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659662 OPTOMETRY AND VISION SCIENCE Copyright 2009 American Academy of Optometry
REVIEW
ABSTRACT Purpose. To describe the clinical characteristics and recent findings in the heterogeneous group of inherited disorders of melanin biosynthesis grouped as albinism. Methods. The current classification of albinism, and the cutaneous, ocular, and central nervous system characteristics are presented. Recent clinical findings are summarized. Results. Albinism is now classified based on genes known to be responsible for albinism. Foveal hypoplasia is invariably present and individuals with albinism often have delayed visual development, reduced vision, nystagmus, a positive angle kappa, strabismus, iris transillumination, and absent or reduced melanin pigment in the fundi. A visual-evoked potential can document the excessive retinostriate decussation seen in albinism. Grating acuity can be used to document delayed visual development in preverbal children. Glasses are often needed to improve visual acuity and binocular alignment. Conclusions. Albinism is caused by several different genes. Heterogeneity in clinical phenotype indicates that expressivity is variable. (Optom Vis Sci 2009;86:659662) Key Words: albinism, vision, genes
lbinism, derived from the Latin, albus, meaning white, is a group of inherited disorders in which melanin biosynthesis is reduced or absent. Several genes have been found to be responsible for albinism. The current classification of albinism is determined by the affected gene, making the previously used terms, partial or complete and tyrosinase-positive or tyrosinasenegative obsolete.1,2 The gene for tyrosinase on chromosome 11q14-21 and the P gene on chromosome 15q11.2 are the most commonly affected genes, mutations on these genes cause oculocutaneous albinism type 1 (OCA1; OMIM 203100) and oculocutaneous albinism type 2 (OCA2; OMIM 203200), respectively. These types of albinism are inherited in an autosomal recessive manner and are expressed in males and females. Another type of albinism caused by mutations on Xp22.3, ocular albinism (OA1; OMIM 300500), affects males because of X-linked inheritance; 85 to 90% of obligate carriers show pigmentary mosaicism in the fundi, representing the lyonization effect (X-inactivation), although there are no functional sequelae for them. Other types of albinism occur more infrequently, including those associated with systemic manifestations, such as Hermansky-Pudlak syndrome (OMIM 203300; bleeding disorder due to absence of dense bodies
*MD Departments of Ophthalmology and Pediatrics, University of Minnesota, Minneapolis, Minnesota.
in platelets) and Chediak Higashi syndrome (OMIM 214500; immunodeficiency and neurologic problems). The prevalence of albinism in the United States is estimated to be 1 in 18,000.2 Table 1 summarizes the genes responsible for albinism. For available testing for mutations, the reader is referred to www.genetests.org.
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Ocular Findings
Gene location
LYSTd
1q42.1-q42.2
GPR143
Xp22.3
Tyrosinase-related protein 1. Also known as MATP gene, encoding membrane-associated transporter protein. c Dysbindin protein. d Lysosomal trafficking regulator. e Other types of OA have been shown to represent OCA.
uals with OCA2 both have pale skin at birth. The phenotype and the normal presence of an immature fovea at birth can delay diagnosis, particularly, in families of European descent in whom reduced melanin pigment in the skin, hair, and eyes is common. However, examination with the slit lamp biomicroscope will show transillumination of the irides in those with albinism, and rarely is any pigment found at the level of the retinal pigment epithelium with careful examination of the fundi in an individual with albinism.
