Oculocutaneous albinism type 1
General Information (adopted from Orphanet):
Synonyms, Signs: |
OCA1 |
Number of Symptoms | 14 |
OrphanetNr: | 352731 |
OMIM Id: |
203100
606952 |
ICD-10: |
E70.3 |
UMLs: |
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MeSH: |
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MedDRA: |
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Snomed: |
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Prevalence, inheritance and age of onset:
Prevalence: | <= 2.5 of 100 000 - PMID: 17980020 [IBIS] |
Inheritance: |
Autosomal recessive Monogenic - PMID: 3109790 [IBIS] |
Age of onset: |
Neonatal Infancy - PMID: 9613388 [IBIS] |
Disease classification (adopted from Orphanet):
Parent Diseases: |
Oculocutaneous albinism
-Rare eye disease -Rare genetic disease -Rare skin disease |
Comment:
Albinism is an autosomal recessive disorder in which congenital hypopigmentation in the skin, hair and eyes (OCA)) or primarily in the eye (ocular albinism or OA) is associated with severe photosensitivity to ultraviolet radiation, and characteristic abnormalities in the visual system including nystagmus, foveal hypoplasia, misrouting of the optic fibers at the chiasm and greatly decreased visual acuity.The TYR gene which encodes a copper-containing enzyme that catalyzes the first two steps in the melanin biosynthetic pathway is responsible for OCA type I (OCAI). To date, 109 pathogenic mutations have been reported in the TYR gene (PMID:11295837). |
Symptom Information:
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(HPO:0007750) | Hypoplasia of the fovea | 11860983 | IBIS | 11 / 7739 | ||
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(HPO:0001107) | Ocular albinism | 3109790 | IBIS | 40 / 7739 | ||
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(HPO:0000486) | Strabismus | 1951438 | IBIS | 576 / 7739 | ||
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(HPO:0000613) | Photophobia | 19060277 | IBIS | 158 / 7739 | ||
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(HPO:0000483) | Astigmatism | 9613388 | IBIS | 67 / 7739 | ||
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(HPO:0000639) | Nystagmus | 115122 | IBIS | 555 / 7739 | ||
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(HPO:0007663) | Reduced visual acuity | 115122 | IBIS | 100 / 7739 | ||
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(HPO:0000505) | Visual impairment | 8190479 | IBIS | 297 / 7739 | ||
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(HPO:0000545) | Myopia | 1951438 | IBIS | 286 / 7739 | ||
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(HPO:0000635) | Blue irides | 8190479 | IBIS | 25 / 7739 | ||
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(HPO:0011364) | White hair | 13680365 | IBIS | 4 / 7739 | ||
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(HPO:0001022) | Albinism | 19060277 | IBIS | 43 / 7739 | ||
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(HPO:0200098) | Absent skin pigmentation | 15059699 | IBIS | 2 / 7739 | ||
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(HPO:0003577) | Congenital onset | 15059699 | IBIS | 133 / 7739 |
Associated genes:
TYR; |
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
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Additional Information:
Diagnosis GeneReviews | The diagnosis of oculocutaneous albinism type 1 (OCA1) [Creel et al 1990] is established by the presence of the following:... Gene 1Test Method Mutations Detected 2PhenotypeMutation Detection Frequency by Test Method 3Test Availability2 mutations1 mutationTYRSequence analysis | Sequence variants 4, 5OCA1A75%-90% 610%-20%ClinicalOCA1B37% 63% 7Deletion/duplication analysis 8Exonic or whole-gene deletions 9Both forms9Unknown1. See Table A. Genes and Databases for chromosome locus and protein name. 2. See Molecular Genetics for information on allelic variants. 3. These data are only estimates based on clinical, assumed diagnoses. In early life, often before age one year, it is difficult to distinguish OCA1A from OCA1B. Other forms of OCA2-4 may result in light pigmentation that may be difficult to distinguish from OCA1, especially OCA1B. Mild forms of albinism are underdiagnosed and confused with other forms of early-onset, infantile nystagmus. 4. Examples of 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. For issues to consider in interpretation of sequence analysis results, click here. 5. In some populations, laboratories may only sequence select exons or specific targeted mutations6. Hutton & Spritz [2008], Rooryck et al [2008], Gronskov et al [2009], Wei et al [2010] 7. This estimate includes individuals who may have milder forms of oculocutaneous albinism (caused by mutations in genes other than TYR) and who, incidentally, also carry one TYR mutation.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 9. Large deletions are quite rare (Albinism Database). Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of OCA1 is usually based on clinical findings, especially for OCA1A. Molecular genetic testing is rarely necessary for diagnosis except in those individuals who develop some cutaneous, hair, and ocular pigment after the first year of life, particularly if the light pigmentation is confused with the clinical appearance of infants and children with OCA2.
