156P Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma in clinically silent and childhood-onset SMA individuals from Serbia

Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. We conducted a longitudinal prospective study to evalu...

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Published in:	Neuromuscular disorders : NMD Vol. 43; p. 104441
Main Authors:	Brkusanin, M., Kosac, A., Brankovic-Sreckovic, V., Jovanovic, K., Karanovic, J., Matijasevic Jokovic, S., Garai, N., Pesovic, J., Radovanovic, N., Radenkovic, L., Dobrijevic, Z., Nikolic, D., Stevic, Z., Brajuskovic, G., Milic-Rasic, V., Savic-Pavicevic, D.
Format:	Journal Article
Language:	English
Published:	Elsevier B.V 01-10-2024
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Summary:	Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n=6, type 2: n=17, type 3: n=6). pNF-H levels before and during treatment were compared with the levels of controls (n=22), patients with Duchenne muscular dystrophy (n=17), myotonic dystrophy type 1 (n=11), untreated SMA individuals with chronic type 3 disease (n=8), and children with presymptomatic SMA (n=3). SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (for SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Clinically silent infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.
ISSN:	0960-8966
DOI:	10.1016/j.nmd.2024.07.600