Albinism: its implications for refractive development. (1/72)

PURPOSE: Albinism involves the mutation of one or more of the genes associated with melanin synthesis and has many ramifications for vision. This study focuses on the refractive implications of albinism in the context of emmetropization. METHODS: Refractive, biometric, and visual acuity data were collected for a group of 25 albino individuals that included the following: 18 oculocutaneous (13 tyrosine positive, 5 tyrosine negative); 7 ocular (2 autosomal recessive, 5 sex-linked recessive). Their age range was 3 to 51 years. All exhibited horizontal pendular nystagmus. RESULTS: There were no statistically significant differences relating to albino subtype for any of the measured parameters. All the subjects had reduced visual acuity (mean: 0.90, logMAR) and overall, there was a bias toward hyperopia in their refractive errors (mean: + 1.07 D). However the refractive errors of the group covered a broad range (SD: 4.67 D) and included both high myopia and high hyperopia. An axial origin to the refractive errors is implied by the high correlation between refractive errors and axial lengths. Refractive astigmatism averaged 2.37 D and was consistently with-the-rule and highly correlated with corneal astigmatism, which was also with-the-rule. Meridional analysis of the refractive data indicated that the vertical meridian for hyperopic subjects was consistently nearer emmetropia compared to their horizontal meridian. Myopic subjects showed the opposite trend. CONCLUSIONS: The overall refractive profile of the subjects is consistent with emmetropization being impaired in albinism. However, the refractive errors of hyperopic subjects also can be explained in terms of "meridional emmetropization." The contrasting refractive profiles of myopic subjects may reflect operational constraints of the emmetropization process.  (+info)

Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1. (2/72)

Ocular albinism type I (OA1) is an X-linked disorder characterized by severe reduction of visual acuity, strabismus, photophobia and nystagmus. Ophthalmologic examination reveals hypopigmentation of the retina, foveal hypoplasia and iris translucency. Microscopic examination of both retinal pigment epithelium (RPE) and skin melanocytes shows the presence of large pigment granules called giant melanosomes or macromelanosomes. In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.  (+info)

Expression pattern of the ocular albinism type 1 (Oa1) gene in the murine retinal pigment epithelium. (3/72)

PURPOSE: Mutations in the OA1 gene cause ocular albinism type 1 (OA1), an X-linked form of albinism affecting only the eye, with skin pigmentation appearing normal. To better understand the pathogenesis of this disease the time of onset and the pattern of expression of the mouse homolog of the OA1 gene were monitored during eye development. The localization of Oa1 mRNA was studied and compared with the expression of other genes involved in melanosomal biogenesis. METHODS: The Oa1 expression pattern during eye development and after birth was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. Localization of Oa1 mRNA was compared with TYROSINASE: (TYR:), pink-eyed dilution (p), and Pax2 expression patterns. RESULTS: RT-PCR revealed that Oa1 expression began at embryonic day (E)10.5 and was maintained until adulthood. By in situ hybridization analysis Oa1 transcripts were detected in the retinal pigment epithelium (RPE) beginning at E10.5 in the dorsal part of the eyecup and in the same area where transcripts of other genes involved in pigmentation are found. Of note, the expression pattern of these genes was complementary to Pax2 expression, which was restricted to the ventral side of the optic cup. At later stages, expression of Oa1, TYR:, and p expanded to the entire RPE and ciliary body. CONCLUSIONS: Oa1 expression can be detected at early stages of RPE development, together with other genes involved in pigmentation defects. Oa1 is likely to play an important function in melanosomal biogenesis in the RPE beginning during the earliest steps of melanosome formation.  (+info)

Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. (4/72)

Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina and the presence of macromelanosomes in the skin and eyes. Various types of mutation have been identified within the OA1 gene in patients with the disorder, including several missense mutations of unknown functional significance. In order to shed light into the molecular pathogenesis of ocular albinism and possibly define critical functional domains within the OA1 protein, we characterized 19 independent missense mutations with respect to processing and subcellular distribution on expression in COS-7 cells. Our analysis indicates the presence of at least two distinct biochemical defects associated with the different missense mutations. Eleven of the nineteen OA1 mutants (approximately 60%) were retained in the endoplasmic reticulum, showing defecNStive intracellular transport and glycosylation, consistent with protein misfolding. The remaining eight of the nineteen OA1 mutants (approximately 40%) displayed sorting and processing behaviours indistinguishable from those of the wild-type protein. Consistent with our recent findings that OA1 represents a novel type of intracellular G protein-coupled receptor (GPCR), we found that most of these latter mutations cluster within the second and third cytosolic loops, two regions that in canonical GPCRs are known to be critical for their downstream signaling, including G protein-coupling and effector activation. The biochemical analysis of OA1 mutations performed in this study provides important insights into the structure-function relationships of the OA1 protein and implies protein misfolding as a major pathogenic mechanism in OA1.  (+info)

Behavioral visual responses of wild-type and hypopigmented zebrafish. (5/72)

Zebrafish possess three classes of chromatophores that include iridophores, melanophores, and xanthophores. Mutations that lack one or two classes of chromatophores have been isolated or genetically constructed. Using a behavioral assay based on visually mediated escape responses, we measured the visual response of fully and partially pigmented zebrafish. In zebrafish that lack iridophores (roy mutants), the behavioral visual responses were similar to those of wild-type animals except at low contrast stimulation. In the absence of melanophores (albino mutants) or both melanophores and iridophores (ruby mutants), the behavioral visual responses were normal under moderate illumination but reduced when tested under dim or bright conditions or under low contrast stimulation. Together, the data suggest that screening pigments in the retina play a role in the regulation of behavioral visual responses and are necessary for avoiding "scatter" under bright light conditions.  (+info)

Correlation between rod photoreceptor numbers and levels of ocular pigmentation. (6/72)

PURPOSE: Ocular melanin synthesis modulates rod photoreceptor production, because in albino eyes, rod numbers are reduced by approximately 30%. In this study, rod numbers and ocular rhodopsin concentrations were measured in intermediate pigmentation phenotypes to determine whether proportional reductions in melanin are correlated with proportional changes in rod numbers. Further, patterns of cell production and death were examined around the time of birth, when rod production peaks, to determine whether there are abnormalities in these features associated with hypopigmentation. METHODS: Four mouse pigmentation phenotypes were used: fully pigmented, albino, Beige, and Himalayan. The latter two are intermediate-pigmentation phenotypes, with Beige having markedly more pigment than Himalayan. Ocular melanin concentrations were measured during development and at maturity. Rods were counted at maturity and measurements of ocular rhodopsin undertaken. Mitotic and pyknotic cells were also counted in neonates. RESULTS: Rods and ocular rhodopsin were reduced in both Beige and Himalayan mice below levels found in fully pigmented mice, but not to levels found in albino animals. This was more marked in Himalayan than Beige mice, reflecting the lower concentration of melanin found in the former compared with the latter, both in development and at maturity. Although patterns of cell production were elevated in the hypopigmented animals, such patterns varied. CONCLUSIONS: Rod numbers are modulated within a range between that in fully pigmented and albino phenotypes by the concentration of ocular melanin. However, in these animals, there is no obvious correlation between these events and patterns of cell production and death in neonates.  (+info)

Motor and sensory characteristics of infantile nystagmus. (7/72)

