Heredity of Refractive Errors
MARY A. O'HARA and LEONARD B. NELSON
Table Of Contents
THE COMPONENTS OF REFRACTION|
GENERAL THEORIES OF INHERITANCE OF AMETROPIA
INHERITANCE OF ASTIGMATISM
INHERITANCE OF HYPEROPIA
INHERITANCE OF MYOPIA
|Refractive errors have been observed in the human race since antiquity. Indeed, the
Emperor Nero was known to have observed the gladiator fights
through an emerald. Historians debate the form of refractive error
that afflicted the Roman emperor, since both concave and convex lenses
were fashioned from glass or transparent gems during this period.1|
Kepler2 was the first to define a form of ametropia when he identified myopia as a condition in 1611. At that time, he expressed the controversial belief that its cause lay in the accommodation and convergence required by near-work. This theory has been both supported and disputed by scholars for centuries.
Observations on the heredity of refractive error were first reported in 1906, when Worth presented several pedigrees that demonstrated an autosomal influence in myopia.3 Crisp expanded on this earlier work, stating that three factors were concerned in the etiology of myopia: heredity, nutrition, and the influence of study and close work.4 Subsequent investigators have sought to define the role of heredity in ametropia. A discussion of the inheritance of ametropia would not be complete without first considering the components of refraction and their role in the development of refractive errors.
|THE COMPONENTS OF REFRACTION|
|Although the eye consists of 14 optical components, total refraction of
the eye is the product of only 6: corneal curvature, anterior chamber
depth, thickness of the lens, anterior and posterior curvatures of the
lens, and axial length. Corneal curvature, power of the crystalline
lens, and axial length are believed to exert the greatest influence on
Several population studies5–8 have demonstrated that the values of each optical component are distributed in a normal binomial curve. However, considerable variation is encountered in the distributions and combinations of these different components. Stenstrom7 determined the axial length of the eyeball radiologically in 1,000 eyes. His findings are summarized in Table 1. Although there was a slight tendency for longer axes to produce myopia and shorter axes to produce hyperopia, the length of the axes varied within the same limits in different types of refraction. Thus, if axial length remained constant, the different combinations of variable but normal measurements for the first three optical components could render a total refraction ranging from +6 to -9 diopters!9
Since each component of refraction follows a normal binomial curve, it would be reasonable to assume that total refraction, the sum of these components, would also be distributed in a normal binomial curve. However, studies by Scheerer,10 Betsch,11 and Franceschetti12 have shown a leptokurtic distribution of refractive error in the measurements of 12,000 eyes when high myopia is omitted (Fig. 1).
Straub13 tried to explain a clinically observed leptokurtic distribution of refractive errors by proposing a process of emmetropization in which the eye tends toward emmetropia by adapting its optical components. Hartridge14 observed that a leptokurtic distribution of refractive errors could also be possible because of greater chance combinations. Nonetheless, several theories about emmetropization have been proposed.
Sorsby and associates8 assumed the retina to be the primary cause of axial length. This “genetic organizer” regulated the size of the sclera, which then determined the curvature of the cornea. Thus, a long eye is compensated by a flat cornea, producing emmetropia.
Van Alphen15 used factor analysis to identify a genetic factor responsible for axial length and corneal curvature, a second factor involving lens power and chamber depth, and a “stretch” factor related to ciliary muscle tone and controlled by the autonomic system and subcortical centers. He postulated that all three factors were interrelated. Thus, stress may lead to hyperopia through parasympathetic overactivity.16
Sorsby and Leary17 conducted a longitudinal study of refraction and its components during childhood and concluded that compensatory mechanisms, in addition to biological growth, can produce emmetropia. Sixty-eight children were examined between the ages of 3 and 8 years and again between the ages of 8 and 14 years. One group showed a decrease in hyperopia of no more than 1.3 D. This group had a mean axial elongation of 0.88 mm. The second group showed a much greater decrease in hyperopia and a greater mean axial elongation (1.62 mm). Sorsby18 postulated the mechanism for this emmetropization to be “largely automatic.”
