Recessive mutations in NAGLU, which encodes α–N-acetylglucosaminidase, cause the severe childhood lysosomal disease mucopolysaccharidosis IIIB. Using whole-exome sequencing of four individuals, Tétreault et al. show that a NAGLU variant also segregates with a dominant late-onset painful sensory neuropathy, with affected individuals showing reduced α–N-acetylglucosaminidase activity.