Abstract
Purpose
Prader-Willi syndrome (PWS) refers to a genetic disorder induced by an anomaly on chromosome 15 occurring with a frequency of one in 10,000 to 20,000. It is characterized by a unique set of features including infantile hypotonia, obesity in childhood, small hands and feet, hypogonadism, and mental retardation. Reported here are the results of ophthalmic examinations of persons with PWS, together with results from controls comparable in age, percentage of body fat, and intelligence. These data bear on the hypothesis that the ocular anomalies in PWS are unique to this syndrome.
Method
A comprehensive investigation of PWS brought children and adults to Vanderbilt University for extended testing, which included an ophthalmic examination. Genetic analysis determined unequivocally the PWS diagnosis and identified subgroups—deletion and maternal disomy. A group of persons without PWS but generally comparable in age, body composition, and intelligence served as controls.
Results
Significant differences between the deletion and disomy subgroups were not found for the clinical ophthalmic measures. The incidence of anomalies in the combined PWS was similar to those reported in previous studies. A similar pattern was present in the control group except for myopia and stereopsis. An effect of genetic subgroup, however, was observed for random element stereopsis with the maternal disomy group having a greater degree of impairment.
Conclusion
The overall similarity between the PWS and control groups on all measures except myopia and stereopsis suggest that many of the anomalies in PWS found in prior studies are due to factors inherent in a general dysfunctional population, rather than reflective of an ocular signature unique to PWS.
Introduction
One consequence of recent advances in genetics has been to spark interest in those syndromes induced by chromosomal anomalies that occur with low frequency. In many respects, Prader-Willi syndrome (PWS) provides a paradigm case. Occurring with the frequency of approximately one in 10,000 to 20,000, it is the most common dysmorphic cause of human obesity.1
Prader-Willi syndrome is characterized by a diverse spectrum of anomalies including infantile hypotonia, obesity in early childhood, mental deficiency, small hands and feet, short stature, and hypogonadism.1,2,3 A chromosomal (15q11-q13) deletion of paternal origin is found in 70% of PWS subjects and maternal uniparental disomy of chromosome 15 (ie, both members of chromosome 15 are from the mother) is seen in the remaining cases.4,5 Angelman’s syndrome (AS), an entirely different clinical condition, also has the 15q1 1-q13 deletion but is of maternal origin in the majority of cases. Both PWS and AS were the first examples in humans of genetic imprinting or the differential expression of genes dependent on the parent of origin.6 Although PWS shares features such as mental retardation with other syndromes, it is the unique combination of characteristics that distinguish it from others.
Several studies have examined the ophthalmic status of persons with PWS.7,8,9 A number of disorders have been noted, occurring with greater frequency than in normal populations. These include strabismus, depressed visual acuity, moderate to high refractive error, and iris hypopigmentation. Individuals with this disorder have been reported with cataracts, congenital ocular fibrosis, diabetic retinopathy, and congenital ectopia uvea.
The present study includes the ophthalmic status of a non-PWS control group generally comparable for age, fat mass, and intelligence with a group of persons with PWS who were recruited as part of a comprehensive investigation of the syndrome. In addition, a complete genetic analysis has been performed rendering it possible to determine unequivocally the genetic status of all subjects including controls, and to identify the two genetic subtypes associated with PWS deletion and maternal disomy.
Subjects
The persons with PWS were obtained through a comprehensive investigation of the syndrome being pursued at Vanderbilt University that involves behavioral, physiological, and genetic assessments. The participants, which were recruited from a region encompassing several states, volunteered to visit Vanderbilt for at least one period of testing extending over 2 days following human subjects committee approval. The results of a standard ophthalmic examination, which comprised one component of the testing are reported here.
To form a control group, participants without PWS were recruited who were comparable to the PWS group in terms of age, fat mass, and intelligence. Because they were more numerous, most of these subjects were recruited locally. Members of the control group underwent the same testing protocols applied to those with PWS.
