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From the Department of Molecular Genetics (Drs. Timmerman, De Jonghe, De Vriendt, Nelis, and Van Broeckhoven, and A. Löfgren), Flanders Interuniversity Institute for Biotechnology and Laboratory of Neurogenetics, Born-Bunge Foundation, University of Antwerp, Department of Biochemistry; the Division of Neurology (Drs. De Jonghe and Martin), University Hospital Antwerpen; the Laboratory of Neuropathology (Drs. Martin and Ceuterick), Born-Bunge Foundation, University of Antwerp, Department of Medicine, Antwerp, Belgium; and the Department of Molecular and Human Genetics (Drs. Warner and Lupski), Baylor College of Medicine, Houston, TX.
Address correspondence and reprint requests to Dr. V. Timmerman, Laboratory of Neurogenetics, University of Antwerp, Department of Biochemistry, Universiteitsplein 1, B-2610 Antwerp, Belgium.
BACKGROUND: Mutations in the early growth response 2 (EGR2) gene have recently been found in patients with congenital hypomyelinating neuropathy and Charcot-Marie-Tooth type 1 (CMT1) disease.
OBJECTIVE: To determine the frequency of EGR2 mutations in patients with a diagnosis of CMT1, Dejerine–Sottas syndrome (DSS), or unspecified peripheral neuropathies.
METHODS: Fifty patients and 70 normal control subjects were screened.
RESULTS: A de novo missense mutation (Arg359Trp) in the 
-helix of the first zinc-finger domain of the EGR2 transcription factor was identified in a patient diagnosed with a clinical phenotype consistent with DSS. This patient had a motor median nerve conduction velocity of 8 m/s. A sural nerve biopsy showed a severe loss of myelinated and unmyelinated fibers, evidence for demyelination, numerous classic onion bulbs, and focally folded myelin sheaths. DSS is a severe, 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 with DSS.
CONCLUSIONS: Hereditary peripheral neuropathies represent a spectrum of disorders due to underlying defects in myelin structure or formation.
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