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Overall Course of Gaucher Disease is Highly Variable Not only is the pattern of organ involvement highly heterogeneous, the rate of disease progression over time is highly variable between patients. My oldest patient with two copies of N370S mutation is an asymptomatic 100 yr. old lady, while in the same clinic I see young children with the same mutation who have suffered painful bone crises. Yet, studies have shown that patients followed for many years in the pre- ERT era had progressive disease, but the rate of progression is highly variable. These factors can present chal-lenges in the clinic to assess when and how to start treatment. I have learned that careful monitoring of patients over time can help establish the tempo of the disease which is helpful in determining optimal timing to start treatment. How to Establish Baseline of Disease in Your First Visit to a Gaucher Center Expert physicians in Gaucher disease in the ICGG Registry led the way in establishing the standards of care for rare disease by developing consensus guidelines for comprehensive evaluation of patients, such that all disease compartments and risks are evaluated. This involves blood work including biomarkers, bone density, x rays and MRI. Again, it is important to individualize evaluation, so we keep to a minimum amount of radiation or discomfort from tests. For example, in children, experts would rely in simple testing such as monitoring growth, symptoms, blood work and using imaging tests only sparingly. In my clinic, for children I make it point to assess bone health by performing a bone density test. This approach is based on a study from the ICGG and our mouse model of Gaucher disease, that osteoporosis is due to impaired bone formation. Thus children and young adults tend to enter adulthood with low peak bone mass and to ensure optimal bone health, it is important that patients achieve normal peak bone mass to prevent osteoporosis and fragility fractures later in life. Here again, evaluation should be tailored to the individual situation. How To Track the Course of Gaucher Disease: Tests, Blood Work and Biomarkers Expert physicians in the ICGG Registry developed a schedule of recommended testing to assess status of Gaucher disease and its response to treatment which are now regarded as the optimal standard of care and also used in conduct of clinical trials. Testing to assess spleen and liver size, blood counts (hemoglobin and platelets), tests of bone health (MRI and bone density) are useful but have limitations as these represent only indirect measures of burden of Gaucher cells. For a long time, researchers have attempted to discover blood tests that accurately reflect the total body burden of Gaucher cells. Most patients have regular blood testing for the biomarker called chitotriosidase but it has significant limitations; moreover it does not seem to be integral to clinical expression of Gaucher disease. At least 6% of individuals in all populations are unable to make this protein due to genetic variation in its gene, CHIT1, yet expression of Gaucher disease is not altered. Recent studies from our group and others have 6 Advances in Gaucher Disease established levels of LGL1 (glucosylsphingosine) in blood as an excellent biomarker of Gaucher disease severity and its response to treatment. LGL1 is intimately involved in the biochemistry and pathophysiology of Gaucher disease as it is one of the accumulating lipids, it has direct effects on bone health as well as the immune system, and recent data show it is also involved in triggering clumping of a neuronal protein, ��-synuclein into damaging aggregates that underlies Parkinson disease. It is expected that LGL1 levels in blood will become the key biomarker of Gaucher disease for monitoring patients in the clinic as well as in assessing response to treatments in clinical trials. There are several initiatives underway to make LGL1 testing widely available and patients should discuss with their treating physicians whether the testing is indicated. Starting Treatment for Gaucher Disease: ERT (Enzyme Replacement Therapy) and SRT (Substrate Reduction Therapy) A new era was launched in the early 1990s with the introduction of ERT which has transformed the lives of patients with Gaucher disease. A recent study from the ICGG Registry has shown that patients in the pre-ERT era had very high rates of splenectomy and associated disabling bone complications but in the new generation of patients, there are strikingly lower rates of surgery to remove the spleen and with that lower rates of bone complications. The tool-kit for Gaucher physicians in the 21st century is crowded with three ERTs and two oral SRTs. There are significant differences in these treatments and outcomes of treatment. Hence decisions regarding when, in which patient and with that medicine to begin treatment has become nuanced and complex. Advances in biomarkers, understanding of mechanisms of Gaucher disease and treatment as well as global studies from registries have enabled physicians to make evidence-based decisions to treat patients in an individualized manner. Therefore, rather than a trial and error strategy until the right treatment is found, with personalized medicine, treatments can be more specifically tailored to an individual. Obtaining the CYP2d6 metabolizer status before starting oral SRT with eliglustat is a great example of application of pharmacogenetics to identify patients who will benefit from treatment and moreover determine the correct dose. Monitoring for Expected Response to Treatment Whatever treatment is begun, it is extremely important to monitor the response and assess it meets the expected effects of treatment as enunciated by expert physicians based on retrospective analysis of hundreds of patients. These ‘therapeutic goals’ have been widely adopted in the clinic as well as in clinical trials of new treatments. Whenever, response is sub-optimal and deviates from these expected results, careful evaluation should be undertaken to determine the underlying reason, such as whether the patient is compliant with medication, whether the dose is correct, in the case of ERT, whether the patient has developed antibodies to enzyme infusions, or whether the patient has developed a concurrent (continued on bottom of inside back cover)


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