This gangliosidosis project will include two studies: 1) Continuation of LDN6713 Natural History of Hexosaminidase Deficiencies and Other Gangliosidoses for patients of all ages with a gangliosidosis disease;2) Syner-G treatment regimen (""""""""synergistic enteral regimen for the gangliosidoses"""""""") for patients with infantile or juvenile forms of the gangliosidoses. Pediatric patients may simutaneously participate in both studies. The Syner-G regimen is a combination, multi-targeted combination therapy for treatment of the gangliosidoses, using FDA approved therapies that have demonstrated safety in children: miglustat, ketogenic diet to minimize gastrointestinal side effects of miglustat and optimize seizure management, and pyrimethamine for patients with mutations responsive to pyrimethamine. The infantile and juvenile forms of gangliosidosis are lethal during childhood. This gangliosidosis project provides a method for systematically gathering serial prospective, retrospective and natural history clinical data, including data on treatments tried by the patient. The ability to participate in the Syner-G treatment protocol, or other clinical treatment trials that may become available, allows for participation of patients who may otherwise be excluded from a natural history study.
Specific Aim 1 : To characterize and describe disease progression and heterogeneity in the gangliosidosis disorders. This natural history study (LDN 6713) seeks to develop quantitative methods to delineate disease progression for the gangliosidosis disorders (Tay-Sachs, Sandhoff, and GM1-gangliosidosis diseases) to better understand the natural history and heterogeneity of disease. Such quantitative methods will also be essential for evaluating any treatments that may become available in the future, such as gene therapy.
Specific Aim 2 : We hypothesize that a combination, multi-targeted therapy for pediatric gangliosidoses, using miglustat with the ketogenic dietand pyrimethamine for patients with responsive mutationswill create synergisms that improve neurodevelopmental outcomes of therapy compared to data reported in previous natural history studies, and previous studies using monotherapy with miglustat.

Public Health Relevance

Gangliosidoses are catastrophic neurodegenerative diseases with lethality during childhood in infantile and juvenile forms and for which no FDA approved treatments exist. Current knowledge of the natural history of gangliosidoses, crucial for treatment development, is limited. Monotherapy with miglustat and pyrimethamine have not shown significant clinical improvement. This project will allow continuation of natural history data collection while simultaneously providing option to participate in a synergistic combination therapy Syner-G.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
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Morris, Jill A
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University of Minnesota Twin Cities
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Ou, Li; Przybilla, Michael J; Whitley, Chester B (2018) Metabolomics profiling reveals profound metabolic impairments in mice and patients with Sandhoff disease. Mol Genet Metab :
McIntosh, Paul T; Hobson-Webb, Lisa D; Kazi, Zoheb B et al. (2018) Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy. Mol Genet Metab 123:85-91
Nestrasil, Igor; Ahmed, Alia; Utz, Josephine M et al. (2018) Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. Mol Genet Metab 123:97-104
Ou, Li; Przybilla, Michael J; Koniar, Brenda et al. (2018) RTB lectin-mediated delivery of lysosomal ?-l-iduronidase mitigates disease manifestations systemically including the central nervous system. Mol Genet Metab 123:105-111
Desai, Ankit K; Walters, Crista K; Cope, Heidi L et al. (2018) Enzyme replacement therapy with alglucosidase alfa in Pompe disease: Clinical experience with rate escalation. Mol Genet Metab 123:92-96
Sindelar, Miriam; Dyke, Jonathan P; Deeb, Ruba S et al. (2018) Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease). Sci Rep 8:15229
Shapiro, Elsa G; Whitley, Chester B; Eisengart, Julie B (2018) Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome. Orphanet J Rare Dis 13:76
Ou, L; Przybilla, M J; Whitley, C B (2018) SAAMP 2.0: An algorithm to predict genotype-phenotype correlation of lysosomal storage diseases. Clin Genet 93:1008-1014
Eisengart, Julie B; Rudser, Kyle D; Xue, Yong et al. (2018) Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison. Genet Med 20:1423-1429
Kazi, Zoheb B; Desai, Ankit K; Troxler, R Bradley et al. (2018) An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease. Genet Med :

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