During his lifetime the practicing ophthalmologist will see more than a few retinitis pigmentosa cases. It is his responsibility not only to diagnose and prognosticate this eye disease, but also to set aside a little time in which to advise the patient and his family on its genetic aspects

Noah, Van B.

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Genetic Counseling 1n Retinitis Pigmentosa VAN B. NOAH, M.D. During his lifetime the practicing ophthalmol-ogist will see more than a few retinitis pigmentosa cases. It is his responsibility not only to diagnose and prognosticate this eye disease, but also to set aside a little time in which to advise the patient and his family on its genetic aspects. Retinitis pigmentosa has been established as a definite hereditary disorder. Therefore, the most important factor to consider for accurate coun-seling is the family history. Unfortunately, for one reason or another, this is not always available, and the investigator may need to rely on the nature and severity of the disease, examination of other mem-bers of the family; and the presence of other dis-orders. Pseudoretinitis pigmentosa caused by in-flammation or drugs should be ruled out. Family pedigrees of typical retinitis pigmentosa exist for nearly every known mode of genetic transmission. Over 90% of these pedigrees are con-cerned with an autosomal recessive gene, while 3 % to 6% are related to an autosomal dominant gene. X-linked genes constitute 1 % to 3% and may be recessive, intermediate, or dominant. It is important to recognize the mode of trans-mission in individual cases. Unless this is done, no reliable eugenic advice can be forthcoming. The autosomal recessive mode of inheritance is characterized by an unrevealing family history, al-though a history of consanguinity may be' discovered (opinions vary, but this could be as high as 40%). This form of the disease is serious, with complete blindness by age fifty to sixty usually the rule. Parents of affected individuals are phenotypically normal. Also characteristic of the recessive gene is the frequent association with other disorders. Such co-existing anomalies may offer a clue to the reces-sive nature of this gene when family history is lack-ing. The relationship of retinitis pigmentosa to any congenital anomaly is too great to be explained by mere coincidence. Most notable are afflictions of MCV QUARTERLY 8(4): 283-285, 1972 the aural, metabolic, genitourinary, musculoskeletal, and central nervous systems. Ten to 40% of retinitis pigmentosa is associated with sensorineural hearing defects alone, either congenital or acquired and with or without mutism. Deafness may be late or incom-plete, and in such instances it is manifested initially by loss of the higher frequency sounds. Indeed, approxi-mately 10% of all children with this type of hearing defect will later show signs of retinitis pigi:nentosa. The penetrance of the involved gene for hearing loss varies among the members of a pedigree of reti-nitis pigmentosa. Probably a single gene with pleio-tropic action is responsible for this close association, and not a situation of polygenic heredity. Of par-ticular interest is the fact that approximately 13 % of heterozygotes demonstrate slight loss of hearing; thus an audiometric examination of non-affected members as well as affected members of a pedigree may prove valuable in determining recessiveness . The CNS associations comprise mostly dience-phalic-hypophyseal manifestations. Epilepsy may be present, as well as mental retardation, EEG ab-normalities, and psychiatric disorders (most notably, recurrent depressive episodes, schizophrenia, and paranoia). Metabolic disorders are usually those of the lipidoses. Many of these genetic combinations form vety interesting and well-recognized syndromes: Usher's Syndrome-retinitis pigmentosa deaf-mutism Hallgren's Syndrome-retinitis pigmentosa, congenital deafness, vestibulo-cerebellar ataxia, schizophrenia-like symptoms, men-tal deficiency Re/sum's Syndrome-atypical retinitis pig-mentosa, polyneuritis, spinocerebellar ataxia Cockayne's Syndrome-retinitis pigmentosa, dwarfism, deafness Bassen-Kornzweig Syndrome-atypical retini-tis pigmentosa, acanthocytosis, Fried-reich 's ataxia 283 284 NOAH: GENETIC COUNSELING IN RETINITIS PIGMENTOSA Spielmeyer-Vogt Syndrome-:--retinitis pigmen-tosa, multiple CNS manifestations Kearns-Sayre Syndrome-retinitis pigmentosa, heart block, progressive ophthalmoplegia extern a Laurence-Moon-Bardet-Biedl Syndrome-re-tinitis pigmentosa, obesity, hypogeni-talism, polydactyly, mental retardation Hurler's Syndrome (and other mucopolysac-charidoses )-retinitis pigmentosa, cor-neal haze, gargoylism The autosomal recessive form of retinitis pig-mentosa is also associated with other eye disorders. Myopia of over two diopters is present in 30 to 40 % . Keratoconus and glaucoma occur more fre-quently than in the normal population. The autosomal dominant mode of