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Oculocutaneous Albinism

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Copyright 1985, 1989, 1992, 1994, 1999, 2007, 2008, 2012

NORD is very grateful to William S. Oetting, PhD, School of Pharmacy, Experimental and Clinical Pharmacology and Institute of Human Genetics, University of Minnesota, for assistance in the preparation of this report.

Synonyms of Oculocutaneous Albinism

Disorder Subdivisions

General Discussion

Oculocutaneous albinism (OCA) is a group of rare inherited disorders characterized by a reduced amount or complete lack of melanin pigment in the skin, hair, and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment in specialized cells called melanocytes. Absent or insufficient melanin pigment results abnormal development in the eyes resulting in vision abnormalities and light skin that is very susceptible to damage from the sun including skin cancer. Oculocutaneous albinism is inherited as an autosomal recessive genetic condition.

Symptoms

There are four types of OCA. Oculocutaneous albinism type 1 (OCA1) is associated with reduced production of melanin in the skin, hair and eyes. Several vision problems can occur with this condition including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment (iris transillumination), reduced retinal pigment, lack of development of the macula (macular hypoplasia) resulting in abnormal foveal development (the area of the eye responsible for visual acuity), poor visual acuity, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together (strabismus) and reduces depth perception. Individuals affected with OCA1A have a complete absence of melanin pigment resulting in white hair and white skin at birth and irises that do not become darker over time. Visual acuity in individuals can range from 20/200 to 20/400. Individuals with OCA1B have white or light yellow hair at birth that darkens over time, white skin that darkens over time and irises that may change to green or brown over time. Vision is usually better in those with OCA1B than in those with OCA1A. OCA1 is associated with mutations in the TYR gene that encodes the enzyme tyrosinase.

Oculocutaneous albinism type 2 (OCA2) is associated with the same vision problems that occur in OCA1. Individuals with OCA2 have a wide range of skin pigmentation that is partially dependent on their genetic background and the mutations present. Hair color is usually not completely white and there can be some pigment present in the skin but skin color is usually lighter than in unaffected relatives. Individuals with extensive sun exposure can develop pigmented nevi and lentigines. This does not occur with other types of OCA. A reduction in skin pigment is apparent in Africans and African-Americans but skin coloration appears close to normal in other populations with normally lighter pigmentation but affected individuals do not tan. Brown OCA is a type of OCA2 where hair and skin coloration is darker. This type of OCA2 has only been reported in individuals with African ancestry. OCA2 is associated with mutations in the OCA2 gene, formerly called the P gene.

Oculocutaneous albinism type 3 (OCA3) was initially described in the African population. Affected individuals have red to reddish-brown skin, ginger or reddish hair, and hazel or brown eyes and the condition was initially termed rufous albinism. OCA3 has now been identified in several additional populations especially of Asian descent including Chinese and Japanese, as well as in Asian Indian and Northern European individuals. Affected individuals of Asian heritage can have blond hair with light brown eyebrows with skin lighter than their parents. Both hair and skin pigmentation increases with age. Vision problems are not as severe as OCA1 or OCA2. Nystagmus and photophobia may not be present. OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene.

Oculocutaneous albinism type 4 (OCA4) is characterized by physical features that are similar to those of OCA2. Hair color of affected individuals can range from yellow to brown. Visual acuity can range from 20/30 to 20/400 depending on the amount of pigment that is present, but acuity is usually in the range of 20/100 to 20/200. Vision is usually stable after childhood. OCA4 was initially identified in an individual of Turkish origin and has been found in Asian populations including Japanese and Korean and German individuals, OCA4 is associated with mutations in the SLC45A2 gene (formerly called MATP), a membrane-associated transport protein.

Causes

Melanin pigment is the major pigment responsible for coloration of skin, hair and eyes. This pigment is produced in specialized cells called melanocytes. Mutations in genes that are responsible for proteins that are necessary for the melanocyte to make melanin pigment result in a reduction or absence of melanin pigment in the skin hair and eyes of the affected individual and is termed oculocutaneous albinism (OCA). OCA is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Four genes have been identified that are associated with different types of OCA. Each of these genes is important in the production of melanin that takes place in cells called melanocytes that are located in the skin, hair follicle and iris and retina of the eye. In the case of skin and hair pigmentation, the melanocyte transfers the melanin pigment to the keritinocyte and make up skin and hair.

