Quantitative Foveal Structural Metrics as Predictors of Visual Acuity in Human Albinism.

Purpose: To assess the degree to which quantitative foveal structural measurements account for variation in best-corrected visual acuity (BCVA) in human albinism. Methods: BCVA was measured and spectral domain optical coherence tomography (SD-OCT) images were acquired for 74 individuals with albinism. Categorical foveal hypoplasia grades were assessed using the Leicester Grading System for Foveal Hypoplasia. Foveal anatomical specialization (foveal versus parafoveal value) was quantified for inner retinal layer (IRL) thickness, outer segment (OS) length, and outer nuclear layer (ONL) thickness. These metrics, participant sex, and age were used to build a multiple linear regression of BCVA. This combined linear model's predictive properties were compared to those of categorical foveal hypoplasia grading. Results: The cohort included three participants with type 1a foveal hypoplasia, 23 participants with type 1b, 33 with type 2, ten with type 3, and five with type 4. BCVA ranged from 0.08 to 1.00 logMAR (mean ± SD: 0.53 ± 0.21). IRL ratio, OS ratio, and ONL ratio were measured in all participants and decreased with increasing severity of foveal hypoplasia. The best-fit combined linear model included all three quantitative metrics and participant age expressed as a binary variable (divided into 0-18 years and 19 years or older; adjusted R2 = 0.500). This model predicted BCVA more accurately than a categorical foveal hypoplasia model (adjusted R2 = 0.352). Conclusions: A quantitative model of foveal specialization accounts for more variance in BCVA in albinism than categorical foveal hypoplasia grading. Other factors, such as optical aberrations and eye movements, may account for the remaining unexplained variance.

Examining Whether AOSLO-Based Foveal Cone Metrics in Achromatopsia and Albinism Are Representative of Foveal Cone Structure.

Purpose: Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable. Methods: The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable. Results: Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups. Conclusions: Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients. Translational Relevance: Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.

Does Early Glasses Wear Improve Visual Outcome in OCA1A?

Purpose: Oculocutaneous albinism type 1A (OCA1A), with lifelong absent melanin in skin, hair, and eyes, is the most severe type of albinism with greatest ametropia and poorest vision. We evaluated the relationship between age when spectacles were begun and visual outcome, in addition to status of refraction, in OCA1A. Methods: After IRB approval, a retrospective review of 70 consecutive charts of patients with OCA1A identified 24 fitting inclusion criterion of BCVA recorded at age 10-12 years. Exclusion criteria were those with other vision-threatening diagnoses and patients seen for a single visit. We recorded sex, age at beginning glasses, and refraction and BCVA at age 10-12 and most recent visit. Data were arbitrarily grouped by those initiating glasses at ≤ age 12 months and > age 12 months. Results: Regression analysis showed a larger degree of astigmatism was weakly associated with worse vision at age 10-12 years. A weakly positive relationship was found between poorer BCVA at last visit and older age at which glasses were initiated. All receiving glasses by age 1 and only half receiving glasses when older had improved visual acuity from age 10-12 years to last follow up. Conclusion: Additional study of a larger sample of this rare disorder is needed to determine if early glasses wear improves later BCVA.

Assessing Ganglion Cell Layer Topography in Human Albinism Using Optical Coherence Tomography.

Purpose: To test whether ganglion cell layer (GCL) and inner plexiform layer (IPL) topography is altered in albinism. Methods: Optical coherence tomography scans were analyzed in 30 participants with albinism and 25 control participants. Horizontal and vertical line scans were acquired at the fovea, then strip registered and averaged. The Duke Optical Coherence Tomography Retinal Analysis Program was used to automatically segment the combined GCL and IPL and total retinal thickness, followed by program-assisted manual segmentation of the boundary between the GCL and IPL. Layer thickness and area under the curve (AUC) were calculated within 2.5 mm of the fovea. Nasal-temporal and superior-inferior asymmetry were calculated as an AUC ratio in each quadrant. Results: GCL and IPL topography varied between participants. The summed AUC in all quadrants was similar between groups for both the GCL (P = 0.84) and IPL (P = 0.08). Both groups showed nasal-temporal asymmetry in the GCL, but only participants with albinism had nasal-temporal asymmetry in the IPL. Nasal-temporal asymmetry was greater in albinism for both the GCL (P < 0.0001) and the IPL (P = 0.0006). The GCL usually comprised a greater percentage of the combined GCL and IPL in controls than in albinism. Conclusions: The GCL and IPL have greater structural variability than previously reported. GCL and IPL topography are significantly altered in albinism, which suggests differences in the spatial distribution of retinal ganglion cells. This finding provides insight into foveal development and structure-function relationships in foveal hypoplasia.

