Ocular albinism type I (OA1) is the most common form of ocular albinism. Clinical presentation of OA1 in Caucasians is characterized by nystagmus, impaired visual acuity, iris hypopigmentation with translucency, albinotic fundus, macular hypoplasia, and normally pigmented skin ... Ocular albinism type I (OA1) is the most common form of ocular albinism. Clinical presentation of OA1 in Caucasians is characterized by nystagmus, impaired visual acuity, iris hypopigmentation with translucency, albinotic fundus, macular hypoplasia, and normally pigmented skin and hair. Carrier females usually have punctate iris translucency and a mottled pattern of fundus pigmentation. In contrast to Caucasian patients, black or Japanese patients with OA1 often have brown irides with little or no translucency and varying degrees of fundus hypopigmentation, the so-called 'nonalbinotic fundus' (summary by Xiao and Zhang, 2009).
In affected men the pupillary reflex is characteristic of albinism. The fundus is depigmented and the choroidal vessels stand out strikingly. Nystagmus, head nodding, and impaired vision also occur. Pigmentation is normal elsewhere than in the eye. In ... In affected men the pupillary reflex is characteristic of albinism. The fundus is depigmented and the choroidal vessels stand out strikingly. Nystagmus, head nodding, and impaired vision also occur. Pigmentation is normal elsewhere than in the eye. In carrier females the fundus, especially in the periphery, shows a mosaic of pigmentation, as first recognized by Vogt (1942). Lyon (1962) pointed out that the fundus finding in heterozygous females supports her theory of X chromosome inactivation. Nystagmus is an associated feature. In fact, the ocular albinism has been commented on only obliquely or not at all in some reports of X-linked nystagmus in families that almost certainly had ocular albinism. The family studied by Waardenburg and Van den Bosch (1956) was earlier reported by Engelhard (1915) as a family with hereditary nystagmus. One family studied by Fialkow et al. (1967) had been reported by Lein et al. (1956) as sex-linked nystagmus. Fundus drawings of heterozygous carriers were provided by Francois and Deweer (1953), and by others. (See frontispiece, McKusick, 1964.) Theoretically one should be able to count the number of pigmented spots and arrive at an estimate of the number of anlage cells present at the time of lyonization. Unfortunately, most of the available drawings are probably too crude to be relied on for this use. Furthermore, the drawings suggest appreciable variation in the number and size of pigmented areas, a finding to be expected from the considerations of the Lyon hypothesis. By electron microscopy, O'Donnell et al. (1976) showed that the skin as well as the eyes shows macromelanosomes in affected males and carrier females. Creel et al. (1978) demonstrated abnormal optic projections similar to those in total albinism. Hence, the abnormal decussation is a consequence of the lack of ocular pigment and not specific for any particular defect. Schnur et al. (1994) studied 119 individuals from 11 families with OA1 with respect to their clinical phenotypes and their linkage genotypes. One of the families was a 4-generation Australian family in which 2 affected males and an obligatory carrier lacked the cutaneous melanin macroglobules (MMGs) considered typical of OA1; ocular features, on the other hand, were identical to those of Nettleship-Falls OA1. Furthermore, in this family, there was no evidence of linkage heterogeneity when compared with 6 families with biopsy-proven MMGs in at least 1 affected male. Rosenberg and Schwartz (1998) determined phenotypic characteristics of 25 male patients from families in Denmark with identified mutations in the GPR143 gene. All patients had congenital nystagmus, and all but 1 had significant iris translucency. Only 1 patient had high myopia. Most of the remaining 24 patients (48 eyes) showed various degrees of hypermetropia. Using MRI, Schmitz et al. (2003) found that the size and configuration of the optic chiasm in humans with albinism are distinctly different from the chiasms of normal control subjects. These chiasmal changes reflect the atypical crossing of the optic fibers, irrespective of the causative gene mutation. Eight patients had tyrosinase gene-related OCA1 (203100), 4 patients had P gene (611409)-related OCA2 (203200), and 1 had ocular albinism; the albinism-causing mutation had not been identified in 4 other patients. - Clinical Variability Preising et al. (2001) reported a 3-generation family in which 3 affected males had variable features of ocular albinism due to a splice site mutation in the GPR143 gene (300808.0010). The male proband was diagnosed with OA1 at age 3 months with typical clinical features, including congenital nystagmus, iris translucency, macular hypoplasia, fundus hypopigmentation, and normal pigmentation of skin and hair. Examination at age 4 years showed increased