results. However, when success of therapy in these cases was measured by visual acuity, it was disheartening to find that barely 40% of these well-controlled eyes had vision between 20/20 and 20/50. Sixty percent had vision poorer than 20/50, and many of these were poorer than 20/200—statistics which reduce the surgeon's sense of accomplishment considerably (figs. 9-12). Analysis of the 60% with poor visual acuity has brought out some interesting and significant etiologic relationships. In only 26% had there been sufficient damage to the
989
optic nerve to account for even a part of the visual loss. When a refraction was done, 65% of the patients had a marked anisometropia, amounting to a difference between the two eyes of at least 2.0D sph or 1.5D cyl. These findings were present both in unilateral and in bilateral cases. Fifty-eight percent of these anisometropic patients had a heterotropia, usually an exotropia. The conclusion which must be made from these findings is that many of these eyes lost their central visual acuity from amblyopia ex anopsia and not from the glaucomatous process itself. In the preoccupation with hypertensive aspects of the disease it is easy to forget that our primary concern must always be vision. Although goniotomy is relatively easy for the practiced surgeon, every step must be performed meticulously. Unless the ophthalmologist is willing to maintain his skill in angle surgery by continuing practice on animal eyes and by gonioscoping infant eyes, he should refer these rare cases to medical centers for definitive therapy. If the child is operated upon at such a center, it is the duty of the surgeon to point out both to the parents and to the referring ophthalmologist that in these cases the patient must be handled like a patient with strabismus, with early refraction and patching of the better eye. GLAUCOMA IN THE YOUNG
The term juvenile glaucoma has long been used for glaucoma in the young. It is a poor term because it includes early developing open-angle and angle-closure glaucoma, latedeveloping infantile glaucoma, and the various congenital anomalies of the anterior segment. It is generally agreed that the term juvenile either should be deleted entirely or should be used only as a modifier of the true diagnosis in order to indicate the age of the patient.12'19·25 Most young people have deep anterior chambers with a perfectly flat iris plane. The presence of even a moderately shallow
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990
P.E. EYE IN BILATERAL CASE WITH POORER VISION. BOTH EYES HAVING GOOD TENSION CONTROL. U. E. INVOLVED EYE IN BILATERAL CASE
P. E.
U.E.
ANISOMETROPIA
P. E. DISC
U. E. DAMAGE
ALL EYES INCLUDED HAVE GOOD CONTROL BUT VISION <20/S0
TENSION
Fig. 10 (Shaffer). Analysis of visual results, showing that poor vision is due to anisometropia rather than disc damage.
PERCENTAGE OF VISION CONTROL % loo80-
BILATERAL CASES BOTH EYES WITH GOOD TENSION CONTROL
ALL WITH GOOD TENSION CONTROL
Fig. 11 (Shaffer). Analysis of visual results of successful operations on eyes with infantile glaucoma.
anterior chamber merits investigation. Shallow chambers and narrow angles are uncommon at any age group, as was shown by a study with Drs. Ariah Schwartz and William van Herick of the University of California. In the Shaffer-van Herick series of 3,251 normal patients of all ages, only 3.3% had angles which were considered capable of occlusion. Of the 108 eyes with angles graded 2 (20 degrees) or less, only three, or 0.1% were truly critically narrowed, and these were in patients over 50 years of age. One 25-year-old man had grade 2 anterior chamber angles. On questioning, it was found that his father had had bilateral acute glaucoma at the age of 45 years. As this patient gets older, the lens will get larger ; the relative pupillary block will increase; the angles will narrow and angle closure will be likely. Here is an excellent example of a patient who can be kept out of severe trouble by instructing him and his family to have
GENETICS AND THE CONGENITAL GLAUCOMAS
991
< 20/50
SIGNIFICANT ANISOHETERODISC METROPIA TROPIA I CHANGE I I EYES WITH GOOD TENS ION CONTROL ("BILATERAL & UNILATERAL CASES INCLUDED) Fig. 12 (Shaffer). Graph shows anisometropia and heterotropia in eyes with poor vision.
increasingly frequent follow-up examinations as he gets older. An open-angle glaucoma which appears in young adults is pigmentary glaucoma. We know that some family members will have a typical depigmentation of the iris, a dense trabecular pigment band, a Krukenberg's spindle and yet not have obvious glaucoma, while others in the same family can have typical open-angle glaucoma without abnormal pigmentation. It has recently been shown by Becker that all family members of patients with pigmentary glaucoma have a positive corticosteroid response.5 The time of onset of the trabecular pigmentation is not known. Our earliest case was diagnosed by Dr. William van Herick in a 15-year-old boy whose mother had pigmentary glaucoma. An unusual example of pigmentary glaucoma was seen in the father of a family manifesting the congenital anomalies of Waardenburg's syndrome (figs. 13-15). He and his daughter also had the typical brachycephaly, lateral displacement
Fig. 13 (Shaffer). Negro man with pigmentary glaucoma whose family manifests the congenital anomalies of Waardenburg's syndrome.
992
R O B E R T N. S H A F F E R
Fig. 14 (Shaffer). Dense frahecular pigment band in the angle of the patient shown in Figure 13.
of canthi, hearing defect, patch of white hair and blue eyes despite their Negro ancestry. It should no longer be necessary to warn ophthalmologists of the danger of prolonged use of corticosteroid drops. We are continuing to see the results of damage produced by such therapy before its side-effects were known. Just recently a 12-year-old boy was seen who had had a severe vernal conjunctivitis. For over a year he had been using Prednefrin-F drops daily. When glaucoma was diagnosed, his tensions were over 50 mm Hg and extensive cupping and posterior subcapsular cataracts were present in both eyes. This implies that marked damage can occur to the optic nervehead in a relatively short period of unremittingly high intraocular pressures. The problem of therapy in these young people is difficult, as we all know. In contrast to more mature patients, they are less apprehensive over a chronic ailment, less reliable in the use of medications which
Fig. 15 (Shaffer). Daughter of patient shown in Figure 13.