Emmetropization may also be vision dependent. Rabin and co-workers19 reported the refractions of persons with early disruption of vision from several causes (e.g., cataract, retinopathy of prematurity) and found a high incidence of myopia. They proposed that early disruption of visual experience disrupted the emmetropization process. When the emmetropization of the eye was disrupted, ametropia resulted.
|GENERAL THEORIES OF INHERITANCE OF AMETROPIA|
|Controversy exists over the exact etiology of ametropia. However, most
investigators agree that heredity is an important component. Early studies
delineated pedigrees that supported autosomal dominant, autosomal
recessive, and X-linked recessive inheritance patterns.4,20–31 Multifactorial inheritance has also been proposed.24 Several authors suggest that heredity does not play a role in the development
of refractive errors.5,32,33 Many investigators noted that high ametropias were transmitted differently
than low ametropias and were often associated with other ocular anomalies.34 Individual ocular components are not considered in many of these studies.|
Twin studies have been used in an effort to further delineate the influence of multiple factors on the heredity of refractive errors. In classic twin research, monozygotic (MZ) twins share identical genetic material and, if raised together, the same environment. Dizygotic (DZ) twins, on the other hand, only share one fourth of their genetic material but do share the same environment if raised together. Concordance rates in both groups are analyzed for the trait under study. If the concordance rate of a trait in MZ twins approaches 100%, while the same rate in DZ twins is significantly less, then genetic transmission is likely. When the concordance rates between MZ and DZ twins do not differ significantly, environmental influences and other random factors assume greater importance in the etiology of the trait under study.
Jablonski35 was the first to recognize the importance of twin studies in ametropia. In 1922, he reported his findings in 28 pairs of MZ twins and 23 pairs of DZ twins. Jablonski found essentially the same refraction in each member of a MZ twin pair. Rarely did the refraction differ more than 0.5 D. In the DZ twins, however, no concordance was noted.
To identify trends in inheritance of refractive errors through twin studies, Waardenberg25,36 reviewed the findings of several other investigators and found a high concordance for hyperopia and low to moderate myopia in MZ twins. He reported on 300 pairs of MZ and 225 pairs of DZ twins. High myopia was excluded from the study. Ninety percent of the MZ twin pairs had less than 1-D difference in refraction. The DZ twins were discordant. Occasional discordance was found in MZ twin pairs. The differences between MZ twin pairs tended to decrease with age, while the differences between DZ twin pairs tended to increase with age. Weekers and colleagues37 examined 14 MZ twin pairs and 14 DZ twin pairs and found results that were similar to those reported by Waardenberg.25,36 Hyperopia and astigmatism were very similar in the MZ twin pairs. High myopia, however, showed wide variations.
Conflicting results have been reported by Otsuka,38 who examined 295 pairs of twins and found no significant difference in refractive error correlation between MZ and DZ twins. Orth39 reported differences in refraction between MZ twins. In one MZ twin pair with identical optical components, one twin had a refraction of -24.00 Sphere/ -25.00 sphere while the other was emmetropic.
Several twin studies were able to document good concordance in MZ twin pairs despite differences in environment. Lisch40 examined a MZ pair with identical myopia despite the fact that one twin had a job involving constant close work while the other did not. Jancke and Holste41 compared 72 MZ twin pairs with 68 DZ twin pairs and found similar refractions in MZ twins despite the fact that one member of each twin pair engaged in strenuous near-work while the other twin did not.
Sorsby and co-workers42 studied 78 MZ twin pairs, 40 DZ twin pairs, and 48 unrelated pairs. Their criteria for concordance was agreement of refraction within 0.50 D. They found concordance was not equally good for all refractive states in the MZ twin pairs. Concordance was high for refractions near emmetropia but not so high for larger refractive errors. Low to moderate astigmatism (0.75–2.0 D) exhibited a high incidence of concordance in the MZ twin pairs. DZ twin pairs and the control pairs both exhibited poor concordance for this level of astigmatism, All pairs showed poor concordance with higher degrees of astigmatism (greater than 2.00 D).
Sorsby and co-workers42 then went on to investigate the separate components of refraction in each of the pairs. Generally, there was an incidence of concordance of 70% to 80% for most of the components of refraction in the MZ twin pairs. The exact numbers are summarized in Table 2.
