DiagnosisClinical DiagnosisThe diagnosis of oculocutaneous albinism type 4 (OCA4) is established by presence of the following features:Hypopigmentation of the skin and hair varying from complete depigmentation to partial depigmentation with brown hair. In some individuals pigmentation increases during the first decade of life [Suzuki & Tomita 2008].Characteristic ocular changes found in all types of albinism, including the following findings detected on routine ophthalmologic examination:NystagmusReduced iris pigment with iris translucencyReduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examinationFoveal hypoplasia associated with reduction in visual acuityMisrouting of the optic nerves at the chiasm associated with alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP)
Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA.Molecular Genetic TestingGene. SLC45A2 (previously called MATP and AIM1) is the only gene in which mutations are known to cause oculocutaneous albinism type 4 (OCA4).Clinical testingSequence analysis. Most individuals with OCA4 are compound heterozygotes.
Approximately 27% of the individuals with OCA4 reported had only one mutation detectable by sequence analysis of the coding region and the intron-exon boundaries of SLC45A2 [Newton et al 2001, Inagaki et al 2004, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005]. In these cases, it is probable that a pathologic mutation is present on the other allele, either in an intron where it produces an alternative gene transcript or in a regulatory region of the gene. To date, techniques that would detect these types of mutations have not been applied to SLC45A2.
In a cohort of Indian patients with clinical features of OCA4 only one SLC45A2 mutation was identified [Sengupta et al 2007]. Attempts to identify the other mutation by cosegregation study using microsatellite markers encompassing SLC45A2 were unsuccessful. Deletion/duplication analysis. Rooryck et al [2008] identified deletion of exon 4 in SLC45A2 in an individual who was described as having a severe phenotype at birth which became milder with age. Table 1. Summary of Molecular Genetic Testing Used in Oculocutaneous Albinism Type 4View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilitySLC45A2Sequence analysisSequence variants 2UnknownClinical Deletion / duplication analysis 3Exonic or whole-gene deletions1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray 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 StrategyTo confirm/establish the diagnosis in a proband. The diagnosis of OCA4 is suspected in an individual based on cutaneous and ophthalmologic findings and confirmed using molecular genetic testing, first using sequence analysis. If neither or only one mutation in SLC45A2 is identified, deletion/duplication analysis may be considered. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder. 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) DisordersOCA4 is the only phenotype known to be associated with mutations in SLC45A2.}

Natural HistoryA wide range of clinical phenotypes has been recognized to date [Suzuki & Tomita 2008]. The amount of cutaneous pigmentation in OCA4 is a continuum from minimal to near normal [Newton et al 2001, Inagaki et al 2004, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005]. The amount of iris and retinal pigment varies and visual acuity covers a wide range; however, no subtypes of OCA4 are recognized. Individuals with albinism (including OCA4) are usually recognized within the first year of life because of the ocular features of nystagmus and strabismus. In many families, particularly in those with darker constitutional pigmentation, the cutaneous hypopigmentation is also obvious at birth and suggests the diagnosis.Eye. Some children with albinism have nystagmus that is noticed by the parents and the examining physician in the delivery room. Many children with albinism do not have nystagmus at birth and the parents note slow wandering eye movements and a lack of visual attention. The parents may become concerned because the child does not seem to "focus well," but the absence of nystagmus may delay the diagnosis. Most children with albinism develop nystagmus by age three to four months, and the diagnosis is often considered at the four-to-six month well-baby checkup. The nystagmus can be rapid early in life and generally slows with time; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when individuals are tired, angry, or anxious, and less marked when they are well-rested and feeling well [Summers 2009].Iris color ranges from blue to brown. In one individual with OCA4, who had been misdiagnosed at birth as having OCA1 because of complete iris transillumination, the amount of iris pigment increased in the first ten years, resulting in blue iris color [Suzuki et al 2005].Visual acuity in individuals with OCA4 ranges from 20/30 to 20/400 and is usually in the range of 20/100 to 20/200 [Rundshagen et al 2004, Suzuki et al 2005]. Vision is likely to be stable after early childhood and no major change or further reduction in vision should occur. The visual changes are likely not progressive, and loss of vision later in life should not be related to the albinism.Skin/hair. The range of skin pigment in individuals with OCA4 is broad [Newton et al 2001, Inagaki et al 2004, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005]. Individuals with OCA4 are often born with some pigment in their hair that ranges in color from silvery white to light yellow. Scalp hair may be very light, but it is usually not completely white (not as white as a sheet of copy paper or fresh snow); some parents may refer to light yellow/blond hair color as "white" or "nearly white" if it is very lightly pigmented or is much lighter than the hair color of other family members at a similar age. Furthermore, the definition of "white" scalp hair is not easy in some young children because the hair may be sparse and short and because some shampoos discolor hair. It is helpful to hold a piece of white paper next to the hair to determine if it is truly white. Hair color may darken with time, but usually the hair color does not change dramatically between childhood and adulthood [Inagaki et al 2004]. When hair color is blond or yellow, the skin is usually creamy white with little or no pigmentation. Skin color in individuals with OCA4 is not usually as white as that in individuals with the OCA1A subtype of oculocutaneous albinism type 1, reflecting the fact that skin melanocytes in individuals with OCA4 can still synthesize some melanin; however, the majority of the melanin is yellow pheomelanin rather than black-brown eumelanin. Skin cancer risk. Over many years, exposure of lightly pigmented skin to the sun can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Melanoma is usually rare in individuals with OCA, even though skin melanocytes are present [Ihn et al 1993].Skin cancer is unusual in individuals with OCA4 in the US because of the availability of sunscreens, the social acceptability of wearing clothes that cover most of the exposed skin, and the fact that individuals with albinism often do not spend a great deal of time outside in the sun. Skin cancer in an individual with any type of OCA is very rare in northern areas of the US. Skin cancer in individuals with albinism is common in some parts of the world such as sub-Saharan Africa because of the increased amount of sun exposure throughout the year, the cultural differences in protective dress, and the lack of skin-protective agents such as sunscreens [Okoro 1975].

