1. To study the pathogenesis and natural history of neuronopathic Gaucher disease: We concentrated on the development of novel clinical outcome measures that will enable us to follow disease progression and test novel therapies. We concluded a study of the saccadic eye movements in patients with type 3. Preliminary analysis of the data showed high reproducibility and a slow decline in saccadic velocity over the years. We also found that the patients with type 3 Gaucher disease perform abnormally on the Purdue Pegboard Test. This manual dexterity deficit was not caused by the supranuclear gaze palsy but likely by a cortical/subcortical dysfunction. This test will be useful in future clinical trials. ? ? 2. To develop novel therapies for neuronopathic Gaucher disease: We conducted a randomized controlled trial of OGT 918 (N-butyldeoxynojirimycin, miglustat) as a substrate reduction approach for the treatment of patients with neuronopathic Gaucher disease. We evaluated primarily the neurological abnormalities, and in particular the slow eye movements of these patients. Although this medication was well tolerated, it had no significant effect on the neurological aspects of this disorder. In a further effort to develop small molecule therapy for neuronopathic Gaucher patients, we initiated a study to evaluate and characterize the Ex-Vivo effect of the pharmacological chaperone isofagomine in blood cell lines derived from patients with Gaucher disease. Preliminary results showed enhanced enzyme activity by this molecule.? ? 3. To study the natural history and pathogenesis of Fabry disease: Patients with this second most common lysosomal disorder have a severely painful peripheral neuropathy, and a systemic vasculopathy leading to premature strokes, cardiac disease, and kidney insufficiency. We found clinical and laboratory evidence that reactive oxygen species have an important role in the vasculopathy of Fabry disease. Our recent finding that intracellular Gb3 is present in various cell structures in cultured cells and in intact organs of Fabry patients, even in the absence of visible storage in lysosomes, indicates numerous possible adverse interactions between this substance and critical cellular components. Using a stable isotope labeling proteomics approach, we recently discovered decreased α-2-antiplasmin and elevated vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in serum of patients with Fabry disease. It is possible that Fabry disease is associated with a mild but lifelong elevated VEGF and that this abnormality is directly responsible for the vascular damage in this disease. In response to ERT, VEGF decreased in some patients and paradoxically increased in others, suggesting heterogeneity in response to specific therapy. Using the Fabry mouse model we characterized the genomic response to ERT in the cardiovascular system. We found the partial normalization of genomic expression was associated with abnormal expression of other sets of genes. Using structural equation modeling we generated the hypothesis that αgalactosidase A is associated with abnormal expression of a number of growth factors (including α-2-antiplasmin), and ERT was associated with a counter-regulatory and adaptive response. ? ? 4. To develop novel therapies for Fabry disease: We previously performed phase I-III clinical trials of enzyme replacement therapy (ERT) in Fabry disease that included a double-blind placebo-controlled trial. We found reduction of neuropathic pain, improvement in cerebral blood flow pattern and regulation, increased sweating and evidence of slowing in the progression of renal disease in adults with Fabry disease. We recently found that increased frequency of ERT administration further slows the progression of renal disease. However, strokes continue to occur, and we do not discern a clear effect on heart disease. Since children may represent a window of therapeutic opportunity, we undertook a short-term pediatric ERT trial that showed improvement in symptoms and in the autonomic control of the heart. We are following these children on long-term ERT. We identified a limited cellular availability of the infused enzyme in patients' organs and in our Fabry disease animal model as a major potential cause of the modest effect of ERT. A differential gene expression microarray study in the αgalactosidase A knockout mouse and in patients' peripheral blood white cells also confirmed a partial correction of the genomic expression with ERT. In order to develop an alternative therapeutic approach we performed a phase II study using 1-deoxygalactonojirimycin, a pharmacological chaperone, in Fabry disease, and found that it is safe and can significantly increase α-galactosidase A activity. Its effects on the accumulated glycolipid and on the functional abnormalities are being analyzed.? ? 5. To study the pathogenesis and natural history of mucolipidosis type IV (MLIV): We continued our investigation of 35 patients with this autosomal recessive neurogenetic disorder that is caused by mutated cation channel mucolipin-1, with particular emphasis on their progressive retinal degeneration. The latter is thought to be caused by death of neurons in the retina. Using electroretinography and visual evoked potential we quantified the decline of retinal function in MLIV. This study will be useful in identifying the optimal stage for therapeutic intervention to prevent progression of the retinal dystrophy in MLIV. We studied extensively a patient with no neurological abnormalities but with progressive dystrophic retinopathy. In order to better understand the reason for his mild disease, we expressed his mutated mucolipin-1 in liposomes and found reduced current conduction compared to normal control. This finding indicates that diminished channel conduction is sufficient for normal brain development but not for maintenance of retinal neurons. ? ? 6. To study the nosology and etiology of the leukodystrophies: We continued studying the novel leukodystrophy syndrome consisting of hypomyelination, hypogonadotropic hypogonadism and hypodontia (termed 4H syndrome). Electron microscopy and myelin protein immunohistochemistry of sural nerve showed unique findings. Using proton NMR spectroscopy we identified a novel leukodystrophy syndrome associated with isolated elevation of free sialic acid in spinal fluid. In collaboration with other investigators in the field, we contributed towards the identification of the etiology of autosomal dominant leukodystrophy and leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. We also used our extensive clinical experience with the diagnosis of the leukodystrophies to initiate the development of a comprehensive algorithm for the diagnosis of white matter disorders based primarily on the characteristics of the head MRI.? ? In FY08, the lead investigator began transitioning these projects to an extramural institution.
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