BACKGROUND/AIMS: Past studies have explored some of the associations between particular motor and sensory characteristics and specific categories of non-neurological infantile nystagmus. The purpose of this case study is to extend this body of work significantly by describing the trends and associations found in a database of 224 subjects who have undergone extensive clinical and psychophysical evaluations. METHODS: The records of 224 subjects with infantile nystagmus were examined, where 62% were idiopaths, 28% albinos, and 10% exhibited ocular anomalies. Recorded variables included age, mode of inheritance, birth history, nystagmus presentation, direction of the nystagmus, waveform types, spatial and temporal null zones, head postures and nodding, convergence, foveation, ocular alignment, refractive error, visual acuity, stereoacuity, and oscillopsia. RESULTS: The age distribution of the 224 patients was between 1 month and 71 years, with the mean age and mode being 23 (SD 16) years and 16-20 years respectively. By far the most common pattern of inheritance was found to be autosomal dominant (n = 40), with the nystagmus being observed by the age of 6 months in 87% of the sample (n = 128). 139 (62%) of the 224 subjects were classified as idiopaths, 63 (28%) as albinos, and 22 (10%) exhibited ocular anomalies. Conjugate uniplanar horizontal oscillations were found in 174 (77.7%) of the sample. 32 (14.3%) had a torsional component to their nystagmus. 182 (81.2%) were classed as congenital nystagmus (CN), 32 (14.3%) as manifest latent nystagmus (MLN), and 10 (4.5%) as a CN/MLN hybrid. Neither CN nor MLN waveforms were related to any of the three subject groups (idiopaths, albinos, and ocular anomalies) MLN was found in idiopaths and albinos, but most frequently in the ocular anomaly group. The most common oscillation was a horizontal jerk with extended foveation (n = 49; 27%). The amplitudes and frequencies of the nystagmus ranged between 0.3-15.7 degrees and 0.5-8 Hz, respectively. Periodic alternating nystagmus is commonly found in albinos. Albino subjects did not show a statistically significantly higher nystagmus intensity when compared with the idiopaths (p>0.01). 105 of 143 subjects (73%) had spatial nulls within plus or minus 10 degrees of the primary position although 98 subjects (69%) employed a compensatory head posture. Subjects with spatial null zones at or beyond plus or minus 20 degrees always adopted constant head postures. Head nodding was found in 38 subjects (27% of the sample). Horizontal tropias were very common (133 out of 213; 62.4%) and all but one of the 32 subjects with MLN exhibited a squint. Adult visual acuity is strongly related to the duration and accuracy of the foveation period. Visual acuity and stereoacuity were significantly better (p<0.01) in the idiopaths compared to the albino and ocular anomaly groups. 66 subjects out of a sample of 168 (39%) indicated that they had experienced oscillopsia at some time. CONCLUSIONS: There are strong ocular motor and sensory patterns and associations that can help define an infantile nystagmus. These include the nystagmus being bilateral, conjugate, horizontal uniplanar, and having an accelerating slow phase (that is, CN). Decelerating slow phases (that is, MLN) are frequently associated with strabismus and early form deprivation. Waveform shape (CN or MLN) is not pathognomonic of any of the three subject groups (idiopaths, albinos, or ocular anomalies). There is no one single stand alone ocular motor characteristic that can differentiate a benign form of infantile nystagmus (CN, MLN) from a neurological one. Rather, the clinician must consider a host of clinical features.  (+info)

Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay. (8/72)

BACKGROUND: X-linked ocular albinism type 1 (OA1) is caused by mutations in OA1 gene, which encodes a membrane glycoprotein localised to melanosomes. OA1 mainly affects pigment production in the eye, resulting in optic changes associated with albinism including hypopigmentation of the retina, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers and reduced visual acuity. Affected Caucasian males usually appear to have normal skin and hair pigment. RESULTS: We identified three previously undescribed mutations consisting of two intragenic deletions (one encompassing exon 6, the other encompassing exons 7-8), and a point mutation (310delG) in exon 2. We report the development of a new method for diagnosis of heterozygous deletions in OA1 gene based on measurement of gene copy number using real-time quantitative PCR from genomic DNA. CONCLUSION: The identification of OA1 mutations in families earlier reported as families with hereditary nystagmus indicate that ocular albinism type 1 is probably underdiagnosed. Our method of real-time quantitative PCR of OA1 exons with DMD exon as external standard performed on the LightCycler trade mark allows quick and accurate carrier-status assessment for at-risk females.  (+info)

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