GENETICS AND THE CONGENITAL GLAUCOMAS handicap them visually, less likely to have successful filtering surgery, and less faithful in their return for follow-up examinations. These negative problems are aggravated by the sad fact that the majority of these young people with glaucoma have severely damaged optic nerves before the condition is diagnosed. T h e task of maintaining a lifetime of vision becomes discouragingly difficult. Many tragedies could have been averted if an earlier diagnosis had been made. H e r e is another area of responsibility for the ophthalmologist in the genetic field. W e can hardly take intraocular pressures of eyes in the whole population every two or three years, but we can urge patients with glaucoma to have their parents, their siblings and their children checked periodically. T h e glaucoma we pick u p in our 45-year-old presbyopic patient often has had its onset in his 30's. H e either has had no reason to visit the ophthalmologist, or no tension was taken earlier because the books tend to urge tension examinations only on "everyone over the age of 40." This should really be changed to read that the intraocular pressure should be measured in any patient old enough to co-operate. Tensions at the upper edge of normal and differences of tension between the two eyes will undoubtedly be found and will be sight-saving for some of these youngsters. The optic disc is always examined by the ophthalmologist in any routine eye examination. Like any routine part of an examination there is a tendency to perform ophthalmoscopy indifferently because no abnormality is expected in the young. An atrophie cupped disc in an adult looks startlingly white, but in the young there may be less contrast between it and the surrounding retina. Particularly in myopic eyes, this can be disastrous, as the myopic cup is shallower and less obvious than in the hyperopic patient. It is sometimes necessary to use the slitlamp with a fundus contact lens or the H r u b y lens to prove the presence of cup-
993
ping. A good example of this problem was seen last year in a beautiful high-school senior. She had had contact lenses prescribed by an excellent ophthalmologist and had spent the summer vacation trying to get used to them. She continued to complain of hazy vision after wearing the glasses, and eventually complained of poor vision in one eye. A re-examination revealed a tension of over 50 mm H g in each eye, extensive shallow cupping of the discs, vision decreased to 20/50 in one eye due to papillomacular bundle involvement, and a field loss to the five-degree isopter in the other. If we made diagrams of all discs, it would force us to look more keenly at the pattern of the cup and would help to avoid tragedies like this one. Finally, the ophthalmologist has a real obligation to bring this genetic concept of the glaucomas to the family physicians, the internists and the pediatricians. It is important that they recognize the obvious anomalies like aniridia or the Sturge-Weber syndrome, and the tearing, haze and enlarging cornea of infantile glaucoma. T h e y must know that early care of such cases by the eye physician helps guard these children from visual loss. Physicians should recognize the symptoms and the shallow anterior chamber of angle-closure glaucoma. They must realize that open-angle glaucoma causes no symptoms. Therefore, the complete examination of older patients should include an ocular tension check or periodic referral to the ophthalmologist. In all of these cases it should be stressed that family members are potentially involved. With the primary glaucomas recognized as genetically determined, it becomes vital for each ophthalmologist to ask every patient he sees whether there has been any history of glaucoma in his family. If so, the patient should be urged to have all of his family checked periodically. T h e most promising method for picking up early primary glaucoma is to follow the family members. The mere mention of the term glaucoma has
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ROBERT N. SHAFFER
publicity value and increases the public's awareness of the menace of the chronic form of this disease, which is certain to become of increasing importance as the human life span lengthens. CONCLUSION It is tempting to project this interest in biogenetics into the future. T h e whole field of pharmacogenetics 17 is now being explored, and it is hoped that this will add to our understanding of responsiveness and resistance to medications. It is to be hoped that
the biochemists may identify some of the enzyme systems responsible for the glaucomas and may lead us to more effective therapy. Since it is probable that environmental factors from intrauterine life to the grave have modifying effects on the various genes involved, it is hoped that physicians may learn to use such factors therapeutically. As a matter of fact, one has greater confidence that the geneticists will learn how to modify the human race than that the human race will use that information constructively. 490 Post Street (2).
REFERENCES