Only slight concordance for components of refraction was found in the DZ twin and control pairs.
Thus, twin studies have shown heredity to be an important factor in determining refraction. However, different forms of ametropia appear to be influenced by different patterns of inheritance. A discussion of the inheritance patterns of each of the individual forms of ametropia is, therefore, warranted.
|INHERITANCE OF ASTIGMATISM|
|François9 has stated that the only certain data about inheritance of ametropia are
that which are concerned with corneal refraction and astigmatism. Steiger5 noted in 1913 that persons with corneal astigmatism tended to have descendants
Similarly afflicted. Twin studies confirm his observation by
demonstrating high concordance rates for astigmatism in MZ twin pairs
and discordance in DZ twins.27,35–37,43–52|
Several family studies have documented pedigrees that transmit not only degree and variety of astigmatism (hyperopic vs. myopic) but also length of the axis itself. The majority of these studies demonstrate an autosomal dominant form of genetic transmission.9,30,47,53–61 Autosomal recessive transmission has been shown occasion ally.47,61 Rarely, X-linked recessive pedigrees have also been reported.62
Rieger and Thums63,64 were so impressed by the similarity in type, degree, and axis of astigmatism exhibited in twin studies and family pedigrees that they proposed astigmatism as a criterion in investigations of disputed paternity.
Astigmatism has rarely been associated with other inherited or sporadic conditions. Zeki65 has reported an association between astigmatism and optic nerve hypoplasia. Astigmatism has also been demonstrated in several forms of albinism.66
|INHERITANCE OF HYPEROPIA|
|The comparative ophthalmology studies of Kardo Sysoeff67 have shown that hyperopia is the most frequent refraction found in mammals, birds, reptiles, amphibians, and fish. Degree of hyperopia is higher
in the smaller animals. Generally, the more highly developed animals
tend toward lower degrees of hyperopia. The most frequent refraction
in humans is a low degree of hyperopia.|
The hereditary character of hyperopia has been demonstrated by numerous twin studies.35,37,44,45,47,49 This hyperopic concordance in MZ twins tends to persist unchanged throughout life. Environmental factors apparently do not exert a great influence.
Differences in inheritance patterns have been encountered in persons with different degrees of hyperopia. Low hyperopes (up to +6 D) exhibit different inheritance patterns than high hyperopes (over +6 D). In addition, highly hyperopic eyes have an increased incidence of pathologic associations.
High hyperopia, on the other hand, is rather uncommon. Most extreme forms, often associated with abnormalities of the eye such as microcornea, can be classified as microphthalmia. Most studies demonstrate an autosomal recessive pattern of genetic transmission.30,69–73 Consanguinity of parents has been found frequently.73–75 Rarely, autosomal dominant transmission has been reported.68,76,77
|INHERITANCE OF MYOPIA|
|Investigations into the cause of myopia have engendered more passionate
debate than those into all other forms of ametropia combined. Twin studies
have helped to establish the hereditary nature of myopia. In general, investigators
make a distinction between low and moderate myopia (up
to -6 D) and high myopia (greater than -6 D).|
A large number of twin studies of low to moderate myopia have been published. The majority show a high degree of concordance in MZ twin pairs when compared with DZ twin pairs.35,37,41–43,45–48,51,83–97 However, occasional examples of discordance between MZ twin pairs have also been reported.39,43,97–105 Concordance rates for myopia in MZ twin pairs have been observed to decrease as the degree of myopia in creases.39,43,50,88,99–105 In addition, the number of twin studies dealing with MZ twins with high myopia is much smaller. However, good concordance has been noted in several studies of high myopia in MZ twins.35,43,48,89,96,100,103,106–110
Although twin studies establish heredity as an important factor in the etiology of myopia, there is very little consensus as to the exact mode of inheritance of myopia. There are several reasons for this.111
Many authors argue that pathologic myopia is an entity distinct from physiologic myopia. However, few genealogic studies make this distinction. Physiologic myopia is mixed with pathologic myopia, confounding the data. In addition, a large number of ocular and systemic diseases are associated with myopia. Many times, cases of myopia associated with an inherited condition are inadvertently included in studies of pedigrees of myopia.
