Melanin - Genetic Disorders and Disease States

Genetic Disorders and Disease States

Melanin deficiency has been connected for some time with various genetic abnormalities and disease states.

There are approximately nine different types of oculocutaneous albinism, which is mostly an autosomal recessive disorder. Certain ethnicities have higher incidences of different forms. For example, the most common type, called oculocutaneous albinism type 2 (OCA2), is especially frequent among people of black African descent. It is an autosomal recessive disorder characterized by a congenital reduction or absence of melanin pigment in the skin, hair, and eyes. The estimated frequency of OCA2 among African-Americans is 1 in 10,000, which contrasts with a frequency of 1 in 36,000 in white Americans. In some African nations, the frequency of the disorder is even higher, ranging from 1 in 2,000 to 1 in 5,000. Another form of Albinism, the "yellow oculocutaneous albinism", appears to be more prevalent among the Amish, who are of primarily Swiss and German ancestry. People with this IB variant of the disorder commonly have white hair and skin at birth, but rapidly develop normal skin pigmentation in infancy.

Ocular albinism affects not only eye pigmentation, but visual acuity, as well. People with albinism typically test poorly, within the 20/60 to 20/400 range. In addition, two forms of albinism, with approximately 1 in 2700 most prevalent among people of Puerto Rican origin, are associated with mortality beyond melanoma-related deaths.

Mortality also is increased in patients with Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. Patients with Hermansky-Pudlak syndrome have a bleeding diathesis secondary to platelet dysfunction and also experience restrictive lung disease (pulmonary fibrosis), inflammatory bowel disease, cardiomyopathy, and renal disease. Patients with Chediak-Higashi syndrome are susceptible to infection and also can develop lymphofollicular malignancy. —

The role that melanin deficiency plays in such disorders remains under study.

The connection between albinism and deafness is well known, though poorly understood. E.g., in his 1859 treatise On the Origin of Species, Charles Darwin observed that "cats which are entirely white and have blue eyes are generally deaf". In humans, hypopigmentation and deafness occur together in the rare Waardenburg's syndrome, predominantly observed among the Hopi in North America. The incidence of albinism in Hopi Indians has been estimated as approximately 1 in 200 individuals. It is interesting to note that similar patterns of albinism and deafness have been found in other mammals, including dogs and rodents. However, a lack of melanin per se does not appear to be directly responsible for deafness associated with hypopigmentation, as most individuals lacking the enzymes required to synthesize melanin have normal auditory function. Instead the absence of melanocytes in the stria vascularis of the inner ear results in cochlear impairment, though why this is, is not fully understood. It may be that melanin, the best sound-absorbing material known, plays some protective function. in alternate fashion, melanin may affect development, as Darwin suggests.

In Parkinson's disease, a disorder that affects neuromotor functioning, there is decreased neuromelanin in the substantia nigra and locus coeruleus as consequence of specific dropping out of dopaminergic and noradrenergic pigmented neurons. This results in diminished dopamine and norepinephrine synthesis. While no correlation between race and the level of neuromelanin in the substantia nigra has been reported, the significantly lower incidence of Parkinson's in blacks than in whites has "prompt some to suggest that cutaneous melanin might somehow serve to protect the neuromelanin in substantia nigra from external toxins.". Also see Nicolaus review article on the function of neuromelanins

In addition to melanin deficiency, the molecular weight of the melanin polymer may be decreased by various factors such as oxidative stress, exposure to light, perturbation in its association with melanosomal matrix proteins, changes in pH or in local concentrations of metal ions. A decreased molecular weight or a decrease in the degree of polymerization of ocular melanin has been proposed to turn the normally anti-oxidant polymer into a pro-oxidant. In its pro-oxidant state, melanin has been suggested to be involved in the causation and progression of macular degeneration and melanoma. Rasagiline, an important monotherapy drug in Parkinson's disease, has melanin binding properties, and melanoma tumor reducing properties.

Higher eumelanin levels also can be a disadvantage, however, beyond a higher disposition toward vitamin D deficiency. Dark skin is a complicating factor in the laser removal of port-wine stains. Effective in treating white skin, in general, lasers are less successful in removing port-wine stains in people of Asian or African descent. Higher concentrations of melanin in darker-skinned individuals simply diffuse and absorb the laser radiation, inhibiting light absorption by the targeted tissue. In similar manner, melanin can complicate laser treatment of other dermatological conditions in people with darker skin.

Freckles and moles are formed where there is a localized concentration of melanin in the skin. They are highly associated with pale skin.

Nicotine has an affinity for melanin-containing tissues because of its precursor function in melanin synthesis or its irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals.