Glycoproteinoses: Clinical features, therapeutic landscape, and regulatory pathways in rare lysosomal disorders

The glycoproteinoses represent a mechanistically related group of ultra-rare lysosomal disorders characterized by progressive neurodegeneration, multisystem involvement, and a profound lack of disease-modifying therapies. These nine distinct disorders, α-mannosidosis, β-mannosidosis, aspartylglucosaminuria, fucosidosis, galactosialidosis, mucolipidosis II, mucolipidosis III, sialidosis, and Schindler disease, share a convergent clinical burden of progressive neurodegeneration, skeletal dysplasia, sensorineural hearing loss, ataxia, recurrent infections, and premature mortality. Despite advances in molecular diagnosis and growing interest in gene- and enzyme-based therapeutics, clinical development across this disease class has stalled. The principal barrier is not biological feasibility, but the absence of regulatory-ready clinical outcome assessments and biomarkers capable of capturing meaningful disease progression and treatment response, particularly within the central nervous system. This review examines the shared translational challenges that currently limit therapeutic advancement in glycoproteinoses, with emphasis on outcome measurement, biomarker validation, and trial interpretability in ultra-rare populations. We highlight recurrent limitations of existing approaches, including reliance on non-validated functional measures, peripheral biomarkers with poor correlation to neurologic disease burden, and fragmented natural history datasets. Building on these insights, we propose a harmonized, cross-disease framework that integrates standardized functional assessments with disease-relevant biochemical profiling to support efficient natural history studies and enable regulatory-aligned clinical trials. Adoption of this unified strategy may accelerate therapeutic development across the glycoproteinoses and serve as a model for other ultra-rare lysosomal disorders.