pigmentation of the iris and fundus and improved visual acuity. A 51-year-old maternal uncle also had congenital nystagmus, clear macular hypoplasia and stromal focal hypopigmentation of the iris, but no iris translucency or fundus hypopigmentation. Macromelanosomes were present on skin biopsy. A 79-year-old maternal relative had congenital nystagmus and high myopia with macular change, but no iris translucency. Two carrier females had mosaic pattern of hypopigmented retinal epithelium, consistent with a carrier status of ocular albinism. Preising et al. (2001) suggested that this mutation results in a hypomorphic allele that causes impaired membrane fusion of melanosomes and the plasma membrane. They proposed a model of OA1 in this family that allowed increase of pigmentation with age. Thus, postnatal normalization of the extracellular dopamine levels due to delayed distribution and membrane budding or fusion of melanosomes in melanocytes could result in increasing pigmentation and a seemingly variable phenotype. Xiao and Zhang (2009) studied a Chinese patient with ocular albinism, who had nystagmus since early childhood, without photophobia or night blindness. He was diagnosed with high myopia and amblyopia at 3 years of age. Ocular examination at age 8 years revealed high myopia and bilateral pendular nystagmus, and there was hyperpigmentation with tiny pigmentary nodules in the pupillary portion of the irides. The peripheral iris was brown without translucency. Fundus changes resembled those seen in high myopia; however, mild variegated pigmentary changes were observed in the midperiphery. Macular hypoplasia was confirmed by optical coherence tomography. The patient's mother had normal visual acuity without nystagmus or photophobia. She had iris hyperpigmentation in the pupillary portion, like her son, but had mild partial hypopigmentation in her peripheral iris. Mild hyperpigmentation was notable in her posterior fundus, and obvious mottled pigmentary deposits were present in the midperipheral retina. The patient's father had a normal iris and fundus.
Bassi et al. (1995) identified 5 patients with OA1 who were carrying mutations within the GPR143 gene. Five intragenic deletions and a 2-bp insertion resulting in a premature stop codon (300808.0001) were identified by DNA analysis of patients ... Bassi et al. (1995) identified 5 patients with OA1 who were carrying mutations within the GPR143 gene. Five intragenic deletions and a 2-bp insertion resulting in a premature stop codon (300808.0001) were identified by DNA analysis of patients with OA1. Some of these deletions were not overlapping, making it highly unlikely that the mutation involved in OA1 is located in an intron of the gene. Fine molecular characterization of the gene in one of these patients demonstrated that the deletion removed part of a coding exon. The APXL gene was completely deleted in 1 patient with isolated OA1. However, an extensive search for point mutations was performed in the 4,848-bp coding region of APXL from 57 patients and no functionally relevant mutation was identified. Schiaffino et al. (1995) screened the entire OA1 coding region and 5-prime and 3-prime sequences for mutations and detected mutations in only one-third (21 of 60) of their patients with OA, including 2 frameshifts (e.g., 300808.0002) and a splice site mutation leading to truncated OA1 proteins, a deletion of a threonine codon at position 290, and 4 missense mutations (e.g., 300808.0008), 2 of which involve amino acids located within putative transmembrane domains. Schnur et al. (1998) reported results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian OA probands, including 5 with additional, nonocular phenotypic abnormalities (Schnur et al., 1994). They detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2 to 8. They also identified 8 novel missense mutations, which clustered within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. All told, 26 (approximately 90%) of 29 probands had detectable alterations in the OA1 gene, thus confirming that OA1 is the major locus for X-linked OA. In Denmark, Rosenberg and Schwartz (1998) performed a retrospective survey of 112 patients with ocular albinism identified in a national register, including 60 male patients with proven or presumed X-linked ocular albinism. Based on the birth year cohorts 1960 to 1989, a point prevalence for OA1 at birth of 1 in 60,000 live born was calculated. They identified 14 OA1 families in the Danish population and obtained DNA from affected persons in 9 families. Mutation analysis demonstrated 7 presumed pathogenic mutations in the 9 families: 5 single nucleotide substitutions predicting a change of conserved amino acids, including G35D (300808.0008) and W133R (300808.0006), when compared with the mouse OA1 homolog, 1 deletion leading to the skipping of exon 2, and 1 example of a single nucleotide substitution expected to affect the 5-prime splice site of intron 2 (300808.0007). Subsequent genealogic investigations in the 3 families harboring the same mutation, W133R, disclosed that 2 of the 3 belonged to the same family. Clinical examination failed to identify any phenotype-genotype pattern except for the finding of a milder phenotype lacking iris translucency in the patient with the 5-prime splice site mutation of intron 2. Oetting (2002) found that a total of 25 missense, 2 nonsense, 9 frameshift, and 5 splicing mutations in the OA1 gene had been reported in association with type I ocular albinism. There were also reports of several deletions of some or all exons of the OA1 gene with deletions of exon 2 resulting from unequal crossing-over, due to flanking Alu repeats. Oetting (2002) referred to an albinism database website. In a Chinese patient with ocular albinism and his carrier mother, who both demonstrated an unusual phenotype of iris hyperpigmentation without translucency, with apparent mosaic pigmentation of the fundus. Xiao and Zhang (2009) identified an intragenic deletion in the GPR143 gene (300808.0013).
Bassi et al. (2001) found a rather striking difference in the frequency of large deletions in the OA1 gene as the cause of ocular albinism type 1 in patients from Europe and North America: large deletions accounted for ... Bassi et al. (2001) found a rather striking difference in the frequency of large deletions in the OA1 gene as the cause of ocular albinism type 1 in patients from Europe and North America: large deletions accounted for only 8% (3 of 36) of mutations identified in European OA1 patients; large deletions were found in 57% (8 of 14) of North American OA1 patients. The explanation for this distribution was unclear. The authors stated that their findings have major relevance for the molecular diagnosis of OA1 and need to be considered in any mutation testing program for this disorder.
Affected males. All forms of albinism share the following ophthalmologic findings: ...
DiagnosisClinical DiagnosisAffected males. All forms of albinism share the following ophthalmologic findings: Infantile nystagmus. Nystagmus usually develops during the first three months of life and may be preceded by a period of poor fixation and poor visual contact, giving rise to a suspicion of delayed visual maturation or cerebral visual impairment (CVI). The nystagmus is most frequently of the pendular or jerk type and is sometimes associated with head nodding (titubation). With age, the nystagmus tends to diminish, although it rarely disappears completely. Nystagmus amplitude and/or frequency often vary with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance. Hypopigmentation of the iris. Iris transillumination caused by hypopigmentation of the iris pigment epithelium (IPE), the posterior layer of the iris, is a frequent finding that is best visualized in a dark room by trans-scleral illumination with a light source placed directly on the bulbar conjunctiva or by slit lamp examination in which a strong beam is directed through an undilated pupil. Normally, incident light reflected from within the eye exits only through the pupil because it is blocked by the IPE. In albinism, reflected light can penetrate the iris. Since punctate iris transillumination defects can be seen in some individuals with light complexion, detection of these defects alone in this group is not a reliable indicator of albinism. Hypopigmentation of the ocular fundus resulting from decreased concentration of pigment in the retinal pigment epithelium (RPE), which allows visualization of the choroidal vessels. The hypopigmentation is generally more profound in the periphery of the ocular fundus. Foveal hypoplasia characterized by diminution or absence of the foveal pit (umbo) and the annular foveal reflex. The foveal area is inconspicuous and sometimes retinal vessels extend through the normally avascular fovea. Optical coherence tomography (OCT) can document the retinal thinning. Some affected males in pedigrees with congenital X-linked nystagmus and molecular confirmation of XLOA have foveal hypoplasia as an isolated finding [Preising et al 2001]. Reduced visual acuity. In most individuals with albinism, the best corrected visual acuity is between 20/40 (6/12) and 20/200 (6/60). XLOA is a non-progressive disorder and the visual acuity typically slowly improves until mid-to-late teens and then remains stable throughout life. Aberrant optic pathway projections consisting of an excessive crossing of the retino-striate fibers in the optic chiasm; i.e., the visual input from the right eye is almost exclusively directed towards the left hemisphere and vice-versa [Schmitz et al 2003, Lauronen et al 2005]. This 'misrouting' can be demonstrated in specialized laboratories by selective VEP technique adapted for use in clinical practice [Soong et al 2000, Hoffmann et al 2005]. Lateral placement of recording electrodes over the occipital area allows for the detection of interhemispheric asymmetries in amplitude