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.

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.

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.

A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9.

Hermansky-Pudlak Syndrome (HPS) is an autosomal-recessive condition characterized by oculocutaneous albinism and a bleeding diathesis due to absent platelet delta granules. HPS is a genetically heterogeneous disorder of intracellular vesicle biogenesis. We first screened all our patients with HPS-like symptoms for mutations in the genes responsible for HPS-1 through HPS-6 and found no functional mutations in 38 individuals. We then examined all eight genes encoding the biogenesis of lysosome-related organelles complex-1, or BLOC-1, proteins in these individuals. This identified a homozygous nonsense mutation in PLDN in a boy with characteristic features of HPS. PLDN is mutated in the HPS mouse model pallid and encodes the protein pallidin, which interacts with the early endosomal t-SNARE syntaxin-13. We could not detect any full-length pallidin in our patient's cells despite normal mRNA expression of the mutant transcript. We could detect an alternative transcript that would skip the exon that harbored the mutation, but we demonstrate that if this transcript is translated into protein, although it correctly localizes to early endosomes, it does not interact with syntaxin-13. In our patient's melanocytes, the melanogenic protein TYRP1 showed aberrant localization, an increase in plasma-membrane trafficking, and a failure to reach melanosomes, explaining the boy's severe albinism and establishing his diagnosis as HPS-9.

Does levodopa improve vision in albinism? Results of a randomized, controlled clinical trial.

BACKGROUND: Dopamine is an intermediate product in the biosynthesis of melanin pigment, which is absent or reduced in albinism. Animal research has shown that supplying a precursor to dopamine, levodopa, may improve visual acuity in albinism by enhancing neural networks. This study examines the safety and effectiveness of levodopa on best-corrected visual acuity in human subjects with albinism. DESIGN: Prospective, randomized, placebo-controlled, double-masked clinical trial conducted at the University of Minnesota. PARTICIPANTS: Forty-five subjects with albinism. METHODS: Subjects with albinism were randomly assigned to one of three treatment arms: levodopa 0.76 mg/kg with 25% carbidopa, levodopa 0.51 mg/kg with 25% carbidopa, or placebo and followed for 20 weeks, with best-corrected visual acuity measured at enrollment, and at weeks 5, 10, 15, and 20 after enrollment. Side-effects were recorded with a symptom survey. Blood was drawn for genotyping. MAIN OUTCOME MEASURES: Side-effects and best-corrected visual acuity 20 weeks after enrolment. RESULTS: All subjects had at least one mutation found in a gene known to cause albinism. Mean age was 14.5 years (range: 3.5 to 57.8 years). Follow up was 100% and compliance was good. Minor side-effects were reported; there were no serious adverse events. There was no statistically significant improvement in best-corrected visual acuity after 20 weeks with either dose of levodopa. CONCLUSIONS: Levodopa, in the doses used in this trial and for the time course of administration, did not improve visual acuity in subjects with albinism.

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.

Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA.

Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrome is a multisystem disorder caused by galactosamine-6-sulfatase deficiency. Skeletal manifestations, including short stature, skeletal dysplasia, cervical instability, and joint destruction, are known to be associated with this condition. Due to the severity of these skeletal manifestations, the non-skeletal manifestations are frequently overlooked despite their significant contribution to disease progression and impact on quality of life. This review provides detailed information regarding the non-skeletal manifestations and suggests long-term assessment guidelines. The visual, auditory, digestive, cardiovascular, and respiratory systems are addressed and overall quality of life as measured by endurance and other functional abilities is discussed. Impairments such as corneal clouding, astigmatism, glaucoma, hearing loss, hernias, hepatomegaly, dental abnormalities, cardiac valve thickening and regurgitation, obstructive sleep apnea, tracheomalacia, restrictive and obstructive respiratory compromise, and muscular weakness are discussed. Increased awareness of these non-skeletal features is needed to improve patient care.

Use of a driving simulator to assess performance under adverse weather conditions in adults with albinism.

