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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 -
Investigative Ophthalmology & Visual... Jun 2022We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.
PURPOSE
We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.
METHODS
AL measurements from IRD natural history study participants were included and compared with reference cohorts (TwinsUK, Raine Study Gen2-20, and published studies). Comparing with the Raine Study cohort, formal odds ratios (ORs) for AL ≥ 26 mm or AL ≤ 22 mm were derived for each IRD (Firth's logistic regression model, adjusted for age and sex).
RESULTS
Measurements were available for 435 patients (median age, 19.5 years). Of 19 diseases, 10 had >10 participants: ABCA4 retinopathy; CNGB3- and CNGA3-associated achromatopsia; RPGR-associated disease; RPE65-associated disease; blue cone monochromacy (BCM); Bornholm eye disease (BED); TYR- and OCA2-associated oculocutaneous albinism; and GPR143-associated ocular albinism. Compared with the TwinsUK cohort (n = 322; median age, 65.1 years) and Raine Study cohort (n = 1335; median age, 19.9 years), AL distributions were wider in the IRD groups. Increased odds for longer ALs were observed for BCM, BED, RPGR, RPE65, OCA2, and TYR; increased odds for short AL were observed for RPE65, TYR, and GPR143. In subanalysis of RPGR-associated disease, longer average ALs occurred in cone-rod dystrophy (n = 5) than rod-cone dystrophy (P = 0.002).
CONCLUSIONS
Several diseases showed increased odds for longer AL (highest OR with BCM); some showed increased odds for shorter AL (highest OR with GPR143). Patients with RPE65- and TYR-associated disease showed increased odds for longer and for shorter eyes. Albinism genes were associated with different effects on AL. These findings add to the phenotype of IRDs and may yield insights into mechanisms of refractive error development.
Topics: ATP-Binding Cassette Transporters; Albinism, Oculocutaneous; Eye Proteins; Genetic Diseases, X-Linked; Humans; Mutation; Myopia; Retina; Retinal Diseases
PubMed: 35704304
DOI: 10.1167/iovs.63.6.15 -
Experimental Eye Research Aug 2022Congenital Stationary Night Blindness type 2 (CSNB2) and Aland island Eye Disease (AIED) associated with CACNA1F mutation demonstrate a significant phenotype...
Congenital Stationary Night Blindness type 2 (CSNB2) and Aland island Eye Disease (AIED) associated with CACNA1F mutation demonstrate a significant phenotype overlapping. We report two cases with different clinical presentation carrying two novel mutations in CACNA1F gene. Subjects underwent a complete neurophtahlmological examination associated with structural and electrofunctional insight. Next Generation Sequencing (NGS) analysis of 31 genes previously associated with retinal dystrophy (RD) was performed. Messenger RNAs derived from probands 'peripheral blood samples were analyzed by RT-PCR and cDNA sequencing. The neuro-ophthalmological examinations revealed different clinical, structural and morphological presentations, more severe in patient 1 compared with patient 2. Molecular analysis revealed, that both patients had the hemizygous form of two novel mutations in CACNA1F gene. Patient 1 presented a duplication (c.425dupC) in exon 4, resulting in shifting of the reading frame with the insertion of a premature Stop codon. In Patient 2 variant c.5156G > C localized in the donor's splicing site of exon 43 was identified. Complementary DNA sequencing demonstrated skipping of exon 43 with a deletion of 55 amino acids that causes a frame shift with insertion of a Stop codon. These findings suggest that the effect and the localization of the mutations in the CACNA1F gene can explain different clinical phenotypes. Clinical spectrum is more severe and resembles the AIED phenotype when the mutation affects the first part of the protein, while it is more similar to CSNB2 if the mutation is localized at the end of the protein. Genetic testing results to be an essential tool to provide more accurate diagnosis and prognosis in patients with inherited retinal degenerative disorders and could help, in the future, to develop more specific therapeutic strategies.