following monocular stimulation with a pattern-onset grating. Rather than the typical near-equal response from each hemisphere, the response amplitude is disproportionately larger in the hemisphere contralateral to the stimulated eye. Some authors contend that this VEP technique, albeit cumbersome, is a highly sensitive indicator of albinism [Sjöström et al 2001]. In several forms of albinism, MR imaging found variations in the size and configuration of the optic chiasm compared to normal controls. However, this feature is neither distinctive nor unique and, thus, is not helpful in clinical diagnosis [Schmitz et al 2003].Note that none of the above findings is either specific or obligate for X-linked ocular albinism, and the diagnosis may be difficult in blond Northern European males with only minimally reduced central visual acuity. The most consistent clinical diagnostic clue for XLOA is the presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers.Carrier females. Depending on overall ethnic and racial skin and adnexal pigmentation, female carriers may show iris transillumination and a coarse pattern of blotchy hypo-and hyperpigmentation of the retinal pigment epithelium that becomes more dramatic outside the vascular arcades. Some carriers have isolated patches of hypopigmented skin that does not tan to the same degree as uninvolved skin.Rarely, female carriers are affected, showing infantile nystagmus, foveal hypoplasia, reduced visual acuity, and diffuse hypopigmentation of the ocular structures. TestingSkin biopsy. Given the dermal and hair manifestations in males with XLOA, light and electron microscopy may demonstrate characteristic aggregates of abnormal epidermal melanosome morphology (macromelanosomes) within keratinocytes and melanocytes in most affected males and carrier females, making microscopy of skin biopsies an additional occasionally useful diagnostic test. However, when molecular genetic testing is available skin biopsy is rarely needed. Molecular Genetic TestingGene. GPR143 (formerly known as OA1) is the only gene in which mutations are known to cause X-linked ocular albinism. Clinical testing Sequencing and deletion/duplication analyses of the GPR143 coding region are possible. Together, such testing is expected to detect more than 90% of hemizygous mutations in affected males [Schnur et al 1998, Hegde et al 2002, Faugère et al 2003]. About 48% of reported mutations are intragenic deletions and about 43% are point mutations [Hegde et al 2002]. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. Table 1. Summary of Molecular Genetic Testing Used in X-Linked Ocular AlbinismView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Rate by Test Method 1Test AvailabilityMalesHeterozygous FemalesGPR143Sequence analysisSequence variants 290% 3, 443% 5ClinicalDeletion / duplication analysis 6Deletion of one or more exons or the whole gene 48% 48%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. 4. Includes the mutation detection frequency using deletion/duplication analysis5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy for a ProbandTo confirm/establish the diagnosis in a probandTo establish the diagnosis of albinism, the presence of nystagmus, reduced iris and retinal pigment, foveal hypoplasia, and reduced visual acuity, taken in concert with hypopigmentation of the skin and hair, are usually sufficient to confirm the clinical diagnosis.If any of the above signs is absent in a person with albinism, selective VEP testing may demonstrate aberrant optical pathways. Note: Electroretinogram (ERG) is not specific and not required. To establish the diagnosis of XLOA in a male who represents a simplex case (i.e., no other known affected males in the family) or who has equivocal findings: Examine the iris and fundus (dilated) of the mother (or any daughter) for carrier state changes; If the mother does not show carrier signs, perform molecular genetic testing of GPR143 of the affected male; If no GPR143 mutation is identified, examine with light microscopy a properly fixed skin biopsy of the affected male to look for characteristic macromelanosomes. Carrier testing for at-risk relatives is most informative after identification of the disease-causing mutations in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may have clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis. (3) Sequence analysis of genomic DNA cannot detect deletion of an exon(s) or whole-gene deletions on the X chromosome in carrier females.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersWith the exception of contiguous gene syndromes, no other phenotypes are associated with mutations in GPR143. Contiguous gene syndromes. In interstitial deletions of the X chromosome involving genes around Xp23, contiguous gene syndromes may arise. In such cases, XLOA may be associated with X-linked ichthyosis [Schnur et al 1989], Kallmann syndrome [Zhang et al 1993] or sensorineural deafness [Bassi et al 1999].
