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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 -
Orphanet Journal of Rare Diseases Nov 2007Oculocutaneous albinism (OCA) is a group of inherited disorders of melanin biosynthesis characterized by a generalized reduction in pigmentation of hair, skin and eyes.... (Review)
Review
Oculocutaneous albinism (OCA) is a group of inherited disorders of melanin biosynthesis characterized by a generalized reduction in pigmentation of hair, skin and eyes. The prevalence of all forms of albinism varies considerably worldwide and has been estimated at approximately 1/17,000, suggesting that about 1 in 70 people carry a gene for OCA. The clinical spectrum of OCA ranges, with OCA1A being the most severe type with a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3 and OCA4 show some pigment accumulation over time. Clinical manifestations include various degrees of congenital nystagmus, iris hypopigmentation and translucency, reduced pigmentation of the retinal pigment epithelium, foveal hypoplasia, reduced visual acuity usually (20/60 to 20/400) and refractive errors, color vision impairment and prominent photophobia. Misrouting of the optic nerves is a characteristic finding, resulting in strabismus and reduced stereoscopic vision. The degree of skin and hair hypopigmentation varies with the type of OCA. The incidence of skin cancer may be increased. All four types of OCA are inherited as autosomal recessive disorders. At least four genes are responsible for the different types of the disease (TYR, OCA2, TYRP1 and MATP). Diagnosis is based on clinical findings of hypopigmentation of the skin and hair, in addition to the characteristic ocular symptoms. Due to the clinical overlap between the OCA forms, molecular diagnosis is necessary to establish the gene defect and OCA subtype. Molecular genetic testing of TYR and OCA2 is available on a clinical basis, while, at present, analysis of TYRP1 and MATP is on research basis only. Differential diagnosis includes ocular albinism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Waardenburg syndrome type II. Carrier detection and prenatal diagnosis are possible when the disease causing mutations have been identified in the family. Glasses (possibly bifocals) and dark glasses or photocromic lenses may offer sufficient help for reduced visual activity and photophobia. Correction of strabismus and nystagmus is necessary and sunscreens are recommended. Regular skin checks for early detection of skin cancer should be offered. Persons with OCA have normal lifespan, development, intelligence and fertility.
Topics: Albinism, Oculocutaneous; Diagnosis, Differential; Humans; Prevalence
PubMed: 17980020
DOI: 10.1186/1750-1172-2-43 -
Progress in Retinal and Eye Research May 2021X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic... (Review)
Review
X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.
Topics: Calcium Channels, L-Type; Eye Proteins; Female; Genes, X-Linked; Genetic Diseases, X-Linked; Humans; Male; Mutation; Night Blindness; Phenotype; Retinal Degeneration
PubMed: 32860923
DOI: 10.1016/j.preteyeres.2020.100898 -
Pediatrics and Neonatology Oct 2014Nystagmus is an involuntary rhythmic oscillation of the eyes, which leads to reduced visual acuity due to the excessive motion of images on the retina. Nystagmus can be... (Review)
Review
Nystagmus is an involuntary rhythmic oscillation of the eyes, which leads to reduced visual acuity due to the excessive motion of images on the retina. Nystagmus can be grouped into infantile nystagmus (IN), which usually appears in the first 3-6 months of life, and acquired nystagmus (AN), which appears later. IN can be idiopathic or associated to albinism, retinal disease, low vision, or visual deprivation in early life, for example due to congenital cataracts, optic nerve hypoplasia, and retinal dystrophies, or it can be part of neurological syndromes and neurologic diseases. It is important to differentiate between infantile and acquired nystagmus. This can be achieved by considering not only the time of onset of the nystagmus, but also the waveform characteristics of the nystagmus. Neurological disease should be suspected when the nystagmus is asymmetrical or unilateral. Electrophysiology, laboratory tests, neurological, and imaging work-up may be necessary, in order to exclude any underlying ocular or systemic pathology in a child with nystagmus. Furthermore, the recent introduction of hand-held spectral domain optical coherence tomography (HH SD-OCT) provides detailed assessment of foveal structure in several pediatric eye conditions associated with nystagmus and it can been used to determine the underlying cause of infantile nystagmus. Additionally, the development of novel methods to record eye movements can help to obtain more detailed information and assist the diagnosis. Recent advances in the field of genetics have identified the FRMD7 gene as the major cause of hereditary X-linked nystagmus, which will possibly guide research towards gene therapy in the future. Treatment options for nystagmus involve pharmacological and surgical interventions. Clinically proven pharmacological treatments for nystagmus, such as gabapentin and memantine, are now beginning to emerge. In cases of obvious head posture, eye muscle surgery can be performed to shift the null zone of the nystagmus into the primary position, and also to alleviate neck problems that can arise due to an abnormal head posture.
Topics: Cataract; Child; Eye Movements; Head; Humans; Nystagmus, Pathologic; Posture
PubMed: 25086850
DOI: 10.1016/j.pedneo.2014.02.007 -
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 -
Therapeutic Advances in Ophthalmology 2022Foveal hypoplasia is the absence of a foveal depression and the presence of the ganglion cell layer in the foveola. A spectrum of clinical characteristics, including... (Review)
Review
Foveal hypoplasia is the absence of a foveal depression and the presence of the ganglion cell layer in the foveola. A spectrum of clinical characteristics, including normal or variably decreased visual acuity, has been described in patients with blunted foveal contours. Multiple systemic and ophthalmologic conditions including albinism, aniridia, nanophthalmos, prematurity, and fovea plana have been associated with this anomaly. This article illustrates select clinical conditions characterized by a blunted foveal contour. Given the heterogeneity of findings, a thorough medical history and detailed physical and ocular examinations are usually sufficient for the clinician to make the correct diagnosis.
PubMed: 35083420
DOI: 10.1177/25158414211070864