1. Armaly, M. F. : Effect of corticosteroids on intraocular pressure and fluid dynamics : I. the effect of dexamethasone in the normal eye. Arch Ophth., 70 :482-491 (Oct.) 1963. 2. : Effect of corticosteroids on intraocular pressure and fluid dynamics: II. the effect of dexamethasone in the glaucomatous eye. Arch Ophth., 70:492-499 (Oct.) 1963. 3. Avery, O. T., MacLeod, C. M., and McCarty, M. : Studies on the chemical nature of the substance inducing transformation of pneumococcal types. J. Exper. Med., 79 :137-1S8 (Feb.) 1944. 4. Becker, B. : Personal communication. 5. : Cited in Glaucoma Research Conference. June 25-27, 1964, Am. J. Ophth., 58:1065-1068 (Dec.) 1964. 6. Becker, B., and Hahn, K. A. : Topical corticosteroids and heredity in primary open-angle glaucoma. Am. J. Ophth., 57 :543-S51 (April) 1964. 7. Becker, B., and Mills, D. W. : Elevated intraocular pressure following corticosteroid eye drops. JAMA, 185:884-886 (Sept. 14) 1963. 8. Delmarcelle, Y. : Considerations sur l'hérédité du glaucome infantile. J. Genet. Hum. 6:33-48 (May) 1957. 9. Duke-Elder, S.: System of Ophthalmology: Vol. VII, The foundations of ophthalmology: heredity, pathology, diagnosis and therapeutics. St. Louis, Mosby, 1962, p. 38. 10. François, J. : Glaucome apparemment simple, secondaire â la cortisonothérapie locale. Ophthalmologica, 142 (Suppl) :517-523, 1961. 11. —: Heredity in Ophthalmology, St. Louis, Mosby, 1961. 12. François, J., Deweer, J.-P., and Van den Berghe, J. : Glaucome chronique simple a hérédité dominante. Ann Ocul., 184:404-422, 1951. 13. Goldmann, H.: Cortisone glaucoma. Arch. Ophth., 68:621-626 (Nov.) 1962. 14. Grunberg-Manago, M., Ortiz, P. T-, and Ochoa, S. : Enzymatic synthesis of nucleic acidlike polynucleotides. Science, 122:907-910 (Nov.)"l9S5. 15. Hershey, A. D., and Chase, M. : Independent functions of viral protein and nucleic acid in growth of bacteriophage. J. Gen. Physiol., 36 :39-56 (Sept.) 1952. 16. Ingram, V. M. : Abnormal human hemoglobins. Proc. Roy. Med., 51:645-646 (Aug.) 1958. 17. Kalow, W. : Pharmacogenetics: heredity and response to drugs. Philadelphia, Saunders, 1962. 18. Kornberg, A.: Enzymatic synthesis of deoxyribonucleic acid. Harvey Lect., 53:83-112, 1957-1958. 19. Malbran, E., and Dodds, R. : Megalocornea and its relation to congenital glaucoma. Am. J. Ophth., 49:908-921 (May, Pt. I) 1960. 20. Meyer, 'S. J., moderator : Symposium : Congenital glaucoma. Tr. Am. Acad. Ophth. Otolary., 59 : 297-345 (May-June) 1955. 21. Strehler, B. L. : Time, Cells and Aging, New York, Academic Press, 1962. 22. Tornquist, R. : Shallow anterior chamber in acute glaucoma. Acta Ophth. (Suppl. 39) 31:1-74, 1953. 23. Waardenburg, P. J., Franceschetti, A., and Klein, D. : Genetics and Ophthalmology, Springfield, 111., Thomas, 1961. 24. Watson, J. D., and Crick, F. H. C. : Genetical implications of the structure of deoxyribonucleic acid. Nature, 171:964-967 (May 30) 1953. 25. Weekers, R., and Watillon, M. : Glaucome congénital sans mégalocornée. Ophthalmologica, 133 : 37-45 (Jan.) 1957.
VOLUME 60
NUMBER 6
GENETICS AND T H E CONGENITAL GLAUCOMAS* XXI
EDWARD JACKSON MEMORIAL LECTURE ROBERT N.
SHAFFER,
M.D.
San Francisco, California
Dr. Edward Jackson was born in 1856 and died in 1942. Although ophthalmic literature has been enriched by hundreds of his contributions, his consuming interest was in promotion of the education of the American ophthalmologist. He founded the AMERICAN JOURNAL OF OPHTHALMOLOGY, whose parent organization, the Ophthalmic Publishing Company, sponsors this lecture. He was president of our American Academy and of the American Ophthalmological Society, and was elected the first president of the American Board of Ophthalmology in honor of his efforts in founding this first examining board of a specialty group in the United States. Most of us in this meeting never had the opportunity to know this giant of American ophthalmology, but all of us are deeply in his debt. To find a subject worthy of Dr. Jackson and of this Academy is a challenging task. The title "Genetics and the congenital glaucomas" has been chosen because of my longterm interest in the subject and because of the. recent amazing developments in the knowledge of genetics and of the congenital anomalies. Environmental factors have held center stage for a century. During this time we have seen great advances in physical diagnosis and knowledge of disease processes, culminating in the largely successful victory * From the Department of Ophthalmology, University of California Medical Center. Presented at the 69th annual session of the American Academy of Ophthalmology and Otolaryngology, Chicago, October 18-23, 1964. 981
over most of the micro-organisms in the past 25 years. It now seems obvious that this generation and the next are to be plagued by embryonic, metabolic and degenerative conditions of genetic origin. Until recently it seemed futile to speculate about such diseases because it had been generally understood that only environmental factors are amenable to control. Discoveries in the biochemical field make new insight into genetic processes a certainty, and actual control of some of those processes an intriguing possibility. The importance of these genetic concepts in the future practice of medicine cannot be overemphasized. Except for those recently out of training, we tend to become a bit vague about the terminology and even the principles. It is the underlying purpose of this paper to review these principles in brief. It is the specific purpose to emphasize that all the primary glaucomas are of genetic origin ; to consider what eye physicians can do to prevent blindness in these glaucomas ; and, hopefully, to kindle interest in the entire area of genetically determined disease. INTRODUCTION TO GENETICS
Since the days of Mendel and Darwin, the science of genetics has trod a path lined by freaks and family pedigrees. Another offshoot of biology, biochemistry, has followed a divergent trail of analysis and synthesis of organic matter. Events of the last 20 years have brought these separate paths together into the exciting new highway of molecular genetics.