The Henle Fiber Layer in Albinism: Comparison to Normal and Relationship to Outer Nuclear Layer Thickness and Foveal Cone Density.

Purpose: Directional optical coherence tomography (D-OCT) allows the visualization of the Henle fiber layer (HFL) in vivo. Here, we used D-OCT to characterize the HFL and outer nuclear layer (ONL) in albinism and examine the relationship between true foveal ONL and peak cone density. Methods: Horizontal D-OCT B-scans were acquired, registered, and averaged for 12 subjects with oculocutaneous albinism and 26 control subjects. Averaged images were manually segmented to extract HFL and ONL thickness. Adaptive optics scanning light ophthalmoscopy was used to acquire images of the foveal cone mosaic in 10 subjects with albinism, from which peak cone density was assessed. Results: Across the foveal region, the HFL topography was different between subjects with albinism and normal controls. In particular, foveal HFL thickness was thicker in albinism than in normal controls (P < 0.0001), whereas foveal ONL thickness was thinner in albinism than in normal controls (P < 0.0001). The total HFL and ONL thickness was not significantly different between albinism and controls (P = 0.3169). Foveal ONL thickness was positively correlated with peak cone density in subjects with albinism (r = 0.8061, P = 0.0072). Conclusions: Foveal HFL and ONL topography are significantly altered in albinism relative to normal controls. Our data suggest that increased foveal cone packing drives the formation of Henle fibers, more so than the lateral displacement of inner retinal neurons (which is reduced in albinism). The ability to quantify foveal ONL and HFL may help further stratify grading schemes used to assess foveal hypoplasia.

Changes in refractive errors in albinism: a longitudinal study over the first decade of life.

PURPOSE: To analyze longitudinal changes in refraction in patients with albinism. METHODS: The medical records of 481 patients were reviewed retrospectively to identify patients who had cycloplegic refractions at three ages: visit A, 0-18 months old; visit B, 4-6 years old; visit C, 8-10 years old. We recorded refraction, type of albinism, glasses wear, and best-corrected visual acuity at visit C. Only right eyes were analyzed. RESULTS: A total of 75 patients were included. Of these, 73 wore glasses. Mean best-corrected visual acuity at visit C was 20/72 (range, 20/25-20/200). Mean spherical equivalent was 2.81 ± 2.4 D at visit A, 2.53 ± 3.4 D at visit B, and 2.15 ± 4.0 D at visit C. These values did not differ significantly from visits A to C (P = 0.0578). Mean astigmatism for the three time points was 1.60 ± 1.00 D, 2.50 ± 1.14 D, and 2.87 ± 1.45 D; these values did differ significantly from A to C (P < 0.0001). Subgroup analysis for OCA1A (16 eyes), OCA1B (20 eyes), and OCA2 (30 eyes) showed an increase in astigmatism from A to C, with a significant difference in means (P < 0.0001, P < 0.0001, and P = 0.0001, resp.). Worse best-corrected visual acuity and higher mean astigmatism at visit C were found for OCA1A (20/104 and +4.08 ± 1.34) compared to OCA1B (20/59 and +2.30 ± 1.36; P < 0.0001) and OCA2 (20/66 and +2.53 ±1.21; P < 0.0001). CONCLUSIONS: Children with albinism require periodic cycloplegic refraction, because astigmatism often increases within the first 10 years of life.

Visual Development During the Second Decade of Life in Albinism.

