Dejerine-Sottas syndrome (DSS), or hereditary motor and sensory neuropathy (HMSN) type 111, is a severe hypertrophic demyelinating neuropathy with infantile onset. The clinical symptoms are similar to those found in Charcot-Marie-Tooth disease type 1 (CMT1) or HMSN type I patients, but they are more severe. DSS is genetically heterogeneous. Dominant mutations in two major peripheral myelin protein genes, PMP22 and Po, are associated with a DSS phenotype. Mutations in the same genes are also responsible for the CMTl phenotype. A 1.5-Mb duplication in 17~11.2 is the major mutation found in familial and sporadic CMTl patients. We studied two genetically sporadic DSS patients. The presence of a de novo duplication in one patient was revealed by Southern blot analysis, using polymorphic markers located in the duplicated area. The 17~11.2 allele segregation in this patient and in her parents suggests that the duplication is of maternal origin. In the other patient, single-strand conformation polymorphism (SSCP) analysis of the 6 exons of the Po gene revealed two additional bands in exon 3. Sequencing of this exon identified a novel dominant mutation replacing a sequence of 8 bp by a mutated sequence of 5 bp. The mutation apparently leads to the replacement of 4 amino acids at positions 86-89 by three different amino acids, in an area that is part of a predicted P-strand. Our findings support the suggestion that DSS and CMTl disease should not be considered as two different clinical entities.