982
ROBERT N. SHAFFER
The first event was the discovery that mutations within the organism can alter the chemical composition of the enzyme proteins, resulting in their inactivation. The second event was the demonstration by Avery, MacLeod and McCarty 3 that the mysterious substance which induced colonies of pneumococci to alter their appearance and properties was the nucleoprotein desoxyribonucleic acid, or DNA. Confirmation came from Hershey and Chase15 in the third event, when they showed that the nucleoprotein of bacteria which was responsible for their characteristic inheritance was also desoxyribonucleic acid. The unification of the two fields came in the fourth event, which was the deduction of the chemical structure of this genetic material by Watson and Crick,24 who inferred from its structure the mechanism of DNA replication and of spontaneous mutation. Finally, Grunberg and her colleagues14 and Kornberg 18 brought about the synthesis of DNA in a cell-free system containing the four nucleotides, the enzyme polymerase and a small amount of DNA to "prime" the reaction. Both DNA and ribonucleic acid (RNA) have been synthesized in vitro and self-duplication has been realized. Lack of both time and talent prevents more than a cursory description of the wonders of the DNA duplicating machinery. We know that each cell is endowed with the potentialities of its parent and passes on to its offspring those potentialities, unaged and undiluted—essentially immortal. NATURE OF THE GENETIC CODE
During cell division, the genetic material is inert, being packaged into the stubby, compact bodies known as chromosomes. These are only a few micra in length. After cell division, the condensed DNA of the chromosomes unravels into a loose form which may be 10 million microns or a meter in length when fully extended. This forms the blueprint, the code of instruction for the manufacture of any living thing, from a
virus to an ophthalmologist. The differentiated cell loses its mantle of immortality to serve the total organism in a specialized capacity. Cells which are likely to be injured, such as the epithelial cells, retain their capacity for regeneration. With aging, this ability slows down. In the highly specialized cells of the nervous system, all replacement capacity is lost. Natural death occurs only in multicellular organisms. Strehler21 states, "Senescence is the price the organism pays for the luxury of differentiation." The molecule, desoxyribonucleic acid, which contains the essential genetic information, is formed of a double-stranded helix of desoxyribose and phosphate. The two long fibers coil about each other and are held together by links resembling the rungs of a long spiral ladder. The rungs of the ladder consist of two of the four purine or pyrimidine bases, guanine, adenine, cytosine and thymine. Each pair fits together to form one rung. The sequence of these bases along the two long ribbons acts like areas of altered magnetism along a tape recorder ribbon to carry the instructions for the manufacture of thousands of protein-buildingblocks. These four bases are like a four-letter alphabet which must be translated into the 20-letter alphabet representing the 20 amino acids. It has been calculated that a simple 100-unit chain of a coded repeat of four components would introduce 10" variants. This is a number vastly in excess of the total living organisms of earth, air and ocean.9 The DNA of a mammalian cell may carry as many as 500 million base pairs, so we can see that the DNA replicating tape is infinite in detail, but of relatively simple construction. During the process of replication, the double spiral of the DNA molecule unwinds at the incredible speed of 10,000 revolutions per second. The base pairs are now split and available to pick up their complementary base from the nucleotides of the cytoplasm of the cell. A duplicate of the original
GENETICS AND THE CONGENITAL GLAUCOMAS
DNA helix will be formed if the cell is a parent cell, or some part of the organism will be formed if it is a differentiated cell. The DNA of the cells does not directly participate in protein synthesis. The long unwound ribbon serves as a template for the formation of smaller molecules, called RNA or ribonucleic acid, which are implanted with the information. The DNA in the nucleus is like a master template kept in the front office of a factory. It is used to stamp out a die of ribonucleic acid, "messenger RNA," which in small segments carries information to the ribosomes within the cytoplasm of cells where the individual protein is to be manufactured (figs. 1, 2 and 3). Many of these proteins are enzymes. From a chemical point of view, in any physical system there is a certain probability that any possible reaction will occur. Living systems use catalysts to increase the probability that certain reactions will predominate. In this way the enzymes serve as directors of the course of chemical reaction in the body.
983
Fig. 2 (Shaffer). Model of DNA molecule as new base pairs fit into the exposed code. (Life Magazine, © Time, Inc., 1963. All rights reserved ) MUTATIONS AND THE MOLECULAR DISEASES
Fig. 1 (Shaffer). Model of DNA molecules. The two strands begin to separate. (Life Magazine, © Time Inc., 1963. All rights reserved.)
With the infinite complexities of the master template, DNA, it would be surprising if copying errors did not appear. It is now becoming obvious that many so-called "metabolic" or "abiotrophic" diseases arc inherited because during the replicating process in some ancestor the pattern slipped and a malpositioning of a base pair resulted —called a mutation. For example, the code of three base pairs, ATT, results in the manufacture of tyrosinase. If the die were incorrectly stamped ATA, no tyrosine could be produced ; the child could not form melanin and would have albinism. Since biochemistry is now proving the chemical characteristics of these metabolic disorders, they should probably be called "molecular diseases." Most mutations are lethal because of the widespread defects in the development of various systems. Some may be of little importance to the health of the organism and escape notice. Of others it has been
984
ROBERT N. SHAFFER
Fig. 3 (Shaffer). Model of the formation of two new DNA molecules in the completion of replication. (Life Magazine, © Time Inc., 1963. All rights reserved.) said, "Mistakes are made in the reproduction of cells; evolution turns such mistakes —mutations—into history." 21 It should be pointed out that there has been a basic change in Mendel's concept of dominant and recessive inheritance. It has been thought that a recessive gene was completely subservient to its companion dominant gene in the hétérozygote and could become clinically apparent only when a pair of recessive genes was present in the homozygous individual. It now seems definite that a mild, but clinically detectable, form of a recessively inherited disease can sometimes be caused by one recessive gene in the hétérozygote. Sickle-cell anemia in Negroes is a good example of a condition with both homozygous and heterozygous expression. The defect of the red blood corpuscles which causes sickling is the result of a defective copying mechanism. Ingram 16 demonstrated by the fragmentation of the molecule of hemoglobin with its complex chain
of about 300 amino acids, that the abnormality was due to a small difference in its chemical constitution—the substitution of valine for the glutamic acid found in normal hemoglobin in an identifiable position. The inheritance of this recessive gene from both parents (homozygosity) expresses itself in childhood as a profound and often fatal anemia. When only one such gene is inherited (heterozygosity), the red blood cell abnormality does not become manifest until adulthood, and then in the relatively benign form of ischémie necrosis of the femur or a kind of Eales' disease of the peripheral retina. Infants with galactosemia are known to be unable to convert galactose to glucose, and they develop cataracts, mental deficiency and hepatosplenomegaly. This is caused by an inherited defect in the enzyme galactose1-phosphate uridyl transferase. The heterozygous parents of such patients have a partial deficiency of transferase, but do not have the disease. Thus, in many diseases the carrier state of a single recessive gene may be demonstrable by extremely careful examination, by enzymatic assays, or by various provocative tests. It is quite probable that such a situation has been discovered in the elevated intraocular pressures which have been caused by the prolonged local or systemic use of corticosteroids. DOMINANT AND RECESSIVE INHERITANCE OF THE GLAUCOMAS
The molecular defect responsible for the congenital glaucomas is completely unknown, but there is general agreement on the usual mode of inheritance. The term congenital glaucoma has been reserved for those inherited conditions in which the anomaly is demonstrable at birth. Infantile glaucoma is the most prevalent, but all are quite rare. Symptoms of infantile glaucoma usually appear during the first year of life, with the great majority occurring before six months. Infantile glaucoma is recessively inherited, which means that both the parents are heter-
GENETICS AND THE CONGENITAL GLAUCOMAS
985
Fig. 4 (Shaffer). Goniophotograph of aniridia, showing short stub of peripheral iris.