Environmental factors also seem to play a role in influencing the hereditary patterns of myopia. However, this is a particularly controversial area. Many authors contest the exact role of the environment, but the majority believe that the person's environment impacts greatly on penetrance and expressivity of myopia.
Difficulties are also encountered in sampling populations. Many studies incorporate children. Since myopia tends to progress into early adulthood, the artifactitiously low degree of myopia or lack of myopia in young children could adversely effect genealogic studies.
In addition, the mode of inheritance of each of the components of refraction has not been fully established. Separate inheritance patterns and hereditary correlations are unknown. However, it is known from Stenstrom's data7 that axial length alone does not determine degree of myopia.
Thus, several factors combine to confound genetic studies of myopia. Nonetheless, most genealogic studies demonstrate a significant familial prevalence of myopia, although there is not good agreement on a single mode of inheritance.
Low to moderate myopia has most commonly been found to be transmitted as an autosomal dominant trait.8,23–26,68,84,112 Autosomal recessive transmission has also been observed by several investigators.4,35,113,114 X-linked recessive transmission has been reported rarely.4,20,22,27 Several studies have also proposed a polygenic pattern of inheritance.8,115
High myopia has been described in several studies as exhibiting characteristics of both autosomal dominant and autosomal recessive inheritance.24,26,30,116 Some authors have documented pure autosomal dominant inheritance,9,117 while others have observed pure autosomal recessive inheritance.68,118 X-linked recessive inheritance is rarely described.119
In an attempt to clarify the conflicting data presented in genealogical studies of myopia, several authors have examined inheritance patterns in each of the separate components of refraction. An attempt was made to relate the inheritance patterns of the separate components of refraction to that of total myopic refraction.
Sorsby and co-workers8 conducted the first large study of components of refraction but were unable to draw any conclusions about the inheritance of myopia. Nakajima120,121 studied the heritability of the individual optical components in twins. Corneal and lens thickness, anterior chamber depth, and radius of curvature of the lens surface were all discordant. Axial length and the other remaining components of refraction all demonstrated concordance. Alsbirk122–125 studied several components of refraction in Greenland Eskimos and found strong heritability for the components measured (60%–80%). However, total ocular refraction demonstrated low heritability, He attributed this finding to environmental effects.
Familial resemblance of myopia has been noted by several authors to be greatest between siblings and less between parent and offspring.125–128 The greater sibling resemblance reopens the question of the role of environment versus heredity in the etiology of myopia.
The genetics versus environment dilemma in myopia is best summed up by Goldschmidt,84 who believed that myopia is unlikely to be the product of single gene transmission. His analysis of proband families and review of the literature found persons with low to moderate myopia had similar values for each of their components of refraction. High myopes, on the other hand, were a wildly heterogeneous group. This led him to propose a polygenic inheritance pattern for myopia.
It is conceivable that environment may have a substantial impact on this polygenic inheritance. Krill29 has observed that myopia produced by multiple genes is particularly susceptible to environmental influences. Indeed, myopia has many associations with systemic syndromes, both inherited and sporadic (Table 4).111,130–133 A large number of ocular conditions are also associated with myopia (Table 5).111,134–136
Chromosome 18 partial deletion (long-arm) syndrome
Cornelia de Lange syndrome
Hereditary ectodermal dysplasia syndrome
Meyer-Schwickerath and Weyers (oculodentodigital) syndrome
Obesity-cerebral-ocular-skeletal anomalies syndrome
Pierre Robin syndrome
Pigmentary ocular dispersion syndrome
Riley-Day syndrome syndrome
Wrinkly skin syndrome
Bilateral blepharoptosis, ectopia lentis and high myopia syndrome
Congenital scleral ectasia
Congenital stationary night blindness
Familial exudative vitreoretinopathy
Hereditary retinal detachment
Myelinated nerve fibers
Nystagmus with or without amblyopia
Progressive bifocal chorioretinal atrophy
To examine the role played by environment in the development of myopia, animal models have been employed. Many of these animal studies focus on the induction of myopia by artificial manipulation of the environment.
The earliest report of an animal model for myopia was made in 1929 when Levensohn137 reported the induction of myopia in macaque monkeys enclosed in a box with their heads held horizontally and extended beyond a table. His results were disputed by subsequent authors.138,139 Young140 went On to induce myopia in monkeys exposed to a restricted visual space.
