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Ocular Albinism, X-Linked

Synonyms: Nettleship-Falls Ocular Albinism, OA1, Ocular Albinism Type 1, XLOA
, MD, MS
Departments of Ophthalmology, Medicine, Pediatrics, and Molecular and Human Genetics / Huffington Center on Aging
Cullen Eye Institute
Baylor College of Medicine
Houston, Texas

Initial Posting: ; Last Update: April 5, 2011.

Summary

Disease characteristics. X-linked ocular albinism (XLOA) is a disorder of melanosome biogenesis leading to minor skin 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 siblings), foveal hypoplasia, reduced visual acuity, and aberrant optic pathway projection as demonstrated by crossed asymmetry of the cortical responses on visual evoked potential testing (VEP). 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 mutations 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 disease-causing mutation 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 mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is possible if the mutation has been identified in the proband. If the familial mutation is not known because an affected male is unavailable for testing, molecular genetic testing can be performed on at-risk female relatives, but with a lower degree of test sensitivity. Prenatal testing is possible for pregnancies at increased risk if the familial mutation is known.

Diagnosis

Clinical Diagnosis

Affected 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.

Testing

Skin 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 Testing

Gene. GPR143 (formerly known as OA1) is the only gene in which mutations are known to cause X-linked ocular albinism.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in X-Linked Ocular Albinism

Gene SymbolTest MethodMutations DetectedMutation Detection Rate by Test Method 1
MalesHeterozygous Females
GPR143Sequence analysisSequence variants 290% 3, 443% 5
Deletion / 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 gene

2. 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 analysis

5. 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 Proband

To confirm/establish the diagnosis in a proband

  • To 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.

Clinical Description

Natural History

XLOA 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.

Genotype-Phenotype Correlations

No 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.

Prevalence

A minimum birth prevalence of one male in 60,000 liveborn children has been reported in a Danish cohort [Rosenberg & Schwartz 1998] and of approximately one in 50,000 in a US cohort [King et al 1995].

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations 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 albinism
  • A complete ophthalmologic evaluation
  • Dilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier state

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

An 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.

Other

Genetic 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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 or be a carrier of the disease-causing mutation.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • 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 the carrier status. Alternatively, if the mutation in the proband is known, the mother should be tested for that mutation. Possible genetic explanations for a single occurrence of an affected male in the family:
    • The proband has a de novo mutation. In this instance, the proband's mother does not have the mutation. The only other family members at risk are the offspring of the proband.
    • The proband's mother has a de novo mutation and may or may not have retinal changes of the carrier state. One of two types of de novo mutations may be present in the mother:
      a.

      A germline mutation 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 mutation 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 mutation, whereas the sibs of the proband's mother are not.

Sibs of a proband

  • The risk to the sibs of a male proband depends on the carrier status of the mother.
  • If the mother has the mutation, the chance of transmitting the GPR143 mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.
  • If the mother is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. The risk for germline mosaicism in mothers is not known but is likely rare.
  • The risk to the sibs of a proband appears to be low in either of the following situations:
    • The mother of a male who is the only affected family member does not have the GPR143 mutation present in her son.
    • The mutation is not known but the mother of a single affected male has normal fundus pigmentation.

Offspring of a proband. Affected males transmit the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers of XLOA, and the aunts' offspring, depending upon their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in the proband.

If the familial mutation is not known because an affected male is unavailable for testing, molecular genetic testing can be performed on at-risk female relatives but with a lower degree of test sensitivity.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers of a known GPR143 mutation. The usual procedure is to perform chromosome analysis on fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~15-18 weeks' gestation) for sex determination. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Organization of Albinism and Hypopigmentation (NOAH)
    PO Box 959
    East Hampstead NH 03826-0959
    Phone: 800-473-2310 (toll-free); 603-887-2310
    Fax: 800-648-2310 (toll-free)
    Email: info@albinism.org
  • PanAmerican Society for Pigment Cell Research (PASPCR)
  • The Vision of Children Foundation
    11975 El Camino Real
    Suite 104
    San Diego CA 92130
    Phone: 858-314-7917
    Fax: 858-314-7920
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

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

Data 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)

300500ALBINISM, OCULAR, TYPE I; OA1
300808G PROTEIN-COUPLED RECEPTOR 143; GPR143

Normal 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].

References

Literature Cited

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Suggested Reading

  1. Sjöström A, Kraemer M, Ohlsson J, Garay-Cerro G, Abrahamsson M, Villarreal G. Subnormal visual acuity (SVAS) and albinism in Mexican 12-13-year-old children. Doc Ophthalmol. 2004;108:9–15. [PubMed: 15104163]

Chapter Notes

Author History

Richard Alan Lewis, MD, MS (2011-present)
Thomas Rosenberg, MD; National Eye Clinic for the Visually Impaired (2003-2011)
Marianne Schwartz, PhD; Rigshospitalet (2003-2011)

Revision History

  • 5 April 2011 (me) Comprehensive update posted live
  • 22 May 2006 (me) Comprehensive update posted to live Web site
  • 12 March 2004 (me) Review posted to live Web site
  • 30 September 2003 (tr) Original submission
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