OCA1 is associated with abnormalities (mutations) in the tyrosinase (TYR) gene. The TYR gene is responsible for the production of the enzyme tyrosinase which is responsible for the first step in the formation of melanin pigment. Some TYR mutations result in the production of a nonfunctioning tyrosinase enzyme and no melanin pigment is formed. This type of OCA1 is called OCA type 1A (OCA1A). Other TYR mutations result in the production of a tyrosinase enzyme with reduced function so that a reduced amount of melanin pigment is formed. This type of OCA1 is called OCA type 1B (OCA1B). In the case of OCA1B, melanin pigment will accumulate with time.

OCA2 is associated with mutations in the OCA2 gene (also called the P gene). The OCA2 gene is responsible for production of the OCA2 protein. The precise function of the OCA2 protein is unknown, but it is thought to be important in regulating the movement of the substrate tyrosine into the melanosome as well as regulating the internal environment of the melanosome.

OCA3 is associated with mutations in the tyrosinase related protein 1 (TYRP1) gene. This gene is responsible for the production of tyrosinase-related protein-1, an enzyme, like tyrosinase, that is involved in the production of melanin. The TYRP1 enzyme is part of a gene family that includes tyrosinase and the tyrosinase related protein-2 (TYRP2), all of which are enzymes involved in melanin biosynthesis. The TYRP1 enzyme is responsible for later steps (after the initial tyrosinase step) in melanin pigment production.

OCA4 is associated with mutations in the SLC45A2 gene (also called the MATP). The SLC45A2 gene is responsible for the production of this membrane associated transporter protein. The precise function of this protein is unknown but it is required for the normal production of melanin by the melanocyte.

It is important to note that all individuals carry 4-5 abnormal genes among the 30,000 or so genes that we have. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

The frequency of OCA1 is approximately 1/40,000 in the world population. Most of the individuals identified with OCA1 have OCA type 1A. The frequency of OCA type 1B is unknown.

The prevalence of OCA2 in some African populations can be as high as 1/1,500-1/8,000. The prevalence in the African American population has been estimated to be as high as 1/10,000. The prevalence of OCA2 in most other populations is approximately 1/38,000-1/40,000.

The prevalence of OCA3 is not known. Individuals with OCA3 have so far been identified in several populations including Asian, Turkish and Northern European.

The prevalence of OCA4 is approximately 1/100,000 in most world populations. OCA4 is most common in Japan but has also been found in Northern European, Indian and Moroccan populations.

It is important to note that common changes in the DNA sequence within these four genes are also associated with normal variation in skin, hair and eye color. For example, variation in the OCA2 gene has been associated with either brown or blue eyes and variation in the TYRP1 gene has been associated with either brown or blond hair.

Related Disorders

Symptoms of the following disorders can be similar to those of oculocutaneous albinism. Comparisons may be useful for a differential diagnosis:

Hermansky-Pudlak syndrome is a rare, hereditary disorder that consists of three characteristics: reduced skin, hair and eye pigmentation (oculocutaneous albinism, with associated vision problems), blood platelet dysfunction leading to prolonged bleeding, and abnormal storage of a fatty-like substance (ceroid lipofuscin) in various tissues of the body. Several different genes have been associated with Hermansky-Pudlak syndrome.
(For more information on this disorder, choose "Hermansky" as your search term in the Rare Disease Database.)

Ocular albinism is an X-linked recessive disorder that affects the pigment cells of the eyes. Affected individuals (mostly males) have vision problems and hair and skin color may be fairer than that of other family members. (For more information on this disorder, choose "albinism, ocular" as your search term in the Rare Disease Database.)

Congenital motor nystagmus is a genetic condition characterized by an involuntary movement of eyes back and forth (nystagmus). Affected individuals will often turn or bob their head to try to improve vision clarity.

Standard Therapies

Diagnosis
Though physical appearance can help in diagnosing the correct type of albinism, DNA sequencing of the four responsible genes is required to accurately determine which type of OCA is present.

In the case of affected individuals with African ancestry, testing for the gene deletion associated within the OCA2 gene is necessary.