Wiesel and associates141 serendipitously found myopia in visually deprived macaque monkeys in their investigations on amblyopia and monocular visual deprivation. Wiesel and Raviola142 went on to show that unilateral lid suture produced high degrees of myopia in macaque monkeys. The degree of myopia was related to the age of the monkey at the time of the lid suture and the duration of the experiment. Axial length and equatorial diameter were increased while the anterior segment was essentially unchanged (Fig. 2). However, when lid-sutured monkeys were raised in the dark, axial lengths and refractions were normal.143 The mechanism of induction of myopia was believed to be reduction in patterned retinal images. To confirm this theory, corneal opacities were then caused in monkeys by injection of a fine suspension of polystyrene beads. This also increased the axial length, while leaving the anterior segment unchanged, thus confirming the investigator's suspicions.144
In 1985, Raviola and Wiesel145 reported a series of experiments that extended their work on induction of myopia. In this series, they explored the role of the central nervous system on eye growth. Removal of the striate cortex had no effect on lid-suture myopia. Topical atropine (and removal of the ciliary ganglion) had no effect on lid-suture myopia in three rhesus macaque monkeys but prevented myopia in four stump-tailed macaques. Isofluorophate, which produces ciliary spasm, had no effect on the development of myopia in both rhesus and stump-tailed macaques. Sympathetic denervation and trigeminal section likewise failed to alter progression of myopia. Optic nerve section prevented myopia in one stump-tailed macaque but failed to prevent lid-fusion myopic progression in three rhesus macaques when all four monkeys underwent unilateral lid fusion and intracranial section of the optic chiasm.
Raviola and Wiesel's work has shown that lid suture (i.e., visual deprivation) causes myopia. Other investigators have documented a similar arrest of emmetropization with disruption of vision. Guyton and colleagues146 found that the eyes of dark-reared rhesus monkeys remained close to the hyperopia common in the neonatal period. Von Noorden and Crawford147 failed to achieve consistent results in their study of lid closure, suggesting that emmetropization may be disrupted in both directions. In reexamining these results, Smith and co-workers148 found myopia after lid suture in 43 of 47 monkeys. Several avian models of myopia are under investigation.149
Clinical models of vision deprivation myopia have also been reported. Unilateral birth injuries of the cornea have been observed to progress toward myopia.150,151 Myopia and increased axial length have been observed in persons with corneal opacities.152 A unilateral posterior subcapsular cataract was noted to be associated with axial myopia in the affected eye in one of a pair of MZ twins.153 Von Noorden and Lewis154 reported on 10 patients with unilateral aphakia. In 7 of these patients, the affected eye demonstrated an axial myopia. Robb155 described orbital and adnexal hemangiomas associated with unilateral ametropia, usually high myopia, in young children. Hoyt and co-workers156 have found a similar association of axial myopia in neonatal lid closure from a variety of causes. Rabin and associates19 found unilateral myopia in association with several monocular visual anomalies. They also reported bilateral myopia in several patients with binocular anomalies. These clinical observations confirm the findings of experimental models of myopia-visual deprivation can produce myopia by interrupting the emmetropization process.
One of the most controversial environmental factors in the development of myopia is its association with near-work (“use-abuse” theory). In general, there is agreement that near-work does not play a substantial part in the development of pathologic myopia. The early presentation of pathologic myopia, usually before reading age, and its lack of correlation with occupations involved in intensive near-work have made “use-abuse” unlikely in this form of myopia.84,157,158
However, studies abound concerning near-work and its role in the development and progression of low and moderate degrees of myopia. Cohn159 first noted an association between education and the development of myopia in 1886. In more recent years, Young and colleagues160 examined schoolchildren in Pullman, Washington, and found myopia most commonly in the school children who did the most near-work. Nadell and co-workers161 found no significant difference in the amount of time spent on near-work by myopic and non-myopic high school students. Angle and Wissmann162 found no significant effect of near-work on refraction in their regression analysis study. Richler and Bear,163 however used multiple regression coefficients in their study and found near-work to induce myopia in the school population who were 5 to 14 years of age.
