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

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.