of having GD, there are some distinctions that are important for diagnosing neuronopathic GD. For example, neuronopathic GD cannot be diagnosed by relying on an absolute or arbitrary level of glucocerebrosidase activity or through identification of a particular genotype. In its mildest forms, GD 3 may be missed in its early stages. This is where observation is important: there may be telltale head jerks while a patient is reading or an “eye lag” when a patient turns around while walking. Neuronopathic disease should also be suspected when there is early onset of disease, aggressive systemic disease, falling or low IQ scores in a patient with a “high risk” genotype.4 Neuropathological Differentiation of GD Type 2 and 3 from Type 1 and the Connection to Parkinson disease Among earlier studies to describe differences between the forms of GD was a report by Wong et al5 that provides insights on the pathogenesis of brain dysfunction in GD. In this study, unique pathologic patterns of disease were identified among the types of GD, thus contributing to an improved understanding of mechanisms underlying the forms of the disease. Wong et al studied brain pathology in seven subjects with GD1 (four of whom had parkinsonism and dementia), three with GD2 and four with GD3. In all three GD phenotypes, unique pathologic patterns of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were found. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were also involved in all GD patients. However, the extent of the changes varied with the severity of disease. The 7 patients with GD1 had astrogliosis in the affected areas but no neuronal loss Neuronal loss predominated in both GD2 and GD3 patients with progressive myoclonic encephalopathy. However, the adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, demonstrating differential specificity of the vulnerability of selective neurons.5 Elevated glucocerebrosidase protein expression by immunohistochemistry was found in CA2-4. Hippocampal 45Ca2+ uptake autoradiography in rat brain was performed demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced, calcium release sensitive (CICR-sensitive). The findings were in accordance with biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity.6 In two patients with GD1 and parkinsonism, numerous synuclein positive inclusions resembling brainstem type Lewy bodies were also found in hippocampal CA2- 4 neurons. Based on these findings, the authors postulated a common mechanism linking aberrant glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in GD.5 Identifying an Authentic Marker of Brain Pathology—GPNMB in Neuronopathic Disease One of the challenges in differentiating one type of disease from the others is that GD encompasses such a wide spectrum of phenotypes and diversity of severity in the same subtype. Sidransky7 for example, described it as a phenotypic continuum. In view of the wide heterogeneity of symptoms found in neuronopathic GD patients, the need for reliable biochemical biomarkers is a key focus of some recent reports. If such biomarkers were identified, perhaps efforts to evaluate candidate drugs would be enhanced. Seeking to evaluate the potential utility of a transmembrane protein expressed in various cell types, Zigdon et al8 identified glycoprotein nonmetastatic B (GPNMB) for its role as a marker for brain pathology in neuronopathic GD. In an analysis of cerebrospinal fluid samples from four GD3 patients and five age-matched controls, three independent techniques corroborated the elevation of GPNMB; this suggested that GPNMB might be a biomarker for following the progression of CNS pathology in neuronopathic GD patients. Significantly, levels of the protein directly correlated with disease severity: higher CSF levels of GPNMB correlated with more severe disease symptoms (assessed by full scale IQ and eye-hand coordination). In a mouse model of GD, GPNMB levels in the CSF also correlated with more severe disease. One question raised by the study—based on additional reports suggesting that GPNMB might be a useful biomarker in other settings such as deterioration in neurodegenerative diseases and inflammatory disease—is whether GPNMB, which is secreted from macrophages, may be elevated to moderate the inflammatory response, such as what occurs in neuronopathic GD. Indeed, GPNMB was found to be elevated in blood of patients with GD1.9 Differentiating GD2 from GD3 Because of the prognostic and therapeutic implications, it is important to discriminate between the two types of neuronopathic Gaucher disease. It is relatively easy to identify the severe forms of GD2, but less so in patients with milder forms. One report offers clues as to how the two neuronopathic forms of GD may be differentiated based on skin findings. In GD2, there is an increased ratio of epidermal glucosylceramide to ceramide and widespread ultrastructural abnormalities that is not present in GD3.3 Lessons from Egypt: A Distinct Phenotype With a Different Clinical Outcome Reports over the last 10 years have focused attention on GD3 in several populations, including the predominance in China, Korea, and Egypt, as noted earlier. The hypothesis of Abdelwahab et al10 is intriguing: because enzyme replacement therapy (ERT) has no reported direct effect on the neurologic aspects of the disease,11,12 if a large cohort of patients could be studied who have been treated with ERT, more information could be obtained on the intrinsic natural history of the CNS pathophysiology in type 3 GD. In a prospective cohort study, the authors followed 78 GD3 patients on ERT for up to 9 years with yearly evaluations that included EEG and cognitive testing.10 Of this cohort 73% had the most common GBA1 genotype known to be associated with neuronopathic Gaucher disease—L444P/L444P. In 91% of the patients, supranuclear gaze palsy with variable but stable cognitive function was observed. The other highlights from this study included the following: 10 Advances in Gaucher Disease
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