Summary
NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.
Clinical characteristics.
X-linked ocular albinism (XLOA) is a disorder of melanosome biogenesis leading to minor cutaneous and adnexal manifestations and congenital and persistent visual impairment in affected males. XLOA is characterized by infantile nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. XLOA is a non-progressive disorder and the visual acuity remains stable throughout life, often slowly improving into the mid-teens.
Diagnosis/testing.
A diagnosis of ocular albinism (OA) is probable in the presence of infantile nystagmus, iris translucency, substantial hypopigmentation of the ocular fundus periphery in males with mildly hypopigmented skin (most notably when compared to unaffected sibs), foveal hypoplasia, reduced visual acuity, and aberrant optic pathway projection as demonstrated by crossed asymmetry of the cortical responses on visual evoked potential testing. X-linked inheritance is documented by either a family history consistent with X-linked inheritance or the presence of typical carrier signs (irregular retinal pigmentation and mild iris transillumination) in an obligate carrier female. Molecular genetic testing of GPR143
(previously OA1) detects pathogenic variants in more than 90% of affected males.
Management.
Treatment of manifestations: Early detection and correction of refractive errors, use of sunglasses or special filter glasses for photoaversion, and prismatic spectacle correction for abnormal head posture. Strabismus surgery is often unnecessary but may be performed to improve peripheral visual fusion fields. The need for vision aids and special consideration in educational settings should be addressed.
Surveillance: For affected children younger than age 16 years: annual ophthalmologic examination (including assessment of refractive error and the need for filter glasses) and psychosocial and educational support. For adults: ophthalmologic examinations as needed.
Genetic counseling.
XLOA is inherited in an X-linked manner. An affected male transmits the pathogenic variant to all of his daughters and none of his sons. The risk to the sibs of a male proband depends on the carrier status of the mother. If the mother is a carrier, the chance of transmitting the GPR143 pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is most informative if the pathogenic variant has been identified in the proband. Prenatal testing is possible for a pregnancy at increased risk if the familial pathogenic variant is known.
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 optic 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. Three X-chromosome loci, Xp11.4, Xp22.2 (GPR143), and Xq26.2 (FRMD7), have been identified. FRMD7 may manifest slightly different clinical and oculomotor characteristics than XLOA [Kumar et al 2011]. See also FRMD7-Related Infantile Nystagmus.
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 pathogenic variants in
TYR that encodes the protein tyrosinase. Individuals with OCA1A (OMIM
203100) have white hair, white skin that does not tan, and fully translucent irides that do not darken with age. At birth, individuals with OCA1B (OMIM
606952) 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) (OMIM
203200) is caused by pathogenic variants 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) (OMIM
203290) is caused by pathogenic variants 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 pathogenic variants in
SLC45A2 (previously called
MATP or
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 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 have 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 inherited in an X-linked manner and caused by pathogenic variants 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 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.) The condition is inherited in an X-linked manner and caused by pathogenic variants in CACNA1F [Bech-Hansen et al 1998]. Female carriers are asymptomatic.
Blue cone monochromacy (OMIM 303700), sometimes referred to as X-linked incomplete achromatopsia, 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 nonfunctional 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].
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 pathogenic variants can result in infantile nystagmus and foveal hypoplasia in individuals with only mild iris hypoplasia (see Aniridia). Such individuals do not have iris transillumination.
Failure to detect a pathogenic variant in GPR143 should lead the clinician to re-assess the patient for other non-ocular and constitutional features that will be useful for additional molecular diagnostic studies.
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 pathogenic variant in TYR (encoding tyrosinase) [Morell et al 1997].
Ocular albinism with late-onset sensorineural deafness (OMIM 300650), an X-linked condition with a disease locus at Xp22.3, was reported in a large Afrikaner kindred. The disorder is possibly caused by an allelic GPR143 variant or a contiguous gene defect [Bassi et al 1999].
