The Spectrum of Gaucher Disease Type 3: Identifying Clinical Syndromes, Phenotypic Variability, and Clues to Neuropathology Abstract Gaucher disease type 3 (GD3) includes several different phenotypes and can present in infancy, childhood and even in adulthood. In addition to organomegaly and bone involvement, individuals with GD3 by definition have neurologic involvement. Visceral and neurological involvement varies widely from one patient to another creating a large spectrum of clinical disease. Here, we discuss emerging knowledge about geographical heterogeneity, underrecognized clinical presentations, longitudinal assessment and definition of evaluable endpoints, and a possible role for modifier genes as contributory determinants of natural history and responses potential future treatments With each new published report, investigators are unraveling more of the unknown features of what is still a complex and challenging picture of GD and its three clinical subtypes, classically divided based on age of onset and signs of nervous system involvement. Although there is still much to be explored and characterized, new information is providing clues to further understanding the pathophysiology, genetic mutations, and the broad spectrum of clinical manifestations of GD. Numerous studies have definitively characterized basic features of GD, one of the most common lysosomal storage diseases. Multiple comprehensive reviews such as Beutler and Grabowski1 and most recently Stirnemann et al2 highlight the finding that the disease is caused by mutations in the GBA1 gene which encodes for acid beta-glucosidase that degrades glucosylceramide. Because of insufficient glucocerebrosidase activity, glucocerebroside and other pathological substrates such as glucosylsphingosine accumulate in macrophages 8 Advances in Gaucher Disease and in some cases, in cells of the central nervous system. This report will focus on GD3, but it is important first to delineate the characteristics of each type of GD to understand what they have in common and what determines their major differences. Gaucher Disease Type 1 (non-neuronopathic, GD1) At onset, patients with GD1 commonly present with painless splenomegaly, anemia, or thrombocytopenia.1-3 They may also have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds, gum bleeding, peri-or post-partum hemorrhage, bleeding after surgical or dental procedures CNS bleeding after trauma.1-3 In symptomatic patients, splenomegaly may be progressive and can become massive. Children with massive splenomegaly may be short in stature because of the energy expenditure required by the enlarged organ.1-3 Most untreated patients with GD1 have radiologic evidence of skeletal involvement, including the Erlenmeyer flask deformity of the distal femur, an early appearing, asymptomatic abnormality caused by failure of bone remodeling. Symptomatic bony involvement, which occurs in more than 20% of patients with GD, can present as bone pain or pathologic fractures. Lytic lesions can develop in the long bones, ribs, and pelvis, and osteosclerosis or osteopenia/osteoporosis may be evident at an early age. Bone crises with severe pain and swelling can occur in individuals with GD1and are frequently mistaken for synovitis or osteomyelitis until other symptoms become apparent. Although GD1 was long believed to be non-neuronopathic, it is now recognized that by age 80, up to 10% of patients with GD1 will develop classical and progressive manifestations of Parkinson’s disease sometimes complicated by Lewy body dementia3. As many as 30% of middle-aged and older adults may have evidence for peripheral neuropathy. In contrast, neuronopathic Gaucher disease is defined as the ap- Raphael Schiffmann, MD, MHSc Director, Institute of Metabolic Disease Baylor Scott & White Research Institute Dallas, Texas Keywords: Gaucher disease,diagnosis, type 2, type 3, non-neuronopathic, neuronopathic, phenotype, cognitive outcome, eye movement abnormalities, modifier genes. Address for reprints and correspondence: Raphael Schiffmann, MD, Institute of Metabolic Disease, 3505 Gaston Avenue, Dallas, TX 75246, email: Raphael.Schiffmann@BSWHealth.org
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