Advances in Gaucher Disease 15 generation sequencing strategies may help us to identify other risk factors, and we are working to organize such a Gaucher consortium in the near future .By examining epigenetic modifications, transcriptomes and proteomic differences in groups of patients sharing the same genotype and genetic background, yet exhibiting different clinical manifestations, we may be able to elucidate important modifiers. Thus, although Gaucher disease has been regarded by many as a “simple’ single disease disorder, the reality is far more complicated. What we learn from these approaches will likely prove valuable for other Mendelian and “complex” genetic disorders. “What initially attracted me to the study of Gaucher disease, and has kept me engaged in this field for almost three decades, is the vast clinical variation encountered in this “simple” single-gene disorder. Although we have gained knowledge about lysosomal pathways and how their dysfunction contributes to some of the clinical symptoms observed in patients, the reasons underlying the heterogeneity observed is still not well understood.” Dr. Weinreb: GD patient genotyping, generally determined by PCR specific oligonucleotide screening for up to 8 common mutations, is often unreliable for predicting phenotype or for making treatment decisions. This will be even more of a problem should newborn screening become more prevalent. Has the time come and is it now feasible to routinely genotype and re-genotype all GD patients with new generation whole exome or even whole genome sequencing? Dr Sidransky: While ultimately next-generation sequencing may have a role in Gaucher diagnosis, it remains to be seen how accurate current strategies are. Genotyping the glucocerebrosidase gene (GBA1) has always been challenging. First of all, there are now several hundred different mutations that have been found in patients with Gaucher disease that are located all throughout the 11 exons of the gene. Furthermore, the presence of a highly homologous pseudogene sequence only 17 kilobases downstream from the GBA1 gene greatly complicates the genotyping. Primers must be designed that exclusively amplify the gene, but not the pseudogene, sequence. Moreover, some patients with Gaucher disease have mutant alleles that likely arose from recombination with the pseudogene, and hence mutant alleles can include varying numbers of changes originating from the pseudogene sequence. Currently, screening for 8-10 common mutant alleles will detect 90-95% of the mutations in Ashkenazi Jewish patients. However, in subjects from other backgrounds these screens are not very accurate and will miss a significant number of mutant alleles. Also, simply identifying a specific mutation is not always adequate. Some patients can have more than one change on the same allele. Thus, it is important that Gaucher genotyping be performed in a laboratory that has a lot of experience with this gene. While ultimately next-generation sequencing may have a role in Gaucher diagnosis, it remains to be seen how accurate current strategies are, because of the homologous pseudogene. In addition, widespread screens such as newborn screening using next generation sequencing run the risk of uncovering variants of unknown significance, which are challenging to interpret, and can, at times, cause undue anxiety. When considering broad genetic testing for Gaucher disease we must also ask how to best deal with that information. Because of the heterogeneity of the disease manifestations and the significant number of individuals who are asymptomatic, it will be essential to have specific biomarkers that identify and predict those with more aggressive disease so that we don’t treat patients who may do very well without treatment for a long period of time Dr. Weinreb: Regarding GD and Parkinsonism, you and your research group have been conducting ongoing rigorous evaluations in patients, carriers and other family relatives. What have these studies revealed to date? In anticipation of the emergence of preventative treatments, what diagnostic studies would you currently recommend to screen patients and known carriers for early Parkinson manifestations and at what age would you start? Dr Sidransky: It has been almost 20 years since we and others established the link between mutations in the GBA1 gene and both Parkinson disease and associated Lewy body disorders known as synucleinopathies. While it is now clear that both patients with Gaucher disease and GBA1 mutation carriers are at increased risk of developing Parkinson disease, by far, most patients and carriers will never develop Parkinsonism. The challenge is to better understand the basis for this association, the other genes or factors that are involvedassociation, and how to best identify who is more prone to this neurodegenerative disorder. In our clinics, we have been prospectively evaluating patients and carriers with Parkinsonism in a uniform fashion. Our goals are to characterize the parkinsonian phenotype in this distinct patient population, to identify potential biomarkers and to define early signs of Parkinson disease in an atrisk population. We recruit patients with Gaucher disease and Gaucher carriers with parkinsonism, or with a strong family history of parkinsonism, for a comprehensive baseline screening, and then follow these subjects longitudinally. The evaluations include olfactory testing with a smell identification test (UPSIT), a standardized neurologic assessment, neurocognitive testing, and surveys for non-motor and/or psychiatric manifestations. This study has solidified our clinical expertise in this field, and has enabled us to better counsel our patients. Recently we published a study detailing the clinical course of 19 patients with both GD and parkinsonism, interrogating this data for indicators regarding prognosis in this rare patient group. This is the largest study published to date describing patients sharing these two phenotypes with sequential evaluations by the same clinical team. As a whole, these patients had an earlier age at disease onset and more cognitive changes than encountered in sporadic Parkinson disease. However, unlike other papers describing the phenotype of GBA1-associated PD in heterozygotes, we did not find a uniformly aggressive clinical course
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