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Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy

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Journal of Neurology

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Open Access 06-09-2024 | Spinal Muscular Atrophy | Short Commentary

Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy

Authors: Vera Dobelmann, Andreas Roos, Andreas Hentschel, Adela Della Marina, Markus Leo, Linda-Isabell Schmitt, Lorenzo Maggi, Ulrike Schara-Schmidt, Tim Hagenacker, Tobias Ruck, Heike Kölbel

Published in: Journal of Neurology | Issue 10/2024

Abstract

Background and purpose

Spinal muscular atrophy (SMA) as the second most common neurodegenerative disorder in childhood is characterized by the deficiency of survival of motor neuron (SMN) protein leading predominantly to degeneration of alpha motor neurons and consequently to progressive muscle weakness and atrophy. Besides some biomarkers like SMN2 copy number therapeutic biomarkers for SMA with known relevance for neuromuscular transmission are lacking. Here, we examined the potential of Thrombospondin-4 (TSP4) to serve as a cerebrospinal fluid (CSF) biomarker, which may also indicate treatment response.

Methods

We used untargeted proteomic analyses to determine biomarkers in CSF samples derived from pediatric pre-symptomatic (n = 6) and symptomatic (n = 4) SMA patients. The identified biomarker TSP4 was then validated in additional 68 CSF samples (9 adult and 24 pediatric SMA patients, 5 adult and 13 pediatric non-disease controls in addition to 17 pediatric disease controls) by enzyme-linked immunosorbent assay (ELISA) as an additional analytical approach.

Results

Untargeted proteomic analyses of CSF identified a dysregulation of TSP4 and revealed a difference between pre-symptomatic SMA patients and patients identified after the onset of first symptoms. Subsequent ELISA-analyses showed that TSP4 is decreased in pediatric but not adult SMA patients. CSF of pediatric patients with other neurological disorders demonstrated no alteration of TSP4 levels. Furthermore, CSF TSP4 levels of pediatric SMA patients increased after first dose of Nusinersen.

Conclusions

We found that TSP4 levels are exclusively reduced in CSF of pediatric SMA patients and increase after treatment, leading us to the hypothesis that TSP4 could serve as a CSF biomarker with the potential to monitor treatment response in pediatric SMA patients. Moreover, TSP4 enable to distinguish pre-symptomatic and symptomatic patients suggesting a potential to serve as a stratification marker.

Available only for authorised users

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Title: Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy
Authors: Vera Dobelmann
Andreas Roos
Andreas Hentschel
Adela Della Marina
Markus Leo
Linda-Isabell Schmitt
Lorenzo Maggi
Ulrike Schara-Schmidt
Tim Hagenacker
Tobias Ruck
Heike Kölbel
Publication date: 06-09-2024
Publisher: Springer Berlin Heidelberg
Keywords: Spinal Muscular Atrophy
Biomarkers
Published in: Journal of Neurology / Issue 10/2024
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-024-12670-0

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Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy

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