Participants with albinism have reduced vision and nystagmus with reduced foveation times. This prospective study evaluated driving in 12 participants with albinism and 12 matched controls. Participants drove a vehicle simulator through a virtual rural course in sunny and foggy conditions. Under sunny conditions, participants with albinism showed a narrower preferred minimum safety boundary during car-following tasks than did controls, but there was no difference under foggy conditions. Their driving did not differ significantly from that of controls when approaching a stop sign or when choosing gap size between oncoming vehicles when crossing an intersection. However, when compared to control drivers, participants with albinism had a decreased minimum safety boundary for car-following that should be included in counseling regarding driving safety.

Ocular manifestations as key features for diagnosing mucopolysaccharidoses.

Diagnosis of mucopolysaccharidosis (MPS) requires awareness of the multisystem disease manifestations and their diverse presentation in terms of time of onset and severity. Many patients with MPS remain undiagnosed for years and progressively develop irreversible pathologies, which ultimately lead to premature death. To foster timely treatment and ensure a better outcome, it is of utmost importance to recognize and evaluate the typical ocular features that present fairly early in the course of the disease in many children with MPS. These include corneal clouding, ocular hypertension/glaucoma, retinal degeneration, optic disc swelling and optic nerve atrophy. Other associations include pseudo-exophthalmos, amblyopia, strabismus and large refractive errors requiring spectacle correction. While some ocular manifestations require specialized equipment for detecting abnormalities, light sensitivity, pseudo-exophthalmos and strabismus are often apparent on a routine physical examination. In addition, patients may be symptomatic from vision impairment, photosensitivity, night blindness and visual field constriction. Combined with the skeletal/joint complications and other manifestations, these ocular features are key in the differential diagnosis of children with joint abnormalities. Rheumatologists should have a high index of suspicion for MPS to facilitate early diagnosis. Referral to a geneticist, a metabolic specialist or physician who specializes in MPS can confirm the diagnosis and provide disease management. Consultation with an ophthalmologist who has expertise in MPS is also needed for thorough examination of the eyes and regular follow-up care.

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.

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.

A caruncular choristoma presenting as an eyelid mass in an infant.

A 7-week-old patient presented for evaluation of a congenital eyelid mass. Following surgical excision of the lesion, histopathologic diagnosis of caruncular choristoma was made. To the authors' knowledge, this is the first report of caruncular tissue presenting as an external eyelid mass.

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 R402Q tyrosinase variant does not cause autosomal recessive ocular albinism.

Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.

Albinism: classification, clinical characteristics, and recent findings.

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.

Neurodevelopment in children with albinism.

OBJECTIVES: To evaluate neurologic development in children with albinism. DESIGN: Observational cohort series. PARTICIPANTS AND/OR CONTROLS: Seventy-eight children with albinism, ages 4 to 18 years. METHODS: Parents completed a developmental questionnaire and were interviewed to evaluate their child for attention deficit hyperactivity disorder (ADHD) utilizing Diagnostic and Statistical Manual IV criteria. Sixty-five children underwent neurologic evaluation of balance and fine and gross motor movements. Results were compared with age-appropriate norms. Standardized reading tests were administered to 44 children. Each of 7 neurodevelopmental parameters were compared in terms of binocular best-corrected visual acuity (BCVA) using the nonparametric Wilcoxon rank-sum test. MAIN OUTCOME MEASURES: Seven neurodevelopmental parameters were measured, including onset of walking, tandem gait, repetitive finger movements, sequential finger movements, standing on one foot, hopping on one foot, and throwing a ball overhand. School performance, reading performance, and presence of ADHD were also measured. RESULTS: The BCVA ranged from 20/20 to 20/800, with median of 20/150. A diagnosis of ADHD was present in 21.8% and pervasive developmental disorder was noted in three children (3.8%). No significant developmental delays were noted in the majority of children. Motor development was generally within the normal range and unaffected by severity of visual impairment. Parents reported that 82% performed at grade level in math and 74% at grade level in reading. Only 18% scored below average on standardized reading tests. CONCLUSIONS: Most children with albinism have normal neurologic development despite visual impairment and increased prevalence of ADHD.

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.].

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.