Topics: Albinism, Ocular; Calcium Channels, L-Type; Eye Diseases, Hereditary; Finland; Genetic Diseases, X-Linked; Humans; Mutation; Myopia; Night Blindness; Phenotype
PubMed: 35697328
DOI: 10.1016/j.exer.2022.109143 -
The CRISPR Journal Jun 2022Mutations in the gene cause X-linked ocular albinism type 1 (OA1), a disease that severely impairs vision. We recently generated induced pluripotent stem cells (iPSCs)...
Mutations in the gene cause X-linked ocular albinism type 1 (OA1), a disease that severely impairs vision. We recently generated induced pluripotent stem cells (iPSCs) from skin fibroblasts of an OA1 patient carrying a point mutation in intron 7 of . This mutation activates a new splice site causing the incorporation of a pseudoexon. In this study, we present a high-performance CRISPR-Cas ribonucleoprotein strategy to permanently correct the mutation in these patient-derived iPSCs. Interestingly, the two single-guide RNAs available for SpCas9 did not allow the cleavage of the target region. In contrast, the cleavage achieved with the CRISPR-AsCas12a system promoted homology-directed repair at a high rate. The CRISPR-AsCas12a-mediated correction did not alter iPSC pluripotency or genetic stability, nor did it result in off-target events. Moreover, we highlight that the disruption of the pathological splice site caused by CRISPR-AsCas12a-mediated insertions/deletions also rescued the normal splicing of and its expression level.
Topics: Albinism, Ocular; CRISPR-Cas Systems; Eye Proteins; Gene Editing; Humans; Induced Pluripotent Stem Cells; Membrane Glycoproteins; Mutation
PubMed: 35686978
DOI: 10.1089/crispr.2021.0110 -
Clinical Ophthalmology (Auckland, N.Z.) 2022Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular... (Review)
Review
Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular abnormalities. The main ocular features common to both oculocutaneous albinism (OCA), and ocular albinism (OA) include reduced visual acuity, refractive errors, foveal hypoplasia, congenital nystagmus, iris and fundus hypopigmentation and visual pathway misrouting, but clinical signs vary and there is phenotypic overlap with other pathologies. This study reviews the prevalence, genetics and ocular manifestations of OCA and OA, including abnormal development of the optic chiasm. The role of visual electrophysiology in the detection of chiasmal dysfunction and visual pathway misrouting is emphasized, highlighting how age-associated changes in visual evoked potential (VEP) test results must be considered to enable accurate diagnosis, and illustrated further by the inclusion of novel VEP data in genetically confirmed cases. Differential diagnosis is considered in the context of suspected retinal and other disorders, including rare syndromes that may masquerade as albinism.
PubMed: 35637898
DOI: 10.2147/OPTH.S329282 -
International Ophthalmology Jul 2022Albinism is known to disrupt emmetropisation in animal models. However, it is not clear if the same effect is seen in humans. This study aimed to investigate the...
PURPOSE
Albinism is known to disrupt emmetropisation in animal models. However, it is not clear if the same effect is seen in humans. This study aimed to investigate the refractive profile in individuals diagnosed with ocular albinism (OA) and oculocutaneous albinism (OCA) based on a large dataset.
METHODS
Required data from 618 individuals (61% males and 39% females) diagnosed with albinism were exported from the eyeSmart electronic medical records of L V Prasad Eye Institute. Overall, there were 112 (18%) individuals diagnosed with OA and 506 (82%) with OCA. Based on the spherical equivalent refraction (SER), individuals were classified as emmetropes, myopes, and hyperopes.
RESULTS
The overall spherical equivalent refraction of the individuals ranged from -25.00D to + 12.00D with a median + 0.25D (-2.00 to + 2.25 D). The proportion of individuals with albinism (combined OA, OCA) having hyperopia and myopia (overall: N = 282;45.6% vs. N = 245;39.6%) were similar (p = 0.18), and the least were with emmetropia (overall: N = 91;14.7%). Across all the age groups (0-10, 11-20, 21-30, > 30 years), the frequency of hyperopes and myopes was significantly higher (p < 0.05) compared to emmetropes. Both high degrees of hyperopia and myopia were found in individuals diagnosed with OA and OCA. Irrespective of the albinism type, with-the-rule (70%) astigmatism was the most prevalent compared to other types of astigmatism. The frequency of with-the-rule astigmatism was significantly high in the presence of nystagmus compared to individuals with no nystagmus in both OA (75% vs 25%, p = 0.01) and OCA (77% vs 23%, p = 0.014) groups.
