Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism
Prashiela Manga, Seth J. Orlow
Prashiela Manga, Seth J. Orlow
Published September 26, 2011
Citation Information: J Clin Invest. 2011;121(10):3828-3831. https://doi.org/10.1172/JCI59763.
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Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism

Abstract

Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by hypopigmentation of the skin, hair, and eyes. Affected individuals experience reduced visual acuity and substantially increased skin cancer risk. There are four major types of OCA (OCA1–OCA4) that result from disruption in production of melanin from tyrosine. Current treatment options for individuals with OCA are limited to attempts to correct visual problems and counseling to promote use of sun protective measures. However, Onojafe et al., reporting in this issue of the JCI, provide hope for a new treatment approach for OCA, as they demonstrate that treating mice that model OCA-1b with nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, elevates plasma tyrosine levels, and increases eye and hair pigmentation.

Authors

Prashiela Manga, Seth J. Orlow

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Figure 2

Tyrosine catabolism.

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Tyrosine catabolism. Five enzymes catalyze the cascade that leads to the...
Five enzymes catalyze the cascade that leads to the degradation of tyrosine, and dysfunction of these enzymes leads to diseases of variable severity (reviewed in ref. 21). Tyrosine is converted to 4-hydroxyphenylpyruvate (HPP) by tyrosine aminotransferase (TAT). Mutations of this enzyme lead to HT-2. HPP is converted to homogentisic acid (HA) by hydroxyphenylpyruvate oxidase (HPD), the target of nitisinone. HPD mutations result in HT-3. HA is converted to 4-maleylacetoacetate (by homogentisate 1,2-dioxygenase [HGD], mutations of which cause alkaptonuria) then fumarylacetoacetate (by malelylacetoacetate isomerase [MAI]). These metabolites are toxic and accumulate, leading to the symptoms common in HT-1 (due to mutations of FAH), which converts fumaryl acetate to fumarate and acetoacetate.