ozygous, carrying the abnormal gene and passing it on to 25 percent of their children (gN X gN = gg + gN + gN + N N ) . Fifty percent of the children are heterozygous and will be carriers of the recessive glaucoma gene ( g N ) . These form the reservoir in the general population which produces the sporadic cases of infantile glaucoma when they crossmate. The pool of pathologic genes is much smaller than in open-angle glaucoma, being estimated by Delmarcelle8 to have a prevalence of 0.028 in the population. It is for this reason that an ophthalmologist will seldom see more than a half-dozen cases of infantile glaucoma in a lifetime of practice. Most of the other glaucoma-associated anomalies tend to be dominantly inherited. These include aniridia, neurofibromatosis, Sturge-Weber's syndrome, and Axenfeld's syndrome or iridocorneal mesodermal dysplasia. Often increased pressure does not become manifest in the first years of life and may be delayed into adulthood (figs. 4, 5, 6 and 7).
Now what contributions can genetics make to the understanding of the so-called primary glaucomas? It is quite certain that the configuration of the anterior chamber which results eventually in angle-closure glaucoma is genetically determined. Törnquist22 measured the anterior chambers of 398 persons with normal eyes in various age
Fig. S (Shaffer). Bilateral Sturge-Weber syndrome
986
R O B E R T N. S H A F F E R
Fig. 6 (Shaffer). Axenf eld's syndrome with microcornea and glaucoma.
groups. With increasing age there was a decrease in depth, but truly shallow chambers were very rare. When he studied relatives of 49 patients who had had typical attacks of acute angle-closure glaucoma, he found that their anterior chambers were significantly shallower than were normal values for the corresponding age. Investigation of 45 pairs of identical twins confirmed the genetic determination. The discovery that local corticosteroid
therapy could cause an increase in intraocular pressure resembling chronic open-angle glaucoma came as a shocking surprise to ophthalmologists.7·10'13 In the investigations which followed, it became apparent that only predisposed persons responded to corticosteroids by pronounced increases in pressure. The nature of this predisposition has been the subject of a great deal of investigation, particularly by Becker4"7 and Armaly. 1 ' 2 It is now apparent that most patients who have proven primary openangle glaucoma will respond to the use of corticosteroid eyedrops by a decreased facility of outflow and a rise in pressure. A similar response can be produced in most children of known open-angle glaucoma patients. An unexpected finding is that the pronounced response occurs in 35 percent of normal volunteers of all ages (tables 1 and 2). These findings cast doubt on the currently held belief in the dominant inheritance of primary open-angle glaucoma. Dominant inheritance can be easily proved, because 50 percent of the offspring will manifest the disease. The careful testing of families of known open-angle
Fig. 7 (Shaffer). Goniophotograph of Axenf eld's syndrome with many iris processes.
GENETICS AND T H E CONGENITAL GLAUCOMAS
987
TABLE 1 COMPARISON OF PRESSURE RESPONSES TO CORTICOSTEROID EYEDROPS (BETAMETHASONE) OF GLAUCOMA, GLAUCOMA SUSPECTS, VOLUNTEERS AND GLAUCOMA OFFSPRING (ALL AGES)*
Diagnosis Glaucoma Suspects Volunteers Offspring
No. Patients
%—Water Provocative Po/C>100
Po/C>100
C<0.18
A>6
50 50 50 75
100 100 0 47
100 100 30 97
98 96 32 96
92 80 32 73
%—Topical Betamethasone (3--6 wk)
A=Applanation pressure. C =Outflow facility.
Po = Schi0tz pressure. * Adapted from Becker and Hahn."
glaucoma patients by water-provocative tests and tonography will bring out significant deviations from the normal in nearly 50% (fig. 8). If open-angle glaucoma is of dominant inheritance, 50% of these subjects will have the dominant gene, but the other 50% should be completely normal (Gn X nn = Gn + Gn + nn + nn). It then becomes hard to explain the tension rise produced by corticosteroid drops in 90 to 100% of such family members. However, it has been pointed out by François 11 and Waardenburg 23 that apparent dominance can be simulated by recessive inheritance if there is a large reservoir of the recessive gene in the general population. The attempt to reconcile these facts has led Dr. Bernard Becker to his hypothesis of the recessive inheritance of primary open-angle glaucoma. He has calculated that the presently known incidence of open-angle glaucoma could be produced by a prevalence of a recessive gene amounting to 0.20 in the general population. According to the HardyWeinberg law, random matings would then
GLAUCOMA RELATIVES : 5 0 9 EYiS
% 60 r
MEAN+20( PREVALENCE 2.5% IN NORMAL EYES )
49%
50
42%
38%
40
30%
30 21%
20 12% Î0
P„>2I
M
CX0.I8
P./OIOO
Fig. 8 (Shaffer). Abnormal responses in the eyes of relatives of known open-angle glaucoma patients before and after water-provocative test.*
* U S P H S grant No. N B 02415. The Collaborative Glaucoma Study, The Johns Hopkins University, Washington University, University of California, The State University of Iowa and New York University.
TABLE 2 COMPARISON OF PRESSURE RESPONSES TO CORTICOSTEROID EYEDROPS (BETAMETHASONE) OF VOLUNTEERS AND GLAUCOMA OFFSPRING 4 0 YEARS OF AGE OR YOUNGER*
Diagnosis Volunteers
Offspring
No. Patients
%—Water Provocative P o / C > 100
Po/C>100
C<0.18
A>6
0 35
25 100
25 95
25 80
20 10
See key for Table 1. * Adapted from Becker and Hahn."
