Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses

Abstract

The gangliosidoses (Tay-Sachs disease, Sandhoff disease, and GM1-gangliosidosis) are progressive neurodegenerative diseases caused by lysosomal enzyme activity deficiencies and consequent accumulation of gangliosides in the central nervous system (CNS). The infantile forms are distinguished from the juvenile forms by age of onset, rate of disease progression, and age of death. There are no approved treatments for the gangliosidoses. In search of potential biomarkers of disease, we quantified 188 analytes in CSF and serum from living human patients with longitudinal (serial) measurements. Notably, several associated with inflammation were elevated in the CSF of infantile gangliosidosis patients, and less so in more slowly progressing forms of juvenile gangliosidosis, but not in MPS disease. Thirteen CSF and two serum biomarker candidates were identified. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1α, MIP-1β, and TNFR2. Correspondence of abnormal elevation with other variables of disease-i.e., severity of clinical phenotype, differentiation from changes in serum, and lack of abnormality in other neurodegenerative lysosomal diseases-identifies these analytes as biomarkers of neuropathology specific to the gangliosidosis diseases.

Keywords: GM1-gangliosidosis; Ganglioside; Glycosphingolipid; Metabolomic; Sandhoff disease; Tay–Sachs disease.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Fig. 1

Among gangliosidosis (Gang) patients (left-side charts), five CSF analytes of inflammation were consistently elevated in patients with the infantile-onset disease in contrast to the normal levels found in patients with juvenile-onset disease. This relationship of severity of disease to analyte elevation is important, this correspondence reflecting the rate of disease progression. CSF and serum inflammatory biomarkers from patients with MPS diseases (right-side charts) showed no abnormalities in either serum or CSF. The analyte differences between gangliosidosis disease and MPS disease emphasize the value of these inflammatory biomarkers, and illustrate that the analyte abnormalities are not general indicators of lysosomal storage or dysfunction, but reflect some other pathologic mechanism of gangliosidosis disease in the central nervous system.

Fig. 1

Among gangliosidosis (Gang) patients (left-side charts), five CSF analytes of inflammation were consistently elevated in patients with the infantile-onset disease in contrast to the normal levels found in patients with juvenile-onset disease. This relationship of severity of disease to analyte elevation is important, this correspondence reflecting the rate of disease progression. CSF and serum inflammatory biomarkers from patients with MPS diseases (right-side charts) showed no abnormalities in either serum or CSF. The analyte differences between gangliosidosis disease and MPS disease emphasize the value of these inflammatory biomarkers, and illustrate that the analyte abnormalities are not general indicators of lysosomal storage or dysfunction, but reflect some other pathologic mechanism of gangliosidosis disease in the central nervous system.