biostudies-literatureSimon CMSMA FoundationGerman Research FoundationNICHD NIH HHSCure SMAAmerican SIDS InstituteNIAAA NIH HHSNINDS NIH HHSRaynor Cerebellum ProjectROCHEProject ALSGrant from F. Hoffmann-La RocheGrant from F. Hoffmann–La Roche2797-2811https://www.ebi.ac.uk/biostudies/studies/S-EPMC12416786biostudies-literatureUnknown148(8)Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that is correlated with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that type 3 SMA patients exhibit impaired proprioception and that their proprioceptive synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex. We also show moderate loss of spinal motor neurons along Brain : a journal of neurologyProprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy.PMC12416786R01-NS114218R01 AA027079R01-NS102451CU18-2886K12HD001399K12 HD001399K01-HD084690K01 HD084690SI-1969/3-1R01 NS102451R01 NS125362SI-1969/2-1R01-NS116400R35 NS122306R01 NS114218R01 NS078375R01 NS116400Buettner JMPagiazitis JGEnsel SMentis GZDelestree NDreilich VGarcia JLDonadio SCarlini MJPellizzoni LDe Vivo DCSimon CMGerstner FKratimenos PSumner CJChung WKCapogrosso MPrat-Ortega GMontes JCarranza EWeimer LHSowoidnich LPirondini EfalseProprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy.Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that is correlated with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that type 3 SMA patients exhibit impaired proprioception and that their proprioceptive synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex. We also show moderate loss of spinal motor neurons along 2025-01-01T00:00:00Z2025 Aug2026-06-03T05:58:47.474Z2026-04-25T03:17:00.052ZS-EPMC124167863998286810.1093/brain/awaf074