Intelligence was defined operationally for all participants by scores on either the Wechsler Adult Intelligence Scale-Revised (WAIS-R) or the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) full scale tests. The majority of scores fell within the 50 to 70 IQ range, which defines the category of mild mental retardation. Individuals with scores between 70 and 79 are classified as borderline and those with scores between 80 and 89 fall in the low normal range. The mean score for all subjects was 66.5, with a standard deviation of 11.4. In selecting members of the control group, an important criterion was that their intellectual status was not related to specific organic factors, nor did they present with specific syndromes. They were part of that substantial population of persons with limited intellectual capacity in which etiology is unknown. On average, the PWS group would be classified as mildly mentally retarded and the control group would be classified as borderline.
The genetic status of each member of each group was determined by one of the authors using established techniques. These included high resolution chromosomal analysis, in situ hybridization, microsatellite DNA analysis with polymerase chain reaction (PCR), and methylation PCR studies.2,10,11,12,13,14 These analyses made it possible to exclude individuals who might have been included on the basis of clinical impressions from the PWS group.
Data concerning age, weight, fat mass (adiposity), and intelligence are summarized in Table 1. The differences between the two groups on age and weight were statistically significant. The short stature of persons with PWS contributed to the difference in weight relative to the control group. There was also a significant difference on the full scale IQ scores between the PWS and control groups. There was no significant difference between the control and PWS individuals on the proportion of body weight that was fat mass.
TABLE 1.
Matching Variables for Control versus PWS Groups
| Group | N | Age (Years) | Weight (lbs) | Fat Mass (%) | Full Scale IQ | ||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| Mean | SD | Mean | SD | Mean | SD | Mean | SD | ||
| Control | 16 | 29.9 | 13.5 | 243.5 | 51.7 | 49.9 | 5.6 | 74.1 | 12.3 |
| PWS | 27* | 22.2 | 8.2 | 174.2 | 49.3 | 51.4 | 7.2 | 62.2 | 8.5 |
The two genetic subtypes were analyzed separately on each of these variables. For each variable, the difference was small and not statistically significant.
Ophthalmology
Participants received complete ophthalmologic examinations. This included visual acuity in each eye obtainable with the current correction, an external examination, ocular motility evaluation, determination of stereoacuity using the Titmus test, a biomicroscopic examination of the anterior segment, a cycloplegic refraction, and an examination of the ocular fundus.
With respect to stereopsis, three assessments were made as part of a separate component of the overall PWS evaluation protocol, which focused on visual perception. Two were clinical tests of stereopsis—the Titmus and Frisby. Performance on these tests was used to define the presence or absence of stereopsis in all analyses of data. The Titmus consisted of a random element stereogram of a butterfly figure and nine circles. All stimuli were presented on an easel 40 cm from the observer whose head position was restrained by a head and chin rest. Polarization was used to produce stereoscopic stimulation. The Frisby test requires four alternative forced choice responses to circles displaced in real depth at fixed intervals that decrease disparity. The third measure of stereopsis was derived from a system, used primarily for research, that generated dynamic random element stereograms on a color monitor that were viewed using the anaglyph method.15,16 In the present application, subjects were required to make forced choice discriminations of the orientation of a global stereoscopic form, 5.7° × 5.5° in area, with a crossed disparity of 30 minutes, configured as the letter E.
One aspect of the performance on this task emerged that merits comment. The random element, stereoscopic stimuli were not presented as a clinical test of stereopsis, wherein disparity was sequentially reduced over test trials until discrimination fails. Rather, the subjects were required to discriminate the orientation of a random element form, which could assume any one of four orientations, up, down, left, and right on a given trial. The disparity did not change. If a form could be correctly discriminated upon initial presentation, then it should be equally discriminable on subsequent presentations. Indeed this is the case for observers with normal stereopsis who are not mentally retarded. But prior research has found that persons with mild mental retardation encounter difficulty perceiving stimuli composed of arrays of random elements over a variety of conditions. Collectively these data have been interpreted as suggesting that a neural deficit is responsible rather than higher order cognitive impairment.17,18
The individuals in this study encountered similar difficulties in that considerable variability was found in their ability to discriminate consistently the correct orientation of the stereoscopic form. An analysis of the patterns of errors revealed a striking difference in performance between the genetic sub-types, maternal disomy, and deletion. The performance of the maternal disomy group (24.4% correct) was substantially inferior to the deletion group (61.5% correct), a difference that is statistically significant (control subjects averaged 75%). Note that this difference does not relate directly to the question of whether these subjects possess stereopsis. Moreover, there appears to be only a modest relationship of scores on the clinical test and performance on the random element stereogram (r=0.39, P=.01). Rather, what has emerged is an unexpected relationship between genetic subtype and random element form discrimination that would seem to warrant further investigation. It would not, however, appear to be a factor in standard ophthalmic examinations.