Clinical Description GeneReviews | Individuals with all variations of OCA1 have white or nearly white scalp hair, brows, and lashes; white skin; and blue irides with extensive transillumination at birth. The presence of white scalp hair at birth should not be the exclusive clinical criterion for OCA1 because some persons with OCA2 may seem exceedingly fair in the first six to twelve months of life as well. ... |
Genotype-Phenotype Correlations GeneReviews | OCA1A is caused by null mutations of TYR that produce a completely inactive or an incomplete tyrosinase enzyme polypeptide [Gronskov et al 2007, Simeonov et al 2013]. The total lack of tyrosinase enzyme function blocks the first step of the melanin biosynthetic pathway and, thus, no melanin forms in any melanocyte. ... |
Differential Diagnosis GeneReviews |
Table 2: Oculocutaneous Albinism: OMIM Phenotypic Series... PhenotypePhenotype MIM numberGene/LocusGene/Locus MIM numberAlbinism, oculocutaneous, type IA | 203100 TYR, SHEP3, CMM8 606933 Albinism, oculocutaneous, type IB 606952 TYR, SHEP3, CMM8 606933 Albinism, oculocutaneous, type II 203200 OCA2, P, PED, D15S12, BOCA, EYCL3, HCL3, SHEP1 611409 {Oculocutaneous albinism, type II, modifier of} 203200 MC1R, SHEP2, CMM5 155555 Albinism, oculocutaneous, type III 203290 TYRP1, CAS2, GP75 115501 Oculocutaneous albinism, type IV 606574 SLC45A2, MATP, AIM1, SHEP5 606202 Albinism, brown oculocutaneous 203200 OCA2, P, PED, D15S12, BOCA, EYCL3, HCL3, SHEP1 611409 Data from Online Mendelian Inheritance in ManAlbinism. The ocular features of all types of oculocutaneous albinism (OCA) and X-linked ocular albinism are similar, and the terms "OCA" and "albinism" can be used interchangeably for these ocular manifestations. Biallelic null mutations of TYR are the only known cause of oculocutaneous albinism with white hair, white skin, and “blue” eyes (OCA1A). As noted in the Clinical Description, the identification of white hair may be difficult because of the sparsity of scalp hair, brows, and lashes in a young child and the different perceptions by family members to describe what qualifies as "white" hair. The differential diagnosis for individuals with albinism who have pigment in the skin and hair (OCA1B) includes OCA2, OCA3, OCA4, Hermansky-Pudlak syndromes 1-7, and X-linked (Nettleship-Falls) ocular albinism (OA1). Previous studies suggested the existence of autosomal recessive ocular albinism, presenting with reportedly normal skin and hair pigment in males and females in a sibship; however, this interpretation seems to have been incorrect, and individuals with this apparent phenotype are now recognized to be part of the spectrum of OCA1B and OCA2. Recently another form of oculocutaneous albinism has been associated with mutations in C10orf11, a melanocyte-differentiation gene [Gronskov et al 2013], and others remain to be discovered.Oculocutaneous albinism type 2 (OCA2) is characterized by hypopigmentation of the skin and hair and the characteristic ocular changes found in all types of albinism, including nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia associated with reduction in visual acuity; and misrouting of the optic nerves at the chiasm associated with strabismus, reduced stereoscopic vision, and altered visual evoked potentials (VEP). Vision is stable to slowly improving after early childhood until mid- to late teens, and no major change or loss of established visual acuity occurs related to the albinism. The amount of cutaneous pigmentation in OCA2 ranges from minimal to near-normal. Newborns with OCA2 almost always have lightly pigmented hair, brows, and lashes, with color ranging from light yellow to blond to brown. Hair color may darken with age but does not vary substantially from adolescence to adulthood. Brown OCA, initially identified in Africans and African Americans with light brown hair and skin, is part of the spectrum of OCA2. The diagnosis of OCA2 is based on clinical findings. OCA2 is inherited in an autosomal recessive manner. OCA2 (previously called P) is the only gene in which mutations are known to cause OCA2. OCA3 is caused by mutations in TYRP1, encoding tyrosinase-related protein 1, which stabilizes TYR in large molecular complexes and without which TYR is degraded rapidly [Kobayashi & Hearing 2007]. Since the gene product is necessary to synthesize the black/brown eumelanin but not the reddish pheomelanin, the phenotype for OCA3 is a milder OCA in which affected individuals accumulate reddish pigment in their hair and skin, particularly noticeable in families of African ancestry. OCA3 is also inherited in an autosomal recessive manner.Oculocutaneous albinism type 4 (OCA4) is characterized by hypopigmentation of the skin and hair plus the ocular characteristics of all other types of albinism. Vision is likely to be stable after early childhood. The amount of cutaneous pigmentation in OCA4 ranges from minimal to near-normal. Newborns with OCA4 usually have some pigment in their hair, the 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. SLC45A2 (previously called MATP and AIM1) is the only gene in which mutation is known to cause OCA4. SLC45A2 encodes membrane-associated transporter protein, the human ortholog to the mouse gene Underwhite [Newton et al 2001]. OCA4 was identified initially in one male of Turkish origin. Studies now suggest that this is the second most common type of OCA in Japanese individuals [Inagaki et al 2004]. Because OCA2 and OCA4 are phenotypically similar, it is not possible to diagnose OCA4 accurately only on clinical findings. OCA4 is inherited in an autosomal recessive manner. Hermansky-Pudlak syndromes (HPS) are nine multi-system disorders characterized by oculocutaneous albinism, a bleeding diathesis resulting from a platelet storage pool deficiency, and, in some cases, pulmonary fibrosis or granulomatous colitis evolving with age. 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. The bleeding diathesis can result in easy bruising, frequent epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and progresses to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. The diagnosis of HPS is established by clinical findings of hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absent dense bodies on whole mount electron microscopy of platelets. Biallelic mutations in HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, or BLOC1S6 are known to be associated with HPS. HPS is inherited in an autosomal recessive manner. X-linked ocular albinism (OA1) is a disorder of melanosome biogenesis leading to minor skin manifestations and congenital and persistent visual impairment in affected males. OA1 is characterized by infantile nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia in affected males. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. OA1 is a non-progressive disorder and the visual acuity remains stable throughout life, often slowly improving into the mid-teens. 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).OA1 is caused by mutations in GPR143 (formerly OA1). 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 partial iris transillumination) in an obligate carrier female. Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop an accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. Adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT) develop neurologic findings during early adulthood.Ophthalmologic findings, history of recurrent or severe infections, and abnormal platelet aggregation studies should prompt evaluation for CHS. Diagnosis is based on identification of abnormal WBC granules on blood smear. Biallelic LYST mutations are causative. Inheritance is autosomal recessive.Congenital motor nystagmus. Congenital motor nystagmus is a phenotype that presents as infantile nystagmus associated with reduced visual acuity. Some individuals with congenital motor nystagmus have been reported to have retinal hypopigmentation and foveal abnormalities; however, the studies were done before the molecular analysis of the different types of OCA was available, implying that the populations may have included individuals with OCA who were diagnosed incorrectly with infantile nystagmus. The visually evoked potential (VEP) analysis to evaluate misrouting of the nerve fibers from the optic nerves is normal in congenital motor nystagmus. A single gene, FRMD7, for congenital infantile nystagmus has been reported.FRMD7-related infantile nystagmus (FIN) is an X-linked disorder characterized by either the onset of horizontal, conjugate, gaze-dependent nystagmus in the first six months of life or periodic alternating nystagmus (with cyclical changes of nystagmus direction) of infantile onset. Binocular vision and color vision are normal and visual acuity is typically better than 6/12. An abnormal head posture is seen in approximately 15% of affected individuals. The eyes are structurally normal and electrophysiologic studies, such as visual evoked potential (VEP) and electroretinogram (ERG), are normal. Affected females report slightly better visual acuity than affected males; however, no differences between males and females in the amplitude, frequency, and waveform of nystagmus are observed. The diagnosis is based on clinical findings and the presence of a hemizygous FRMD7 mutation in males and a heterozygous FRMD7 mutation in females.Other considerations. Additional confusion may occur among infants with blue cone monochromacy (males, X-linked) or rod monochromacy (both genders, autosomal recessive) in which nystagmus begins early in life, the foveas are underdeveloped, and myopia is common, leading to an exaggerated impression of underpigmented retinas. The severe loss of color perception clinically and the electroretinographic responses of abnormal cone and rod signals should separate these two entities from the albinisms. Hypopigmentation of hair, skin, and fundus and iris transillumination are not features. Many other ocular disorders present with infantile nystagmus; that differential diagnosis is beyond the scope of this review.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).
Management GeneReviews | To establish the extent of disease and needs of an individual diagnosed oculocutaneous albinism type 1 (OCA1), the following evaluations are recommended: ... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTYR11q14 | TyrosinaseAlbinism Database Mutations of the tyrosinase gene