KIF1A-associated neurological disorders: therapeutic opportunities and challenges

KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.