From Molecule to Meaning: Neuronopathic Biomarkers and Clinical Relevance in GM1

GM1 gangliosidosis is a rare, progressively neurodegenerative lysosomal storage disorder characterized by profound central nervous system involvement and substantial clinical heterogeneity. The development of reliable biomarkers is essential for tracking disease progression, stratifying patients, and advancing clinical trial readiness. Primary substrate markers, including cerebrospinal fluid (CSF) GM1 ganglioside and related lysosphingolipids, provide direct biochemical indices of lysosomal dysfunction. Emerging glycan signatures may further reflect disruptions in glycosylation pathways and responses to therapeutic intervention. Neurofilament light chain (NfL), a sensitive indicator of axonal injury, is consistently elevated in GM1 and shows promise as a fluid biomarker, although it does not convey regional specificity. Neuroimaging offers complementary insight into the structural and metabolic consequences of disease. Characteristic findings include diffuse white matter abnormalities, thalamic and basal ganglia signal changes, cortical and cerebellar atrophy, and ventriculomegaly. Quantitative MRI and magnetic resonance spectroscopy (MRS) reveal longitudinal declines in tissue volume and neuronal integrity that parallel functional deterioration. Diffusion‐based methods, including differential tractography, highlight progressive loss of white matter microstructure relative to age‐matched controls. However, severe anatomical distortion in GM1 limits the applicability of standard neuroimaging atlases, necessitating manual or semi‐automated segmentation approaches. Together, fluid biomarkers (gangliosides, lysosphingolipids, glycans, NfL) and advanced neuroimaging metrics (volumetry, MRS, diffusion imaging) establish a multimodal framework for evaluating disease burden and therapeutic response. Standardized methodologies, harmonized natural history datasets, and genotype‐stratified analyses will be critical for validating these biomarkers across GM1 subtypes. Strengthening this biomarker ecosystem will enable sensitive and clinically meaningful endpoints to support future therapeutic development in GM1 gangliosidosis.