A Gaucher Disease Update from the Medical Genetics Branch, NHGRI, NIH Interview with the Senior Investigator, Ellen Sidransky, MD In this wide ranging interview covering new information, including genetic findings and emerging data about pathophysiology, Ellen Sidransky, MD, discusses aspects of her research that reveal why Gaucher disease is far more complicated than many clinicians suspect. The interview was conducted by Neal J. Weinreb, MD, Regional Coordinator and Chair of the International Collaborative Gaucher Group University of Miami UHealth Sylvester Cancer Center Coral Springs, Florida. Dr Sidransky is Chief of the Molecular Neurogenetics Section and a pediatrician and clinical geneticist in the Medical Genetics Branch of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) in Bethesda, Maryland. Dr. Weinreb: Your research has shown that Gaucher disease is best conceived of as a continuum of phenotypes and clinical manifestations that appear and develop over a patient’s lifetime much as branches of varying size and strength emerge at different times and levels from the main trunk of a tree. What is the current state of knowledge about why this is so? Dr Sidransky: What initially attracted me to the study of Gaucher disease, and has kept me engaged in this field for almost three decades, is the vast clinical variation encountered in this “simple” single-gene disorder. Although we have gained knowledge about lysosomal pathways and how their dysfunction contributes to some of the clinical symptoms observed in patients, the reasons underlying the heterogeneity observed is still not well understood. Patient phenotypes range from fetal death to asymptomatic octogenarians, with an ever-expanding range of associated manifestations in between. Some patients with Gaucher disease have brain involvement and others do not. In recent years, there has been an increased awareness of patients presenting on both ends of this broad spectrum. The perinatal/neonatal presentation, which received more attention after the generation of a null-allele Gaucher mouse with a similar phenotype, includes the hydrops fetalis phenotype, as well as infants with the collodian baby phenotype. The skin involvement in these severely affected infants is related to 14 Advances in Gaucher Disease the deficiency of glucocerebrosidase in the outer layers of skin, where the ratio of glucosylceramide to ceramide is crucial for maintenance of the skin barrier function. Gaucher disease should be considered in the differential diagnosis when confronted with a “cellophane-skin” baby, a fetus or newborn with hydrops, and in families with a history of multiple late fetal losses. On the other hand, we are also becoming increasingly aware how many patients with Gaucher disease actually have no symptoms of the disorder. Frequently, especially in the Ashkenazi Jewish sector, patients are being identified when they come in for prenatal or other genetic screening programs and after direct-to consumer testing. Others are only identified because of an affected child or sibling. Recently, as large cohorts of patients with Parkinson disease are being screened for mutations in GBA1, additional older patients are being identified. Many of these individuals would have never reached medical attention for this disorder. Identification of very mild cases is likely to continue to occur as more sequencing and genetic screens become commonly incorporated into medical practice. We still don’t know all of the factors that contribute to this clinical spectrum. Clearly the DNA mutations present on the glucocerebrosidase gene (GBA1) play a role. Some mutations like the common N370S allele are exclusively associated with non - neuronopathic Gaucher disease. Other patients with two null or particularly severe alleles are likely to have type 2 Gaucher disease. Actually, having two null alleles results in perinatal lethality. However, patients sharing the same genotype can have vastly different symptoms, organ involvement and responses to therapy. This is seen among siblings with the same mutations and even identical twins. Thus, other factors, such as modifier genes, epigenetics and environmental factors must also contribute to the phenotypic variation observed among patients with Gaucher disease. To date, it has been quite difficult to tease out what these other “modifying” factors might be. Studies in mice have provided a few potential clues, as have some limited genomewide association studies (GWAS). One problem in the identification of such modifiers is the large number of samples required to achieve meaningful results. After all, Gaucher disease is a relatively rare disorder. However, large collaborative studies between different Gaucher centers utilizing next- AGD Interview
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