Nystagmus Characteristics in Albinism: Unveiling the Link to Foveal Hypoplasia and Visual Acuity.

Purpose: The purpose of this study was to describe the association among nystagmus characteristics, foveal hypoplasia, and visual acuity in patients with albinism. Methods: We studied nystagmus recordings of 50 patients with albinism. The nystagmus waveform was decomposed into two types: dominantly pendular and dominantly jerk. We correlated the nystagmus type, amplitude, frequency, and percentage of low velocity (PLOV) to Snellen visual acuity and foveal hypoplasia grades. Results: The grade of foveal hypoplasia and visual acuity showed a strong correlation (r = 0.87, P < 0.0001). Nystagmus type and PLOV had the strongest significant (P < 0.0001) correlation with visual acuity (r = 0.70 and r = -0.56, respectively) and with foveal hypoplasia (r = 0.76 and r = -0.60, respectively). Patients with pendular nystagmus type had the lowest PLOV, and the highest grade of foveal hypoplasia (P < 0.0001). Severe foveal hypoplasia (grade 4), was almost invariably associated with pendular nystagmus (86%). Conclusions: Foveal hypoplasia grade 4 is associated with pendular nystagmus, lower PLOV, and worse visual acuity. Based on these results, nystagmus recordings at a young age may contribute to predicting visual outcomes.

The retinal pigmentation pathway in human albinism: Not so black and white.

Albinism is a pigment disorder affecting eye, skin and/or hair. Patients usually have decreased melanin in affected tissues and suffer from severe visual abnormalities, including foveal hypoplasia and chiasmal misrouting. Combining our data with those of the literature, we propose a single functional genetic retinal signalling pathway that includes all 22 currently known human albinism disease genes. We hypothesise that defects affecting the genesis or function of different intra-cellular organelles, including melanosomes, cause syndromic forms of albinism (Hermansky-Pudlak (HPS) and Chediak-Higashi syndrome (CHS)). We put forward that specific melanosome impairments cause different forms of oculocutaneous albinism (OCA1-8). Further, we incorporate GPR143 that has been implicated in ocular albinism (OA1), characterised by a phenotype limited to the eye. Finally, we include the SLC38A8-associated disorder FHONDA that causes an even more restricted "albinism-related" ocular phenotype with foveal hypoplasia and chiasmal misrouting but without pigmentation defects. We propose the following retinal pigmentation pathway, with increasingly specific genetic and cellular defects causing an increasingly specific ocular phenotype: (HPS1-11/CHS: syndromic forms of albinism)-(OCA1-8: OCA)-(GPR143: OA1)-(SLC38A8: FHONDA). Beyond disease genes involvement, we also evaluate a range of (candidate) regulatory and signalling mechanisms affecting the activity of the pathway in retinal development, retinal pigmentation and albinism. We further suggest that the proposed pigmentation pathway is also involved in other retinal disorders, such as age-related macular degeneration. The hypotheses put forward in this report provide a framework for further systematic studies in albinism and melanin pigmentation disorders.

The Phenotypic and Mutational Spectrum of the FHONDA Syndrome and Oculocutaneous Albinism: Similarities and Differences.

Purpose: The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities (FHONDA syndrome), to describe the phenotypic spectrum, and to compare it to albinism. Subjects and Methods: We retrospectively collected molecular, ophthalmic, and electrophysiological data of 28 patients molecularly confirmed with FHONDA from the Netherlands (9), Israel (13), France (2), and the United States of America (4). We compared the data to that of 133 Dutch patients with the 3 most common types of albinism in the Netherlands: oculocutaneous albinism type 1 (49), type 2 (41), and ocular albinism (43). Results: Patients with FHONDA had a total of 15 different mutations in SLC38A8, of which 6 were novel. Excluding missing data, all patients had moderate to severe visual impairment (median visual acuity [VA] = 0.7 logMAR, interquartile range [IQR] = 0.6-0.8), nystagmus (28/28), and grade 4 foveal hypoplasia (17/17). Misrouting was present in all nine tested patients. None of the patients had any signs of hypopigmentation of skin and hair. VA in albinism was better (median = 0.5 logMAR, IQR = 0.3-0.7, P 0.006) and the phenotypes were more variable: 14 of 132 without nystagmus, foveal hypoplasia grades 1 to 4, and misrouting absent in 16 of 74. Conclusions: Compared to albinism, the FHONDA syndrome appears to have a more narrow phenotypic spectrum, consisting of nonprogressive moderately to severely reduced VA, nystagmus, severe foveal hypoplasia, and misrouting. The co-occurrence of nystagmus, foveal hypoplasia, and misrouting in the absence of hypopigmentation implies that these abnormalities are not caused by lack of melanin, which has important implications for understanding the pathogenesis of these features.

