Albinism

Updated: Mar 22, 2016
  • Author: Mounir Bashour, MD, PhD, CM, FRCSC, FACS; Chief Editor: Hampton Roy, Sr, MD  more...
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Overview

Background

Albinism consists of a group of inherited abnormalities of melanin synthesis and are typically characterized by a congenital reduction or absence of melanin pigment. Albinism results from defective production of melanin from tyrosine through a complex pathway of metabolic reactions.

Several types of albinism are recognized. The phenotypic heterogeneity of albinism is due to the different gene mutations affecting various points along the melanin pathway, resulting in varying degrees of decreased melanin production. Additionally, associated developmental changes occur in the optic system as a result from this hypopigmentation.

The ophthalmologist plays an important role in detecting albinism because most forms of albinism present with ocular features as the primary morbidity. The changes to the optic system associated with hypopigmentation include decreased visual acuity secondary to foveal hypoplasia and misrouting of the optic nerves at the chiasm. Other features include photophobia, iris transillumination, nystagmus, and pigment deficiency in the peripheral retina. These ocular changes are common to all types of albinism.

Classification of albinism

Traditionally, albinism has been classified according to clinical phenotype, and the 2 main categories are oculocutaneous albinism (OCA) and ocular albinism (OA).

The albinism subtypes were reclassified in 2009. With the availability of new molecular genetic studies, the classification of albinism has shifted emphasis to genotype as opposed to phenotype alone. [1] Hence, this has led to redefining existing phenotypic categories and the addition of new subtypes based on specific genetic mutations. The following is a brief overview of the current classification of albinism.

OCA is characterized by the reduction or absence of melanin in the skin, hair, and optic system (including the eyes and optic nerves). The lack of skin pigment results in a pale skin appearance and an increased risk of skin cancer. As shown in Table 1, OCA is divided further into several subtypes based on the distinct genetic mutation.

Table 1. Oculocutaneous Albinism Types (Open Table in a new window)

OCA Subtypes Gene Position Affected Protein
OCA 1
  • OCA 1A (tyrosinase-negative OCA)
  • OCA 1B (yellow-mutant/Amish/
  • xanthous, temperature-sensitive)
  • OCA 1A/1B heterozygote
11q14-21 Tyrosinase
OCA 2



(tyrosinase-positive OCA, brown OCA)



15q11-13 P protein
OCA 3 9p23 Tyrosinase-related protein

 

OA is characterized by changes in the optic system only with no clinical difference in skin and hair color. As shown in Table 2, two major disorders exist in this category, ocular albinism 1 (OA 1) and autosomal recessive ocular albinism (AROA).

Table 2. Ocular Albinism Types (Open Table in a new window)

OA Subtypes Gene Position Affected Protein
OA 1 (X-linked recessive OA/Nettleshop-Falls type) X p22.3-22.2 The protein product of the OA 1 gene named OA 1 (and also identified as GPR143 in GenBank) [2, 3]
AROA Not a distinct position Tyrosinase in some cases;



P protein in some cases



 

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Pathophysiology

Melanin is a photoprotective pigment in the skin that absorbs UV light from the sun, thereby preventing skin damage. With sun exposure, the skin normally tans as a result of increased melanin pigment in the skin. However, many albinos are sensitive to sunlight and develop a sunburn because of the lack of melanin.

In addition to the skin, melanin is important to other areas of the body, such as the eyes and brain, although the function in these areas is not currently known.

Melanin in the eye

The eye has 2 origins from which pigmented cells are derived, as follows:

  • The neuroectoderm of the primitive forebrain is the origin of melanocytes in the retinal pigment epithelium, iris epithelium (anterior and posterior), and ciliary epithelium (outer pigmented and inner nonpigmented).
  • The neural crest is the origin of melanocytes in the iris stroma, ciliary stroma, and choroid. Melanoblasts from the neural crest migrate to the skin, inner ear, and uveal tract.

The presence of melanin during ocular development is important. The fovea fails to develop properly if melanin is absent during development. Other areas of the retina develop normally regardless of the presence of melanin. Additionally, neural connections between the retina and the brain are altered if melanin in the retina is absent during development. The amount of pigment necessary for appropriate ocular development is currently unknown. More research needs to be completed.

Melanin pathway

Melanin is formed in the melanosome organelle of the melanocyte. Melanocytes are found in the skin, hair follicles, and pigmented tissues of the eye. The melanin pathway consists of a series of reactions that converts tyrosine into 2 types of melanin, as follows: black-brown eumelanin and red-blond pheomelanin. Genetic mutations affecting proteins/enzymes along this pathway inevitably result in reduced melanin production.

