Sacsin levels in PBMCs: A diagnostic assay for SACS variants in peripheral blood cells – A PROSPAX study

• Published in: Movement disorders 2024-12, Vol.39 (12), p.2291-2297
• Main Authors: Tunca, Ceren, İşlek Camadan, Eylül Ece, Smolina, Natalia, Palvadeau, Robin J., Öztop Çakmak, Özgür, Vural, Atay, Traschütz, Andreas, Santorelli, Filippo M., Brais, Bernard, Schüle, Rebecca, Synofzik, Matthis, Başak, A. Nazlı
• Format: Article
• Language: English
• Subjects: Adult; ARSACS; Ataxia; Biomarkers; Biomarkers - blood; Blood cells; Blood levels; diagnostic assay; Female; Fibroblasts; Fibroblasts - metabolism; Heat-Shock Proteins - genetics; Heterozygote; Humans; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Male; Molecular weight; Muscle Spasticity - diagnosis; Muscle Spasticity - genetics; PBMC; Peripheral blood mononuclear cells; Phenotypes; Spinocerebellar Ataxias - blood; Spinocerebellar Ataxias - congenital; Spinocerebellar Ataxias - diagnosis; Spinocerebellar Ataxias - genetics
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.30012

Background Autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) is a common recessive ataxia that is still underdiagnosed worldwide. An easily accessible diagnostic biomarker might help to diagnostically confirm patients presenting SACS variants of unknown significance (VUS) or atypical phenotypes. Objectives To detect sacsin in peripheral blood mononuclear cells (PBMCs) and to validate its diagnostic biomarker quality to discriminate biallelic SACS patients (including patients with VUS and/or atypical phenotypes) against healthy controls, non‐ARSACS spastic ataxia patients, and heterozygous SACS carriers. Methods Sacsin protein levels in PBMCs were assessed in patients versus controls and validated in skin‐derived fibroblasts. Results Patients with biallelic SACS variants – including patients with VUS and/or atypical phenotypes – showed loss of sacsin in PBMCs, with discriminative performance against healthy, heterozygous, and non‐ARSACS controls. This included all investigated SACS missense variants. Also, C‐terminal variants escaping nonsense‐mediated decay, while not differing from controls in expression level, showed lower molecular weight in this assay. Conclusions Assessing sacsin levels using PBMCs offers an easy, peripherally accessible diagnostic biomarker for ARSACS, with PBMCs being much less invasive and easier to handle than fibroblasts. Additionally, this might be a potential target‐engagement blood biomarker for sacsin‐increasing therapies.