AFTERWORD Some two decades have passed since the introduction of the first effective, specific therapy for an intracellular enzyme deficiency state, Gaucher disease, and this therapy provided a positive transformation of the lives of people suffering from this devastating disease. As is evident from the contributions in this supplement, much more has been learned than just the ability to alleviate many of the Gaucher disease manifestations in afflicted individuals. Fundamental to progress in learning more about Gaucher disease has been the compilation and analysis of Gaucher disease manifestations, their natural progression, their response to specific therapies, and the emergence of comorbidities. This knowledge can only be derived from datasets of sufficient size to allow rigorous analyses. The International Collaborative Gaucher Group (ICGG) Gaucher Registry (clinicaltrials.gov NCT00358943), with its independent oversight, continues to provide detailed and expanding datasets to facilitate such analyses and encourage investigators to ask penetrating, patientrelevant questions. As Grabowski et al. point out in their contribution to this supplement, ICGG Gaucher Registry analyses have radically changed the perception of Gaucher disease type 1 from a late-onset indolent disorder to a disease that has onset during the pediatric years in >50% of patients with the disease (i.e., a progressive disease of childhood and adolescence). This is true even in patients with the “mild N370S/N370S genotype,” indicating the need to abandon such subjective attributions to genotypes. As highlighted by Mistry et al. in the first review of this supplement, long-term, progressive morbidity of untreated or late-treated adults with Gaucher disease type 1 is now well-delineated and an essential part of the decision-making process around treatment options. Also, as reviewed by Charrow et al., sufficient data are now becoming available from the ICGG Gaucher Registry to track treatment outcomes over the long-term, and identify the limits of enzyme replacement therapies (ERTs). Certainly, these outcomes provide comparison standards for other new therapeutic approaches. Critically important has been the emerging recognition of comorbidities in Gaucher disease type 1, including malignancies and Parkinson’s/Lewy body disease, which Cox et al. review in their contribution to this

supplement. Clearly, further studies/analyses will elucidate the expected ethnic and demographic variations in Gaucher disease type 1 so that therapeutic interventions can not only be tailored to the individual, but also to his/her specific ethnic predilections to ensure greater personalized treatment programs and enhanced outcomes. Of additional significance to the field of lysosomal storage diseases (LSDs), the ICGG Gaucher Registry is a prototype for the other LSD registries, analyses, and directions. These other registries are now becoming sufficiently mature to contribute, similarly to the ICGG Gaucher Registry, to enhanced and data-driven improvements in patient care. In this way, the ICGG Gaucher Registry, similar to ERT for Gaucher disease type 1, has been transformative for patients and for the field of LSDs and their treatments.

䊏 Acknowledgments The author thanks Laura Croal, PhD (medical communications manager for Gaucher disease, Genzyme Global Medical Affairs), Pam Pickering of Conscience Creative, and Cheryl Lathrop for editorial assistance, which was funded by Genzyme, a Sanofi company. This publication was supported by an unrestricted grant from Genzyme, a Sanofi company. The opinions expressed in this article are those of the author and do not necessarily reflect those of Genzyme. GREGORY A. GRABOWSKI*

Division of Genetics, Children’s Hospital Medical Center, Cincinnati, Ohio Conflict of interest: G.A.G. has received honoraria for consultation and Advisory Board participation from Genzyme, a Sanofi company, and Shire, has received lecture fees or honoraria for speaking at the invitation of Genzyme, a Sanofi company, and has received grant support from Shire and the NIH. He has equity/stock options in Synageva BioPharma Corp. and holds patents on the therapeutic use of lysosomal acid lipase. He is currently employed by Synageva as Chief Scientific Officer. *Correspondence to: Gregory A. Grabowski, M.D., Division of Human Genetics, Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 4006, Cincinnati, OH. E-mail: [email protected] Contract grant sponsor: Genzyme, a Sanofi company DOI: 10.1002/ajh.24058

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