HomeResearchIntramural ResearchResearch Branches at NHGRIMedical Genetics Branch Sidransky Lab

Ellen Sidransky, M.D. Senior Investigator Medical Genetics Branch Head Molecular Neurogenetics Section B.A. Brandeis University, 1977 M.D. Tulane University, 1981 (301) 451-0901 (301) 402-6438 es30e@nih.gov Building 35, Room 1A213 35 Convent Dr, MSC 3708 Bethesda, MD 20892-3708 Selected Publications

Dr. Sidransky's research focuses on the genetics of Gaucher (pronounced "go-SHAY") disease, a rare, recessively inherited disorder with highly variable symptoms. Her work has been instrumental in uncovering the spectrum of symptoms and some of the mechanisms underlying the pathology of this disorder. Ultimately, the goal of her research is the translation of basic research findings into new therapeutic approaches for this condition. She and her colleagues also have discovered potential links between this single-gene disorder and the more common, multi-gene disorder, Parkinson disease.

Gaucher disease results from mutations in the GBAM gene, which codes for the enzyme glucocerebrosidase. This lysosomal enzyme is responsible for breaking down a specific kind of fat called glucocerebroside. People with Gaucher disease cannot properly produce this enzyme, so the glucocerebroside in their cells is not broken down and accumulates - mostly in the liver, spleen, and bone marrow cells. This accumulation can result in pain, fatigue, jaundice, bone damage, anemia, and even death. Gaucher disease is the most common lysosomal storage disorder in the general population, affecting an estimated 20,000 to 30,000 people in the United States, although many cases may go undiagnosed. It is the most prevalent hereditary disorder among Ashkenazi Jews; in this population, about 1 in 15 people are carriers, compared with about 1 in 100 in the general population. Currently, the primary treatment for Gaucher disease is enzyme replacement therapy, which has helped many patients but is inconvenient because it requires life-long intravenous infusions every two weeks and also is extremely expensive.

For reasons still not well understood, the manifestations of Gaucher disease vary dramatically from one individual to another. Some people with glucocerebrosidase deficiency never have symptoms, whereas others have enlarged spleens and livers as well as bone problems, blood abnormalities, and growth retardation. Still others have devastating lung, skin, and nervous system manifestations. Although more than 200 different disease-associated mutations in GBA have been identified, patients with the same mutations (or genotypes) can have quite different clinical manifestations (or phenotypes). Thus, for this disease, patient genotyping is not a reliable guide for prognosis, therapy, or genetic counseling. Gaucher disease researchers have to rely more on the careful analysis of phenotypes to guide their studies.

Traditionally, patients with Gaucher disease have been classified into three separate and distinct phenotypes. Dr. Sidransky's research, however, has shown that Gaucher disease phenotypes actually form a continuum, with a major factor being the degree of neurologic damage involved. Dr. Sidransky's laboratory has described several new Gaucher phenotypes that lie along this continuum. For example, studies of a GBA-knockout mouse model helped her group identify a previously unrecognized phenotype involving prenatal or immediate postnatal death. Additionally, her laboratory was the first to describe the clinical and genetic characteristics of a rare Gaucher disease phenotype in which myoclonic epilepsy (characterized by quick little jerks of the arms, shoulder and legs) is a significant component.

Dr. Sidransky and her colleagues are continuing to explore vast phenotypic heterogeneity of Gaucher disease by sequencing and comparing the GBA gene and nearby genomic regions in groups of patients who share atypical phenotypes. Their studies show that the GBA gene lies in a gene-rich region of chromosome 1q. Interestingly, there is a closely related pseudogene nearby that plays a role in causing some mutations resulting in Gaucher disease. Dr. Sidransky believes that analyses of both the differences and similarities in the GBA sequences in different patient groups and in different organisms may improve our understanding of how genotype influences phenotype in patients with Gaucher disease.

A second major project in Dr. Sidransky's laboratory involves investigating a potential link between mutations in the GBA gene and Parkinson disease. Her group recently discovered that several families carrying GBA mutations had an unusually high incidence of Parkinson disease. In a complementary study, they analyzed brain tissue samples from patients with and without Parkinson disease and found that 14 percent of the Parkinson disease samples had at least one mutated GBA gene, compared with none in the non-affected samples. Similar result were found in patients with a related disorder, Lewy body dementia. Thus, heterozygosity for GBA mutations may be a risk factor for different forms of parkinsonism in some individuals. This insight has given Parkinson disease researchers a new, exciting avenue for studying the mechanisms of the disease. Dr Sidransky's groups is now engaged in a comprehensive clinical evaluation of such patients, with studies including new Positron Emission Tomography (PET) scans.

In addition, the Sidransky laboratory, in collaboration with Dr. Chris Austin and others at the new National Chemical Genomics Center, have been screening collections of thousands of small molecules to discover potential new therapies for patients with Gaucher disease. Their initial screening identified three novel classes of drugs that may work to salvage the mutant enzyme, enabling it to function. This approach has promise for the treatment of some individuals with Gaucher disease.

Top of page

Last Reviewed: April 1, 2008