%—Topical Betamethasone (3--6 wk)
ROBERT N. SHAFFER
988
result in 4 % homozygotes with glaucoma ( g g ) ; ° 4 % normal homozygotes ( N N ) ; and 3 2 % heterozygous ( N g ) carriers. T h e offspring of any open-angle glaucoma patient (gg) would be certain to carry the recessive gene ( g ) whatever the genetic makeup of the mate. This would then account for the 100% responsiveness to corticosteroids of such offspring. T h e following are the possible offspring combinations which can occur when a known glaucoma patient (gg) mates: gg X gg = 100% gg (all with glaucoma) gg X NN (normal) = 100% Ng (all carriers; none with glaucoma) Kg X Ng (carriers) = 50% gg (glaucoma), 50% Ng (carriers) Finally, sporadic cases of open-angle glaucoma appear by the mating of two apparent normals who are carriers ( N g ) : Ng X Ng (2 carriers) = 25% NN (normal), 50% Ng (carriers) and 25% gg (glaucoma) W h e n normal volunteers are tested and found to be 35 percent responsive to steroids, this is easily explained by the presence of 32 percent carriers of the recessive gene ( N g ) in the general population. Dr. Becker's hypothesis is well documented and fits the facts surprisingly well. C L I N I C A L APPLICATIONS OF GENETIC CONCEPTS
It has been customary to classify the glaucomas into primary, secondary, and congenital. The definition of the primary glaucomas usually states that these are bilateral glaucomas of unknown etiology; the secondary glaucomas have a known cause; and the congenital glaucomas are caused by anomalies of the anterior chamber present at birth. It now seems obvious that a change in classification is required. T h e genetic glaucomas still include those present at birth, but they must also include the primary glaucomas, angle-closure and open-angle, which must be considered as examples of genetically determined defects whose manifestations appear later in life. Obviously no
one gene can be responsible for the various glaucoma entities, but the acceptance of a genetic origin for all the primary glaucomas removes them from the "unknown or idiopathic" category. It should re-orient the research ophthalmologist in his search for etiology and therapy of the primary glaucomas. It forces the ophthalmologist to face up to his responsibility in understanding genetic concepts and genetic counseling. P R E V E N T I O N OF BLINDNESS I N T H E CONGENITAL GLAUCOMAS
W e are well aware of the importance of early diagnosis and treatment of infantile glaucoma. I n 1954, the Symposium on Congenital Glaucoma given at the annual session of the Academy presented the statistics that the intraocular pressure of nearly 8 0 % of infants with infantile glaucoma can be controlled. 20 A note of caution should be sounded here. At the time of examination under anesthesia one must find a tension of more than 24 to 30 mm H g to justify goniotomy. Some of the other stigmas, such as actual corneal haze, corneal enlargement, tears in Descemet's membrane and the usual symptoms of photophobia and epiphora, should also be present. In a series of 30 patients with unilateral infantile glaucoma, the second, essentially normal eye was never operated upon, yet the initial tension in the second eye in all but three cases was between 20 and 29. T h e final tensions in subsequent examinations were almost all between 15 and 20. These eyes could have been unnecessarily subjected to the risk of surgery. Most of the children were still too young in 1954 for an analysis to be made of the outcome of the disease in terms of central visual acuity. Dr. Joseph H a a s at that time pointed out the danger of the development of amblyopia ex anopsia in unilateral cases. A recent study at the University of California by Dr. Kenneth Richardson has shown that the danger of amblyopia is far more prevalent than was realized and that
GENETICS AND THE CONGENITAL GLAUCOMAS 88
TENSION CONTROL <24mmHq
EYES
|
20/2020/50
VISUAL
> 20/5 0 CONTROL
Fig. 9 (Shaffer). Analysis of visual results of successful operation on eyes with infantile glaucoma. both unilateral and bilateral cases are involved, The combined patients of Drs. Barkan, Ferguson and Shaffer were used. When last tabulated, 54 patients whose ages ranged from five to 26 years had been traced. Thirtyfour of these cases were bilateral and 20 were unilateral. Complete results will be published in the future. Of the 88 eyes included in the study at this time, 92% had maintained satisfactory tension control (24 mm Hg or less). Since the goal of glaucoma therapy is control of the intraocular pressure, the ophthalmologist is tempted to be pleased with these results. However, when success of therapy in these cases was measured by visual acuity, it was disheartening to find that barely 40% of these well-controlled eyes had vision between 20/20 and 20/50. Sixty percent had vision poorer than 20/50, and many of these were poorer than 20/200—statistics which reduce the surgeon's sense of accomplishment considerably (figs. 9-12). Analysis of the 60% with poor visual acuity has brought out some interesting and significant etiologic relationships. In only 26% had there been sufficient damage to the
989
optic nerve to account for even a part of the visual loss. When a refraction was done, 65% of the patients had a marked anisometropia, amounting to a difference between the two eyes of at least 2.0D sph or 1.5D cyl. These findings were present both in unilateral and in bilateral cases. Fifty-eight percent of these anisometropic patients had a heterotropia, usually an exotropia. The conclusion which must be made from these findings is that many of these eyes lost their central visual acuity from amblyopia ex anopsia and not from the glaucomatous process itself. In the preoccupation with hypertensive aspects of the disease it is easy to forget that our primary concern must always be vision. Although goniotomy is relatively easy for the practiced surgeon, every step must be performed meticulously. Unless the ophthalmologist is willing to maintain his skill in angle surgery by continuing practice on animal eyes and by gonioscoping infant eyes, he should refer these rare cases to medical centers for definitive therapy. If the child is operated upon at such a center, it is the duty of the surgeon to point out both to the parents and to the referring ophthalmologist that in these cases the patient must be handled like a patient with strabismus, with early refraction and patching of the better eye. GLAUCOMA IN THE YOUNG
The term juvenile glaucoma has long been used for glaucoma in the young. It is a poor term because it includes early developing open-angle and angle-closure glaucoma, latedeveloping infantile glaucoma, and the various congenital anomalies of the anterior segment. It is generally agreed that the term juvenile either should be deleted entirely or should be used only as a modifier of the true diagnosis in order to indicate the age of the patient.12'19·25 Most young people have deep anterior chambers with a perfectly flat iris plane. The presence of even a moderately shallow
ROBERT N. SHAFFER
990
P.E. EYE IN BILATERAL CASE WITH POORER VISION. BOTH EYES HAVING GOOD TENSION CONTROL. U. E. INVOLVED EYE IN BILATERAL CASE
P. E.
U.E.
