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Genes Jan 2023The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes...
The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes of 53 patients who presented between 2006-2022 with OA/OCA were retrospectively correlated with genetic testing results. Genetic diagnostic yield was defined as detection of pathogenic/likely pathogenic variant(s) matching the anticipated inheritance for that gene-disease relationship. Variant reclassifications of those with variants of uncertain significance (VUS) and without positive diagnostic yield were completed. Overall initial genetic diagnostic yield of OA/OCA was 66%. There was no significant difference ( = 0.59) between race and ethnicities (Black (78%), White (59%), Hispanic/Latino (64%)); however, the diagnostic yield of OA (33%) was significantly lower ( = 0.007) than OCA (76%). Causative variants in (28%) and (20%) were most common. Further, Hermansky-Pudlak syndrome variants were identified in 9% of patients. Re-classification of VUS in non-diagnostic cases resulted in genetic diagnoses for 29% of individuals and increased overall diagnostic yield to 70% of all subjects. There is a high diagnostic yield of genetic testing of patients overall with OA/OCA in a diverse U.S. based pediatric population. Presence or absence of cutaneous involvement of albinism significantly affects genetic diagnostic yield.
Topics: Child; Humans; Retrospective Studies; Mutation; Membrane Transport Proteins; Genetic Testing; Albinism, Ocular; Hermanski-Pudlak Syndrome
PubMed: 36672876
DOI: 10.3390/genes14010135 -
Journal of Psychiatric Practice Jan 2023Copy number variations, which manifest primarily as deletions and duplications, contribute significantly to the genetic risk of schizophrenia. Specific syndromes...
Mutation of GPR143 Associated With Ocular Albinism Type 1, Intellectual Disability, and Schizophrenia: The Complex Biological and Social Interactions Between Genetic Syndromes and Mental Illness.
Copy number variations, which manifest primarily as deletions and duplications, contribute significantly to the genetic risk of schizophrenia. Specific syndromes associated with copy number variations, exemplified by the 22q11 deletion syndrome, confer both congenital abnormalities and an elevated risk of schizophrenia. We report the case of a patient with a deletion of exons 2 through 8 of GPR143. In addition to having the ophthalmologic disorder ocular albinism type 1 (OA1), a well-established consequence of mutations of GPR143, the patient is also intellectually impaired and impulsive, and he developed schizophrenia at age 15. Psychiatric manifestations of OA1 have not previously been reported, yet remain plausible, as the GPR143 protein is widely distributed in the brain and may function as an L-DOPA receptor. However, the patient described here also had a family history of psychiatric disorders independent of OA1, in utero exposure to heroin and cocaine, and challenging family circumstances. We suggest that the relationship between his GPR143 mutation and his psychiatric disorders is complex. The mutation may have directly contributed to his cognitive and psychiatric disorders, but we also suspect that OA1, present in multiple family members, contributed to multigenerational familial instability. Further, OA1 likely exacerbated our patient's cognitive and social impairment by interfering with his education, while his neuropsychiatric status frequently interfered with the assessment and treatment of his OA1. We conclude that the psychiatric and nonpsychiatric manifestations of a genetic syndrome are best managed in parallel and that psychiatrists and other mental health providers may be in the best position to assure that patients receive appropriate genetic and medical care.
Topics: Male; Humans; Adolescent; Schizophrenia; Membrane Glycoproteins; Intellectual Disability; Social Interaction; DNA Copy Number Variations; Eye Proteins; Mutation
PubMed: 36649556
DOI: 10.1097/PRA.0000000000000685 -
Neuron Jan 2023Visual impairments in albinism result from decreased ipsilateral retinal projections. In this issue of Neuron, Slavi, Balasubramanian, and colleagues demonstrate how low...
Visual impairments in albinism result from decreased ipsilateral retinal projections. In this issue of Neuron, Slavi, Balasubramanian, and colleagues demonstrate how low CyclinD2 in the ciliary marginal zone perturbs generation of ipsilaterally projecting RGCs and that restoring CyclinD2 improves vision in albino mice.
