The ultra-rare lysosomal diseases collectively affect 1 in 3,000 individuals and are responsible for significant morbidity and disability. The Lysosomal Disease Network (LDN) has created a community of clinical investigators, patient advocacy groups (PAG), and other interested parties, to become a synergistic research and educational consortium advocating advancement of treatment for these diseases. In the past three decades, lysosomal diseases have been a test bed for some of the most innovative therapeutic modalities. In the past 4 years of NIH funding, the LDN has accelerated knowledge acquisition in the field - with 33 MyNCBI cited publications, and 12 more in press/review/preparation-and furthered the development of therapeutic options. For the next 5 years, this proposal describes 9 longitudinal studies of natural history and/or treatment, and 5 pilot studies for novel ideas under the central theme of """"""""discovery in ultra-orphan diseases"""""""". Because central nervous system (CNS) disease is the most difficult to treat and measure, there is a major emphasis on quantitative analysis of CNS structure, function and biomarkers for relevant conditions: mucopolysaccharidoses (MPS), mucolipidosis IV, Batten disease, gangliosidoses (Tay-Sachs, Sandhoff and GM1 gangliosidosis diseases), globoid cell leukodystrophy. Projects will (a) evaluate immune modulatory factors affecting treatment response in Pompe disease;(b) assess bone disease in MPS, (c) correlate renal structure and function in Fabry disease;(d) search for undiagnosed Fabry disease in high-risk populations;(e) determine outcomes of newborn screening for Krabbe disease;and (f) shorten the diagnostic odyssey. Productivity is assured by a new performance-based model, with proposals initially vetted for rigorous statistical significance, and reimbursement to investigators governed by DMCC data submission. In addition, this network: (a) supports two postdoctoral fellows each year;(b) organizes a scientific meeting """"""""WORLD Symposium"""""""" published annually (February, Molecular Genetics &Metabolism);and (c) a didactic course for experts, """"""""Lysosomes 101"""""""". Global communication is provided by a list-serve with more than 3,000 subscribers, webinars, and the website

Public Health Relevance

The combined and integrated efforts of the Lysosomal Disease Network focus limited resources toward creating a network of centers with expertise in these diseases in order to solve major challenges in diagnosis, disease management, and therapy. Solutions to these problems will have direct impact on patients suffering from lysosomal diseases, with important implications for medical practice and individual quality-of-life.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Schools of Medicine
United States
Zip Code
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 :

Showing the most recent 10 out of 118 publications