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What I Have Learned About a Personalized Approach to Management of Gaucher Disease The physician should not treat the disease but the patient who is suffering from it. ~ Maimonides (Physician, Rabbi and Philosopher; Egypt, eleventh century C.E.) n his inaugural address as the new CEO/President of the National Gaucher Foundation at Yale Club in Manhattan in the fall of 2016, Brian Berman articulated the core mission of ‘Optimal Health Initiative’ which embodies the concept of tailoring treatment for the needs of the individual patient to prevent complications of Gaucher disease. This model known as personalized medicine is predicated on the ways in which risks of complications of a disease such as Gaucher’s in individuals is uniquely determined by what else is written into the genome at birth other than Gaucher mutations (variants in other genes that may aggravate Gaucher disease and even variants that may attenuate it), combined with non-genetic factors such as previous splenectomy, environment and life-style. Thus personalized medicine for Gaucher disease promises a future of accurate prediction of future course in affected individuals to achieve maximum health for maximum amount of time to prevent disabling painful complications and enhance quality of life. Gaucher Disease, a Disorder of Single Enzyme Caused by Mutation in a Single Gene Gaucher disease is a rare disorder affecting ~1 in 40,000 individuals in the general population but in the Ashkenazi Jewish community it affects as many as 1 in 850 individuals. It is due to genetic alteration in a gene called GBA which codes for an enzyme, lysosomal glucocerebrosidase (GCase). Thus normal function of GCase is disrupted and leads to build up of a lipid, glucocerebroside (GL1) in cells of the body. Excessive GL1 is harmful and in an attempt to process the accumulating lipid, an alternative pathway is activated in Gaucher disease leading to formation of downstream lipid called glucosylsphingosine (LGL1), which unfortunately is even more deleterious to cells. We and others have shown that 4 Advances in Gaucher Disease these accumulating lipids activate cells of the immune system which secrete cytokines and this process underlie many of the symptoms that patients with Gaucher disease experience, such as fatigue, bone pain, enlarged organs, low bone density and growth failure. Recent studies from our lab and others have shown that blood levels of LGL1 can be monitored as an accurate biomarker to assess activity of Gaucher disease, disease severity and its response to treatment. Gaucher Disease is Highly Variable, Even Among the Affected Individual Within a Family As a genetic disease arising from defect in one gene and the defective enzyme it encodes, researchers have conducted many studies over past 2 decades in the hope that the type of mutation would predict severity of Gaucher disease, enabling a physician to personalize management of Gaucher disease in the clinic. More than 400 mutations have been described but only 4 account for more than 90% of mutations in the US: N370S, L444P, 84GG, IVS2+1. We have learned that individuals with two copies of the N370S mutation or one copy in conjunction with another GBA pathological allele invariably develop type 1 Gaucher disease. Patients with two copies of an L444P mutation develop neuronopathic disease but this can vary widely from deadly type 2 disease in infants to later onset type 3 neurological disease. There is extraordinary variation in disease severity, the pattern of disease (predominant bone disease vs predominant liver/spleen enlargement/ low blood counts) and natural course among patients with the same mutation. Many studies have been conducted to examine this phenomenon, including from the ICGG Registry involving large number of patients from around the world. We found vast variation of disease severity in patients with two copies of N370S mutation, ranging from no disease manifestations whatsoever or patients becoming ill during childhood with painful bone crises. It is remarkable that disabling bone crises can occur at any age and in a study from the ICGG Registry, we learned that occurrence of disabling bone crises does not correlate at all with the extent of Pram Mistry, MD Yale School of Medicine Yale-New Haven Hospital New Haven, Connecticut I


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