Topics: Animals; Mice; Retinal Ganglion Cells; Retina; Albinism; Vision, Ocular; Visual Pathways
PubMed: 36603550
DOI: 10.1016/j.neuron.2022.12.017 -
Genes Nov 2022Albinism is a genetic disorder, present worldwide, caused by mutations in genes affecting melanin production or transport in the skin, hair and eyes. To date, mutations...
Albinism is a genetic disorder, present worldwide, caused by mutations in genes affecting melanin production or transport in the skin, hair and eyes. To date, mutations in at least 20 different genes have been identified. Oculo-cutaneous Albinism type IV (OCA4) is the most frequent form in Asia but has been reported in all populations, including Europeans. Little is known about the genotype-phenotype correlation. We identified two main phenotypes via the analysis of 30 OCA4 patients with a molecularly proven diagnosis. The first, found in 20 patients, is clinically indistinguishable from the classical OCA1 phenotype. The genotype-to-phenotype correlation suggests that this phenotype is associated with homozygous or compound heterozygous nonsense or deletion variants with frameshift leading to translation interruption in the gene. The second phenotype, found in 10 patients, is characterized by very mild hypopigmentation of the hair (light brown or even dark hair) and skin that is similar to the general population. In this group, visual acuity is variable, but it can be subnormal, foveal hypoplasia can be low grade or even normal, and nystagmus may be lacking. These mild to moderate phenotypes are associated with at least one missense mutation in .
Topics: Humans; Piebaldism; Mutation; Mutation, Missense; Phenotype; Genotype
PubMed: 36553465
DOI: 10.3390/genes13122198 -
Cureus Oct 2022Albinism is a group of heritable illnesses defined by a lack or loss of melanin in tissues originating from the ectoderm (most notably the skin, hair, and eyes). The...
Albinism is a group of heritable illnesses defined by a lack or loss of melanin in tissues originating from the ectoderm (most notably the skin, hair, and eyes). The most common kind of albinism is oculocutaneous albinism (OCA). Clinical evidence of less pigmentation of the hair and skin, as well as the characteristic ocular symptoms, are used to diagnose OCA. Nystagmus is one of the impacts of albinism on the eyes. Nystagmus is a term for involuntary ocular movements that are usually conjugate and rhythmic. Almost always, vertigo, dizziness, and loss of balance occur when nystagmus is accompanied by a condition of the inner ear's vestibular system or the brain. Nystagmus, which is induced by the rotation of an optokinetic drum or the rotation of the body in space, aids in visual maintenance. This case report describes the case of a 10-year-old male child with nystagmus associated with albinism, with typical complaints of dizziness that are scored on a Vanderbilt Pediatric Dizziness Handicap Inventory for Patient Caregivers (DHI-PC). Vestibular rehabilitation for nystagmus aids gaze stabilization, ocular muscle strength improvement, and vestibular function maintenance. The patient recovered with well-planned vestibular rehabilitation, which included gaze stability exercises, Cawthorne-Cooksey exercises, habituation exercises, eyeball resistance exercises, eye-hand coordination exercises, and parent education and home exercise programs.
PubMed: 36407240
DOI: 10.7759/cureus.30452 -
[Zhonghua Yan Ke Za Zhi] Chinese... Nov 2022A 16-year-old male patient had poor binocular vision, alternating exotropia, horizontal nystagmus, and no obvious pigmentation loss in the eyes and other parts of the...
A 16-year-old male patient had poor binocular vision, alternating exotropia, horizontal nystagmus, and no obvious pigmentation loss in the eyes and other parts of the body. Optical coherence tomographic examination showed no normal central macular depression. The three-channel flash visual evoked potential method was used to examine each eye. The left and right channel reactions were found to be significantly asymmetric, and the clinical diagnosis was ocular albinism.