Several populations have been studied in an effort to determine the role of near-work in the genesis of myopia. Sorsby164 studied the frequency of myopia among Jewish and non-Jewish children in London and found increased prevalence of myopia in the Jewish children. Myopic shift during the school years, however, was equal in both groups. Sorsby attributed the increased prevalence of myopia in the Jewish children to hereditary influence. Young and co-workers128 studied 508 Eskimo subjects and found myopia rarely in parents and grandparents. However, 58% of the children were myopic. This was attributed to the introduction of Western-style education during the past generation. Post165 compared the refractions of Gabon blacks, Eskimos, Germans, Swedes, and Britons. The Europeans manifested excesses of both hyperopia and myopia. This increased incidence of ametropia in the subjects of industrialized nations was attributed to “relaxation of the pressures of natural selection.” The Chinese population is noted to have a very high incidence of myopia, but 90% of the population is illiterate. Similarly, literate European settlers and native tribesmen in equatorial Africa both display the same incidence of myopia.165 Thus, the controversy surrounding the “use-abuse” theory rages on.
|Twin studies have confirmed that heredity plays a significant role in the
development of refractive errors. However, different forms of ametropia
appear to be influenced by different patterns of inheritance.|
Astigmatism most consistently follows an autosomal dominant mode of transmission with rare reports of autosomal and X-linked recessive pedigrees noted. Associated conditions are rare.
Low hyperopia is the norm in most populations.
Its most consistent mode of transmission is autosomal dominant. High hyperopia is uncommon and often associated with abnormalities of the eye and various systemic syndromes. The usual form of transmission is autosomal recessive.
Heredity plays an important role in the development of myopia, but difficulties in population sampling have precluded a straightforward assessment of inheritance pattern. Multifactorial inheritance appears most likely, with environmental factors playing an important, albeit ill-defined role. High myopia is a heterogeneous group of conditions with many systemic and ocular associations, making inheritance patterns difficult to define.
Thus, different forms of refractive error display different inheritance patterns. Environmental influences vary with the form of ametropia. Ongoing investigations into heredity of refractive errors concentrate on inheritance patterns of the individual components of refraction and how these factors interact and combine to form the final refraction.
8. Sorsby A, Benjamin B, Davey JB et al: Emmetropia and its Aberrations, a Study in the Correlation of the Optical Components of the Eye. Medical Research Council Report No. 293, London, Her Majesty's Stationery Office, 1957
23. Holm S: Les de la refraction oculaire chez les paleonegrieles au Gabon Afrique Equatoriale François. Acta Ophthalmol 13(suppl): Vol 15, 1937. In Borish I: Clinical Refraction pp 5–148. Chicago, The Professional Press, 1975
44. Siemens HW: Die Zwillingspathologie: Zur Aetiologie des Turmschädels nebst mitteilung einer dermatologischen Methode zur Diagnose der Eineiigkeit bei Zwillingen. Virchows Arch Pathol Anat 253:746, 1924
56. Czellitzer A: Der Hornhautastigmatismus, seine Darstel-lung und seine Vererbung. Proceedings of the International Congress on Ophthalmology, Amsterdam, September 1929. Klin Monatsbl Augenheilkd 83:613, 1929
68. Waardenberg PJ: Total refraction and the variability of its individual components. In Waardenberg PJ, Franceschetti A (eds): Genetics and Ophthalmology, pp 1201–1285. Oxford, Blackwell Scientific Publications, 1963
75. Scardiaccione M: Sopra una malformazione oculare congenita caratterizzata da pseudopapilla da stasi con membrana epipapillare, ipermetropia elevata e formazioni verrucoidi del fondo. Boll Ocul 19:703, 1940
121. Nakajima A: The hereditability estimates of the optical components of the eye and their mutual relationship by a new method of measurements on twins. In: Proceedings of the Second International Congress of Human Genetics, vol 1. Rome, Instituto G. Mendel, 1961
158. Tscherning M: Studier uber die Aetiology de Myopic. Graefes Arch Klin Exp Ophthalmol 29:201, 1883. In Curtin BJ: The Myopias: Basic Science and Clinical Management. Philadelphia, Harper & Row, 1985