Akademik Veri Yönetim Sistemi
MOVEMENT DISORDERS, cilt.39, sa.12, ss.2291-2297, 2024 (SCI-Expanded, Scopus)
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 mono-nuclear cells (PBMCs) and to validate its diagnostic bio-marker 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 bio-marker 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.