Clinical, Cellular, and Molecular Investigation Into Oculocutaneous Albinism

Oculocutaneous albinism (OCA) is a term used to describe inherited forms of hypopigmentation
associated with 1) variable levels of cutaneous hypopigmentation, ocular hypopigmentation,
and visual deficits, and 2) involvement of both of the major developmental types of pigmented
cells, i.e., melanocytes and retinal pigment epithelium. OCA that affects

only usually-pigmented tissues is termed isolated OCA. There are currently seven albinism

types (OCA-1 to OCA-7). With the exception of OCA-5, eash is associated with a specific

gene and is inherited in an autosomal recessive manner (see Table 1). OCA-5 is a proposed

type of albinism associated with the chromosomal location 4q24. OCA-1 results from defects

in the enzyme tyrosinase, which catalyzes the rate-limiting step in melanin synthesis. The

precise functions of the remaining genes are not yet fully understood, but several may be

associated with the regulation of pH in the subcellular organelle where melanin in

manufactured the melanosome. The majority of persons with OCA have two pathogenic

mutations identified in a known OCA-causing gene, but a substantial minority to not. Ocular

albinism (OA) is an X-linked disorder caused by mutations in the GPR143 gene. It affects the

eye in a manner similar to OCA, but has minimal or no skin manifestations.

In this protocol, we have four major goals:

1. To clinically and comprehensively characterize OCA types 1 7, and OA, with respect

to the degree of hypopigmentation, genetic mutations, extent of ocular involvement,

and longitudinal variation.

2. To use study participants cultured melanocytes to study pigment biology, variability

in pigment formation related to genotype, and response to proposed treatments. Some

of this work will be performed collaboratively

3. To recruit study participants with hypopigmentation not due to known albinismcausing

genes.

4. To evaluate methods of quantifying eye pigmentation, skin pigmentation and other

clinical parameters that may be usable as outcome measures in future treatment studies.

To achieve those goals, we will perform clinical evaluations of persons with OCA and OA at

the NIH Clinical Center; obtain cultured cells, plasma, serum and urine for future studies;
and,

perform mutation analysis on known OCA and/or OA genes and search for other genes

responsible for albinism. Routine admissions will last 3 - 4 days and occur every 2 - 3
years.

- INCLUSION CRITERIA:

Patients will be screened by requesting copies of the following materials at the time they
contact the program:

1. An indication of ethnic background by the potential participant, which may be unknown
.

2. Photographs of the potential participant that give an indication of skin
complexion/pigmentation and undyed hair color (if available).

3. Ophthalmology or other visual specialist records documenting visual exam
characteristics, potentially including iris transillumination, visual evoked potential
and or characteristic eye findings (if available).

4. Genetic testing results (if available).

EXCLUSION CRITERIA:

Exclusion from the study will be made based on one or more of the following criteria:

1. Significant evidence that the potential participant has either OCA1A or OCA2 with a
typical presentation, AND has an ethnic background that is wellrepresented in the
current study (proportion in study exceeding the proportion in the United States
population).

The rationale for this exclusion is that: 1) from a biologicaland clinicalresearch
perspective, we have an adequate number of OCA1A/

OCA2 cases in the current study population; and 2) that, despite this, persons with
ethnicities that are underrepresented in the study may inform our understanding of
populationlevel molecular patterns in OCA1A/ OCA2 and cultural implications of
albinism.

2. Persons who are under 1 year of age. This exclusion occurs because there is no urgency
for a very early evaluation. Also, the Clinical Center staff and resources are more
suited for the care of older children.

3. Persons who are too sick to travel safely to the NIH Clinical Center.

4. A judgment by the principal investigator that clinical resources are not available to
enroll additional patients at any given time.

5. Persons who are currently incarcerated.

6. Adults who are incompetent to consent to the protocol.

7. Persons who have been diagnosed with a known nonoculocutaneous disorder of
hypopigmentation such as HemanskyPudlak Syndrome, ChediakHigashi Syndrome, or
Griscelli Syndrome.

8. Persons who have been diagnosed with a known disorder of focal hypopigmentation such
as Waardenburg syndrome.