ANISOMETROPIA
P. E. DISC
U. E. DAMAGE
ALL EYES INCLUDED HAVE GOOD CONTROL BUT VISION <20/S0
TENSION
Fig. 10 (Shaffer). Analysis of visual results, showing that poor vision is due to anisometropia rather than disc damage.
PERCENTAGE OF VISION CONTROL % loo80-
BILATERAL CASES BOTH EYES WITH GOOD TENSION CONTROL
ALL WITH GOOD TENSION CONTROL
Fig. 11 (Shaffer). Analysis of visual results of successful operations on eyes with infantile glaucoma.
anterior chamber merits investigation. Shallow chambers and narrow angles are uncommon at any age group, as was shown by a study with Drs. Ariah Schwartz and William van Herick of the University of California. In the Shaffer-van Herick series of 3,251 normal patients of all ages, only 3.3% had angles which were considered capable of occlusion. Of the 108 eyes with angles graded 2 (20 degrees) or less, only three, or 0.1% were truly critically narrowed, and these were in patients over 50 years of age. One 25-year-old man had grade 2 anterior chamber angles. On questioning, it was found that his father had had bilateral acute glaucoma at the age of 45 years. As this patient gets older, the lens will get larger ; the relative pupillary block will increase; the angles will narrow and angle closure will be likely. Here is an excellent example of a patient who can be kept out of severe trouble by instructing him and his family to have
GENETICS AND THE CONGENITAL GLAUCOMAS
991
< 20/50
SIGNIFICANT ANISOHETERODISC METROPIA TROPIA I CHANGE I I EYES WITH GOOD TENS ION CONTROL ("BILATERAL & UNILATERAL CASES INCLUDED) Fig. 12 (Shaffer). Graph shows anisometropia and heterotropia in eyes with poor vision.
increasingly frequent follow-up examinations as he gets older. An open-angle glaucoma which appears in young adults is pigmentary glaucoma. We know that some family members will have a typical depigmentation of the iris, a dense trabecular pigment band, a Krukenberg's spindle and yet not have obvious glaucoma, while others in the same family can have typical open-angle glaucoma without abnormal pigmentation. It has recently been shown by Becker that all family members of patients with pigmentary glaucoma have a positive corticosteroid response.5 The time of onset of the trabecular pigmentation is not known. Our earliest case was diagnosed by Dr. William van Herick in a 15-year-old boy whose mother had pigmentary glaucoma. An unusual example of pigmentary glaucoma was seen in the father of a family manifesting the congenital anomalies of Waardenburg's syndrome (figs. 13-15). He and his daughter also had the typical brachycephaly, lateral displacement
Fig. 13 (Shaffer). Negro man with pigmentary glaucoma whose family manifests the congenital anomalies of Waardenburg's syndrome.
992
R O B E R T N. S H A F F E R
Fig. 14 (Shaffer). Dense frahecular pigment band in the angle of the patient shown in Figure 13.
of canthi, hearing defect, patch of white hair and blue eyes despite their Negro ancestry. It should no longer be necessary to warn ophthalmologists of the danger of prolonged use of corticosteroid drops. We are continuing to see the results of damage produced by such therapy before its side-effects were known. Just recently a 12-year-old boy was seen who had had a severe vernal conjunctivitis. For over a year he had been using Prednefrin-F drops daily. When glaucoma was diagnosed, his tensions were over 50 mm Hg and extensive cupping and posterior subcapsular cataracts were present in both eyes. This implies that marked damage can occur to the optic nervehead in a relatively short period of unremittingly high intraocular pressures. The problem of therapy in these young people is difficult, as we all know. In contrast to more mature patients, they are less apprehensive over a chronic ailment, less reliable in the use of medications which
Fig. 15 (Shaffer). Daughter of patient shown in Figure 13.
GENETICS AND THE CONGENITAL GLAUCOMAS handicap them visually, less likely to have successful filtering surgery, and less faithful in their return for follow-up examinations. These negative problems are aggravated by the sad fact that the majority of these young people with glaucoma have severely damaged optic nerves before the condition is diagnosed. T h e task of maintaining a lifetime of vision becomes discouragingly difficult. Many tragedies could have been averted if an earlier diagnosis had been made. H e r e is another area of responsibility for the ophthalmologist in the genetic field. W e can hardly take intraocular pressures of eyes in the whole population every two or three years, but we can urge patients with glaucoma to have their parents, their siblings and their children checked periodically. T h e glaucoma we pick u p in our 45-year-old presbyopic patient often has had its onset in his 30's. H e either has had no reason to visit the ophthalmologist, or no tension was taken earlier because the books tend to urge tension examinations only on "everyone over the age of 40." This should really be changed to read that the intraocular pressure should be measured in any patient old enough to co-operate. Tensions at the upper edge of normal and differences of tension between the two eyes will undoubtedly be found and will be sight-saving for some of these youngsters. The optic disc is always examined by the ophthalmologist in any routine eye examination. Like any routine part of an examination there is a tendency to perform ophthalmoscopy indifferently because no abnormality is expected in the young. An atrophie cupped disc in an adult looks startlingly white, but in the young there may be less contrast between it and the surrounding retina. Particularly in myopic eyes, this can be disastrous, as the myopic cup is shallower and less obvious than in the hyperopic patient. It is sometimes necessary to use the slitlamp with a fundus contact lens or the H r u b y lens to prove the presence of cup-