XLOA is a disorder of melanosome biogenesis leading to congenital and persistent visual impairment and mild to moderate skin changes in affected males....
Natural HistoryXLOA is a disorder of melanosome biogenesis leading to congenital and persistent visual impairment and mild to moderate skin changes in affected males.Affected males. All types of albinism share a similar ophthalmologic phenotype, which in typical cases includes infantile nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the retinal pigment epithelium, foveal hypoplasia, and abnormal optic pathway projections. None of these findings is, however, either specific or obligate. Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom.Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia may occur in some affected individuals.Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [Brodsky & Fray 2004], but is neither distinctive nor characterizing.Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [Charles et al 1993]. XLOA is characterized by mild cutaneous and adnexal involvement (albinismus solum bulbi), and the universal defect in melanosome biogenesis that may escape clinical notice, if not compared to unaffected siblings. Nevertheless, in families with dark complexion, affected males tend to be more lightly pigmented than their unaffected sibs. In some affected males, irregular hypopigmented spots are present on the arms and legs. Persons with XLOA have normal life span, development, intelligence, and fertility.Carrier females may be considered mosaic with respect to the GPR143 mutation because random X-chromosome inactivation leads to variable degrees of ocular and cutaneous hypopigmentation. Most carrier females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA. On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a GPR143 mutation, or partial monosomy of the X chromosome.
No genotype-phenotype correlations have been identified [Schiaffino et al 1999]....
Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been identified [Schiaffino et al 1999].Even in the same family, the cutaneous and adnexal coloration and the visual acuities may vary widely.
“Congenital” nystagmus is usually the initial clinical sign leading to suspicion of an underlying visual sensory or central nervous system disorder and to an ophthalmologic examination. Congenital or infantile nystagmus (which typically begins two to eight weeks after birth) is not specific or unique to XLOA, as it can appear as an isolated finding (so-called primary motor nystagmus) or as part of a hereditary ocular disorder, some of which are X-linked. Although infantile nystagmus is often a secondary manifestation of bilateral congenital eye disorders associated with vision loss (e.g., corneal opacities, aniridia, cataracts, retinopathy of prematurity, and optic nerve hypoplasia), the differential diagnosis in males with XLOA is usually limited to visual disorders in which infantile nystagmus is the predominant finding and the eye is anatomically normal. ...
Differential Diagnosis“Congenital” nystagmus is usually the initial clinical sign leading to suspicion of an underlying visual sensory or central nervous system disorder and to an ophthalmologic examination. Congenital or infantile nystagmus (which typically begins two to eight weeks after birth) is not specific or unique to XLOA, as it can appear as an isolated finding (so-called primary motor nystagmus) or as part of a hereditary ocular disorder, some of which are X-linked. Although infantile nystagmus is often a secondary manifestation of bilateral congenital eye disorders associated with vision loss (e.g., corneal opacities, aniridia, cataracts, retinopathy of prematurity, and optic nerve hypoplasia), the differential diagnosis in males with XLOA is usually limited to visual disorders in which infantile nystagmus is the predominant finding and the eye is anatomically normal. A family history of X-linked inheritance for similarly affected individuals along with typical clinical findings supports the diagnosis of XLOA and further testing may not be indicated. However, when the family history is negative, XLOA must be distinguished from other forms of albinism and from X-linked disorders associated with infantile nystagmus.X-linked congenital nystagmus (OMIM 310700) is a diagnosis of exclusion, characterized by normal electroretinogram (ERG) and normal optical pathways. In the absence of any demonstrable sensory defect, the involuntary eye movements are denoted 'motor nystagmus.' More than 50% of carrier females manifest congenital nystagmus, simulating autosomal dominant inheritance [Kerrison et al 1999]. Families with X-linked