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Evaluation of cerebrospinal fluid biomarkers in pediatric patients with spinal muscular atrophy

      Abstract

      Background

      Spinal muscular atrophy (SMA) is a rare neuromuscular disorder characterised by muscle weakness and muscle atrophy and classified into five known subtypes based on clinical features. The recent development of novel drugs to treat SMA has been encouraging, and nusinersen is the first drug approved to treat SMA.

      Objective

      To explore cerebrospinal fluid (CSF) biomarkers of SMA and investigate their relationship with symptoms and the treatment response in pediatric patients.

      Methods

      We analyzed the CSF levels of chitotriosidase 1 (CHIT1) and inflammatory cytokines (tumor necrosis factor [TNF]-α and interferon [INF]-γ) using enzyme-linked immunosorbent assays in pediatric SMA patients treated at Hiroshima University Hospital over 2 years.

      Results

      This study analyzed pediatric SMA patients. While the CSF inflammatory cytokines (TNF-α and INF-γ) in these SMA children were unchanged, the CHIT1 levels decreased significantly from year 1 to 2 of treatment. We also found a trend toward an inverse correlation between the motor function score (HINE-2 scores) and CHIT1 level from year 1 to 2 of treatment.

      Conclusions

      CHIT1 may be a CSF biomarker of the treatment response in pediatric SMA.

      Keywords

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      References

        • Sugarman E.A.
        • Nagan N.
        • Zhu H.
        • Akmaev V.R.
        • Zhou Z.
        • Rohlfs E.M.
        • et al.
        Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of 972,400 specimens.
        Eur J Hum Genet. 2012; 20: 27-32
        • Finkel R.S.
        • Chiriboga C.A.
        • Vajsar J.
        • Day J.W.
        • Montes J.
        • De Vivo D.C.
        • et al.
        Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open label, dose-escalation study.
        Lancet. 2016; 388: 3017-3026
        • Pino M.G.
        • Rich K.A.
        • Kolb S.J.
        Update on biomarkers in spinal muscular atrophy.
        Biomarkers Insights. 2021; 16: 1-14
        • Rosa M.D.
        • Dell’Ombra N.
        • Zambito A.M.
        • Malaguarnera M.
        • Nicoletti F.
        • Malaguarnera L.
        Chitotriosidase and inflammatory mediator levels in Alzheimer’s disease and cerebrovascular dementia.
        Eur J Neurosci. 2006; 23: 2648-2656
        • Verbeek M.M.
        • Notting E.A.
        • Faas B.
        • Claessens-Linskens R.
        • Jongen P.J.H.
        Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis.
        Acta Neurol Scand. 2010; 121: 309-314
        • Ando S.
        • Osanai D.
        • Takahashi K.
        • Nakamura S.
        • Shimazawa M.
        • Hara H.
        Survival motor neuron protein regulates oxidative stress and inflammatory response in microglia of the spinal cord in spinal muscular atrophy.
        J Pharm Sci. 2020; 144: 204-211
        • Freigang M.
        • Steinacker P.
        • Wurster C.D.
        • Schreiber-Katz O.
        • Osmanovic A.
        • Petri S.
        • et al.
        Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy.
        Orphanet J Rare Dis. 2021; 16330
        • Passini M.A.
        • Bu J.
        • Richards A.M.
        • Kinnecom C.
        • Sardi S.P.
        • Stanek L.M.
        • et al.
        Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy.
        Sci Transl Med. 2011; 3
        • Varghese A.M.
        • Ghosh M.
        • Bhagat S.K.
        • Vijayalakshmi K.
        • Preethish-Kumar V.
        • Vengalil S.
        • et al.
        Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation.
        J Neuroinflammation. 2020; 17232
        • Drannik A.
        • Martin J.
        • Peterson R.
        • Ma X.
        • Jiang F.
        • Turnbull J.
        • et al.
        Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function.
        PLoS ONE. 2017; 12
        • Olsson B.
        • Malmeström C.
        • Basun H.
        • Annas P.
        • Höglund K.
        • Lannfelt L.
        • et al.
        Extreme stability of chitotriosidase in cerebrospinal fluid makes it a suitable marker for microglial activation in clinical trials.
        J Alzheimers Dis. 2012; 32: 273-276