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Retinal disorders and sleep disorders: are they genetically related?

Since the late 1950s, the link between sleep and visual impairment has been a point of interest. Some early studies focused on how dreams are experienced by those with no sight (Blank, 1958; Kirtley & Sabo, 1979; Sabo & Kirtley, 1980) and, later, attention turned to the sleep habits of children with visual impairments (Fazzi et al., 2008; Salzarulo, 1975; Stores & Ramchandani, 1999). More recently, there have been occasional suggestions that visually impaired individuals may be at risk of sleep disorders (Asplund, 2005; Lockley, Dijk, Kosti, Skene, & Arendt, 2008; Tabandeh et al., 1998). Further investigation of this topic is warranted, given the importance of sleep in the life of most animals, including humans.

Sleep is a major contributing factor to optimal physical health and vitality. The right amount of sleep has also been shown to be preventative in the development of ailments including hypertension (Bansil, Kuklina, Merritt, & Yoon, 2011) and weight gain (Lyytikainen, Lallukka, Lahelma, & Rahkonen, 2011). Sleep disturbances are typically regarded as secondary problems, and it is hoped that they will be spontaneously resolved with the resolution of primary health issues. This attitude toward sleep disturbances explains why little attention has been devoted to how lack of sleep affects the rehabilitation process, particularly in the field of visual impairment.

Without fear of contradiction, one may assume memory is important when adapting to vision loss. Not only is day-to-day life changed by the onset of visual impairment, but the affected individual is asked to learn new behaviors related to the use of impaired vision with or without assistive devices, adjust to changing psychosocial roles, and more. Learning is especially impaired by sleep deprivation when the task entails adopting a new behavioral strategy (Maquet, 2001) such as learning to use the peripheral retina instead of the fovea for reading. Additionally, several decades of research have shown that sleep is important for consolidation, integration, and maintenance of memories (Hennevin, Hars, Maho, & Bloch, 1995; Lockley et al., 2008; Maquet, 2001; Rasch & Born, 2013; Saletin & Walker, 2012; Smith, 1985; Stickgold, James, & Hobson, 2000). Eye care and rehabilitation specialists need to be aware of the influence poor sleep quality can have on people with retinal disorders, since this situation may have an important impact on memory and learning, both of which are vital in successful rehabilitation.

The sleep-wake cycle is controlled by an individual's endogenous circadian rhythm. This rhythm is regulated by the pineal gland, a neuro-endocrine organ located at the base of the brain. The major environmental factor contributing to the synchronization of circadian rhythms is ocular light exposure (Tabandeh et al., 1998). Light activates the photoreceptors that, in turn, pass information on to the suprachiasmatic nuclei in the anterior hypothalamus via the optic nerves. This retino-hypothalamic pathway then leads to the pineal gland that, among other functions, secretes melatonin. Normally, this hormone is secreted rhythmically on a 24-hour schedule, with a surge at night, controlling the sleep-wake cycle (Franzco, 2005; Gordo, Recio, & SanchezBarcelo, 2001; Tabandeh et al., 1998). When kept in darkness, typically sighted individuals lose synchrony between their sleep rhythms and the 24-hour light-dark cycle (Ionescu, Driver, Heon, Flanagan, & Shapiro, 2001; Tabandeh et al., 1998). In individuals with no light perception, circadian rhythms have to function independently of environmental light, which can cause difficulty sleeping (Gordo et al., 2001).

The epidemiology of insomnia indicates that one-third of the general population experiences at least one symptom as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (Ohayon, 2002). Studies have shown that individuals with light perception have fewer sleep problems than those with no light perception. One investigation utilizing a postal survey showed that 76% of totally blind subjects had sleep problems and 36% had symptoms that were severe enough to interfere with their daily tasks (Tabandeh et al., 1998). Of the few studies that have investigated the sleep quality of those with low vision, two were focused on individuals with retinitis pigmentosa. In one of these studies, it was hypothesized that a smaller visual field would lead to decreased light input to the suprachiasmatic nuclei, thus creating sleep problems (Gordo et al., 2001). Using the Pittsburgh Sleep Quality Index (PSQI) questionnaire, both studies reported that 75% of individuals with retinitis pigmentosa, a hereditary disorder that results in the loss of rod vision and a severely decreased visual field, had scores of five or higher, indicating significantly reduced sleep quality (Gordo et al., 2001; Ionescu et al., 2001). Severity of vision loss was also correlated with poorer sleep and reduced daytime alertness (Ionescu et al., 2001). However, daily fluctuations in visual field did not correlate with symptoms of sleepiness (Bittner, Haythornthwaite, Diener-West, & Dagnelie, 2013).