CONCLUSION
The presence of both high hyperopia and high myopia and very few numbers with emmetropia across all age groups indicates disrupted normal refractive development in individuals with albinism. With-the-rule astigmatism and nystagmus may result in meridional degradation of the retinal image leading to impairment of normal emmetropisation process in individuals with albinism.
Topics: Adult; Albinism, Oculocutaneous; Astigmatism; Female; Humans; Hyperopia; Male; Myopia; Nystagmus, Pathologic; Refraction, Ocular
PubMed: 35587842
DOI: 10.1007/s10792-021-02165-6 -
Frontiers in Molecular Biosciences 2022GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G... (Review)
Review
GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G protein-coupled receptors (GPCRs) hold the potential to pave the way for development of new, innovative therapeutic strategies. In this review we will introduce G protein-coupled receptor 143 (GPR143), an enigmatic receptor in terms of classification within the GPCR superfamily and localization. GPR143 has not been assigned to any of the GPCR families due to the lack of common structural motifs. Hence we will describe the most important motifs of classes A and B and compare them to the protein sequence of GPR143. While a precise function for the receptor has yet to be determined, the protein is expressed abundantly in pigment producing cells. Many GPR143 mutations cause X-linked Ocular Albinism Type 1 (OA1, Nettleship-Falls OA), which results in hypopigmentation of the eyes and loss of visual acuity due to disrupted visual system development and function. In pigment cells of the skin, loss of functional GPR143 results in abnormally large melanosomes (organelles in which pigment is produced). Studies have shown that the receptor is localized internally, including at the melanosomal membrane, where it may function to regulate melanosome size and/or facilitate protein trafficking to the melanosome through the endolysosomal system. Numerous additional roles have been proposed for GPR143 in determining cancer predisposition, regulation of blood pressure, development of macular degeneration and signaling in the brain, which we will briefly describe as well as potential ligands that have been identified. Furthermore, GPR143 is a promiscuous receptor that has been shown to interact with multiple other melanosomal proteins and GPCRs, which strongly suggests that this orphan receptor is likely involved in many different physiological actions.
PubMed: 35495622
DOI: 10.3389/fmolb.2022.873777 -
Frontiers in Genetics 2022is a nuclear transcription factor gene that is highly conserved among species. Variants within could result in optic nerve colobomas and kidney hypoplasia. However,...
is a nuclear transcription factor gene that is highly conserved among species. Variants within could result in optic nerve colobomas and kidney hypoplasia. However, little clinical and genetic information is currently available about variants in Chinese children. This study aims to further understand the clinical manifestations and genetic characteristics of variants in Chinese population. In this single-center retrospective study, we analyzed the clinical data of 10 children identified as carriers of variants by gene sequencing. All the variants found in this study were analyzed using prediction and American College of Medical Genetics and Genomics (ACMG) standards and guidelines. The mean age for developing the first symptom in 10 unrelated children was 7.2 years old. Proteinuria and bilateral kidney dysplasia were found in every patient. Two children underwent kidney histological examination; one child showed high-intensity C1q deposition in the kidney, and the other child showed focal segmental glomerular sclerosis (FSGS). Three children had -related ocular abnormalities, including nystagmus, retinal exudation, amblyopia, microphthalmia, microcornea, and total blindness. In addition, one patient had the comorbidity of oculocutaneous albinism (OCA). Eight different variants were found in ten patients, three of which were reported for the first time. We reported some patients with unique manifestations and comorbidities, and we reported three variants that have not been previously identified. The gene is prone to spontaneous variants, and the outcome of patients is unfavorable. Because of the lack of specific therapy, genetic testing should be recommended for individuals with obvious evidence of kidney dysplasia and eye abnormalities, and kidney protective treatment should be initiated early.
PubMed: 35444690
DOI: 10.3389/fgene.2022.799562