Type 1 Gaucher disease (GDI) is the most common form of the disorder with an incidence of 1 in 50,000 births. The underlying problem is accumulation of glucocerebroside due to a lysosomal enzyme deficiency, which may cause oxidative stress and inflammation contributing to the onset of symptoms. Standard texts state that GDI does not involve the brain. This view is now being challenged based on imaging, postmortem, and clinical studies. For example, individuals with GDI have an elevated risk of Parkinson's disease, indicating brain involvement. Current therapies significantly improved outcomes, but do not completely return glucocerebroside levels to the normal range nor completely resolve symptoms or prevent continuing tissue injury. Thus, additional treatments that target oxidative stress and inflammation have the potential to ameliorate both systemic and brain symptoms and may alter disease progression. Our central hypothesis is that relative to healthy subjects, GDI patients exhibit increased systemic and brain oxidative stress and inflammation. Further, we hypothesize that antioxidant/anti-inflammatory therapy can improve oxidative stress/inflammation in GDI patients. We propose the following aims to test these hypotheses.
In Aim 1 we will compare in GDI patients and healthy subjects oxidative stress and inflammatory markers in plasma and blood using bioanalytical methods and in brains using magnetic resonance spectroscopy.
In Aim 2 we will study GDI patients to: a) determine if oral N-acetylcysteine (NAC) improves plasma, blood and brain measures of oxidative stress and inflammation;b) evaluate correlations between plasma/blood NAC, cysteine, and glutathione (GSH) concentrations with brain GSH levels;and c) characterize NAC and GSH pharmacokinetics using validated bioanalytical methods and construct models linking pharmacokinetics with biomarkers. Impact: our results will lead to a greater understanding of GDI pathophysiology;identify potential biomarkers for use in diagnosis, monitoring disease progression, and therapy;provide information needed to determine if phase III clinical trials of NAC or other antioxidants/anti-inflammatories are warranted; and guide study design and sample size estimation.

Public Health Relevance

Current therapeutic interventions for GD1 have improved outcomes, but patients continue to suffer from persistent symptoms such as pain, fatigue, and joint stiffness that limit their quality of life and substantially increase health care costs. Oxidative stress and/or inflammation may cause or contribute to these symptoms, but systematic studies are needed to determine if this is the case. The availability of low cost, safe antioxidant/anti-inflammatory therapy offers the potential to correct this problem and improve outcomes.

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
United States
Zip Code
Mauer, Michael; Glynn, Emily; Svarstad, Einar et al. (2014) Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. PLoS One 9:e112188
Rumsey, Robin K; Rudser, Kyle; Delaney, Kathleen et al. (2014) Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr 164:1147-1151.e1
Schiffmann, Raphael; Forni, Sabrina; Swift, Caren et al. (2014) Risk of death in heart disease is associated with elevated urinary globotriaosylceramide. J Am Heart Assoc 3:e000394
Polgreen, Lynda E; Thomas, William; Fung, Ellen et al. (2014) Low bone mineral content and challenges in interpretation of dual-energy X-ray absorptiometry in children with mucopolysaccharidosis types I, II, and VI. J Clin Densitom 17:200-6
Polgreen, Lynda E; Thomas, William; Orchard, Paul J et al. (2014) Effect of recombinant human growth hormone on changes in height, bone mineral density, and body composition over 1-2 years in children with Hurler or Hunter syndrome. Mol Genet Metab 111:101-6
Stevenson, David A; Rudser, Kyle; Kunin-Batson, Alicia et al. (2014) Biomarkers of bone remodeling in children with mucopolysaccharidosis types I, II, and VI. J Pediatr Rehabil Med 7:159-65
Prater, Sean N; Banugaria, Suhrad G; Morgan, Claire et al. (2014) Letter to the Editors: Concerning "CRIM-negative Pompe disease patients with satisfactory clinical outcomes on enzyme replacement therapy" by Al Khallaf et al. J Inherit Metab Dis 37:141-3
Schiffmann, Raphael; Mayfield, Joan; Swift, Caren et al. (2014) Quantitative neuroimaging in mucolipidosis type IV. Mol Genet Metab 111:147-51
Wang, Raymond Y; Braunlin, Elizabeth A; Rudser, Kyle D et al. (2014) Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness. Mol Genet Metab 111:128-32
Ahmed, Alia; Whitley, Chester B; Cooksley, Renee et al. (2014) Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the *-L-iduronidase gene in Hurler-Scheie syndrome. Mol Genet Metab 111:123-7

Showing the most recent 10 out of 34 publications