Many people with visual disorders suffer from irregular sleep, sleep disturbances, or even sleep disorders. The exact causes of these disturbances are not yet fully understood. External factors such as exercise, smoking, and a stressful lifestyle may contribute in many cases. A number of researchers, however, are now showing that the causes could also be internal and that sleep disorders may be encoded in our genetic makeup.

In 2002, several studies described a subset of retinal ganglion cells that project to the suprachiasmatic nuclei and produce or express the photopigment melanopsin (Hannibal & Fahrenkrug, 2002; Panda et al., 2002; Ruby et al., 2002). The relationship between the gene encoding melanopsin, Opn4, and the sleep-wake cycle has been examined in mouse models: mice were genetically altered to have no Opn4 or rods and cones had no suppression of melatonin from the pineal gland in the presence of light (Bailes & Lucas, 2010). Lack of melanopsin has also shown a delay in the light-induced transition from wakefulness to sleep (Dijk & Archer, 2009). Mouse studies have concluded that melanopsin has effects on sleep duration, wake consolidation, sleep homeostasis, and quality of wakefulness (Bailes & Lucas, 2010; Dijk & Archer, 2009; Lucas, Freedman, Munoz, Garcia-Fernandez, & Foster, 1999). "Melatonin receptor agonists" (analogues of melatonin designed to bind to melatonin receptors with a greater potency than melatonin itself), such as the drug tasimelteon, have been investigated in the treatment of circadian rhythm disorders. Tasimelteon was shown to improve sleep initiation and maintenance in individuals with no light perception in the human trials named Safety and Efficacy of Tasimelteon (SET) and Randomized Withdrawal Study of the Efficacy and Safety of Tasimelteon (RESET) (Johnsa & Neville, 2014; Lankford, 2011).

Studies have recently examined several other genes that are involved in retinal dystrophies that potentially lead to blindness, and they found that these genes are also expressed in the pineal gland (Bailey et al., 2009; Hu, Wan, Hackler, Zack, & Qian, 2010). The aim of the present study was, first, to replicate the previous work on retinitis pigmentosa-related sleep disturbances (Gordo et al., 2001; Ionescu et al., 2001) and to determine whether individuals with other retinal disorders experienced similar problems. In addition, the goal was to examine the possible link between subjectively reported sleep problems and the presence of particular genes that are expressed either in the retina alone or in the retina and the pineal gland.

Method: Phase I

PURPOSE

Phase I of this investigation consisted of two segments. In the first, the self-reported sleep problems of individuals with retinitis pigmentosa were examined and, in the second, an attempt was made to determine if those who have a genetic mutation that causes their visual disorder but is also expressed in the pineal gland are more likely to experience sleep-related difficulties than those whose mutation is expressed only in the retina.

PARTICIPANTS

At the outset of Phase I, a retrospective review of patients' charts was conducted in the Department of Ophthalmology at the Montreal Children's Hospital, Quebec, Canada, in order to identify potential participants for the study. One of this study's authors (Koenekoop) had examined the vast majority of people in Quebec with genetic eye disorder diagnosis, and all of their files, for children as well as adults, were maintained at the children's hospital. From this chart review, 103 individuals who had been diagnosed as having retinitis pigmentosa were recruited for the present study. They ranged in age from 19 to 81 years (mean: 50.33 years).

The study protocol was approved by the McGill University Health Centre research ethics committee and followed the tenets of the Declaration of Helsinki. All participants gave signed informed consent prior to their participation in the study.

MATERIALS

Three questionnaires were utilized and were administered either in person or over the telephone, with a research assistant reading the questions and noting the responses given by the participants on the answer key.

The main questionnaire was the PSQI, a 19-question scale that evaluates seven components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of prescribed sleep medications, and daytime dysfunction (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). Each question is focused on sleep-related issues experienced by the individual over the past month; for example, "During the past month, how long (in minutes) has it usually taken you to fall asleep each night?" The Epworth Sleepiness Scale (ESS), a seven-question scale that results in scores from 0 to 24, was utilized to examine daytime sleepiness. Higher scores (9 or greater) on this test indicate more difficulties in staying awake during the day. Examples of daytime activities during which an individual may "nod off" are: watching television, conversing with someone, or riding in or driving an automobile (Johns, 1992).

