Clinical and neurophysiological studies were performed on 4 girls aged 9 to 19 years with the Rett syndrome (RS) (stages II and III). In addition to constant foot deformity (pes planus) and brisk tendon reflexes in the lower limbs, they showed muscular atrophy of the calves and mild atrophy of the extensor digitorum brevis muscle. Motor NCVs were within normal values for age, but distal latencies in two girls and compound action potential in one were abnormal, suggesting mild distal, predominantly motor neuropathy. The upper limbs showed nothing abnormal except for mild hand deformities. Neuropathology in 2 autopsy cases (aged 11 and 17 years, stage IV) and sural nerve biopsies in three girls aged 2, 3 and 17 years, all clinical stage II-III without inanition, revealed mild distal axonopathy without demyelination. Selected axons in sural nerve of a girl aged 17 and in the dental pulp of a girl aged 9, both at clinical stage II, showed increased numbers of neurofilaments. Skeletal muscle in two girls aged 11 and 17 years (both stage IV) exhibited mild alterations in the sarcoplasmic reticulum with occasional disordered myofibrils and tubular structures in the Z-filaments, but no neurogenic atrophy or abnormal mitochondria. The reported data do not support spinal denervation (motor neuron degeneration) in RS, but suggest late onset denervation due to mild distal axonopathy of hitherto unknown origin.