Linking Lysosomal Dysfunction to Severe Neurological Disorders - News Center

Mutations in BORCS5 were identified as the cause of a previously unrecognized spectrum of severe neurological disorders. Genetic sequencing across multiple countries found independent mutations in the same gene among families with severe, unexplained neurodevelopmental or neurodegenerative conditions. BORCS5 regulates lysosomes, which break down and recycle waste and are critical for neuron function and long-distance axonal transport. Sixteen patients from nine families had mutations affecting both copies of BORCS5. Disease severity depended on mutation type: complete loss produced a devastating prenatal syndrome with brain malformations, abnormal fetal movements, and neuroaxonal dystrophy. Partial loss led to a chronic progressive disorder with epilepsy, movement problems, intellectual disability, and loss of developmental milestones, with survival into adulthood but profound disabilities. Brain imaging showed hypomyelination, corpus callosum structural defects, and progressive brain atrophy.

"Through genetic sequencing of multiple unrelated families whose children presented with severe, unexplained neurodevelopmental or neurodegenerative conditions, several teams across multiple countries, from the UK to Spain to Oman to Egypt, independently identified mutations in the same gene: BORCS5,"

"Within the cell, BORCS5 is known to regulate lysosomes: structures that break down and recycle waste. These organelles are particularly critical in neurons, which must maintain long-distance transport systems along axons."

"In the study, investigators identified 16 patients from nine families with mutations affecting both copies of BORCS5. The severity of disease depended on the type of mutation, with mutations that completely eliminate the BORCS5 protein producing the most devastating outcomes."

"Patients with complete loss of the protein have a devastating prenatal syndrome - brain malformations, abnormal fetal movements and neuroaxonal dystrophy. By contrast, patients with partially functioning mutations experienced a chronic but progressive neurological disorder, which featured epilepsy, movement problems, intellectual disability and loss of developmental milestones over time."

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