Finally, the Brief General Health Assessment (BGHA) questionnaire was used to exclude potential participants whose sleep disorder may have been caused by other conditions. These included depression, convulsions or epilepsy, nocturnal acid reflux, attention deficit hyperactivity disorder, obstructive sleep apnea, and restless leg syndrome. Prospective participants who were taking medications that could cause drowsiness, such as painkillers, tranquilizers, antidepressants, sedatives or hypnotics, medication for digestive problems, and allergy medications, were also excluded.

PROCEDURES

Medical charts were reviewed to determine diagnosis, age, visual acuity, and visual field defects of potential participants. Only adults (18 years of age or older) were admitted to this study. Individuals who met the inclusion criteria were interviewed by telephone or in person in order to complete the PSQI, ESS, and BGHA questionnaires. In all cases, the questions were read aloud by a research assistant who also recorded the participants' responses.

Prior to the onset of this study, blood samples had been taken from the recruited individuals and were submitted for genetic testing. Gene identification was completed in Radboud University Medical Center, Nijmegen, Netherlands. Identified genes were then determined to have retinal expression only or both retinal and pineal expression (see Table 1). Gene expression patterns were estimated based on a murine model (Bailey et al., 2009). The circadian rhythm is an evolutionary conserved process whose gene expression patterns have been shown to be consistent across mammalian species (Li et al., 2013).

Method: Phase II

PURPOSE

Phase II of the study expanded the subject pool by examining the quality of sleep of the individuals with other retinal disorders. Stargardt's disease and age-related macular degeneration are different diseases with similar symptoms. It is known that the gene that causes Stargardt's disease (ABCA4) is only expressed in the retina, whereas the genes that have to date been linked to age-related macular degeneration show both forms of expression in a manner comparable to those responsible for retinitis pigmentosa (Bailey et al., 2009; Cook, Patel & Tufail, 2008; Lambertus et al., 2015). The objective of this segment of the study was to examine whether individuals with Stargardt's disease would experience good sleep quality, given the site of their gene expression, and whether the findings for individuals with age-related macular degeneration would be comparable to those with retinitis pigmentosa.

PARTICIPANTS

In Phase II, individuals with Stargardt's disease or age-related macular degeneration were identified either from the files of the practice described above (Stargardt's disease) or from a list of patients of the Montreal Retina Institute who had previously consented to blood sampling for the purpose of genotyping (age-related macular degeneration). From these two sources, 12 men and 19 women with Stargardt's disease, ranging in age from 19 to 67 (mean: 39.81 years) and 16 men and 27 women with age-related macular degeneration, ranging in age from 69 to 93 (mean: 81.51 years) were recruited into the study.

MATERIALS AND PROCEDURES

Other than the genetic testing, the materials and procedures in Phase II were identical to those of Phase I. Genetic testing for those with Stargardt's disease was unnecessary, because the gene responsible for this disorder (ABCA4) has been recognized for 16 years (Azarian & Travis, 1997). The genotyping of the age-related macular degeneration group was performed by the above-named center. Identified genes were then determined to have retinal expression only or both retinal and pineal expression (see Table 2). Risk mutations as well as protective mutations influencing age-related macular degeneration were identified. Most participants had combinations of risk and protective genes having both forms of expression. These combinations made analysis for Phase II much more complicated compared to the retinitis pigmentosa population in Phase I.

Results: Phase I

On the basis of the chart review, 103 individuals with retinitis pigmentosa were recruited into the study and tested using the three questionnaires (PSQI, ESS, and BGHA). Of these, 49 were excluded because the mutation causing their retinitis pigmentosa was not identified. A further 21 were excluded on the basis of their BGHA responses that indicated they were on prescribed sleep medications; had sleep apnea, epilepsy, or other systemic disorders; or had other conditions that could account for disturbed sleep. The test results of the remaining 33 participants were entered into the final data analysis.

