Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease).

TitleUntargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease).
Publication TypeJournal Article
Year of Publication2018
AuthorsSindelar M, Dyke JP, Deeb RS, Sondhi D, Kaminsky SM, Kosofsky BE, Ballon DJ, Crystal RG, Gross SS
JournalSci Rep
Volume8
Issue1
Pagination15229
Date Published2018 10 15
ISSN2045-2322
KeywordsAcetates, Adolescent, Adult, Aged, Aminopeptidases, Animals, Biomarkers, Brain, Child, Child, Preschool, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Disease Models, Animal, Female, Humans, Male, Metabolome, Metabolomics, Middle Aged, Mitochondria, Neuronal Ceroid-Lipofuscinoses, Neurons, Serine Proteases, Severity of Illness Index, Tripeptidyl-Peptidase 1, Young Adult
Abstract

Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare lysosomal storage disorder caused by a monogenetic deficiency of tripeptidyl peptidase-1 (TPP1). Despite knowledge that lipofuscin is the hallmark disease product, the relevant TPP1 substrate and its role in neuronal physiology/pathology is unknown. We hypothesized that untargeted metabolite profiling of cerebrospinal fluid (CSF) could be used as an effective tool to identify disease-associated metabolic disruptions in CLN2 disease, offering the potential to identify biomarkers that inform on disease severity and progression. Accordingly, a mass spectrometry-based untargeted metabolite profiling approach was employed to differentiate CSF from normal vs. CLN2 deficient individuals. Of 1,433 metabolite features surveyed, 29 linearly correlated with currently employed disease severity scores. With tandem mass spectrometry 8 distinct metabolite identities were structurally confirmed based on retention time and fragmentation pattern matches, vs. standards. These putative CLN2 biomarkers include 7 acetylated species - all attenuated in CLN2 compared to controls. Because acetate is the major bioenergetic fuel for support of mitochondrial respiration, deficient acetylated species in CSF suggests a brain energy defect that may drive neurodegeneration. Targeted analysis of these metabolites in CSF of CLN2 patients offers a powerful new approach for monitoring CLN2 disease progression and response to therapy.

DOI10.1038/s41598-018-33449-0
Alternate JournalSci Rep
PubMed ID30323181
PubMed Central IDPMC6189193
Grant ListU54 NS065768 / NS / NINDS NIH HHS / United States
R01 NS061848 / NS / NINDS NIH HHS / United States
P01 HD067244 / HD / NICHD NIH HHS / United States
Related Institute: 
MRI Research Institute (MRIRI)

Weill Cornell Medicine
Department of Radiology
525 East 68th Street New York, NY 10065