PURPOSE: To evaluate change in best corrected visual acuity (BCVA) during the second decade of life and the effects of albinism type and extraocular muscle surgery on BCVA in children with albinism. METHODS: In this retrospective longitudinal study, 41 patients with albinism with clinic visits recording binocular BCVA at least once between the ages of 10 and 13 years (visit A) and again between the ages of 17 and 20 years (visit B) were included. Type of albinism, age at each visit, and interval eye muscle surgeries were recorded for each patient. RESULTS: Forty (98%) patients showed BCVA improvement or stability between visits A and B. There was no significant effect of interval extraocular muscle surgery on BCVA. Those carrying either a clinically presumed or moleculary confirmed diagnosis of oculocutaneous albinism types 1B and 2 had the best visual outcomes, consistent with previous studies. CONCLUSIONS: In the majority of patients with albinism, significant improvement in BCVA occurs during the second decade of life. Extraocular muscle surgery was not a significant factor in BCVA improvement in albinism. Overall, the assessments support the finding of improvement of visual acuity in children with albinism at earlier ages and provide new information beneficial in predicting visual outcomes in the second decade of life. [J Pediatr Ophthalmol Strabismus. 2018;55(4):254-259.].

Retinal dystrophy in two boys with Costello syndrome due to the HRAS p.Gly13Cys mutation.

Features of Costello Syndrome, a systemic disorder caused by germline mutations in the proto-oncogene HRAS from the RAS/MAPK pathway, include failure-to-thrive, short stature, coarse facial features, cardiac defects including hypertrophic cardiomyopathy, intellectual disability, and predisposition to neoplasia. Two unrelated boys with Costello syndrome and an HRAS mutation (p.Gly13Cys) are presented with their ophthalmologic findings. Both had early symptoms of nystagmus, photophobia, and vision abnormalities. Fundus examination findings of retinal dystrophy were present at age 3 years. Both boys have abnormal electroretinograms with reduced or undetectable rod responses along with reduced cone responses consistent with rod-cone dystrophy. Our observations suggest that early ophthalmic examination and re-evaluations are indicated in children with Costello syndrome.

Outcomes of keratoplasty in the mucopolysaccharidoses: an international perspective.

OBJECTIVE: To describe visual outcomes after penetrating keratoplasty and deep anterior lamellar keratoplasty in patients with mucopolysaccharidoses. METHODS: This is a retrospective review of keratoplasty in consecutive patients from Brazil, England, Finland, Germany, Portugal, Sweden and the USA. All patients had corneal clouding due to mucopolysaccharidoses. Preoperative and postoperative visual outcome and ocular comorbidities were identified. Success was arbitrarily defined as any improvement in visual acuity or best-corrected visual acuity better than logarithm of the minimum angle of resolution 0.30 (20/40). Statistical analysis included only data from first operated eyes in the 16 patients who underwent bilateral keratoplasty. RESULTS: Forty-eight eyes from 32 patients with mucopolysaccharidoses I, IV or VI are reported. Mean follow-up was 70 months (range: 5-186). Penetrating keratoplasty was performed in 45 eyes and deep anterior lamellar keratoplasty in 3 eyes. At last follow-up, a successful visual outcome for penetrating keratoplasty in first operated/only operated eyes was found in 63%. Rejection episodes occurred in 23% of grafts; however, a clear graft was recorded at last follow-up in 94%. Ocular pathway comorbidities were identified in 63% of eyes transplanted. CONCLUSIONS: Clear corneal grafts can be obtained for patients with corneal clouding due to mucopolysaccharidosis with improvement in visual acuity in the majority.

A cross-sectional examination of visual acuity by specific type of albinism.

PURPOSE: Reports of best-corrected visual acuity (BCVA) in albinism are often based on overlapping clinical phenotypes. BCVA in albinism has been shown to improve with age. This study reports a large cross-sectional investigation to determine whether BCVA differs by specific type of albinism when age-corrected. METHODS: This retrospective review identified 170 individuals with a specific type of albinism identified by mutation(s) in a gene known to cause albinism (for OCA1, OCA2, and Hermansky-Pudlak syndrome ([HPS]) or a specific phenotype (white hair and no melanin pigment in OCA1A; pigmentary mosaicism in the obligate carriers for males with OA1). We recorded optotype binocular BCVA at final follow-up. Patients were age-grouped (2-5 years, 6-14 years, and ≥15 years) for comparison. RESULTS: The greatest visual acuity deficit was found for OCA1A in all age groups. At age ≥15 years (n = 79), mean BCVA was 20/128 for OCA1A, 20/37 for OCA1B, 20/59 for OCA2, 20/63 for OA1, and 20/121 for HPS. Significant differences between BCVA at ≥15 years were found in the following: OCA1A vs OCA1B, OCA1A vs OCA2, OCA1A vs OA1, OCA1B vs HPS, OCA2 vs HPS, and OA1 vs HPS (P ≤ 0.02). CONCLUSIONS: This study provides a large sample size and includes only those with a specific type of albinism. BCVA varies by albinism type, and there is overlap in BCVA, particularly in the younger age groups. For ages ≥15 years, there are significant differences in BCVA between several types of albinism.

Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects.

Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.

Concordance of visual and structural features between siblings with albinism.

PURPOSE: To evaluate similarities and differences in visual function and ocular structure between siblings with albinism. METHODS: The medical records of all siblings diagnosed with albinism were retrospectively reviewed. Comparisons were made using examination at oldest age for younger sibling and examination closest to that age for older siblings. RESULTS: A total of 111 patients from 54 families were studied. Mean age was 12.9 years (range, 2 months to 44.2 years). Mean difference in ages between sibling pair examinations was 11.5 months (range, 0-87 months). Of 45 families, best-corrected visual acuity was equal in 9 (20%), within 1/2 octave in 9 (20%), >1/2 but <1 octave in 21 (47%), and ≥1 octave difference in 6 (13%). Of 27 families, stereoacuity was present in all siblings in 9 (33%), absent in 9 (33%), and present in only 1 sibling in 9 (33%). Of 54 families, grading of iris translucency was equal in 35 (65%) and different by 1 grade in 19 (35%). Of 54 families, foveal grading was equal in 39 (72%), different by 1 grade in 14 (26%), and different by ≥2 grades in 1 (2%). Macular melanin was present in all siblings in 16 of the 54 families (30%), absent in all siblings in 36 (67%), and present in only 1 sibling in 2 (4%) families. CONCLUSIONS: The strong concordance of structural features is contrasted with discordance in visual function. Families of siblings with albinism should be counseled with due caution because visual function is often disparate despite similar structural findings.

Comprehensive Adult Medical Eye Evaluation Preferred Practice Pattern(®) Guidelines.

UNLABELLED: COMPREHENSIVE ADULT MEDICAL EYE EVALUATION® PREFERRED PRACTICE PATTERN® GUIDELINES: Evidence-based update of the Comprehensive Adult Medical Eye Evaluation Preferred Practice Pattern® (PPP) guidelines, discussing the rationale and components of an ophthalmic evaluation for adult patients with and without risk factors.

Posterior staphyloma in oculocutaneous albinism: another possible cause of reduced visual acuity.

Posterior staphyloma is typically associated with myopic degeneration and has not been recognized as a cause of reduced visual acuity in albinism. We report 3 cases of posterior staphyloma, each with oculocutaneous albinism (OCA) defined by phenotype and genotype. Two cases are biological sisters with OCA type 2; one was myopic and the other was hyperopic. The third case involves a man with OCA associated with Hermansky-Pudlak syndrome (HPS-5). Staphyloma may be another cause of reduced visual acuity in albinism, particularly with increasing age. It may occur in association with myopia or hyperopia.

Clinical Insights Into Foveal Morphology in Albinism.

PURPOSE: A hallmark of albinism is foveal hypoplasia. However, literature suggests variable foveal development. This study evaluates the association between ocular phenotype and foveal morphology to demonstrate the broad structural and functional spectrum. METHODS: Best-corrected visual acuity (BCVA), nystagmus, angle kappa, stereoacuity, iris transillumination, macular melanin presence, foveal avascular zone, and annular reflex were recorded in 14 patients with albinism. Spectral-domain optical coherence tomography provided macular images. RESULTS: The clinical phenotype was broad, with BCVA varying from 20/20 to 20/100. Better BCVA was associated with a preserved foveal avascular zone, annular macular reflex, stereoacuity, and macular melanin. Imaging demonstrated a continuum of foveal development correlating with BCVA. Individuals with a rudimentary pit had normal inner and outer segment lengthening and better BCVA. CONCLUSIONS: The spectrum of ocular structure and visual function in albinism is broad, suggesting a possible diagnosis of albinism in a patient with an even more normal clinical presentation.

Relationship between foveal cone specialization and pit morphology in albinism.

PURPOSE: Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism. METHODS: We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured. RESULTS: We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism. CONCLUSIONS: Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue.