Of interest, volumetric MRI reconstructions revealed a significant reduction in whole-brain white matter (figure e-2, A–D, links.lww.com/NXG/A149) in Hace1 KO adult mice as compared with their WT littermates, substantiated by myelin basic protein staining and volumetric MRI analysis (figure e-2, B–D), similar to findings in reported SPPRS patients5, –, 7 and patient 9 described here (figure 1C and table). Here, HACE1 is linked to spastic paraplegia-severe developmental delay-epilepsy syndrome.