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Translational Vision Science &... Oct 2022Complement alternative pathway (AP) dysregulation has been implicated in geographic atrophy, an advanced form of age-related macular degeneration. Danicopan is an...
PURPOSE
Complement alternative pathway (AP) dysregulation has been implicated in geographic atrophy, an advanced form of age-related macular degeneration. Danicopan is an investigational, first-in-class inhibitor of factor D, an essential AP activation enzyme. We assessed danicopan distribution to the posterior segment of the eye after oral dosing.
METHODS
Tissue distribution of drug-derived radioactivity was evaluated using whole-body autoradiography following oral administration of [14C]-danicopan to pigmented and albino rats. Pharmacokinetics and ocular tissue distribution were studied in pigmented and albino rabbits following single and multiple oral dosing of danicopan. The melanin binding property was characterized in vitro.
RESULTS
Radioactivity was distributed widely in rats and became nonquantifiable in most tissues 24 hours postdose except in the pigmented rat uvea (quantifiable 672 hours postdose). Danicopan binding to melanin was established in vitro. After single dosing, the maximum concentration (Cmax) and area under the curve (AUC) in neural retina and plasma were similar in both rabbit types. After multiple dosing, AUC in neural retina was 3.4-fold higher versus plasma in pigmented rabbits. Drug levels in choroid/Bruch's membrane (BrM)/retinal pigment epithelium (RPE) were similar to plasma in albino rabbits but higher in pigmented rabbits: Cmax and AUC were 2.9- and 23.8-fold higher versus plasma after single dosing and 5.8- and 62.7-fold higher after multiple dosing. In pigmented rabbits, ocular tissue exposures slowly declined over time but remained quantifiable 240 hours postdose.
CONCLUSIONS
The results demonstrate that danicopan crosses the blood-retina barrier and binds melanin reversibly, leading to a higher and more sustained exposure in melanin-containing ocular tissues (choroid/BrM/RPE) and in the neural retina as compared to in plasma after repeated oral dosing in pigmented animals.
TRANSLATIONAL RELEVANCE
These findings suggest that oral danicopan possesses potential for treating geographic atrophy because AP dysregulation in the posterior segment of the eye is reported to be involved in the disease pathogenesis.
Topics: Animals; Albinism; Complement Factor D; Geographic Atrophy; Melanins; Retina; Rats
PubMed: 36301553
DOI: 10.1167/tvst.11.10.37 -
Ophthalmology Science Dec 2021To assess the impact of two hypomorphic alleles (R402Q and S192Y) on foveal pit and foveal avascular zone (FAZ) morphology.
PURPOSE
To assess the impact of two hypomorphic alleles (R402Q and S192Y) on foveal pit and foveal avascular zone (FAZ) morphology.
DESIGN
Prospective, cross-sectional study.
PARTICIPANTS
A total of 164 participants with normal vision (67 male and 97 female; mean ± standard deviation [SD] age = 30.5 ± 12.8 years) were recruited.
METHODS
Sequencing of more than 100 pigmentation-related genes was performed, and results were reviewed for the presence or absence of the polymorphisms R402Q (rs1126809) and S192Y (rs1042602). Volumetric scans of the macula were obtained for each participant using OCT, and retinal thickness maps were analyzed using custom software. OCT angiography was used to image the FAZ, which was manually segmented and measured. Linear mixed model analysis was used to assess associations between genotype and foveal pit morphology.
MAIN OUTCOME MEASURES
Foveal pit depth, diameter, volume, and FAZ area in relation to the presence of hypomorphic alleles R402Q and S192Y on the gene.
RESULTS
Heterozygosity for the R402Q allele was associated with decreased pit diameter ( 0.0094) and decreased FAZ area ( 0.025). Homozygosity for the R402Q allele was associated with reduced pit volume ( 0.0005), decreased pit depth ( 0.007), reduced pit diameter ( 0.0052), and reduced FAZ area ( 0.0012). Homozygosity for S192Y was associated with reduced FAZ area ( 0.016). Heterozygosity for the S192Y allele was not associated with differences in foveal pit depth, diameter, volume, or FAZ area ( > 0.05).
CONCLUSIONS
Although the role of the R402Q and S192Y hypomorphic alleles in albinism remains controversial, our data suggest that these variants contribute to the extensive inter-individual variability in foveal morphology in the normal population. Our results contribute to the evolving picture of the relationship between ocular pigmentation and foveal morphology.
PubMed: 36246950
DOI: 10.1016/j.xops.2021.100077 -
Frontiers in Genetics 2022Idiopathic infantile nystagmus (IIN) is an inherited disorder occurring in the first 6 months of life, with no underlying retinal or neurological etiologies and is...
