G.P.296: Severe, early onset Charcot-Marie-Tooth disease with rare presentations

Abstract

Charcot–Marie–Tooth disease (CMT) has diverse clinical presentations and molecular genetic heterogeneity. Herein we describe the clinical features, neurophysiological and morphological studies of 2 fatal cases of CMT. Case 1 was a healthy newborn who developed foot drop, daily frequent vomiting and severe constipation at 7 months of age. His arm and leg weakness rapidly progressed within a few months. He subsequently developed diaphragmatic paralysis and died at 2.5 years of age due to respiratory failure. NCS/EMG showed a severe, axonal sensory and motor neuropathy. He had a novel and de novo mutation (c.296–297dupAAG) of the MFN2 gene. Case 2 had congenital hypomyelinating neuropathy confirmed by NCS and nerve biopsy, associated with a novel and de novo missense mutation (p.His384Arg) of the EGR2 gene. The patient presented a few weeks after birth with failure to thrive and hypotonia. She had facial, severe proximal > distal arm and leg weakness, pain insensitivity, areflexia and symptoms of autonomic dysfunction. She progressed to respiratory failure requiring mechanical ventilation. Her CSF protein was elevated (136 mg/dl). She had a fluctuating clinical course that let to the initial consideration of chronic inflammatory demyelinting polyneuropathy. She did not respond to prednisone, but she responded to IVIG therapy initially with some improvement of muscle strength and decrease autonomic dysfunction. She subsequently experienced deterioration of weakness not responding to either IVIG or plasmapheresis, and died at 16.5 months of age. Our report expanded the genotype and phenotype of MFN2 and EGR2 mutations. Although early onset CMT has been well described, autonomic features and fatality due to respiratory failure are rarely described. MFN2 mutations frequently cause severe phenotype, but diaphragmatic paralysis and autonomic dysfunction have not been described. Similarly, severe autonomic dysfunction has not been reported to be associated with EGR2 mutations.