congenital nystagmus have absence of male-to-male transmission. Two X-chromosomal loci, Xp11.4-p11.3 and Xq27, have been identified. For the latter locus, mutations in FRMD7 have been shown to cosegregate with the phenotype [Tarpey et al 2006].Ocular albinism with sensorineural deafness (OMIM 103470) is characterized by ocular albinism indistinguishable from XLOA (including the presence of macromelanosomes in the skin); additional findings are congenital deafness and vestibular dysfunction. In some affected individuals, heterochromia iridis and a prominent white forelock are present. Inheritance is autosomal dominant. A relation between this disorder and Waardenburg syndrome type 2 has been suggested and may result from digenic interaction between a transcription factor, MITF, and a missense mutation in the tyrosinase gene, TYR [Morell et al 1997].Ocular albinism with late-onset sensorineural deafness (OMIM 300650). This X-linked condition with a disease locus at Xp22.3 was reported in a large Afrikaner kindred. The disorder is possibly an allelic GPR143 variant or a contiguous gene defect [Bassi et al 1999].The oculocutaneous albinisms, inherited in an autosomal recessive manner, include types with moderate pigmentation of skin and hair that may be occasionally misinterpreted as “ocular albinism.” Oculocutaneous albinism type 1 (OCA1) is caused by mutations in TYR that encodes the protein tyrosinase. Individuals with OCA1A have white hair, white skin that does not tan, and fully translucent irides that do not darken with age. At birth, individuals with OCA1B have white or very light yellow hair that darkens with age, white skin that over time develops some generalized pigment and may tan with sun exposure, and blue irides that change to green/hazel or brown/tan with age. Ocular findings are very similar to those of XLOA. The diagnosis of OCA1 is established by clinical findings of hypopigmentation of the skin and hair and characteristic eye findings. Oculocutaneous albinism type 2 (OCA2) is caused by mutations in OCA2 (previously called P). The amount of cutaneous pigmentation in OCA2 ranges from minimal to near normal. Newborns with OCA2 almost always have pigmented hair, with color ranging from light yellow to blond to brown. Hair color may darken with time. Brown OCA, initially identified in Africans and African Americans with light brown hair and skin, is part of the spectrum of OCA2.Oculocutaneous albinism type 3 (OCA3) is caused by mutations in TYRP1 (encoding tyrosinase-related protein 1, also called Glycoprotein 75 or GP 75). Originally described in Southern African blacks, the disorder is characterized by bright copper-red hair, lighter tan skin, and diluted pigment in the iris and fundus. This has been called “rufous oculocutaneous albinism.”Oculocutaneous albinism type 4 (OCA4) is caused by mutations in MATP (previously called AIM1). The amount of cutaneous pigmentation in OCA4 ranges from minimal to near normal. Newborns with OCA4 usually have some pigment in their hair, with color ranging from silvery white to light yellow. Hair color may darken with time, but does not vary significantly from childhood to adulthood. This form of albinism is rarer than OCA2, except in the Japanese population. Complete congenital stationary night blindness. This X-linked condition is characterized by night blindness (nyctalopia), moderate to severe myopia, normal fundi, complete lack of dark adaptation, and characteristic ERG. A subset of affected individuals has congenital nystagmus and mildly reduced visual acuity. The rod (dark-adapted) ERG shows a normal a-wave, indicating normal photoreceptor function, but an undetectable b-wave, indicating post-receptor dysfunction. This response pattern is often referred to as a "negative ERG" because the negative potential of the initial a-wave is not followed by the positive potential of the b-wave. The cone (light-adapted) ERG is mildly reduced and can show a squared-off b-wave caused by loss of the ON-response. The condition is caused by a mutation in NYX (nyctalopin), a member of the leucine-rich proteoglycan family involved in cell adhesion and axon guidance. The protein product is found in ON-bipolar cells connected to both rods and cones.Incomplete congenital stationary night blindness. This X-linked condition is characterized by congenital nystagmus, reduced visual acuity, and moderate night-blindness. Iris translucency is not part of the disorder and ERG shows characteristic negative ERG and severely reduced double-peaked cone amplitudes. (The designation "negative ERG" describes an ERG with an a:b wave ratio above unity.) Female carriers are asymptomatic. The