PURA Syndrome as a Congenital Myasthenic Disorder: Evidence from Muscle Morphology, Proteomics, and Blood Biomarkers

Dominant PURA variants cause a neurodevelopmental disorder with hypotonia, cognitive impairment, and variable neuromuscular symptoms. Clinical response to pyridostigmine suggests neuromuscular junction (NMJ) involvement, but NMJ architecture, molecular mechanisms, and minimally invasive biomarkers remain unclear. This study investigated NMJ pathology in PURA patients using integrated clinical, histological, ultrastructural, and molecular approaches. Patients presented with hypotonia, ptosis, ocular weakness, and myopathic facies, consistent with impaired neuromuscular transmission. Electron microscopy revealed vesicle accumulation and NMJ alterations, providing the first ultrastructural evidence of NMJ pathology in PURA. Muscle proteomics showed reduced PURA protein and dysregulation of transcriptional regulation, vesicle transport, extracellular matrix remodeling, and complement activation. qPCR confirmed POSTN and PHGDH upregulation among others. Serum analyses demonstrated elevated TSP4, identifying the first blood biomarker for PURA-associated NMJ dysfunction. EV proteomics revealed dysregulated immunoglobulins, complement components, and novel candidates including NOTCH2, TARSH, and PON1.