Results and Discussion
Table 2 presents the ophthalmic examination results of the persons with PWS and Table 3 presents comparable results for the members of the control group. There were no significant differences between the deletion and disomy genetic subtypes on any of the standard ophthalmic measures; therefore, these categories were combined into one PWS group for further analyses. Excluded from consideration here is the unique difference in response to the random element stimuli described earlier.
TABLE 2.
Ophthalmic Data for All PWS Subjects (n=27)
| Subject | Acuity | OD | OS | Iris Trans | Astigmatism | Amblyopia | Anisometropia | Foveal Hypoplasia | Strabismus | Stereo* |
|---|---|---|---|---|---|---|---|---|---|---|
| Deletion | ||||||||||
|
| ||||||||||
| A003 | 20/25-20/25 | −7.50 | −7.50 | + | + | − | − | − | + | + |
| A004 | 20/25-20/25 | −1.00 | −0.25 | − | − | − | − | − | − | + |
| A007 | 20/70-20/80 | −9.00 | −15.00 | − | − | + | + | − | + | − |
| A009 | 20/20-20/20 | +0.25 | +0.50 | − | − | − | − | − | − | − |
| A012 | 20/40-20/70 | −2.50 | −1.50 | − | + | − | − | − | − | + |
| A013 | 20/60-20/60 | −4.75 | −5.25 | − | + | + | − | − | − | − |
| A014 | 20/100-20/100 | −5.75 | −5.75 | − | − | − | − | − | − | + |
| A015 | 20/30-20/30 | −4.75 | −4.75 | + | + | + | − | − | − | + |
| A017 | 20/70-20/80 | −19.50 | −23.50 | − | − | + | + | − | − | − |
| A019 | 20/40-20/40 | −2.25 | −2.25 | − | + | − | − | − | + | − |
| A021 | 20/30-20/20 | +1.00 | +0.75 | − | − | − | − | − | − | − |
| A031 | 20/200-20/160 | −2.00 | −2.00 | + | + | − | − | − | − | − |
| A032 | 20/60-20/50 | −2.00 | −2.00 | − | + | − | − | − | − | + |
| A041 | 20/20-20/20 | plano | plano | − | − | − | − | − | − | + |
| A043 | 20/40-20/20 | +1.75 | +1.50 | − | + | + | − | − | + | + |
| A045 | 20/20-20/30 | −1.50 | −5.75 | − | + | + | + | − | + | − |
| A047 | 20/70-20/60 | −4.25 | −4.75 | + | − | − | − | − | − | − |
| A050 | 20/30-20/25 | +0.50 | +0.25 | − | − | − | − | − | − | − |
| A053 | 20/30-20/100 | −1.00 | −2.00 | − | − | − | − | − | + | − |
| A058 | 20/20-20/20 | −1.50 | −5.75 | − | + | − | + | − | − | + |
| Disomy | ||||||||||
|
| ||||||||||
| A005 | 20/40-20/20 | −5.25 | −4.50 | − | . | + | − | − | − | − |
| A023 | 20/20-20/20 | −2.75 | −3.00 | − | + | − | − | − | + | + |
| A030 | 20/100-20/40 | −2.50 | −2.75 | − | + | − | − | − | + | − |
| A033 | 20/20-20/25 | plano | plano | − | − | − | − | − | − | − |
| A035 | 20/70-20/60 | N/E | N/E | − | + | − | − | − | − | + |
| A038 | 20/60-20/30 | −9.75 | −9.50 | − | + | + | − | − | + | + |
| A048 | 20/30-20/30 | −0.75 | +0.50 | − | − | − | + | − | + | − |
Stereo is defined as a score of 800 or better on the Titmus or a score of 321 or better on the Frisby. Optic nerve appeared normal unless otherwise noted.
