Great progress has been made in understanding the genetic basis of Gaucher disease (GD) and its underlying pathology; and we also know much more than in the past about disease biomarkers, phenotypic variability, and complications and comorbidities. Knowing more about these factors may ultimately support individualization of therapy for patients with GD. Biomarkers play central roles in the diagnosis, prediction of outcomes, and assessment of responses to treatment in many diseases and some have become targets for therapy. An ideal biomarker provides indirect but ongoing determinations of disease activity. Lyso-Gb1 appears to fulfill of these criteria and a growing body of evidence supports the view that it may be a surrogate marker for clinical outcomes in GD. Novel biomarkers, such as osteoactivin and progranulin, may also have value. GD is characterized by a wide variety of clinical presentations, even within families and among those carrying the same mutations in the primary gene of interest. This variability in patient presentation for a monogenetic disease is likely due to a multitude of factors, including genetic background, environment, and epigenetic status, which are specific to each patient. Our understanding of the relationships between GD and other diseases is also growing rapidly. For example, it has been known for many years that patients with GD and heterozygous carriers are at increased risk of developing Parkinson disease (PD) disease and Dementia with Lewy Bodies. It is now known that there is an inverse relationship between glucocerebrosidase and α-synuclein levels, and that even patients with sporadic PD have decreased glucocerebrosidase. Glucocerebrosidase may interact with α-synuclein to maintain basic cellular functions, or impaired glucocerebrosidase could contribute to PD pathogenesis by disrupting lysosomal homeostasis, enhancing endoplasmic reticulum stress or contributing to mitochondrial impairment. There are now multiple options for treating patients GD, including enzyme replacement therapy, substrate reduction therapy, and soon molecular chaperones, combination therapy, and possibly also gene replacement therapy will be available. At present, it is not completely clear which of these interventions are likely to be most effective in different subsets of patients. However, initial steps have been taken with respect to rational individualization of therapy and it may soon be possible to combine information about biomarkers, patient genotype and phenotype, and the presence of specific subsets of complications and comorbidities to guide treatment selection.
