Challenges in Gaucher disease: Perspectives from an expert panel.

This focused review concentrates on eight topics of high importance for Gaucher disease (GD) clinicians and researchers: 1) The consideration of GD as distinct types rather than a spectrum. A review of the literature clearly supports the view that there are distinct types of GD. Type 1 is characterized by the absence of primary neuronopathic involvement, while types 2 and 3 are characterized by progressive primary neuronopathic disease. 2) Neurologic and neuronopathic manifestations. A growing body of evidence indicates that the peripheral nervous system may be involved in GD type 1 and that there may also be signs and symptoms of central nervous system (CNS) disease in this group. However, GD type 1 is characterized by the absence of primary neuronopathic disease, whereas GD types 2 and 3 are characterized by progressive, albeit variable, primary neuronopathic disease. Abnormalities in saccadic eye movements have been suggested as being diagnostic for neuronopathic GD, but they may also occur in GD type 1 and in other inflammatory diseases. 3) The importance of whole GBA1 sequencing. This approach is superior to exome sequencing because of potential effects of deep intronic variants on gene expression. It also has the capacity to detect variant alleles that might be missed with gene panels. 4) Monoclonal gammopathy of undetermined significance (MGUS). The risks of MGUS, multiple myeloma, and non-Hodgkin's lymphoma are elevated in patients with GD compared to the general population and strong evidence indicates that lyso-Gb1 stimulates the formation of monoclonal immunoglobulins (M-protein) in patients with GD and MGUS. 5) Pulmonary involvement in GD. Pulmonary complications can be identified through spirometry in up to 45 % of patients with GD type 1 and 55 % of those with GD type 3. Limited evidence exists that enzyme replacement therapy (ERT) reduces the severity of these complications in patients with GD type 1. 6) Gaucheromas. These may occur in patients with GD types 1 or 3, but there is little detailed information about their inception, mechanisms underlying growth, cellular organization, and biochemical activities, and no definitive guidance for their management. Gaucheromas behave like benign (i.e. non-metastasizing) neoplasms, and it may be reasonable to classify them as such. 7) Bone and joint involvement. Dual-energy X-ray absorptiometry scans alone are insufficient for monitoring all changes in bone that may occur in patients with GD. Quantitative magnetic resonance imaging (MRI) techniques using Dixon quantitative chemical shift imaging have provided results that correlate with GD severity scores, bone complications, and biomarkers for GD bone involvement. Thoracic kyphosis is a common complication of GD types 1 and 3, and there is very limited information regarding the effects of ERT or substrate synthesis inhibition therapy (SSIT) on this condition. 8) Treatment initiation, selection, combination, and switching. Prompt initiation of treatment in pediatric patients is important as GD can lead to impaired growth, lower peak bone mass, and delayed puberty. These adverse outcomes can often be ameliorated or prevented with timely treatment. Either ERT or eliglustat, a SSIT agent, is suitable as first-line treatment of adults with GD. Studies of switching from ERT to eliglustat, or between different ERT products, have indicated that changing treatment is safe, although efficacy outcomes vary. A critical remaining issue is the lack of treatments capable of reaching the CNS to slow or halt the progression of neuronopathic disease in patients with GD type 2 or 3 and potentially reduce the risk of Parkinson's disease in GD type 1 patients and heterozygotes for GBA1 variants.