Two families with novel PMP22 point mutations: genotype-phenotype correlation.

We report two novel PMP22 point mutations identified in two unrelated families with a moderate and slowly progressive Charcot-Marie-Tooth type 1 (CMT1) phenotype, with the exception of the proband of Family 2 who presented a clinical picture complicated by perinatal asphyxia. Nerve conduction study (NCS) revealed very slow motor nerve conduction velocities and sural nerve biopsy, performed in one patient, showed severe demyelination and hypomyelination. In the first family, a missense mutation (Leu78Pro) was identified, whereas in the second family a nonsense mutation (Gln103X) was found. Both families had clinical and neurophysiological aspects overlapping between CMT1 and Dejerine-Sottas syndrome (DSS). We point out that the type of PMP22 point mutations, the nature of the amino acid change, as well as the position of the altered amino acid play a role in determining the severity of the clinical picture. Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and it includes a group of clinically and genetically heterogeneous disorders. CMT type 1A is the most common form of CMT and is caused by a duplication of a 1.5 Mb region on chromosome 17 that includes the gene encoding the peripheral myelin protein 22 (PMP22). Point mutations in PMP22, far less common than duplication, also cause CMT1A (Reilly, 2007). Herein, we describe clinical, electrophysiological, and molecular findings of two CMT1 families carrying two novel mutations of the PMP22 gene