Gaucher Disease-Multiple Lessons from a Single Gene Disease

The E. Donnall Thomas Award Lecture, Gaucher Disease: Multiple Lessons from a Single Gene Disease, will be presented tomorrow by Dr. Ernest Beutler. Dr. Beutler and colleagues' extensive work in Gaucher disease has resulted in the development of a diagnostic blood test for the disease, the identification of the glucocerebrosidase (GBA) gene with subsequent identification of causative genetic mutations, and the development of therapeutic enzyme replacement therapy now utilized as a treatment modality in certain patients.

The clinical syndrome of Gaucher disease was first described by the French physician, Phillipe Charles Ernest Gaucher, in 1882. It is the most commonly diagnosed lipid storage disease, affecting approxi- mately 1/50,000 to 1/100,000 of the general population, and 1/450 in the Ashkenazi Jewish population. Inheritance is autosomal recessive, with over 150 single gene mutations currently identified. The gene mutations N370S, L444P, 84gg, and IVS2[1+] are seen most commonly, particularly in Ashkenazi Jews with Gaucher disease (>90%).

While Gaucher disease is now felt to be a disease continuum that encompasses a broad spectrum of clinical symptoms, it continues to be classified into different clinical subtypes (see below) that help determine prognosis and treatment approaches. In general, clinical sequelae result from an abnormal production of the glucocerebrosidase enzyme, which is required to properly break down glucocerebroside, leading to the abnormal accumulation of this lipid. Glucocerebroside subsequently accumulates in mac- rophages in various organs that may include the liver, spleen, bones, bone marrow, and the neurologic system. Patients can present with pain resulting from splenic and hepatic infiltration and enlargement, anemia and thrombocytopenia, bone pain and skeletal abnormalities, and central nervous system ab- normalities.

Type 1 disease, the most common form, is characterized by bone and organ involvement but these patients do not have primary central nervous system involvement. Type II disease describes an acute neuropathic form which generally presents in infancy and is usually fatal in early childhood, whereas Type III describes a chronic, progressive, neuropathic form that generally presents later in childhood. A perinatal lethal form and a cardiovascular form have also been described.

Monday's lecture (9:30 a.m., Halls F-G) on Gaucher disease will highlight current understandings regarding its pathogenesis, prevalence, diagnosis, molecular biology, genetics, and treatment. Current understanding regarding the correlation between genotype and phenotype will be explored. A review of current treatments, including novel therapies, will also be discussed. Dr. Beutler and colleagues' work in the development of recombinant gluco-cerebrosidase enzyme replacement therapy, Cerezyme®, which became clinically available in 1991, has changed the clinical course of Gaucher disease patients, although the benefit for those with neurologic disease is not yet established. Benefits that have been seen in patients include: improved hemoglobin values, improved platelet count, decreases in liver and spleen volumes, improvement in bone disease, and improved quality of life. While enzyme replacement therapy is life-long and costly, Dr. Beutler offers clinical evidence that dosing does not need to exceed 30 U/kg/month. Hematopoetic stem cell transplant, gene transfer therapy, substrate reduction, and treat- ment with chaperone molecules are potential treatment strategies that will also be discussed.