transmission is usually more benign and much later in onset. Related congenital anomalies are not common; hearing loss is rare. Complicated cataracts are, however, more common than in the recessive form . At least three consecutive generations of affected individuals should be elicited from the family his-tory to firmly establish this mode of inheritance. But this gene is not always regular; it may skip one or more generations, although such an occurrence is rare. According to most genetic investigators, muta-tions do not occur. This form of retinitis pigmentosa is apparently on the increase because of the gene's dominant nature and because "survival of the fit-test" hardly holds true in today's society. Since one-half of an affeded person's offspring (without re-gard to sex) will similarly be affected, prevention of such requires sterilization or abstinence from procreation. Proper thinking on the part of most should dictate their not bringing into the world others who inevitably would go blind. Counseling should be guided by this philosophy. Pseudodominance refers to that situation where an affected individual (with recessive genes) mates with a heterozygous person, resulting in one-half of offspring affected. Such circumstances could easily fool the investigator into believing a domiriant gene to be responsible. Consanguinity is almost always the rule in these cases. The X-linked mode of inheritance is, as pre-viously mentioned, of three types. Generally these modes are manifested by retinitis pigmentosa of the severest order. Of these, the X-linked recessive is the most frequent. in nearly 100% of such cases there is myopia of greater than two diopters. The X-linked dominant is very rare and typically abortive with little pigment. In this instance the female carrier is herself affected, usually at a later age. The X-linked intermediate form is equally rare. Of par-ticular interest is the so-called "tapetoretinal reflex" in the female carrier, a brilliant silvery scintillatiori more pronounced in the macular area but covering the entire fundus in many cases. The affected males may have choroidal sclerosis in addition to the pig-mentary degeneration. Female carriers should be made aware that half of their male offspring will be affected. Affected males should realize that all of their daughters will be carriers. In offering genetic counseling, one would be wise to realize that patients and members of their families prefer that probability figures be expressed as "odds." Fraser Robert's yardstick, specifically that one of 40 random pregnancies will yield a child with one or more congenitai anomalies, should sug-gest to the physician that absolute assurance might not be a sound policy. The autosomal dominant and X-linked modes of transmission are easily recognized in most instances, and the subsequent counseling is rather straightforward. Most counseling will, of course, be concerned with the autosomal recessive gene. Here one would do well to remember an important statistic. The frequency of affected homozygous persons within the human population is one in twenty thousand. If "p" is the frequency of the normal gene and "q" the frequency of the defective gene, then p + q = 1. Squaring both sides gives p2 + 2pq '+ q2 = 1, which is the binominal equation of probability. Here, p2 is the frequency of normal homozygotes, 2pq of nor-mal heterozygotes, and q2 of affected hcimozygotes. Since q2 = 1/ 20,000, then q = 1/ 141 , this being the frequency of the defective gene. The frequency of heterozygotes is thus 2pq = (2) (1 - 1/ 141) (1/ 141), or 1/ 71. This means that the prob-ability that an affected individual married to a normal person with no family history of the disease will give birth to an affected child is ( 1h )( 1/ 71), or one chance out of 142. The probability that a known heterozygote married to a normal person will have an affected child is ( 14 ) ( 1 / 71), or one chance out of 284. These odds are more than favorable, and the physician is not justified in recommend-ing that such individuals should not rear children. Eugenically speaking, such needless advice would serve only to reduce very slightly the frequency of the defective gene, and at the sacrifice of the happi-ness derived from a new face in the home. NOAH: GENETIC COUNSELING IN RETINITIS PIGMENTOSA 285 BIBLIOGRAPHY DUKE-ELDER, SIR STEWART AND DOBREE, JOHN H. System of Ophthalmology. Vol. X, Diseases of the Retina. St. Louis, C. V. Mosby Co., 1967. FRAN<;OIS, JULES. Heredity in Ophthalmology. St. Louis, C. V. Mosby Co., 1961. GEERAETS, WALTER J. Ociliar Syndromes. 2nd ed. , Phil-adelphia, Lea & Febiger, 1969. WALSH, FRANK B. AND HOYT, WILLIAM FLETCHER. Clinical Neuro-ophtlwlmology. Baltimore, Williams & Wilkins Co., 1969. 

Genetic Counseling in Retinitis Pigmentosa

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Genetic Counseling in Retinitis Pigmentosa

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