Advances in Understanding the Hermansky-Pudlak Syndrome

National Institute of ChildHealth, and Human DevelopmentEMBARGOED FOR RELEASE, Wednesday, April 29, 1998, 5:00 PM Eastern Time, Robert Bock

Forty-nine patients with Hermansky-Pudlak syndrome (HPS), a genetic disorder, have been studied at the NIH to provide improved diagnostic and clinical approaches. The research is published in the April 30 New England Journal of Medicine. The syndrome is characterized by a rare form of albinism, which is associated with low visual acuity, bruising and prolonged bleeding, lung fibrosis and occasionally, inflammatory bowel disease and reduced kidney function. HPS is seen in many countries, but is quite common in northwest Puerto Rico, where one in every 1800 individuals is affected, one in 21 is a gene carrier and over 400 individuals have the syndrome. Several cases have also been reported in the Puerto Rican community in New York City.

Twenty-seven Puerto Rican patients and 22 non-Puerto Ricans were diagnosed by two symptoms characteristically seen in this syndrome: albinism and defective blood platelets. Twenty-five of the 27 Puerto Rican patients had a specific mutation (a small region of DNA duplication) in the recently cloned gene, HPS, associated with the syndrome.. Non-Puerto Ricans did not have this particular mutation. Several different mutations are thought to lead to HPS. Patients with and without the duplication were then compared using clinical and laboratory characteristics.

The cause of this inherited disease, which was first described in 1959 and is named after its discoverers as the Hermansky-Pudlak syndrome (HPS), is being investigated by physicians, geneticists, and biochemists at the National Institute of Child Health and Human Development (NICHD), the National Heart, Lung and Blood Institute (NHLBI), and the National Eye Institute (NEI).

All HPS patients suffer from varying degrees of albinism (lack of skin and eye pigment); this lack of pigment impairs the vision of patients with albinism and often leads to involuntary rhythmic eye movements called nystagmus. However, the most serious health problems are the progressive deterioration in lung function, which is particularly prevalent in the Puerto Rican patients carrying the DNA duplication, and the tendency to bruise easily and bleed. At times women with HPS need medical intervention during their menstrual cycles or at childbirth. HPS patients are advised to avoid blood anticoagulants, such as aspirin, and drugs can be used to prevent excessive bleeding during dental extractions and other surgical procedures. The reason HPS patients bleed easily is that their blood platelets are deficient in so-called dense bodies. These subcellular organelles release their contents to make other platelets stick together and form a clot. Without the dense bodies, the clot forms very slowly.

The lung dysfunction begins with restrictive disease and then progresses inexorably to death, usually in the fourth or fifth decade.

HPS patients have a biochemical storage disorder, that is, they accumulate a fatty product called ceroid lipofuscin. The researchers think that this causes inflammation in tissues such as bowel and lung. Prolonged inflammation leads to fibrosis, which in the case of the lung impairs its ability both to expel air and to exchange carbon dioxide for oxygen.

From the gene sequence, researchers know what the protein encoded by the HPS gene should look like, but it is not yet known what such a protein actually does. According to Dr. William Gahl, the lead author of the paper, many patients with albinism are not aware that they have HPS. They are thus at risk for hemorrhage. Anyone suffering from albinism who bruises easily should be checked for HPS, which is diagnosed by observing blood platelets under the electron microscope or by performing platelet aggregation studies.

Gahl's group in the NICHD has started a trial of an investigational drug, which, in animal tests, has been shown to prevent inflammation. With this drug, the researchers hope they can prevent the inflammation that leads to the loss of lung function that shortens the lives of these patients.