Session Time: 1:45pm-3:15pm
Location: Hall 3FG
Objective: ALSP belongs to the large group of rare neurogenetic, adult-onset leukodystrophies. For most of these leukodystrophies, including ALSP, no causative treatment exists. Biomarkers facilitate the diagnostic workup and the monitoring of therapeutic agents. This study aimed at evaluating chitotriosidase activity for its potential as biomarker in ALSP.
Background: ALSP is a devastating disease characterized by rapidly progressing motor impairment and cognitive decline. It is caused by autosomal-dominant mutations in the gene Colony-stimulating factor 1 receptor (CSF1R) . In the CNS, the principal cell type expressing CSF1R is microglia, the tissue-resident macrophage of the brain. CSF1R signalling is crucial for microglia survival, suggesting that impaired microglia function might be responsible for the pathological changes in ALSP.
Methods: Serum and/or CSF from 8 ALSP patients, and 7 presymptomatic carriers with genetically confirmed CSF1R mutation were obtained during routine diagnostic workup. Control CSF was obtained from 10 healthy controls from the HIH Biobank, University of Tuebingen. Chitotriosidase activity was measured according to Hollak et al. . Statistical significance was assessed by t- or Mann-Whitney-test using GraphPad Prism 7. Results are mean ± SEM.
Results: As a specialised centre for adult-onset leukodystrophies we have noticed during routine diagnostic workup that among symptomatic patients later diagnosed with ALSP (n=8), serum chitotriosidase activity level was repeatedly at the upper limit of the normal range. This led us to the analysis of chitotriosidase in the CSF of ALSP patients, as the CNS is the compartment most affected by cell degeneration. We found CSF chitotriosidase to be highly increased (73.88 ± 20.45 nmol/h/ml) compared to controls (2.1 ± 0.53 nmol/h/ml; n=10; p=0.0011) (Figure 1). We next addressed the question whether chitotriosidase is also elevated in serum of presymptomatic CSF1R mutation carriers. The levels were not elevated (23.86 ± 3.25 nmol/h/ml; n=7), but significantly lower than those of ALSP patients (44.13 ±7.47; p=0.0256) (Figure 2).
Conclusions: We found highly increased CSF chitotriosidase levels in ALSP patients compared to controls. In serum, the level in ALSP patients was significantly higher than in CSF1R mutation carriers, indicating that an increase in chitotriosidase concentration is associated with a symptomatic state. Whether chitotriosidase can serve as a diagnostic biomarker for ALSP has to be evaluated by analysing its levels in other leukencephalopathies with similar clinical presentation. Likewise, longitudinal measurements of chitotriosidase will reveal whether the enzyme is suitable as a monitoring marker for disease progression and treatment response.
References: 1. Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, et al.: Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 2012, 44:200–5. 2. Hollak CEM, Van Weely S, Van Oers MHJ, Aerts JMFG: Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 1994, 93:1288–1292.
To cite this abstract in AMA style:S. Hayer, J. Böhringer, L. Schöls. Chitotriosidase is a biomarker for Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/chitotriosidase-is-a-biomarker-for-adult-onset-leukoencephalopathy-with-axonal-spheroids-and-pigmented-glia-alsp/. Accessed December 1, 2023.
« Back to 2018 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/chitotriosidase-is-a-biomarker-for-adult-onset-leukoencephalopathy-with-axonal-spheroids-and-pigmented-glia-alsp/