condition is caused by mutations in CACNA1F [Bech-Hansen et al 1998].Blue cone monochromacy (OMIM 303700) (sometimes referred to as X-linked incomplete achromatopsia). Blue cone monochromacy is a rare disorder (<1 in 100,000) characterized by X-linked inheritance, photophobia, congenital nystagmus, reduced visual acuity (20/60-20/200), impaired red-green color perception, and characteristic ERG. Fundi are usually normal, but atrophic macular changes have been reported. Formal color vision testing reveals absent or severely reduced responses to red-green stimuli and normal responses to blue stimuli. Standard ERG testing shows absent cone responses with normal rod responses. The S-(blue) cone response is normally undetectable by ERG because S-(blue) cones constitute about 5% of the total cone population. By special techniques, the blue cone response can be amplified and measured in a clinical setting. Two common molecular defects are associated with this phenotype [Nathans et al 1989]. One is a deletion of a regulatory sequence (locus control region) upstream of the visual pigment genes, which consists of one red pigment (opsin) gene and one or more green (opsin) genes. The second defect involves unequal homologous recombination between red and green opsin genes (coding to a single mutated red opsin) or a 5' red-green hybrid gene having a p.Cys203Arg (c.607T>C, NM_000513.2) substitution that encodes for a non-functional protein. A rare third molecular defect found in a single family involved a deletion of exon 4 in an isolated red gene [Ladekjaer-Mikkelsen et al 1996]. (See Red-Green Color Vision Defects for more information about the red pigment and green pigment genes.)Other disorders with sensory retinal early-onset nystagmus include autosomal dominant motor nystagmus, complete and incomplete achromatopsia, blue cone monochromacy, and other autosomal recessive stationary cone dysfunctions including enhanced S-cone syndrome, cone dystrophy with supernormal rod response, and Leber congenital amaurosis. In most of these diagnostic groups, the ERG is essential to establish the diagnosis.PAX6 mutations can result in infantile nystagmus and foveal hypoplasia in individuals with only mild iris hypoplasia (see Aniridia). Such individuals do not have iris transillumination. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with X-linked ocular albinism (XLOA), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with X-linked ocular albinism (XLOA), the following evaluations are recommended:Medical history and physical examination, including a careful evaluation of pigmentation status at birth and later to distinguish between oculocutaneous and ocular albinismA complete ophthalmologic evaluationDilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier stateTreatment of ManifestationsRefractive errors should be treated with appropriate spectacle correction as early as possible.Photodysphoria can be relieved by sunglasses, transition lenses, or special filter glasses, although many prefer not to wear them because of the reduction in vision from the dark lenses when indoors.Abnormal head posture with dampening of the nystagmus in a null point may be modified with prismatic spectacle correction. Strabismus surgery is usually not required but may be performed for cosmetic purposes, particularly if the strabismus or the face turn is marked or fixed. The need for vision aids and the educational needs of the visually impaired should be addressed. Dermatologic counseling for age-appropriate sun-protective lotions and clothing should be sought.Prevention of Secondary ComplicationsAppropriate education for sun-protective lotions and clothing (preferably by an informed dermatologic consultant) is indicated to moderate the cumulative lifelong effects of solar radiation.SurveillanceChildren younger than age 16 years with ocular albinism should have an annual ophthalmologic examination (including assessment of refractive error and the need for filter glasses) and psychosocial and educational support. In adults, ophthalmologic examinations should be undertaken when needed, typically every two to three years. Agents/Circumstances to AvoidAlthough no formal trials exist, standard care avoids use or application of sun-sensitizing drugs or agents.