Serum Neurofilament Light Chain in Replication Factor Complex Subunit 1 CANVAS and Disease Spectrum

Author:

Quartesan Ilaria12,Vegezzi Elisa12,Currò Riccardo13,Heslegrave Amanda45,Pisciotta Chiara6,Iruzubieta Pablo7,Salvalaggio Alessandro8,Fernández‐Eulate Gorka9,Dominik Natalia3,Rugginini Bianca1,Manini Arianna310,Abati Elena311,Facchini Stefano2,Manso Katarina12,Albajar Ines7,Laban Rhiannon5,Rossor Alexander M.3,Pichiecchio Anna12,Cosentino Giuseppe12,Saveri Paola6,Salsano Ettore6ORCID,Andreetta Francesca6,Valente Enza M.12ORCID,Zetterberg Henrik45121314,Giunti Paola15,Stojkovic Tanya9,Briani Chiara8,López de Munain Adolfo7,Pareyson Davide6,Reilly Mary M.3,Houlden Henry3ORCID,Tassorelli Cristina12,Cortese Andrea13ORCID

Affiliation:

1. Department of Brain and Behavioral Sciences University of Pavia Pavia Italy

2. IRCCS Mondino Foundation Pavia Italy

3. Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London United Kingdom

4. Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology London United Kingdom

5. UK Dementia Research Institute at UCL London United Kingdom

6. Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

7. Neurology Department, Donostia University Hospital Osakidetza, and Biodonostia Health Research Institute‐UPV‐EHU San Sebastián Spain

8. Department of Neuroscience University of Padova Padova Italy

9. Neuro‐myology Department, Institut de Myologie, Pitié‐Salpêtriére Hospital APHP, Sorbonne University Paris France

10. Department of Neurology and Laboratory of Neuroscience IRCCS Istituto Auxologico Italiano Milan Italy

11. Department of Pathophysiology and Transplantation (DEPT) University of Milan Milan Italy

12. Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

13. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden

14. Hong Kong Center for Neurodegenerative Diseases Clear Water Bay Hong Kong China

15. Department of Clinical and Movement Neuroscience UCL Queen Square Institute of Neurology London United Kingdom

Abstract

AbstractBackgroundBiallelic intronic AAGGG repeat expansions in the replication factor complex subunit 1 (RFC1) gene were identified as the leading cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome. Patients exhibit significant clinical heterogeneity and variable disease course, but no potential biomarker has been identified to date.ObjectivesIn this multicenter cross‐sectional study, we aimed to evaluate neurofilament light (NfL) chain serum levels in a cohort of RFC1 disease patients and to correlate NfL serum concentrations with clinical phenotype and disease severity.MethodsSixty‐one patients with genetically confirmed RFC1 disease and 48 healthy controls (HCs) were enrolled from six neurological centers. Serum NfL concentration was measured using the single molecule array assay technique.ResultsSerum NfL concentration was significantly higher in patients with RFC1 disease compared to age‐ and‐sex‐matched HCs (P < 0.0001). NfL level showed a moderate correlation with age in both HCs (r = 0.4353, P = 0.0020) and patients (r = 0.4092, P = 0.0011). Mean NfL concentration appeared to be significantly higher in patients with cerebellar involvement compared to patients without cerebellar dysfunction (27.88 vs. 21.84 pg/mL, P = 0.0081). The association between cerebellar involvement and NfL remained significant after controlling for age and sex (β = 0.260, P = 0.034).ConclusionsSerum NfL levels are significantly higher in patients with RFC1 disease compared to HCs and correlate with cerebellar involvement. Longitudinal studies are warranted to assess its change over time.

Funder

Fondazione Cariplo

Fondazione Regionale per la Ricerca Biomedica

Medical Research Council

Ministero della Salute

Ministero dell'Università e della Ricerca

Publisher

Wiley

Subject

Neurology (clinical),Neurology

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