Hermansky-Pudlak Syndrome (HPS) is a multisystem disorder characterized by: tyrosinase-positive oculocutaneous albinism; a bleeding diathesis resulting from a platelet storage pool deficiency; and, in some cases, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. The albinism is characterized by: hypopigmentation of the skin and hair; and ocular findings of reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. Because of the wide phenotypic variability in the colors of skin and hair in HPS, an observer might initially consider ocular albinism in the differential diagnosis, especially in a person of the less common ethno-geographic backgrounds; however, the clinician should always query the manifestations of the common bleeding diathesis in HPS. HPS is inherited in an autosomal recessive manner and is caused by pathogenic variants in HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN).
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs 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 albinism
A complete ophthalmologic evaluation
Dilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier state
Dermatologic consultation for sun-protective lotion and sun-protective clothing and avoidance of associated cumulative solar damage
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Refractive 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 Complications
Appropriate education for sun-protective lotions and clothing (preferably by an informed dermatologic consultant) is indicated to moderate the cumulative lifelong effects of solar radiation.
Surveillance
Children 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 Avoid
Although no formal trials exist, standard care avoids use or application of sun-sensitizing drugs or agents.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.
Other
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
X-linked ocular albinism is inherited in an X-linked manner.
Risk to Family Members
Parents of a proband
The father of an affected male will not have ocular albinism nor will he be hemizygous for the GPR143 pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child with the same pathogenic variant and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
If pedigree analysis reveals that the proband is the only affected family member, it is appropriate to examine the retina of the mother for evidence of classic mosaic pigmentation of the retinal pigment epithelium. Alternatively, if the GPR143 pathogenic variant in the proband is known, the mother should be tested for that pathogenic variant. Possible genetic explanations for a single occurrence of an affected male in the family:
The proband has a de novo pathogenic variant. In this instance, the proband's mother does not have the pathogenic variant. The only other family members at risk are the offspring of the proband.
The proband's mother has a de novo pathogenic variant and may or may not have retinal changes. One of two types of de novo pathogenic variants may be present in the mother:
a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or
b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members.
Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not.
Sibs of a proband
The risk to sibs depends on the genetic status of the mother.
If the GPR143 pathogenic variant has been detected in the mother’s leukocyte DNA, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and will usually not be affected.
If the proband represents a simplex case (i.e., a single occurrence in a family) and the GPR143 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism. Germline mosaicism in mothers is not reported in XLOA but has been documented in other X-linked disorders and is likely rare.
If the pathogenic variant is not known but the mother of a single affected male has normal fundus pigmentation, the risk to the sibs of a proband appears to be low but is likely to be greater than that of the general population because of the possibility of maternal germline mosaicism.
Offspring of a male proband. An affected male will transmit the GPR143 pathogenic variant to:
All his daughters, who will be heterozygotes and will usually not be affected (see Clinical Description,
Heterozygous Females);
None of his sons.
Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts' offspring, depending on their sex, may be at risk of being carriers or of being affected.
Heterozygote (Carrier) Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the GPR143 pathogenic variant has been identified in an affected male.
Prenatal Testing and Preimplantation Genetic Testing
Once the GPR143 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for X-linked ocular albinism are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Molecular Genetics
Information 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 Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure.
GPR143 contains nine exons (NM_000273.2) spanning 40 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.
Benign variants. Normal variants have been reported, including a highly polymorphic dinucleotide repeat (OA1-CA) with more than five different alleles at intron 1 [Schiaffino et al 1995, Oetting 2002].
Pathogenic variants. More than 115 different pathogenic variants have been reported; most appear to be private. They include missense and splice site variants, small deletions and insertions, and large deletions covering multiple exons of GPR143. Studies suggest that the spectrum of pathogenic variants (e.g., prevalence of deletions) 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 canonic GPCR in mammalian cells [Innamorati et al 2006].
Abnormal gene product. Most individuals with XLOA have a small intragenic GPR143 pathogenic variant which 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 pathogenic variants are expected to produce either no product or rapidly degraded truncated proteins. By expressing mutant proteins in COS cells, pathogenic missense variants 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 pathogenic variants result in a gene product that is unable to exit the ER, presumably because of misfolding. The pathogenesis of these variants is therefore similar to that of the larger deletions/splice pathogenic variants. Class II pathogenic variants exit the ER with low efficiency. Class III pathogenic variants 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 abnormal alleles [d'Addio et al 2000, Shen et al 2001].