The total PSQI scores showed that 21 (64%) of the participants with retinitis pigmentosa had a score of five or higher, indicating poor sleep quality (see Table 3). The subscales that produced the highest scores were sleep latency, subjective sleep quality, and sleep disturbances. The responses to the ESS questionnaire showed that 21% of the retinitis pigmentosa sample experienced daytime sleepiness (see Table 4). Age did not correlate with PSQI score (r = 0.177, p = 0.324) or ESS score (r = -0.058, p = 0.748).

Expression data from Bailey et al. (2009) revealed that of the 33 participants with identified retinitis pigmentosa mutations, 20 of them had mutations expressed only in their retinas, while 13 had mutations that were also expressed in their pineal glands. A greater percentage of those with a mutation expressed in the pineal gland considered themselves sleepy according to PSQI, compared to those who carried a mutation in the retina only; however, the mean score of both groups was the same (see Table 5). ESS showed that individuals with retina-only mutations had more daytime sleepiness than those who had mutations in their pineal glands (see Table 6). Neither the PSQI nor the ESS scores differed significantly between expression groups (PSQI: p = 1.00; ESS: p = 0.144).

Results: Phase II

The chart and database review led to the recruitment of 36 participants with a diagnosis of Stargardt's disease and 51 with age-related macular degeneration. The Stargardt's disease cohort ranged in age from 19 to 67 years, and those with age-related macular degeneration ranged from 68 to 93 years of age. Of these, 5 individuals in the Stargardt's disease group and 8 in the age-related macular degeneration group were excluded based on their BGHA results, leaving a final sample of 31 participants with Stargardt's disease and 43 with age-related macular degeneration.

PSQI scores indicated that 15 (48%) of individuals with Stargardt's disease and 23 (53%) with age-related macular degeneration had reduced sleep quality (see Table 3). Like the retinitis pigmentosa group, the Stargardt's disease group scored highest on sleep latency, subjective sleep quality, and sleep disturbance. However, the age-related macular degeneration group scored highest on sleep disturbance, habitual sleep efficiency, and duration. Responses to the ESS questionnaire showed that, similar to the retinitis pigmentosa group, 16% of the individuals with Stargardt's disease experienced daytime sleepiness. However, only one person in the age-related macular degeneration group was affected in this way (see Table 4). Age did not correlate with PSQI scores for participants with Stargardt's disease (r = -0.152, p = 0.414), but did for those with age-related macular degeneration (r = 0.32, p = 0.036). No significant differences in PSQI scores were found between diagnostic groups (see Table 7) but there were significant differences for the ESS (F[2,104] = 3.460, p = 0.035). Post hoc comparisons using the Fischer's Least Significant Difference (LSD) test indicated that the mean ESS score for the age-related macular degeneration group was significantly different from both the retinitis pigmentosa and Stargardt's disease groups. However, the retinitis pigmentosa and Stargardt's disease groups were not significantly different from each other (see Table 8).

Discussion

The present study aimed to replicate previous findings that indicated that 75% of people with retinitis pigmentosa reported sleep difficulties (Gordo et al., 2001; Ionescu et al., 2001). In our sample, however, slightly more than 50% had sleep problems. This discrepancy may be because BGHA was used in the current study, which probably provided a cleaner sample. Analysis of the PSQI subscales revealed that retinitis pigmentosa participants, particularly, had trouble falling asleep and experienced sleep disturbances (53%). Approximately half of the people with Stargardt's disease and age-related macular degeneration reported sleep difficulties as well. This finding was greater than the expected percentage of individuals without retinal disease. According to the PSQI, approximately 30% of both middle-aged adults and older adults experienced sleep difficulties, with average global scores of 2.67 and 4.98, respectively (Cole et al., 2006; Knutson, Rathouz, Yan, Liu, & Lauderdale, 2006). Age did not correlate with PSQI scores in the Stargardt's disease and retinitis pigmentosa diagnostic groups (retinitis pigmentosa: r = 0.177, p = 0.324; Stargardt's disease: r = -0.152, p = 0.414), but did in the age-related macular degeneration group (r = 0.32, p = 0.036). This discovery is not surprising, since the progression of age-related macular degeneration is dependent on age as its name implies. The low percentage of individuals with age-related macular degeneration exhibiting daytime sleepiness compared to other diagnostic groups was also not surprising. A PSQI study showed a negative correlation between age and daytime sleepiness in a population without visual impairments (Buysse et al., 1989). The combined results for participants with retinitis pigmentosa, Stargardt's disease, and age-related macular degeneration show that poor sleep quality is common in people with retinal disease.

