Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.

Original publication

DOI

10.1172/JCI72835

Type

Journal article

Journal

J Clin Invest

Publication Date

03/2014

Volume

124

Pages

1320 - 1328

Keywords

1-Deoxynojirimycin, 2-Hydroxypropyl-beta-cyclodextrin, Animals, B-Lymphocytes, Biomarkers, Bone Marrow Transplantation, Case-Control Studies, Child, Child, Preschool, Humans, Infant, Lysosomes, Mice, Mice, Inbred BALB C, Mice, Knockout, Niemann-Pick Disease, Type C, Prospective Studies, Proteins, Severity of Illness Index, Treatment Outcome, beta-Cyclodextrins