As infants with albinism develop a fixation response, additional findings may be noted. Nystagmus is initially slow and has a large amplitude, but the amplitude typically decreases within the first year of life. One study found that, with monocular fixation on a light, 99.6% of patients had a corneal light reflex deviated nasal to the center of the pupil, known as a positive angle kappa.18 Prism and alternate cover test at a more rapid rate than usual (to diminish effect of increased nystagmus amplitude with monocular occlusion) often discloses strabismus. Because of the positive angle kappa, an esotropia may be masked or appear diminished in amount on causal gaze, compared with the measured deviation, whereas an exotropia may appear larger than measured. Even individuals with albinism who are orthophoric seem to have a small exotropia, causing parents to report that the child does not look directly at them. A study of 178 individuals with albinism showed a mean exoshift of 17.11 prism diopters because of the presence of a positive angle kappa when prism and alternate cover measurements were compared with Krimsky assessment of binocular alignment.18 Other ocular findings in albinism are iris transillumination and absent or poor foveal development. Iris transillumination is best performed in a dark room after the examiner has become adapted to the darkness. The tonometer platform is rotated 90 to avoid having it touch the childs chest, and a small, bright light is directed through the pupil while the examiner fixates on the iris. The amount of iris transillumination can vary and a grading scheme has been described: grade 1, punctate areas of transillumination, indicating that a marked amount of pigment is present in the posterior iris epithelium; grade 2, moderate iris pigment; grade 3, minimal iris pigment; and grade 4, full transillumination of the iris because of the absence of melanin pigment.19 Examination of the fundi typically shows that foveal development is absent. A few patients with albinism, who have vision 20/50 or better, have some rudimentary foveal development, and some thinning of the retina in the foveal area has been demonstrated with optical coherence tomography.4,5,20 The appearance of the macula has been graded as follows: grade 1, choroidal vessels easily seen in macula; grade 2, choroidal vessels less distinctly seen because of translucent retinal pigment epithelium; and grade 3, opaque macula so that choroidal vessels are not visible.19 These grading scales for the iris and macula can be useful in clinical studies to more precisely describe the study population because these characteristically persist over time. In addition, careful inspection can show granular melanin pigment in the macula in a few patients with albinism and occasionally finely granular pigment has been identified beyond the macula. The presence of melanin pigment in the macula correlates with better visual acuity.15
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account for absent stereoacuity that is often found in albinism. A study of 45 individuals with albinism and strabismus 10 prism diopters identified 19 with stereoacuity measured with the Titmus vectrograph (Stereo Optical Co., Chicago, IL).22 These individuals had significantly better visual acuity, more pigment in their iris, reduced or absent nystagmus, and more frequently had melanin pigment identified in their maculae and the development of a rudimentary foveal reflex when compared with those without measurable stereoacuity.
with albinism who are beginning to learn to fixate will typically respond more readily to vertical presentation of the cards. However, as children mature, standard horizontal presentation of the TAC is most often used. Because of the presence of increased nystagmus amplitude with monocular occlusion, monocular grating acuity is frequently worse than binocular grating acuity. Parents often ask how impaired their childs vision is when vision is measured with the TAC and what their childs vision will be when the children are older. A cross-sectional study of 64 children with albinism showed that visual acuity measured with the TAC was 2.3, 2.1, and 1.7 octaves lower than norms at ages 1, 2, and 3 years, respectively.31 Another study of children with albinism compared grating acuity measured with the TAC at ages 1 (n 30), 2 (n 29), and 3 years (n 19) with recognition acuity measured at ages 4 to 6 years.32 In this study, the mean binocular grating acuity was 2.0, 1.9, and 1.5 octaves below norms at ages 1, 2, and 3 years, respectively. Grating acuity at ages 1, 2, and 3 years correlated moderately with recognition acuity at ages 4 to 6. This correlation improved when grating and recognition acuities were analyzed in a subgroup of nine patients who were followed up longitudinally. Binocular grating acuity in both the subgroup and the larger group at ages 1 and 2 was significantly worse than recognition acuity, but was not significantly different from binocular letter acuity at age 3. Recognition visual acuity among persons with albinism varies from 20/20 to 20/400, but is commonly close to 20/80. Foveal hypoplasia, nystagmus, and refractive errors contribute to reduced acuity.33 A prospective evaluation of 35 individuals with albinism (median age 9.5 years) who had received glasses (spherical equivalent from 9.75 D to 8.88 D) had a mean uncorrected visual acuity of 20/107.6 at 6 m, improving to 20/80.9 with glasses.34 Mean uncorrected near acuity was 20/41, improving to 20/28.4 with correction. In addition, with glasses, mean strabismus improved from 10 to 7.2 prism diopters at distance, and from 14 to 10.8 prism diopters at near. Compliance with wearing refractive correction was generally good, despite the absence of normal corrected visual acuity. Guidelines for prescribing glasses in children with albinism are given in Table 2.
a Refraction is made after cycloplegia appropriate for age. Please note that these are minimal guidelines for glasses for refractive error meeting the above criteria in at least one eye, and that, in some cases, glasses may be prescribed for a lesser amount of ametropia.
662 AlbinismSummers
SUMMARY
In summary, patients with albinism have delayed visual development that can be monitored by measuring grating acuity. Cycloplegic refraction can determine refractive errors that should prompt consideration of glasses. A spectrum of structure and function exists in albinism. Examination may disclose absence of nystagmus, measurable stereopsis, melanin pigment in the macula, and presence of a rudimentary annular reflex in the macula that tend to be associated with better vision than when these findings are absent. As research progresses, other methods of improving visual acuity in children and adults may emerge.