Based on our findings, the expression patterns of the mutated genes giving rise to retinitis pigmentosa are not the underlying cause of the poor sleep experienced by a large number of the participants we studied. Individuals with retinitis pigmentosa who had variants expressed solely in the retina had the same average global PSQI score as those who had variants expressed in the retina and pineal gland. There was no significant difference between expression groups on the ESS. As with the retinitis pigmentosa diagnostic group, 50% of the Stargardt's disease participants experienced poor sleep. The mutation causing Stargardt's disease is in ABCA4, a gene that is not expressed in the pineal gland. Although these findings dismiss our original hypothesis about the expression of retinal disease genes, the genetic influence on sleep cannot be discredited altogether. There is no evidence to date that the gene encoding melanopsin (Opn4) contributes to the retinal diseases involved in this study, since the subset of retinal ganglion cells expressing it are widespread throughout the retina. The involvement of Opn4 in melatonin regulation and the expression of the gene in both the retina and the pineal gland provide an alternate genetic target to investigate further.

This study is not without limitations. The method of interview administration was not specified during data collection, which prevented the comparison of in-person to phone interview results that could have been an influencing factor. Also, details outlining the severity of visual impairment, such as visual acuity and visual field information, were not recorded. This information could have been used to validate previous findings demonstrating a positive correlation between the severity of visual impairment and the severity of sleep difficulties (Ionescu et al., 2001). The degree of severity of visual impairment could explain why not all individuals with retinal disorders experience sleep problems. Little is known about individual circadian sensitivity to light, but studies have shown that timing, intensity, duration, and wavelength of light can all have an effect on the regulation of melatonin. It must be noted that the pineal gland receives input from other sources, but the light exposure that regulates the circadian rhythm originates in the retina. To date, the relative contribution of the different types of photoreceptors to circadian light response is not well understood (Duffy & Czeisler, 2009).

In the field of low vision, sleep is one of the aspects of functioning that may be least taken into account, because attention is focused on establishing visual functioning. Given the efforts and costs of rehabilitation programs and the prevalence of sleep disturbances among visually impaired people, it is important to consider sleep problems as possible inhibitors of the entire rehabilitation process. The further challenge lies in allocating the appropriate attention and resources to this issue. There is successful development of sleep aids, like tasimelteon, that regulate melanopsin and treat some of the symptoms of sleep-wake disorders, but more research is needed to understand the etiology and evolution of sleep problems in individuals with retinal disorders and how they affect their rehabilitation. For those who do not want to use sleep medication, meditation may be the answer. Yoga has been shown to improve sleep quality and reduce the need for sleep medication in cancer survivors (Jeter, Dagnelie, Khalsa, Haaz, & Bittner, 2012; Mustian et al., 2013), and cognitive behavior therapy and mindfulness have been shown to reduce sleep disturbances for those with insomnia (Brand, Holsboer-Trachsler, Naranjo, & Schmidt, 2012; Ong & Sholtes, 2010). If all else fails, clinicians and practitioners need to be aware of their clients' sleep problems. A simple conversation can determine when an individual is most alert and consequently when rehabilitation sessions should be scheduled.

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Caitlin Murphy, M.Sc., doctoral candidate, School of Optometry, University of Montreal, P.O. Box 6128, Station Centre-ville, Montreal, Quebec H5C 5J7, Canada; e-mail: <caitlin.murphy@ umontreal.ca>. Nathalie Duponsel, M.Sc., doctoral candidate, Concordia University, Department of Education, Room LB-579 1455 de Maisonneuve Boulevard West, Montreal, Quebec H5G 1M8, Canada; e-mail: <nw_de@education. concordia.ca>. Xi Sheila Huang, M.D., comprehensive ophthalmologist, CSSS du Suroit, St. Mary's Hospital and Jewish General Hospital, 160 Rue Saint Thomas, Salaberry-de-Valleyfield, Qc J6T 2N6, Canada; e-mail: <xi.huang@ mail.mcgill.ca>. Walter Wittich, Ph.D., FAAO, ClVT, assistant professor, School of Optometry, University of Montreal; resident researcher, CRIR/MAB-Mackay Rehabilitation Centre; adjunct professor, Department of Psychology, Concordia University; adjunct professor, School of Physical and Occupational Therapy, University of Montreal; e-mail: <walter.wittich@umontreal.ca>. Robert K. Koenekoop, M.D., Ph.D., chief, Pediatric Ophthalmology, Montreal Children's Hospital, 1001 Boulevard Decarie, Montreal, Quebec H4A 5J1, Canada; clinician-scientist and director, McGill Ocular Genetics Laboratory; associte professor of ophthalmology, McGill University; e-mail: <robert.koenekoop@mcgill.ca>. Olga Overbury, Ph.D., associate professor, School of Optometry, University of Montreal; e-mail: <olga.overbury@umontreal.ca>.
Table 1
Retinitis pigmentosa gene expression.