The Detection Of Misrouting In Albinism: Evaluation of Different VEP Procedures in a Heterogeneous Cohort.

Purpose: To investigate the optimal procedures for multichannel visually evoked potentials (VEPs) to detect misrouting in albinism subjects. Methods: Investigations were done in a phenotypically heterogeneous group of 180 albinism subjects and 187 controls with and without ocular pathology. We retrospectively compared standard flash VEP (fVEP), high-frequency fVEP with a handheld device (hh fVEP), pattern-onset VEP (poVEP), and short-onset acuity sweep VEP. The diagnostic power of these stimuli were estimated by calculating the area under the curve (AUC). Subjects were divided in three age groups (<3, 3-6 [toddler], and ≥6 years). Subjects ≥6 years of age were further divided in two visual acuity groups (≤0.3 logMAR and >0.3 logMAR). Results: The optimal stimulus was hh fVEP, standard fVEP, and poVEP 60' for subjects <3, 3-6, and ≥6 years of age, respectively. In subjects ≥6 years old with poor visual acuity, the area under the curve of fVEP was almost equal to that of poVEP 60'. Conclusions: For the optimal detection of misrouting with multichannel VEP recordings, we recommend using a high-frequency hh fVEP in children <3 years of age, standard fVEP in toddlers, and poVEP 60' in subjects ≥6 years of age. fVEP can also be used in the oldest age group for subjects with visual acuity of >0.3 logMAR. Remarkably, some albinism subjects showed misrouting on full-field stimulation but normal routing of the central retina, suggesting that not the whole line of decussation is shifted temporally.

The Phenotypic Spectrum of Albinism.

PURPOSE: To describe the phenotypic spectrum of a large cohort of albino patients, to investigate the relationship between the ocular abnormalities and the visual acuity (VA), and to define diagnostic criteria for the white population. We also estimated the prevalence of albinism in The Netherlands. DESIGN: Retrospective cohort study. PARTICIPANTS: We investigated the phenotype of 522 patients with albinism from the databases of Bartiméus (452 patients), Leiden University Medical Center (44 patients), and the Academic Medical Center Amsterdam (26 patients). METHODS: We collected clinical, genetic, and electrophysiologic data of patients with albinism. We used grading schemes for iris translucency, fundus hypopigmentation, and foveal hypoplasia. MAIN OUTCOME MEASURES: Visual acuity, nystagmus, iris translucency, fundus pigmentation, foveal hypoplasia, and misrouting. RESULTS: Nystagmus was absent in 7.7% (40/521), iris translucency could not be detected in 8.9% (44/492), 3.8% (19/496) had completely normal fundus pigmentation, 0.7% (3/455) had no foveal hypoplasia, and misrouting was not established in 16.1% (49/304). The VA varied from -0.1 to 1.3 logarithm of the minimum of angle of resolution (logMAR). The foveal hypoplasia grading correlated best with the VA (r = 0.69, P < 0.001), whereas iris translucency, fundus pigmentation, and misrouting did not predict the VA significantly. We estimated a prevalence of albinism in The Netherlands of at least 1:12 000. CONCLUSIONS: None of the characteristics of albinism were consistently present in our cohort. To be able to distinguish albinism from other conditions with similar ocular features, especially in northern and western European countries, we propose major and minor clinical criteria. Major criteria would be (1) foveal hypoplasia grade 2 or more, (2) misrouting, and (3) ocular hypopigmentation, either iris translucency or fundus hypopigmentation grade 2 or more. Minor criteria would be (1) nystagmus, (2) hypopigmentation of skin and hair, (3) grade 1 fundus hypopigmentation, and (4) foveal hypoplasia grade 1. We propose that 3 major criteria or 2 major and 2 minor criteria are necessary for the diagnosis. In the presence of a molecular diagnosis, 1 major criterion or 2 minor criteria will be sufficient.