Work

Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA

Year: 2026

Type: article

Abstract: Mitochondrial diseases are genetic disorders caused either by nuclear or mitochondrial DNA (mtDNA) alterations and characterized by high genetic and phenotypic variability. The common mtDNA m.3243 A > G variant in the MT-TL1 gene leads to clinical manifestations ranging from the classical MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome to milder phenotypes such as MIDD (maternally inherited diabetes and deafness) or a spectrum of clinical features of intermediate severity defined as MELAS-Spectrum. The heterogeneous disease course makes the identification of biomarkers for monitoring disease progression challenging, particularly if we consider the occurrence of stroke-like episodes (SLEs), which remain unpredictable events. Here, we assessed two biomarkers, neurofilament light chain (NF-L) and circulating cell free-mtDNA (ccf-mtDNA), in a cross-sectional study in MELAS patients, including both patients in the interictal period and during SLEs, and MELAS-Spectrum patients. Both biomarkers were significantly elevated in MELAS patients during SLEs, compared to the other patients. In addition, we found significant correlation between NF-L and m.3243 A > G blood heteroplasmy in MELAS patients, as well as between NF-L and clinical severity in the whole patients cohort. Despite the limitations derived from the small sample size and the cross-sectional sample collection, our study confirms the value of NF-L and ccf-mtDNA as biomarkers efficiently hallmarking SLEs, highlighting their potential use to monitor the progression of MELAS.

Source: Molecular Genetics and Metabolism

DOI: 10.1016/j.ymgme.2026.109753