Gene       Retina   Pineal

CNGB1        *        *
CYP4V2       *
IMPDH1       *
MERTK1       *
NPHP1        *
PDE6A        *
PED6B        *        *
PRPH2        *        *
RDH12        *        *
RDS          *
RHO          *
ROM1         *        *
RPGR         *
SPATA7       *
TOPORS       *
TULP1        *        *
USH2A        *        *
CHR14        *
SNRNP200     *

Table 2
Age-related macular degeneration gene expression.

Gene        Retina   Pineal

ABCA1         *        *
ABCA4         *
APOE          *
ARMS2         *
C3            *
CEPT          *
CFH (t/c)     *
CFHY402H      *
CFI           *
FADS1         *
LPL           *
TLR4          *
VEGFA         *

Table 3
Pittsburgh Sleep Quality Index (PSQI) results.

Diagnosis   Poor sleepers   Mean    Standard    Total
             (scored 5+)    score   deviation    (N)

SD             15(48%)      4.94      3.37       31
AMD           23 (53%)      5.26      3.60       43
RP            21 (64%)      6.00      3.22       33

Note: SD = Stargardt's disease; AMD = age
related macular degeneration; RP = retinitis pigmentosa.

Table 4
Eppworth Sleepiness Scale (ESS) results.

Diagnosis     Daytime     Mean score   Standard    Total (N)
            sleepiness                 deviation
            (scored 9+)

SD            5 (16%)        5.58        4.49         31
AMD           1 (2%)         3.65        3.01         43
RP            7(21%)         5.58        3.75         33

Note: SD = Stargardt's disease; AMD =
age-related macular degeneration; RP = retinitis
pigmentosa.

Table 5
Pittsburgh Sleep Quality Index (PSQI) results:
Pineal and retina compared to retina-only gene expression
in retinitis pigmentosa.

Gene expression     Poor sleepers   Mean    Standard    Total
                     (scored 5+)    score   deviation    (N)

Pineal and retina     11 (85%)      6.00      2.00       13
Retina only           10 (50%)      6.00      3.866      20

Table 6
Eppworth Sleepiness Scale (ESS) results: pineal
and retina compared to retina-only gene expression in
retinitis pigmentosa.

Gene            Daytime     Mean    Standard    Total
expression    sleepiness    score   deviation    (N)
              (scored 9+)
Pineal and
  retina        1 (8%)      4.38      3.36       13
Retina only     6 (43%)     9.65      3.87       20

Table 7
Pittsburgh Sleep Quality Index (PSQI) between-group results.

Diagnosis   Mean   Standard    Total (N)   95% confidence   Range
                   deviation                  interval

SD          4.94     3.37         31         3.73-6.14      1-13
AMD         5.26     3.60         43         4.23-6.28      1-14
RP          6.00     3.22         33          4.83-717      1-81

Note: SD = Stargardt's disease; AMD = age-related
macular degeneration; RP = retinitis pigmentosa.

Table 8
Eppworth between-group results.

Diagnosis   Mean   Standard    Total (N)   Range
                   deviation

SD          5.58     4.49         31       1-17
AMD         3.65     3.01         43       1-15
RP          5.58     3.75         33       1-14

Note: SD = Stargardt's disease; AMD = age-related
macular degeneration; RP = retinitis pigmentosa.
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Article Details
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Author:Murphy, Caitlin; Duponsel, Nathalie; Huang, Xi Sheila; Wittich, Walter; Koenekoop, Robert K.; Overbu
Publication:Journal of Visual Impairment & Blindness
Article Type:Report
Date:Sep 1, 2015
Words:5397
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