Advances in Gaucher Disease 5 spleen/liver enlargement or genotype. Therefore, we caution doctors to evaluate all disease compartments (blood, liver, spleen and bones) to assess patients and not to make the error of pronouncing disease is mild or non-expressing based only on normal-looking blood counts and lack of obvious spleen/liver enlargement on physical exam. N370S mutation (replacement of amino acid asparagine at position 370 in GCase enzyme) has very interesting human history. It is believed to have arisen in late antiquity or early medieval Europe rather than in the Middle East. As Middle Eastern Jews settled in Italy, Germany and France, as suggested by MT DNA studies. Jewish women married or mated (not always by choice) with the indigenous population with subsequent introduction of the N370S gene. With subsequent migration of these so-called Ashkenazi Jews to central and Eastern Europe, cycles of population expansions and contractions (due to epidemic diseases such as bubonic plague and periodic massive violent anti-semitic pogroms), bottle-necking and centuries of geographic isolation and inbred marriages have caused the N370S allele frequency in Ashkenazi Jews to rise to high levels so that as many as ~1 in 15 individuals are carriers of this mutation. Although the historical record is probably an adequate explanation and at least 20 other genetic diseases are highly prevalent among Ashkenazi Jews, it is nonetheless widely believed this mutation may confer biological advantages to survive many adversities and numerous yet unproven theories have been proposed including favorable effects on metabolism and the immune system or even intelligence! It will be fascinating to unravel the biology underlying putative selective advantage of N370S mutation. There is striking variability of Gaucher disease among patients with the same genetic mutations that is seen not only among unrelated subjects but also among multiple affected individuals within the same family. There are major efforts underway by several laboratories using powerful genomic technologies to discover what other genetic variants contribute to expression of specific complications of Gaucher disease. The most striking examples of variable expression of disease are illustrated by small number of type 1 Gaucher disease patients (~ 4%) who develop Parkinson disease/Lewy body dementia or multiple myeloma. Knowledge of variants in the genome that act in concert with Gaucher mutations underlying these devastating complications could truly usher in an era of personalized, precision medicine, so that we can target the small number of at-risk patients for appropriate monitoring (and in not-too distant future also appropriate treatment) but at the same time reassure the majority of other patients who will not be at risk of these fearsome complications. Of course, genetic variation will not on its own explain all of the variability in Gaucher disease; environment likely also plays a role. For example, years ago, Dr Edwin Kolodny, Emeritus Professor of Neurology at NYU, showed that EBV, the virus that causes infectious mononucleosis, may be a trigger for some of the complications of Gaucher disease. Deeper understanding of Gaucher disease from genetic and mechanistic research may transform the way in which patients receive their medical care in the 21st century. Patterns of Organ Involvement in Gaucher Disease Across the Ages A puzzling aspect of Gaucher disease is variable pattern of organ involvement, for example involving spleen, liver, bone marrow and skeleton. One would expect that having a devastating complication as bone crises would be associated with equally severe involvement of the spleen, liver and blood counts. Interestingly, there is virtually no consistent relationship between these organ compartments in disease involvement such that a person with minimal alteration of blood counts or spleen/liver could suffer from painful bone crises. Such dichotomy is seen at every age of Gaucher disease, i.e., children, teenagers, young adults, women in reproductive years and older adults. This phenomenon is all the more puzzling as the enzyme defect in Gaucher disease leads to build up of lipids mostly in one cell type, macrophages which appear as typical lipid-filled Gaucher cells and build- up of these cells should occur in proportion to what occurs in healthy individuals (i.e., largest number of these cells are in the liver, followed by the spleen, followed by the lungs and least number proportionally in the bone marrow) Yet, the most devastating complications involve the bone marrow and it is uncommon for lungs to be involved in in Gaucher disease type 1. Similarly, when seeing patients in their 50s or 60s in the clinic it is almost impossible to predict which 4% of patients are at risk of Parkinson disease/Lewy body dementia. We need genetic and/or blood biomarkers that will help us identify the few high risk individuals and at the same time reassure vast majority who are at low risk. So striking is the variable pattern of organ involvement in Gaucher disease, that of the many hundreds of patients I have cared for over more than 2 decades, no two patients have been exactly alike. It almost seems that the signature of Gaucher disease is unique to every individual. These considerations underscore how much more we need to understand mechanisms of Gaucher disease in order to refine its management in the clinic and make the greatest impact on the lives of our patients. A glimpse of the future is provided by small number of patients who develop multiple myeloma; although only ~4% of patients develop this complication, its actual risk in Gaucher disease is extremely high estimated at >30-fold compared to the general population. Here, we are fortunate to have ‘biomarker’ that helps to identify the high risk individuals – it is called SPEP (Serum Protein Electrophoresis) which we perform on all adults at their annual evaluation. Presence of a protein spike at low level is called MGUS (Monoclonal Gammopathy of Unknown Origin), which is precursor of myeloma: it is estimated 1% of all individuals with MGUS, with or without Gaucher disease, progress to multiple myeloma each year. Recent research from our group has shown that this protein spike is directed to the lipids that build up in Gaucher disease and early data suggest that treatment to lower immunogenic Gaucher lipids can lower the level of MGUS.
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