Tyrosinase is the major enzyme (coded on chromosome 11) involved in the series of conversions to form melanin from tyrosine. It is responsible for converting tyrosine to DOPA and then to dopaquinone. Through a sequence of steps, dopaquinone subsequently is converted to either eumelanin or pheomelanin. Mutation to the tyrosinase enzyme produces either OCA 1 or AROA.

Additionally, 2 other enzymes involved in the formation of eumelanin are tyrosinase-related protein 1 (TRP1; DHICA oxidase) and tyrosinase-related protein 2 (TRP2; dopachrome tautomerase). Both of these enzymes are coded on chromosome 9. Mutation to the TRP1 gene causes OCA 3. Mutation to the TRP2 gene does not produce albinism.

Finally, P protein is a melanosomal membrane protein that is believed to be involved in the transport of tyrosine prior to melanin synthesis. Mutation to this P gene produces OCA 2.

Pathogenesis of ocular features

The development of the optic system is highly dependent on the presence of melanin. If melanin is absent or reduced, the ocular features appear. The mechanisms for these changes include the following:

  • Abnormal decussation of optic nerve fibers is due to misrouting of the retinogeniculate projections. It is postulated that melanin determines neuronal target specificity in the brain. Therefore, when pigmentation is incomplete, the developing optic tracts almost completely cross at the chiasm. In nonalbino persons, 45% of axons originating in the temporal half of the retina remain uncrossed as they pass through the chiasm and project to the ipsilateral lateral geniculate nucleus. Most of these fibers serve the central 20° of the temporal retina. However, in albino persons, most of the fibers decussate at the chiasm and synapse in the contralateral lateral geniculate nucleus. This leads to a predominance of monocular vision and decreased binocular depth perception.
  • Light scattering within the eye causes the sensation of photophobia and decreased visual acuity. The translucent irides cause increased light to enter the eye, resulting in light scattering. Patients typically have a supernormal electroretinography (ERG) recording.
  • Light-induced retinal damage has been postulated as a contributing mechanism to decreased visual acuity. With increased light scattering, it has been proposed that light-generated free radicals are responsible for nonthermal light damage to the retina. Additionally, it is believed that melanin may play a protective role in reducing these free radicals.
  • Foveal hypoplasia is the most significant factor causing decreased visual acuity. The macula lutea pigment is believed to be absent. Currently, the etiology of foveal hypoplasia is not completely known; however, it may be due to the decreased melanin in the retinal pigment epithelium (RPE).
  • Congenital nystagmus usually occurs in the first 3 months of life and may lead to the misdiagnosis of congenital motor nystagmus.
  • Light-induced subclinical damage to the corneal epithelium and its binding to the Bowman membrane have been postulated as a contributing mechanism to the decreased adhesion of the corneal epithelium in LASIK surgery, leading to a very high risk of epithelial abrasion during LASIK in patients with albinism. Possibly, the increased light scattering produces light-generated free radicals that are responsible for nonthermal light damage to the epithelial linking proteins. Additionally, it is believed that melanin may play a protective role in reducing these free radicals.
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Epidemiology

Frequency

United States

An estimated 1 in 17,000 people have one of the types of albinism. Approximately 18,000 people in the United States have albinism.

OCA 1 occurs in approximately 1 in 40,000 individuals in most populations.

OCA 2 is the most common type of albinism and is especially frequent among African Americans and Africans. The estimated frequency in African Americans is 1 case per 10,000 population, while in whites, the frequency is 1 case per 36,000 population. The overall frequency is 1 case per 15,000 population across all races.

Hermansky-Pudlak syndrome (HPS) s the most common type of albinism in Puerto Rico, with a frequency of 1 case per 2,700 population. This disorder is very rare in other parts of the world.

Mortality/Morbidity

Albinism is not associated with mortality. Lifespan is within normal limits. Because the reduction of melanin in the hair, skin, and eyes should have no systemic effects, the general health of a child and an adult with albinism is normal. The growth and intellectual development of a child with albinism should be normal, with developmental milestones expected for age.

The morbidity associated with albinism pertains to visual impairment, skin photosensitivity, and increased cutaneous cancer risk. Patients who have syndromes associated with albinism (eg, HPS) may have hearing difficulties or abnormalities of blood clotting. Albinism also has social ramifications because patients may feel alienated as a result of the difference in appearance from their families, peers, and other members of their ethnic group.

Race

Albinism affects all persons of races.

Parents of most children with albinism have normal eye color for their ethnic background.

A high incidence of HPS exists among Puerto Ricans.

Sex

Both males and females can be affected. However, in OA 1 (X-linked recessive OA), males are affected, while females are only carriers.

Age

All types of albinism are usually congenital.

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