tients but there was a striking difference between verbal and performance scores. PIQ scores were significantly lower than VIQ scores. • Although ERT can reduce organ size, improve hematologic measurements, and enhance bone density, it has no effect on neurologic manifestations because the circulating lysosomal enzyme cannot cross the bloodbrain barrier. • Neurodevelopmental screening should be part of routine medical care for children with GD3. Correlating Eye Movement Abnormalities With Progression in GD3 Although the hallmark clinical abnormality of patients with neuronopathic GD consists of markedly slow horizontal saccades, several reports, including one by Benko et al16 have observed that vertical saccades are also slow but to a lesser extent. To further quantitate and better characterize the neurological course of type 3 GD, the authors evaluated vertical saccadic function as the primary outcome measure because this abnormality was much less affected than horizontal saccades. In some patients, horizontal saccades were so abnormal that they were unreportable. In a 4-year follow-up, the study determined that there was a significant correlation between pronounced saccadic abnormalities and other neurologic parameters, including IQ and brainstem auditory function. The authors concluded that measurement of vertical saccadic eye movements could be a viable indicator of neurological deficit in GD3 patients. In keeping with that suggestion, Benko et al propose that saccadic eye movements could be a useful biomarker when patients undergo neuropsychological and neurophysiological testing. In addition to slow saccadic eye movements, virtually all patients with neuronopathic GD—even when there is normal cognition—have a deficit in eye-hand coordination seen on the Purdue Pegboard test. Future Directions: Identifying Modifier Genes That Determine GD Severity There has been exciting progress in the identification of modifier genes in GD. Although a study by Klein et al17 is not the first attempt to discover modifier genes for GD, the mouse model used in this report is an indication as to how the role of specific genes could be evaluated in neuronopathic GD. This study identified certain genes deemed to be important because of their involvement in pathways related to neuronal excitability. The genes with the highest significance in the model wereAdk (dysfunction of which may cause epileptogenesis and inflammation18), Dpp10 (malfunctioning is associated with neurodegenerative conditions like Alzheimer and frontotemporal dementia19), Ctnnd2 (deletions associated with abnormal neuronal development and with intellectual impairment20) and Grin2b. The N-methyl-D-aspartate receptor (NMDA), is a glutamate receptor and ion channel protein found in nerve cells. Grin2b codes for a subunit of this receptor. Grin2b gene variants have been implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia.21 Memantine, an antagonist of the NMDA receptor (encoded partly by Grin2b) and a drug approved by FDA for patients with moderate to severe Alzheimer’s disease significantly increased the lifespan of conduritol-B-epoxide- GD mouse strains that would otherwise have lived for only a short time17. Other potential modifier genes identified by Klein et al included Plekhf2 and Atp6v1b2, genes that are critical in endo-lysosomal biology. Klein et al conclude that activity states of modifier genes that control CNS electrophysiology, neurodevelopment, and endo-lysosomal function may help determine whether or not mice with induced glucocerebrosidase deficiency will develop symptomatic neuronopathic GD17. Presumably, modifier gene polymorphisms and disease-variants are also involved in determining human GD severity and phenotypic variability in patients with identical GBA1 genotypes. A case in point are two GD siblings in whom lymphoblastic lymphoma occurred in childhood. Whole genome testing detected a concurrent mutation in MSH6, a known cause for this type of childhood lymphoma22. Moreover, pharmacological modulation of modifier genes and their products could conceivably be used improve the clinical outcome of patients with neuronopathic GD. Summary As new therapies for lysosomal storage disorders that target both CNS and non-CNS systemic manifestations become available and patients are living longer, the natural history of these disorders is being reevaluated and redefined. Previously unknown aspects of GD3 are being revealed that are specific and unique for this heterogeneous phenotype. More information is emerging about underrecognized syndromes, the neuropathology of the disease, and biomarkers that could help identify brain pathology. One recommendation suggested by current results is that this complex disorder should be rigorously evaluated longitudinally with objective testing of neurological, neurophysiological and neuropsychological endpoints. With increasing availability of whole exome and whole genome sequencing, there should be increasing opportunities to investigate the role of modifier mutations as determinants of GD3 phenotypes and responses to new forthcoming treatments. Disclosure Statement Dr. Schiffmann has received research support and honoraria from Genzyme – a Sanofi Company, Shire HGT and Amicus Therapeutics. References 1. Grabowski GA, Beutler E (2006) The online metabolic and molecular bases of inherited diseases Chapter 146: Gaucher disease. Valle D, Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, editors New York: McGraw-Hill. 2. Stirnemann J, Belmatoug N, Camou F, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci. 2017 Feb 17;18(2). pii: E441. 3. Sidransky E. Gaucher Disease. Aug. 18,2016. http://emedicine.medscape. com/article/944157-overview#a6 12 Advances in Gaucher Disease
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