TABLE 3.
Ophthalmic Data for Control Group (n=16)
| Subject | Acuity | OD | OS | Iris Trans | Astigmatism | Amblyopia | Anisometropia | Foveal Hypoplasia | Strabismus | Stereo* |
|---|---|---|---|---|---|---|---|---|---|---|
| A002 | 20/30-20/20 | +4.50 | +4.25 | − | − | − | − | − | + | + |
| A006 | 20/20-20/20 | plano | plano | − | − | − | − | − | − | + |
| A016 | 20/25-20/30 | −0.25 | −0.75 | − | + | − | − | − | − | + |
| A022 | 20/200-20/50 | −2.50 | −0.75 | − | − | − | + | − | − | + |
| A024 | 20/25-20/25 | −1.00 | −1.00 | − | − | − | − | − | − | + |
| A026 | 20/30-20/25 | −1.75 | −1.75 | − | + | − | − | − | − | + |
| A027 | 20/40-20/30 | −4.25 | −4.50 | − | + | + | − | − | − | + |
| A028 | 20/15-20/15 | +0.75 | +0.50 | − | − | − | − | − | − | + |
| A034 | 20/20-20/20 | −4.50 | −4.00 | − | + | − | − | − | − | + |
| A036 | 20/30-20/100 | plano | −2.25 | − | + | + | + | − | − | + |
| A037 | 20/25-20/40 | −3.75 | −3.50 | − | + | − | − | − | + | − |
| A040 | 20/15-20/15 | −0.75 | −1.25 | − | − | − | − | − | − | + |
| A044 | 20/20-20/200 | −4.75 | −4.50 | − | + | − | − | − | + | + |
| A049 | 5/200-20/50 | N/E | N/E | − | + | − | + | − | − | − |
| A051 | 20/25-20/25 | −0.25 | plano | − | + | − | − | − | + | − |
| A056 | 20/25-20/30 | −0.75 | −0.50 | − | − | − | − | − | − | + |
Stereo is defined as a score of 800 or better on the Titmus test, or a score of 321 or better on the Frisby test. Optic nerve appeared normal unless otherwise noted.
With respect to the results from the PWS group, the incidence of specific anomalies is in general agreement with those reported in prior studies,1,19,20 even though refined comparisons among studies are difficult because of variety of methods and procedures used. The frequency of strabismus in this study is relatively low (37%) but falls within the range reported previously.1 One exception is the study by Bray et al20 who report an incidence of strabismus of 95% in their sample of PWS patients. But as Hered et al7 point out, that value is much higher than reported in other studies and could well reflect the method used to assess strabismus.19
The inclusion of a comparable control group in this study provides for a refined analysis of the relationship between PWS and ophthalmic variables. Comparison of the frequency of each of the conditions given in Tables 2 and 3 reveals statistically significant differences for only two measures—myopia and stereopsis. For myopia, the control group’s statistics are mean refractive error = −2.33, standard deviation = 1.65, and range = −0.25 to −4.75. The PWS group’s statistics are mean refractive error = −5.56, standard deviation =5.38, and range = −0.25 to −23.5. Not only is the difference in means statistically significant (P<.05), but the distributions are not comparable via nonparametric testing (P=.01), findings that reflect the large refractive errors extant in some members of the PWS group. For stereopsis, the relevant index is the number of members of each group classified as possessing stereopsis by performance on at least one of the clinical tests. For the control group, 81% have stereopsis; for the PWS group, 44% have stereopsis, which is a statistically significant association by chi-square.
These differences in myopia and stereopsis between the PWS and control groups suggest that PWS may contribute directly to variation of these anomalies. In other respects, however, the incidence of disorders reported previously may largely reflect the factors inherent in a general dysfunctional population composed of unknown etiologic factors. In this regard, it should be noted that the hypothesis of a link between PWS and the misrouting of segments of the optic nerve associated with albinism8 has not been confirmed.9,19
Acknowledgments
Support for this project was provided by grant PO1HD30329 from NICHD. Special assistance provided by the Quantitative and Psychobehavioral core support. We thank Dr Deborah Mauk for her contributions to an earlier stage of the project.
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