Genotype-Phenotype CorrelationsThe lack of a functional assay for the SLC45A2 protein and the limited data from SLC45A2 molecular genetic testing make genotype-phenotype correlations difficult [Newton et al 2001, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005, Konno et al 2009]. In Japanese individuals, two frequent mutant alleles, p.Asp157Asn and p.Gly188Val, have been reported. The p.Asp157Asn allele may have very low functional activity in melanogenesis; p.Gly188Val may have some residual functional activity [Inagaki et al 2004].The degree of cutaneous pigmentation, ocular pigmentation, and visual development resulting from particular SLC45A2 mutations cannot be predicted at this time.

Differential DiagnosisAlbinism. Most types of albinism are associated with the development of some cutaneous pigmentation. The differential diagnosis of albinism with pigmentation of the skin and hair includes the OCA1B subtype of oculocutaneous albinism type 1; oculocutaneous albinism type 2 (OCA2); oculocutaneous albinism type 3 (OCA3); Hermansky-Pudlak syndrome (HPS); and X-linked ocular albinism (OA1).OCA1. Visual acuity in individuals with OCA4 is likely to be better than that in individuals with OCA1, but may overlap [Summers 1996, King et al 2001a, King et al 2001b, Inagaki et al 2004, Rundshagen et al 2004].OCA2. Since clinical features of OCA2 are similar to OCA4, molecular genetic testing is necessary to distinguish them.OCA3. Mutations of TYRP1, the gene encoding tyrosinase-related protein-1, are associated with rufous or red OCA3 [Boissy et al 1996, Manga et al 1997]; this phenotype has only been described in individuals from African, Pakistani, German, and Indian populations [Forshew et al 2005, Rooryck et al 2006, Rooryck et al 2008, Chiang et al 2009].Hermansky-Pudlak syndrome (HPS). A medical history of bleeding or bruising and an analysis of platelet dense bodies are necessary to establish the diagnosis of HPS.OA1. Males with X-linked ocular albinism have normal skin and hair pigment, which is obvious in families with darker constitutional pigmentation. In families with light constitutional pigmentation, a young boy with OA1 may have light hair (even be "tow-headed") and appear to have oculocutaneous albinism rather than ocular albinism. The correct diagnosis may be established by family history; it usually becomes clear with time. Molecular genetic testing of OA1 provides an objective and noninvasive means of diagnosis.Other. Although individuals with red skin and light hair have been described in Papua, New Guinea, the association of this phenotype with OCA3 found in Africa is unknown. Affected individuals in Papua, New Guinea have nystagmus and reduced visual acuity, but the retina is normally pigmented and foveal hypoplasia is not present [Hornabrook et al 1980]. Molecular studies of this phenotype are not available. The existence of another autosomal gene associated with either ocular albinism or oculocutaneous albinism has not been substantiated, although families with OCA that do not map to the loci for TYR (OCA1), OCA2, TYRP1 (OCA3), or SLC45A2 (OCA4) have been reported.Congenital motor nystagmus. Congenital motor nystagmus presents with nystagmus associated with reduced visual acuity. Some individuals with congenital motor nystagmus have been reported to have retinal hypopigmentation and foveal abnormalities; however, these studies were done before the molecular basis of OCA was understood, suggesting that individuals with OCA may have been included incorrectly. The visual evoked potential analysis to evaluate misrouting of the optic nerves is normal in congenital motor nystagmus.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).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with oculocutaneous albinism type 4 (OCA4), the following evaluations are recommended:Complete ophthalmologic evaluation including measurement of visual acuity and refractive error Assessment for strabismusTreatment of ManifestationsOphthalmologic care is the most important part of the ongoing care for most individuals with OCA4.The majority of individuals with albinism have significant hyperopia or myopia and astigmatism. Correction of these refractive errors with spectacles or contact lenses can improve visual acuity. Except in the very unusual individual, correction of refractive errors cannot restore visual acuity to normal because of the foveal hypoplasia.Photophobia is common in individuals with OCA, but the degree of discomfort varies and does not depend entirely on the amount of melanin