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAn animal model, the Oa1 knock-out mouse, has been constructed displaying the essential characteristics of XLOA [Surace et al 2005]. Decreased a- and b-wave ERG amplitudes in the Oa1 (-/-) model, however, are not present in humans with XLOA. Adeno-associated viral vector-mediated Oa1 transfer to the retina of the Oa1(-/-) mouse model results in significant rescues of both functional and morphologic abnormalities. These experiments open potential therapeutic perspectives. Tissue-specific control of Oa1 transcription is regulated by the microphthalmia transcription factor Mitf [Vetrini et al 2004]. Subretinal injections of an adeno-associated virus-mediated construct consisting of a small fragment of the Oa1 promotor cloned in front of a reporter gene was expressed specifically in the retinal pigment epithelium. These results point to a possibility for future therapeutic measures to influence melanosome biogenesis [Vetrini et al 2004]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherGenetic counseling should be offered routinely to parents of newly diagnosed children and to adults in the reproductive age groups.Nystagmus dampening has been achieved by bilateral horizontal rectus recession surgery in some centers, but this is not a generally accepted treatment nor is there evidence from a comparative clinical trial that such intervention improves the final visual outcome.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Ocular Albinism, X-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGPR143Xp22.2G-protein coupled receptor 143Albinism Database Mutations of the Ocular Albinism-1 gene Retina International Mutations of the OA1 GeneGPR143Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Ocular Albinism, X-Linked (View All in OMIM) View in own window 300500ALBINISM, OCULAR, TYPE I; OA1 300808G PROTEIN-COUPLED RECEPTOR 143; GPR143Normal allelic variants. GPR143 contains nine exons (NM_000273.2) spanning 40 kb of genomic DNA. Normal benign variants have been reported, including single nucleotide-polymorphisms and a highly polymorphic dinucleotide repeat (OA1-CA) with more than five different alleles at intron 1 [Schiaffino et al 1995, Oetting 2002]. Pathologic allelic variants. More than 100 different mutations have been reported; most seem to be private mutations. They include missense mutations, splice mutations, small deletions and insertions, and large deletions covering multiple exons of GPR143. Studies suggest that the mutation profile (e.g., prevalence of deletion mutations) may vary between the European and North American populations [Bassi et al 1995, Rosenberg & Schwartz 1998, Schnur et al 1998, Bassi et al 2001, Oetting 2002, Camand et al 2003, Faugère et al 2003]. (See Table A: HGMD and Albinism databases.) Normal gene product. GPR143 encodes a protein of 404-424 (NP_000264.2) amino acids that is expressed exclusively in the retinal pigment epithelium and the iris pigment epithelium of the eye and in the melanocytes of the skin. The mature GPR143 product is a 60-kd pigment cell-specific integral membrane glycoprotein, which represents a novel member of the G-protein coupled receptor (GPCR) superfamily (GPCR-143) [Schiaffino et al 1996]. In contrast to other GPCRs that localize to the plasma membrane, the protein encoded by GPR143 is targeted to intracellular organelles and may regulate melanosome biogenesis through signal transduction from the organelle lumen to the cytosol [Schiaffino & Tacchetti 2005]. When expressed in COS7 cells that lack melanosomes, GPCR-143 displays a considerable and spontaneous capacity to activate heterotrimeric G proteins and the associated signaling cascade. These findings indicate that heterologously expressed GPCR-143 exhibits two fundamental properties of GPCRs: being capable of activating heterotrimeric G proteins and providing proof that GPCR-143 can actually function as a canonical GPCR in mammalian cells [Innamorati et al 2006].Abnormal gene product. Most individuals with XLOA have a small intragenic GPR143 mutation that results in a phenotype similar to that observed in those exhibiting a complete deletion of GPR143, suggesting that most GPR143 alleles are null. Deletions and splice mutations are expected to produce either no product or rapidly degraded truncated proteins. By expressing mutant proteins in COS cells, missense mutations could be divided into three groups (I, II, and III) based on the ability to exit the endoplasmic reticulum (ER) and traffic to the lysosomal compartment. Class I mutations result in a gene product that is unable to exit the ER, presumably because of misfolding. The pathogenesis of these mutations is therefore similar to the larger deletions/splice mutations. Class II mutants exit the ER with low efficiency. Class III mutants are able to exit the ER and traffic to the lysosomal compartment, and loss of function rather than incorrect trafficking is responsible for the disease in individuals expressing these mutant alleles [d'Addio et al 2000, Shen et al 2001].