Idiopathic infantile nystagmus (IIN) is an inherited disorder occurring in the first 6 months of life, with no underlying retinal or neurological etiologies and is predominantly caused by mutations in the gene. IIN poses a diagnostic challenge as underlying pre-symptomatic "multisystem" disorders varying from benign to life-threatening should first be ruled out before nystagmus can be labeled as idiopathic. A multidisciplinary approach including multimodal ocular investigations and next-generation sequencing with whole-genome sequencing (WGS) or targeted gene panel testing is required to delineate the exact etiology. We report the clinical and genetic outcomes of 22 patients, from 22 unrelated families of diverse ethnicities, with IIN seen in the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between 2016 and 2022. Thirty-six percent (8/22) received a confirmed molecular diagnosis with eight mutations identified in two genes (seven in including one novel variant c.706_707del; p. [Lys236Alafs*66], and one in ). This study expands the mutational spectrum of IIN and highlights the significant role of an integrated care pathway and broader panel testing in excluding underlying pathologies.
PubMed: 36072665
DOI: 10.3389/fgene.2022.977806 -
Journal of Optometry 2023To describe the prevalence and severity of photosensitivity in patients with albinism, and to compare with ocular features and how this correlated with use and choice of...
PURPOSE
To describe the prevalence and severity of photosensitivity in patients with albinism, and to compare with ocular features and how this correlated with use and choice of optical filters.
METHODS
Cross-sectional study on 81 participants with ocular or oculocutaneous albinism. An ophthalmic evaluation including visual acuity, contrast sensitivity and evaluation of iris translucency and fundus hypopigmentation was performed. Participants were offered optical rehabilitation with testing of a wide panel of filters. The associations between ocular characteristics, subjective photosensitivity complaints, and filter choice were evaluated.
RESULTS
Photosensitivity was rated as "some" to "worst imaginable" in 77.8% of participants. Severity of photosensitivity correlated significantly with fundus hypopigmentation (p = 0.04) but not with iris translucency (p = 0.14) and it was worse in those with poor visual acuity but there was no association between photosensitivity and contrast vision. Seventy-four new pairs of spectacles were prescribed in the study. All outdoor spectacles contained a filter, whereas 26.5% of new indoor spectacles did not. Relatively neutral filter colors (gray, brown or a combination of gray and brown with other colors) and low transmission were preferred.
DISCUSSION
Photosensitivity is common in albinism, but research targeting treatment is limited. Color and neutral filters with a low light transmission were preferred, with participants having a large number of spectacles, presumably to meet their needs in different situations.
Topics: Humans; Cross-Sectional Studies; Albinism; Albinism, Oculocutaneous; Vision, Ocular; Visual Acuity
PubMed: 36028395
DOI: 10.1016/j.optom.2022.07.002 -
International Journal of Molecular... Jul 2022Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency,...
Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located with a pathogenic variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.
Topics: Albinism; Albinism, Oculocutaneous; Eye Diseases, Hereditary; Fovea Centralis; Humans; Nystagmus, Congenital; Vision Disorders; Visual Acuity
PubMed: 35887175
DOI: 10.3390/ijms23147825 -
Genes Jul 2022Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive syndromic form of albinism, characterized by oculocutaneous albinism (OCA) and other systemic...
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive syndromic form of albinism, characterized by oculocutaneous albinism (OCA) and other systemic complications. The purpose of this study was to investigate patients with HPS-associated gene mutations and describe associated ocular and extraocular phenotypes. Fifty-four probands clinically diagnosed as albinism were enrolled. Ophthalmic examinations and genetic testing were performed in all subjects. The phenotypic and genetic features were evaluated. HPS-associated gene mutation was identified in four of the patients with albinism phenotype. Clinically, photophobia, and nystagmus was detected in all (4/4) patients, and strabismus was found in one (1/4) patient. Fundus examination revealed fundus hypopigmentation and foveal hypoplasia in all (8/8) eyes. Eight novel causative mutations were detected in these four HPS probands. Five (62.5%, 5/8) of the mutations were nonsense, two of the mutations were missense (25%, 2/8), and one of the mutations was frameshift (12.5%, 1/8). All patients in our study carried compound heterozygous variants, and all these pathogenic variants were identified to be novel, with most (62.5%, 5/8) of the mutations being nonsense. Our results improved the understanding of clinical ocular features, and expanded the spectrum of known variants and the genetic background of HPS.
Topics: Eye; Genetic Testing; Hermanski-Pudlak Syndrome; Humans; Mutation; Phenotype
PubMed: 35886065
DOI: 10.3390/genes13071283 -
Indian Journal of Ophthalmology Jul 2022To assess the clinical profiles, presenting ocular features, and variations in the phenotypic features in siblings with oculocutaneous albinism (OCA).
PURPOSE
To assess the clinical profiles, presenting ocular features, and variations in the phenotypic features in siblings with oculocutaneous albinism (OCA).
METHODS
Electronic medical records of consecutive siblings diagnosed with albinism from January 2016 to December 2020 were reviewed to identify the affected siblings. The variations in their phenotypic characteristics were studied.
RESULTS
Significant variations were observed in the clinical features between the siblings (n = 42). A difference of >2 lines in visual acuity was observed in 50% (n = 21) of the sibling pairs. Compound hyperopic astigmatism was the commonest refractive error. The refractive status was different in 80.95% (n = 34) pairs. Although individually strabismus and abnormal head posture were observed in one-third and one-fourth of individual children, respectively, both siblings with similar strabismus were seen in only 16.67% (n = 7) and with a similar abnormal head posture in 13.33% (n = 5). Nystagmus was the most consistent finding across these siblings with a similar nature of horizontal jerk or pendular in 65% of sibling pairs.