ACKNOWLEDGMENTS
I gratefully acknowledge the constant encouragement and support of my friend and colleague, Dr. Velma Dobson, during this study of visual development in albinism. This work was supported, in part, by an unrestricted grant from Research for the Prevention of Blindness, New York, NY. Received September 3, 2008; accepted December 11, 2008.
REFERENCES
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13. Tresidder J, Fielder AR, Nicholson J. Delayed visual maturation: ophthalmic and neurodevelopmental aspects. Dev Med Child Neurol 1990;32:87281. 14. Fielder AR, Dobson V, Moseley MJ, Mayer DL. Preferential looking: clinical lessons. Ophthalmic Paediatr Genet 1992;13:10110. 15. Summers CG. Vision in albinism. Trans Am Ophthalmol Soc 1996; 94:1095155. 16. Oetting WS, Summers CG, King RA. Albinism and the associated ocular defects. Metab Pediatr Syst Ophthalmol 1994;17:59. 17. Kutzbach BR, Summers CG, Holleschau AM, MacDonald JT. Neurodevelopment in children with albinism. Ophthalmology 2008;115: 18058. 18. Merrill KS, Lavoie JD, King RA, Summers CG. Positive angle kappa in albinism. J AAPOS 2004;8:2379. 19. Summers CG, Knobloch WH, Witkop CJ Jr, King RA. HermanskyPudlak syndrome. Ophthalmic findings. Ophthalmology 1988;95: 54554. 20. Izquierdo NJ, Emanuelli A, Izquierdo JC, Garcia M, Cadilla C, Berrocal MH. Foveal thickness and macular volume in patients with oculocutaneous albinism. Retina 2007;27:122730. 21. Creel DJ, Summers CG, King RA. Visual anomalies associated with albinism. Ophthalmic Paediatr Genet 1990;11:193200. 22. Lee KA, King RA, Summers CG. Stereopsis in patients with albinism: clinical correlates. J AAPOS 2001;5:98104. 23. Kestenbaum A. [New operation for nystagmus]. Bull Soc Ophtalmol Fr 1953;6:599602. 24. Anderson JR. Causes and treatment of congenital eccentric nystagmus. Br J Ophthalmol 1953;37:26781. 25. Helveston EM, Ellis FD, Plager DA. Large recession of the horizontal recti for treatment of nystagmus. Ophthalmology 1991;98:13025. 26. von Noorden GK, Sprunger DT. Large rectus muscle recessions for the treatment of congenital nystagmus. Arch Ophthalmol 1991;109: 2214. 27. Hertle RW, Anninger W, Yang D, Shatnawi R, Hill VM. Effects of extraocular muscle surgery on 15 patients with oculo-cutaneous albinism (OCA) and infantile nystagmus syndrome (INS). Am J Ophthalmol 2004;138:97887. 28. Egbert JE, Anderson JH, Summers CG. Increased duration of low retinal slip velocities following retroequatorial placement of horizontal recti. J Pediatr Ophthalmol Strabismus 1995;32:35963. 29. Sebris SL, Dobson V, MacDonald MA, Teller DY. Acuity cards for visual acuity assessment of infants and children in clinical settings. Clin Vision Sci 1987;2:4558. 30. Meiusi RS, Lavoie JD, Summers CG. The effect of grating orientation on resolution acuity in patients with nystagmus. J Pediatr Ophthalmol Strabismus 1993;30:25961. 31. Whang SJ, King RA, Summers CG. Grating acuity in albinism in the first three years of life. J AAPOS 2002;6:3936. 32. Louwagie CR, Jensen AA, Christoff A, Holleschau AM, King RA, Summers CG. Correlation of grating acuity with letter recognition acuity in children with albinism. J AAPOS 2006;10:16872. 33. Summers CG. Causes of abnormal refractive errors in children. Am Orthop J 2006;56:10815. 34. Anderson J, Lavoie J, Merrill K, King RA, Summers CG. Efficacy of spectacles in persons with albinism. J AAPOS 2004;8:51520.
C. Gail Summers University of Minnesota Department of Ophthalmology, MMC 493 420 Delaware St. SE Minneapolis, MN 55455 e-mail: summe001@umn.edu