Gaucher Disease: Opening a Window Into More Common Disorders
Genomics in Action,
Novel Approach Targets an Inherited Disorder
News Release, July 2007
Researchers Uncover Genetic Clues to a Common Form of Age-Related Dementia
News Release, July 2006
Ellen Sidransky, M.D.
Medical Genetics Branch
Molecular Neurogenetics Section
B.A. Brandeis University, 1977
M.D. Tulane University, 1981
35A CONVENT DR, MSC 3708
BETHESDA, MD 20892-3708
Dr. Sidransky's research focuses on the genetics of Gaucher 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, her research goal is the translation of basic research findings into new therapeutic approaches for this and other inherited disorders. She and her colleagues have also discovered potential links between this single-gene disorder and the multi-gene disorder, Parkinson disease.
Gaucher disease results from mutations in the GBA 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 degraded 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. It is the most prevalent hereditary disorder among Ashkenazi Jews, of whom about 1 in 15 are carriers, compared with ~1 in 100 in the general population. Currently, the primary treatment for Gaucher disease is enzyme replacement therapy, which requires life-long intravenous infusions every two weeks. It is inconvenient and extremely expensive.
For reasons still not well understood, the manifestations of Gaucher disease vary dramatically. Some people with glucocerebrosidase deficiency have no symptoms, whereas some have enlarged spleens and livers, bone problems, blood abnormalities, and growth retardation. Others have devastating lung, skin and nervous system manifestations. Although almost 300 different disease-associated mutations in GBA have been identified, patients with the same genotypes can have quite different clinical manifestations (or phenotypes). Thus, patient genotyping is not always a reliable guide for prognosis, therapy or genetic counseling. Rather, researchers have to rely on careful phenotyping to guide their studies.
Dr. Sidransky's research has shown that, while patients have traditionally been classified into three distinct phenotypes, their symptoms actually form a continuum; her laboratory has described several new Gaucher phenotypes along this spectrum. For example, studies of a GBA-knockout mouse model helped her group identify a previously unrecognized phenotype involving prenatal or immediate postnatal death. They also described the clinical and genetic characteristics of a rare Gaucher phenotype with myoclonic epilepsy (characterized by quick jerks of the arms, shoulder and legs).
Dr. Sidransky and her colleagues continue to explore the vast phenotypic heterogeneity associated with Gaucher disease by sequencing and comparing the GBA gene and nearby genomic regions in patients who share atypical phenotypes. Their studies show that the GBA gene lies in a gene-rich region of chromosome 1q. Interestingly, a closely related pseudogene nearby plays a role in causing some mutations that result in Gaucher disease. Dr. Sidransky believes that analyses of both the differences and similarities in the GBA sequences in different patient groups and different species 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 an association between mutations in the GBA gene and Parkinson disease. Her group discovered that patients and families carrying GBA mutations had an increased incidence of this disorder. In several subsequent studies, they analyzed samples from patients with Parkinson disease and Lewy body dementia, and found that GBA mutations were more frequent than anticipated. Additional studies performed at centers around the world confirm that heterozygosity for GBA mutations is an important risk factor for Parkinson disease and related disorders. This insight has given Parkinson disease researchers a new, exciting avenue for studying the mechanisms of the disease.
In addition, Dr. Sidransky's laboratory, in collaboration with the NIH Chemical Genomics Center, has been screening collections of thousands of small molecules to discover potential new therapies for patients with Gaucher disease. Their initial screening has identified three novel classes of drugs that may work to salvage the mutant enzyme, enabling it to function. This approach offers promise for the treatment of some individuals with Gaucher disease.
Last Reviewed: August 19, 2013