CONCLUSION
This study observed significant variations in phenotypic presentations among siblings with OCA. Such differences in clinical manifestations and severity would be helpful in appropriate counseling of these families as the need for rehabilitation services is likely to vary across siblings.
Topics: Albinism, Oculocutaneous; Biological Variation, Population; Child; Eye; Humans; Siblings; Strabismus
PubMed: 35791147
DOI: 10.4103/ijo.IJO_1025_22 -
Indian Journal of Ophthalmology Jul 2022To study the retinal and choroidal thickness variations on enhanced depth imaging optical coherence tomography scans in ocular albinism (OA) and compare with age-matched... (Observational Study)
Observational Study
PURPOSE
To study the retinal and choroidal thickness variations on enhanced depth imaging optical coherence tomography scans in ocular albinism (OA) and compare with age-matched healthy subjects.
METHODS
This retrospective observational study had 48 eyes of 24 patients diagnosed clinically as OA and age, sex, and axial length-matched control healthy subjects. All patients underwent detailed ophthalmic examination and a single-line horizontal-raster enhanced depth imaging - optical coherence tomography scan (Spectralis, Heidelberg Engineering). Retinal and choroidal thickness was measured, compared, and analyzed between the two groups. Mann-Whitney U test was used for analysis between the two groups. P < 0.05 was considered significant.
RESULTS
The mean age was 28.3 ± 11.6 and 29.9 ± 10.6 years in the OA group and control group, respectively. Spherical equivalents ranged from -8.5D to +10.5D in the OA group and from -8.0D to +10.0D in the control group. The mean axial length between the two groups (P = 0.652) were comparable. The average retinal thickness (272 ± 34.3 vs. 213 ± 13.8 μm; P < 0.001) was greater in the OA group as compared to controls. The mean choroidal thickness (184 ± 78.4 vs. 287 ± 46.4 μm; P < 0.001) was significantly thinner in the OA group.
CONCLUSION
Acquisition of OCT scans in OA can be challenging. This study showed that the subfoveal retinal thickness and choroidal thickness measured across the scans were significantly different in the OA group compared to controls. In the future, more studies are required to evaluate the role of the choroid and its relationship to emmetropization in albinism.
Topics: Adolescent; Adult; Albinism, Ocular; Choroid; Humans; Retina; Retrospective Studies; Tomography, Optical Coherence; Young Adult
PubMed: 35791146
DOI: 10.4103/ijo.IJO_2907_21 -
Indian Journal of Ophthalmology Jul 2022To describe the distribution of ocular disorders in patients with a family history of consanguinity presenting to a multi-tier ophthalmology hospital network in India.
PURPOSE
To describe the distribution of ocular disorders in patients with a family history of consanguinity presenting to a multi-tier ophthalmology hospital network in India.
METHODS
This cross-sectional hospital-based study included 2,805,267 new patients presenting between August 2010 and April 2021. Patients with a family history of consanguinity were included as cases. The sociodemographic and clinical data were collected using an electronic medical record system.
RESULTS
Overall, 20,445 (0.73%) new patients were documented to have a family history of consanguinity. The prevalence rates were 4.04% in children (age: <16 years) and 0.21% in adults. The mean age of the patients was 11.87 ± 11.06 years. The majority of the patients were males (56.48%) and students (54.43%) by profession. The majority (93.05%) of the patients were in the 0-30-years age bracket, with over half of them (53.71%) presenting in the first decade of life. A significant number of patients were from higher socioeconomic status (73.48%) and the rural region (47.62%). The most common degree of consanguinity documented was second degree (3.95%). The most common ocular disorders associated with a high proportion of consanguinity were congenital hereditary endothelial dystrophy (CHED) (100%), corneal macular dystrophy (83.78%), xeroderma pigmentosum (80.95%), and ocular albinism (73.59%). A tenth of the patients (9.8%) reported a similar history of ocular disorders among the family members and more commonly among the siblings (70.4%).
CONCLUSION
Consanguineous marriages are not uncommon in India. They cause ocular disorders that cause visual impairment in a significant majority of those affected in their early decades of life. Genetic counseling plays a role in prevention.
Topics: Adolescent; Adult; Child; Child, Preschool; Consanguinity; Cross-Sectional Studies; Data Science; Electronic Health Records; Eye Diseases; Female; Humans; India; Infant; Male; Young Adult
PubMed: 35791120
DOI: 10.4103/ijo.IJO_1553_21 -
Progress in Retinal and Eye Research Nov 2022Albinism is a pigment disorder affecting eye, skin and/or hair. Patients usually have decreased melanin in affected tissues and suffer from severe visual abnormalities,... (Review)
Review
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.
Topics: Humans; Melanins; Mutation; Albinism; Retina; Pigmentation
PubMed: 35729001
DOI: 10.1016/j.preteyeres.2022.101091