Topics: Male; Humans; Adolescent; Albinism, Ocular; Evoked Potentials, Visual; Visual Acuity; Vision, Binocular; Tomography, Optical Coherence
PubMed: 36348533
DOI: 10.3760/cma.j.cn112142-20220303-00092 -
Ophthalmic Genetics Aug 2023To report a case of concurrent pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) with dual PANK2 and OCA2 variants in a Chinese...
PURPOSE
To report a case of concurrent pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) with dual PANK2 and OCA2 variants in a Chinese patient who presented with early-onset reduced vision, nyctalopia, and neurological symptoms.
MATERIALS AND METHODS
Based on the ocular phenotype and provisional diagnosis of rod-cone dystrophy, genetic testing was pursued. Peripheral blood DNA extraction was carried out with the next-generation sequencing technique, which involved a population-specific medical exome virtual panel. Pre- and post-test counseling were carried out by clinical geneticists.
RESULT
Homozygous missense variants in PANK2 {NM_153638.3}:c.655 G>A (p.(Gly219Ser)) and OCA2{NM_025160.6}:c.1327 G>A(p.(Val443Ile)) were identified. The molecular diagnoses of pantothenate kinase associated neurodegeneration (OMIM#234200) and albinism, oculocutaneous, type II (OMIM#203200) were supported by clinical findings.
CONCLUSION
Two rare autosomal recessive diseases, pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) were detected in our patient. Ocular and systemic manifestations, as well as neuroimaging findings were compatible with the diseases identified. Genetic analysis is imperative in making an accurate molecular diagnosis in these rare conditions to allow timely counseling, disease prognostication and management.
Topics: Humans; Mutation; Pantothenate Kinase-Associated Neurodegeneration; Albinism, Oculocutaneous; Retinal Dystrophies; Phosphotransferases (Alcohol Group Acceptor); Membrane Transport Proteins
PubMed: 36330599
DOI: 10.1080/13816810.2022.2135107 -
Ophthalmic Genetics Feb 2023Oculocutaneous albinism (OCA) could be either non-syndromic or syndromic. There are significant challenges in clinically recognizing and differentiating Hermansky-Pudlak...
BACKGROUND
Oculocutaneous albinism (OCA) could be either non-syndromic or syndromic. There are significant challenges in clinically recognizing and differentiating Hermansky-Pudlak syndrome (HPS) from non-syndromic OCA.
MATERIALS AND METHODS
In a prospective consecutive case series, 63 patients (less than 18 years old) with a molecular genetic diagnosis of albinism (except ), Ocular albinism (OA) and Hermansky-Pudlak syndrome seen over a 3-year period were evaluated and analyzed. Hair colour, iris colour was graded, compared and correlated with the degree of fundus pigmentation and foveal development.
RESULTS
A total of 63 patients were evaluated. Forty-five patients had non-syndromic OCA (11 OCA1B, 24 OCA2, 9 OCA4, and 1 OCA6), 5 patients had OA and 13 patients had HPS. All 3 BLOC-related HPS categories were seen (1 with BLOC1, 7 with BLOC-2 and 5 with BLOC-3 related HPS). All patients with OA were hyperopic, had darker fundus pigmentation, but had poor foveal development. All HPS patients had lighter fundus pigmentation. The degree of fundus pigmentation correlated positively with the iris pigmentation and also with the foveal development only in OCA2.
CONCLUSIONS
Careful observation of the phenotype by comparison of the skin, hair, iris colour, with the degree of fundus pigmentation and foveal development may help clinically differentiate HPS from OCA patients of Chinese ethnicity even in the absence of any bleeding tendency.
Topics: Humans; Hermanski-Pudlak Syndrome; East Asian People; Prospective Studies; Albinism, Oculocutaneous; Albinism; Albinism, Ocular; Hair; Iris
PubMed: 36316991
DOI: 10.1080/13816810.2022.2135109 -
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