pigment present in the iris or skin. In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because of the reduction in vision from the dark lenses. A hat with a brim (such as a baseball hat with a visor) is often the best way to achieve reduction in photophobia and sun protection.The alternating strabismus found in most individuals with albinism is generally not associated with the development of amblyopia. Strabismus surgery is usually not required, but can be considered for cosmetic reasons if the strabismus is marked or fixed.Prevention of Secondary ComplicationsThe skin care necessary for individuals with OCA4 to prevent sunburn and secondary skin changes is determined by the amount of pigment in the skin and the cutaneous response to sunlight. The amount of skin pigmentation varies, and protection of the skin with sunscreen correlates with skin pigmentation and the ability to tan. Individuals with white skin that does not tan need to be protected from any prolonged sun exposure. This can be for exposures as short as five to ten minutes in very sensitive individuals and 30 minutes or more in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, socks) and sun screen with a high SPF number (total blocks with SPF 45-50+). Sunscreens with lower SPF values (for example, SPF 8, 15, or 30) can be used if the individual does not burn routinely with sun exposure.SurveillanceAnnual ophthalmologic examination and reassessment for accurate correction of refractive error are appropriate.Agents/Circumstances to AvoidAvoid excessive exposure of the skin to the sun.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

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. Oculocutaneous Albinism Type 4: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC45A25p13​.2Membrane-associated transporter proteinAlbinism Database Mutations of the Membrane Associated Transporter Protein (MATP) Gene (aka SLC45A2)
Retina International Mutations of the Membrane-associated Transport Protein Gene (MATP)SLC45A2Data 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 Oculocutaneous Albinism Type 4 (View All in OMIM) View in own window 606202SOLUTE CARRIER FAMILY 45, MEMBER 2; SLC45A2 606574ALBINISM, OCULOCUTANEOUS, TYPE IV; OCA4Molecular Genetic PathogenesisAlthough not yet observed in humans, the phenotype resulting from heterozygosity of a single Slc45a2 mutation in mice results in hypopigmentation that may be analogous to some of the so-called autosomal dominant forms of albinism reported in humans.Normal allelic variants. SLC45A2 has seven exons (NM_016180.3), and normal sequence variants are found in many exons and adjacent introns throughout the gene. Eight polymorphisms have been described.Pathologic allelic variants. See International Albinism home page. Forty-five mutations of SLC45A2 have been reported. Most are missense mutations, but deletions of one or a small number of bases and base changes have been detected [Newton et al 2001, Inagaki et al 2004, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005, Suzuki et al 2005, Sengupta et al 2007, Gronskov et al 2009, Konno et al 2009]. The most common SLC45A2 mutation in Japanese individuals, accounting for 39% of mutant alleles, is the p.Asp157Asn missense mutation [Inagaki et al 2004]. Most individuals with OCA4 are compound heterozygotes for SLC45A2 mutations, with different maternal and paternal mutations. Approximately 17% of reported Japanese individuals and a cohort from Japan have only one identifiable mutation; the second mutation cannot be detected with the methods used [Inagaki et al 2004, Sengupta et al 2007]. (For more information, see Table A.)Table 2. Selected SLC45A2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.469G>Ap.Asp157AsnNM_016180​.3
NP_057264​.3 c.563G>Tp.Gly188ValSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The MATP protein consists of 530 amino acids and contains 12 transmembrane domains (NP_057264.3) [Newton et al 2001]. The precise function of the MATP protein is unknown, although it shares high homology with known sucrose proton symporters.Abnormal gene product. The mechanisms by which the mutant protein alters the ability of the cell to synthesize melanin are unknown. However, tyrosinase, the rate-limiting enzyme in the biosynthesis of melanin that is associated with OCA1, appears to be mislocalized in mouse melanocytes that are homozygous for mutant SLC45A2 alleles [Costin et al 2003]. This phenotype is shared with melanocytes that are mutant for OCA2, the gene in which mutation causes OCA2 [Toyofuku et al 2002].