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ping. A good example of this problem was seen last year in a beautiful high-school senior. She had had contact lenses prescribed by an excellent ophthalmologist and had spent the summer vacation trying to get used to them. She continued to complain of hazy vision after wearing the glasses, and eventually complained of poor vision in one eye. A re-examination revealed a tension of over 50 mm H g in each eye, extensive shallow cupping of the discs, vision decreased to 20/50 in one eye due to papillomacular bundle involvement, and a field loss to the five-degree isopter in the other. If we made diagrams of all discs, it would force us to look more keenly at the pattern of the cup and would help to avoid tragedies like this one. Finally, the ophthalmologist has a real obligation to bring this genetic concept of the glaucomas to the family physicians, the internists and the pediatricians. It is important that they recognize the obvious anomalies like aniridia or the Sturge-Weber syndrome, and the tearing, haze and enlarging cornea of infantile glaucoma. T h e y must know that early care of such cases by the eye physician helps guard these children from visual loss. Physicians should recognize the symptoms and the shallow anterior chamber of angle-closure glaucoma. They must realize that open-angle glaucoma causes no symptoms. Therefore, the complete examination of older patients should include an ocular tension check or periodic referral to the ophthalmologist. In all of these cases it should be stressed that family members are potentially involved. With the primary glaucomas recognized as genetically determined, it becomes vital for each ophthalmologist to ask every patient he sees whether there has been any history of glaucoma in his family. If so, the patient should be urged to have all of his family checked periodically. T h e most promising method for picking up early primary glaucoma is to follow the family members. The mere mention of the term glaucoma has
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publicity value and increases the public's awareness of the menace of the chronic form of this disease, which is certain to become of increasing importance as the human life span lengthens. CONCLUSION It is tempting to project this interest in biogenetics into the future. T h e whole field of pharmacogenetics 17 is now being explored, and it is hoped that this will add to our understanding of responsiveness and resistance to medications. It is to be hoped that
the biochemists may identify some of the enzyme systems responsible for the glaucomas and may lead us to more effective therapy. Since it is probable that environmental factors from intrauterine life to the grave have modifying effects on the various genes involved, it is hoped that physicians may learn to use such factors therapeutically. As a matter of fact, one has greater confidence that the geneticists will learn how to modify the human race than that the human race will use that information constructively. 490 Post Street (2).
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1. Armaly, M. F. : Effect of corticosteroids on intraocular pressure and fluid dynamics : I. the effect of dexamethasone in the normal eye. Arch Ophth., 70 :482-491 (Oct.) 1963. 2. : Effect of corticosteroids on intraocular pressure and fluid dynamics: II. the effect of dexamethasone in the glaucomatous eye. Arch Ophth., 70:492-499 (Oct.) 1963. 3. Avery, O. T., MacLeod, C. M., and McCarty, M. : Studies on the chemical nature of the substance inducing transformation of pneumococcal types. J. Exper. Med., 79 :137-1S8 (Feb.) 1944. 4. Becker, B. : Personal communication. 5. : Cited in Glaucoma Research Conference. June 25-27, 1964, Am. J. Ophth., 58:1065-1068 (Dec.) 1964. 6. Becker, B., and Hahn, K. A. : Topical corticosteroids and heredity in primary open-angle glaucoma. Am. J. Ophth., 57 :543-S51 (April) 1964. 7. Becker, B., and Mills, D. W. : Elevated intraocular pressure following corticosteroid eye drops. JAMA, 185:884-886 (Sept. 14) 1963. 8. Delmarcelle, Y. : Considerations sur l'hérédité du glaucome infantile. J. Genet. Hum. 6:33-48 (May) 1957. 9. Duke-Elder, S.: System of Ophthalmology: Vol. VII, The foundations of ophthalmology: heredity, pathology, diagnosis and therapeutics. St. Louis, Mosby, 1962, p. 38. 10. François, J. : Glaucome apparemment simple, secondaire â la cortisonothérapie locale. Ophthalmologica, 142 (Suppl) :517-523, 1961. 11. —: Heredity in Ophthalmology, St. Louis, Mosby, 1961. 12. François, J., Deweer, J.-P., and Van den Berghe, J. : Glaucome chronique simple a hérédité dominante. Ann Ocul., 184:404-422, 1951. 13. Goldmann, H.: Cortisone glaucoma. Arch. Ophth., 68:621-626 (Nov.) 1962. 14. Grunberg-Manago, M., Ortiz, P. T-, and Ochoa, S. : Enzymatic synthesis of nucleic acidlike polynucleotides. Science, 122:907-910 (Nov.)"l9S5. 15. Hershey, A. D., and Chase, M. : Independent functions of viral protein and nucleic acid in growth of bacteriophage. J. Gen. Physiol., 36 :39-56 (Sept.) 1952. 16. Ingram, V. M. : Abnormal human hemoglobins. Proc. Roy. Med., 51:645-646 (Aug.) 1958. 17. Kalow, W. : Pharmacogenetics: heredity and response to drugs. Philadelphia, Saunders, 1962. 18. Kornberg, A.: Enzymatic synthesis of deoxyribonucleic acid. Harvey Lect., 53:83-112, 1957-1958. 19. Malbran, E., and Dodds, R. : Megalocornea and its relation to congenital glaucoma. Am. J. Ophth., 49:908-921 (May, Pt. I) 1960. 20. Meyer, 'S. J., moderator : Symposium : Congenital glaucoma. Tr. Am. Acad. Ophth. Otolary., 59 : 297-345 (May-June) 1955. 21. Strehler, B. L. : Time, Cells and Aging, New York, Academic Press, 1962. 22. Tornquist, R. : Shallow anterior chamber in acute glaucoma. Acta Ophth. (Suppl. 39) 31:1-74, 1953. 23. Waardenburg, P. J., Franceschetti, A., and Klein, D. : Genetics and Ophthalmology, Springfield, 111., Thomas, 1961. 24. Watson, J. D., and Crick, F. H. C. : Genetical implications of the structure of deoxyribonucleic acid. Nature, 171:964-967 (May 30) 1953. 25. Weekers, R., and Watillon, M. : Glaucome congénital sans mégalocornée. Ophthalmologica, 133 : 37-45 (Jan.) 1957.