Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype

Background: Mutations in the early growth response 2 (EGR2) gene have recen tly been found in patients with congenital hypomyelinating neuropathy and C harcot-Marie-Tooth type 1 (CMT1) disease. Objective: To determine the frequ ency of EGR2 mutations in patients with a diagnosis of CMT1, Dejerine-Sotta s syndrome (DSS), or unspecified peripheral neuropathies. Methods: Fifty pa tients and 70 normal control subjects were screened. Results: A de novo mis sense mutation (Arg359Trp) in the alpha-helix of the first zinc-finger doma in of the EGR2 transcription factor was identified in a patient diagnosed w ith a clinical phenotype consistent with DSS. This patient had a motor medi an nerve conduction velocity of 8 m/s. A sural nerve biopsy showed a severe loss of myelinated and unmyelinated fibers, evidence for demyelination, nu merous classic onion bulbs, and focally folded myelin sheaths. DSS is a sev ere, childhood-onset demyelinating peripheral neuropathy initially thought to be inherited as an autosomal recessive trait. However, several dominant heterozygous mutations in the peripheral myelin protein 22 (PMP22) gene and dominant mutations in the peripheral myelin protein zero (MPZ) gene, both in the heterozygous and homozygous state, have been reported in patients wi th DSS. Conclusions: Hereditary peripheral neuropathies represent a spectru m of disorders due to underlying defects in myelin structure or formation.