Boerkoel et al. (2001) reported 2 patients with Dejerine-Sottas neuropathy (145900) and an arg359-to-trp (R359W) mutation in the EGR2 gene. In both patients, the mutation appeared to be de novo dominant. One patient presented with hypotonia and hip dysplasia immediately after birth. She gained minimal use of her hands and feet during the first 6 months of life and then gradually lost motor function, developing paralysis distal to the knees and elbows by 2 years of age. A sural nerve biopsy demonstrated a marked decrease of myelinated fibers, evidence of demyelination and remyelination, and onion bulb formation. The course of her disease was characterized by increasing difficulty swallowing and breathing, and she died of respiratory failure at 6 years of age. The other patient had difficulty grasping objects and strabismus secondary to lateral recti weakness by 4 to 5 months of age. At 3 years of age, she had severe distal muscle weakness and atrophy, areflexia, and decreased pain and temperature sensation; in the lower extremities, she had less severe distal muscle weakness and atrophy, hyporeflexia, and intact sensation. As a complication of her hand involvement, she developed bilateral fixed contractures of the fourth and fifth fingers by 15 years of age. At 3 years of age nerve conduction velocities could not be measured in the median and ulnar nerve, but tibial nerve conduction velocity was 8 m/s. Sural nerve biopsy showed typical changes of DSN, including onion bulb formation. She developed severe thoracolumbar scoliosis, requiring spinal fusion at 15 years of age. At age 22 years she was following a rigorous physical exercise program, including weight lifting and walking on a treadmill, and she had completed a university education.
Chung et al. (2005) identified a heterozygous R359W mutation in a Korean father with Charcot-Marie-Tooth disease-1D (607678) and a daughter with Dejerine-Sottas syndrome. In addition, the daughter was found to have a de novo mutation in the GJB1 gene (V136A; 304040.0021). The father had pes cavus and developed difficulty walking at age 8 years, but had a milder phenotype than the daughter, who had experienced gait difficulties since infancy and facial weakness. She also had bilateral hand muscle weakness and atrophy and had sensory impairment of both upper and lower extremities. Warner et al. (1999) had shown that the R359W substitution occurs in the first zinc finger domain and results in very low DNA-binding activity as well as decreased transcriptional activity of GJB1, resulting in abnormal myelination. Chung et al. (2005) concluded that the more severe phenotype in the daughter was caused by an additive effect of the 2 mutations.
