William A. Gahl, M.D., Ph.D.
National Human Genome Research Institute
Office of the Clinical Director
Medical Genetics Branch
Human Biochemical Genetics Section
B.S. Massachusetts Institute of Technology, 1972
M.D. University of Wisconsin, Madison, 1976
Ph.D. University of Wisconsin, Madison, 1981
10 Center Dr, MSC 1851
Bethesda, MD 20892-1851
Dr. Gahl studies rare inborn errors of metabolism through the observation and treatment of patients in the clinic and through biochemical, molecular biological, and cell biological investigations in the laboratory. His group focuses on a number of diseases, including cystinosis, Hermansky-Pudlak syndrome, alkaptonuria, and disorders of sialic acid metabolism.
Dr. Gahl has a long-standing research interest in cystinosis, a lysosomal storage disorder caused by a mutation in the CTNS gene that occurs in one in every 100,000 to 200,000 live births. The CTNS gene encodes the protein cystinosin, and mutations in CTNS lead to impaired transport of cystine out of lysosomes and the formation of cystine crystals in most cells in the body. Untreated, the disease causes kidney failure in childhood, along with a host of other severe complications. Over the past two decades, Dr. Gahl's laboratory has elucidated the pathogenesis of this disease and demonstrated the safety and efficacy of cysteamine (β-mercaptoethylamine) therapy, a treatment that depletes cells of cystine. In fact, cysteamine therapy, along with kidney transplantation, has improved the future for many cystinosis patients from a life filled with debilitating complications to one marked by chronic yet manageable symptoms. Dr. Gahl's group is following about 125 pre- and post-transplant cystinosis patients to track their clinical course, identify additional mutations, and document complications of the disease and therapy.
Another of Dr. Gahl's major research areas is Hermansky-Pudlak syndrome (HPS), a group of vesicle formation and transport disorders characterized by albinism and bleeding. In some cases, HPS is also characterized by pulmonary fibrosis or colitis. HPS was first described in 1959 and was thought to be a single-gene disorder affecting vesicles involved in intracellular transport. Since then, eight human genes — including two discovered by Dr. Gahl's group — have been identified as causes of HPS. Because some HPS patients have no identifiable genetic mutation, it is believed that proper vesicle formation and movement may require other genes. No treatment has been developed for the underlying disorder, but Dr. Gahl's group has demonstrated that an anti-fibrotic agent shows promise in slowing the development of the fatal lung disease of some HPS patients.
His laboratory also studies alkaptonuria, a condition in which mutations in the HGD gene cause a buildup of homogentisic acid (HGA), which discolors the eyes and damages the connective tissues in major joints and cardiac valves. Dr. Gahl's group conducted a three-year clinical trial of nitisinone, an inhibitor of HGA production; the results are currently being analyzed for publication.
Dr. Gahl also studies disorders of sialic acid, a charged sugar. Deficiency of sialic acid production causes a severe muscle-wasting disease that often forces patients into wheelchairs, ultimately leading to death by respiratory failure. Excess sialic acid is also detrimental to health. Three rare childhood diseases, characterized by growth retardation and developmental delays, are caused by excess sialic acid. One of these diseases is so rare that only seven patients have been identified worldwide. Dr. Gahl's laboratory has done mutation analysis on six of them. Research on treating sialic acid disorders is just beginning.
Dr. Gahl's group includes national experts in autosomal recessive polycystic kidney disease and congenital hepatic fibrosis, Chediak-Higashi syndrome, and Gray Platelet syndrome, and additional expertise is accruing in different types of albinism.
Dr. Gahl also directs the NIH Undiagnosed Diseases Program (UDP), an initiative that attempts to obtain a diagnosis for patients who have long been unable to achieve that goal. The UDP intends to identify new diseases that will provide insights into normal cell biology, biochemistry and physiology.
Last Updated: May 12, 2011