Treatment
Individuals diagnosed with OCA should be evaluated by an ophthalmologist at the time of diagnosis to determine the extent of the disease and have ongoing ophthalmologic examinations annually. Glasses or contact lenses can improve vision. Additionally, visual acuity can improve with age, so regular visits to the ophthalmologist are necessary. Dark glasses or a hat with a wide brim can help to reduce sun sensitivity. Affected individuals should also be evaluated to determine the amount of pigment in the skin. Skin should be protected from sun exposure with the use of clothing and sun block to reduce the risk of sunburn, skin damage and skin cancer. Specific recommendations for skin care depend on the pigment status.

Investigational Therapies

Research using animal model systems is now being done to test the effect of different interventions to reduce the effects of albinism on the visual system. Studies in mice have shown that Nitisinone can improve abnormalities of the eye and coat color associated with albinism. Human trials are ongoing to determine the effect of Levodopa (L-DOPA) on its ability to improve vision in individuals with albinism.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Oculocutaneous Albinism Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
King RA, Oetting WS, Summers CG, Creel DJ, Hearing VJ. Abnormalities of Pigmentation. In Principles and Practice of Medical Genetics, 5th ed. Rimoin DL, Connor JM, Pyeritz RE Korf BR, eds. Edinburgh, Scotland: Churchill Livingstone; 2007:3380-3427.

King RA, Oetting WS. 2006. Oculocutaneous Albinism. In The Pigmentary System: Physiology and Pathophysiology, 2nd ed. Nordlund JJ, Boissy RE, Hearing VJ, King RA, Oetting WS, Ortonne J-P, eds. New York, NY: Oxford University Press; 2006:599-613.

King RA Hearing VJ, Creel DJ, et al. Albinism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. New York, NY: McGraw-Hill; 2001;5587-627.

JOURNAL ARTICLES
Dijkstal JM, Cooley SS, Holleschau AM, King RA, Summers CG. Change in visual acuity in albinism in the early school years. J Pediatr Ophthalmol Strabismus. 2012;49:81-6.

Macdonald JT, Kutzbach BR, Holleschau AM, Wyckoff S, Summers CG. Reading skills in children and adults with albinism: the role of visual impairment. J Pediatr Ophthalmol Strabismus. 2012;49:184-8.

Levin AV, Stroh E. Albinism for the busy clinician. J AAPOS. 2011;15(1):59-66.

Onojafe IF, Adams DR, Simeonov DR, et al. Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism. J Clin Invest. 2011;121:3914-23.

White D, Rabago-Smith M. Genotype-phenotype associations and human eye color. J Hum Genet. 2011;56:5-7.

Kosmadaki MG, Stratigos AJ, Antoniou Ch, Katsambas A. DNA polymorphisms: what they are and their role in human pigmentation. Actas Dermosifiliogr. 2009;100(suppl 2):84-7.

King Ra, Pietsch J, Fryer, et al. Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype. Hum Genet. 2003;113:502-13.

Toyofuku K, Valencia JC, Kushimoto T, et al. The etiology of oculocutaneous albinism (OCA) type II: the pink protein modulates the processing and transport of tyrosine. Pigment Cell Res. 2002;15:217-24.

Oetting WS, Gardner JM, Fryer JP, et al. Mutations of the human P gene associated with type II oculocutaneous albinism (OCA2). Hum Genet. 1998;12:4334.

Oetting WS and King. Molecular basis of type I (tyrosinase-related) oculocutaneous albinism: mutations and polymorphisms of the human tyrosinase gene. Hum Mut. 1993:2:1-7.

INTERNET
Suzuki T, Hayashi M. (Updated September 15, 2011). Oculocutaneous Albinism Type 4. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed May 23, 2012.

King RA, Oetting WS. (Updated June 20, 2007). Oculocutaneous Albinism Type 2. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed May 23, 2012.

King RA. (Updated October 1, 2004). Oculocutaneous Albinism Type 1. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed May 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Albinism, Oculocutaneous, Type II; OCA2. Entry No: 203200. Last Edited April 12, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Albinism, Oculocutaneous, Type III; OCA3. Entry No: 203290. Last Edited March 26, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Albinism, Oculocutaneous, Type IA; OCA1A. Entry No: 203100. Last Edited June 7, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Albinism, Oculocutaneous, Type IV; OCA4. Entry No: 606574. Last Edited May 19, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Albinism, Oculocutaneous, Type IB; OCA1B. Entry No: 606952. Last Edited September 2, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 23, 2012.

Report last updated: 2012/05/25 00:00:00 GMT+0