Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker
Danielle te Vruchte, … , Mario Cortina-Borja, Frances M. Platt
Danielle te Vruchte, … , Mario Cortina-Borja, Frances M. Platt
Published February 3, 2014
Citation Information: J Clin Invest. 2014;124(3):1320-1328. https://doi.org/10.1172/JCI72835.
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Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker

Abstract

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.

Authors

Danielle te Vruchte, Anneliese O. Speak, Kerri L. Wallom, Nada Al Eisa, David A. Smith, Christian J. Hendriksz, Louise Simmons, Robin H. Lachmann, Alison Cousins, Ralf Hartung, Eugen Mengel, Heiko Runz, Michael Beck, Yasmina Amraoui, Jackie Imrie, Elizabeth Jacklin, Kate Riddick, Nicole M. Yanjanin, Christopher A. Wassif, Arndt Rolfs, Florian Rimmele, Naomi Wright, Clare Taylor, Uma Ramaswami, Timothy M. Cox, Caroline Hastings, Xuntian Jiang, Rohini Sidhu, Daniel S. Ory, Begona Arias, Mylvaganam Jeyakumar, Daniel J. Sillence, James E. Wraith, Forbes D. Porter, Mario Cortina-Borja, Frances M. Platt

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Figure 2

Relative LE/Lys volume identifies pediatric patients with NPC1 disease.

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Relative LE/Lys volume identifies pediatric patients with NPC1 disease. ...
Data were collected prospectively on NPC1 patients (n = 97, aged 2 months to 53 years), heterozygous carriers (NPC Het; n = 40, aged 23 to 76 years), age-matched controls (n = 53, aged 4 months to 64 years), and 2 pediatric patients with Tay-Sachs disease (TS). (A) Lysotracker values from circulating B cells were measured by flow cytometry and plotted against patient age. Each patient only appears once, standardized to the first sample analyzed for each patient. ***P < 0.01. (B) When the same patients’ data were plotted as unadjusted severity score (with higher value denoting greater disease burden) against age, multiple subgroups were identified. These were designated according to decreasing severity, from the severest (subgroup a) to the mildest (subgroup f). Rate of change per year is indicated for each subgroup. (C) Total severity score (without hearing, as this was not measured by all clinical centers) for each patient was divided by patient age to generate ASIS. When plotted against MEFL, a statistically significant correlation was found (P = 0.017). (D) When each patient’s plasma cholestane-3β,5α,6β-triol level was plotted against their MEFL value, a statistically significant correlation was observed in all patients (P < 0.01). A piecewise linear model significantly improved the goodness-of-fit with respect to a single linear model (P < 0.001); in this model, the initial slope was significant (P = 0.015), and the second was not (P = 0.228), with the estimated change point being 21,269 MEFL.