HomeResearchIntramural ResearchResearch Branches at NHGRIMedical Genetics Branch Gahl Lab

William A. Gahl, M.D., Ph.D. Clinical Director National Human Genome Research Institute Senior Investigator Medical Genetics Branch Head 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 (301) 402-2739 (301) 402-2740 bgahl@helix.nih.gov Building 10, Room 10C103 10 Center Dr, MSC 1851 Bethesda, MD 20892-1851 Selected Publications Office of the Clinical Director

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 disorders, including cystinosis, Hermansky-Pudlak syndrome, alkaptonuria, and sialic acid diseases.

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 od 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 changed the life course of many cystinosis patients from one filled with debilitating complications to one marked by chronic, yet manageable symptoms. His group is following about 125 pre- and post-transplant cystinosis patients to track their clinical course, identify additional mutations, and document any complications of their cysteamine therapy.

Another major research focus for Dr. Gahl is Hermansky-Pudlak syndrome (HPS), a group of vesicle formation and transport disorders characterized by albinism and bleeding. In some cases, HPS also is 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, seven 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 had success in slowing the development of some HPS symptoms in a small group of patients.

His laboratory also studies alkaptonuria, a condition in which mutations in the HGO gene cause a buildup of homogentisic acid (HGA), which discolors the eyes and damages the connective tissues in major joints and cardiac valves. By closely monitoring 58 alkaptonuria patients, Dr. Gahl's group produced the first modern characterization of the disease and found a potential therapy involving small doses of the drug nitisinone, which decreases HGA production. The next step is a three-year clinical trial to determine whether the drug can slow or halt the hip damage caused by the disease.

Dr. Gahl also studies sialic acid disorders, as his laboratory is a reference laboratory for this rare group of conditions. Sialic acid deficiency causes a severe muscle-wasting disease that often forces patients into wheelchairs, ultimately leading to death by respiratory failure. Excess sialic acid is equally 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. In the meantime, Dr. Gahl's group has developed phenotypic descriptions of the different disorders and provides diagnostic assistance to other laboratories.

Dr. Gahl's laboratory also is developing a strong research interest in other genetic disorders. These include Autosomal Recessive Polycystic Kidney Disease, Congenital Hepatic Fibrosis, Chediak-Higashi Syndrome, Gray Platelet Syndrome, Hutchinson-Gilford Progeria Syndrome, Hartnup Disorder, 3-Methylglutaconic Aciduria, and various forms of renal Franconi Syndrome.

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Last Reviewed: June 16, 2008