Simultaneous <i>MFN2</i> and <i>GDAP1</i> mutations cause major mitochondrial defects in a patient with CMT

WITH CMTMutations in the MFN2 gene are associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a dominant axonal CMT, whereas mutations in GDAP1 are associated with recessive demyelinating CMT (CMT4A), recessive axonal CMT (AR-CMT2), and dominant axonal CMT (CMT2K).Both proteins are involved in energy metabolism and dynamics of the mitochondrial network.[1][2][3] We have previously reported that, in fibroblasts from patients with CMT, MFN2 mutations resulted in a mitochondrial energy coupling defect, 4,5 whereas dominant mutation in GDAP1 resulted in defective complex I activity.6 In this study, we investigated mitochondrial bioenergetics from a severely affected patient with CMT harboring combined mutations in both GDAP1 and MFN2 genes. Methods.For details, see e-Methods on the Neurology ® Web site at www.neurology.org. Patients.Patient II-5 (figure 1A), a 71-year-old woman of Spanish origin, had severe distal muscle weakness from the age of 3, becoming wheelchairbound during her third decade.Clinical examination showed severe weakness of limbs with proximal and distal amyotrophy, tactile and nociceptive hypoesthesia with a gloves-and-socks distribution, and abolition of the limb reflexes.She had pes cavus and moderate vocal cord paresis.Electrophysiologic studies (table e-1) indicated a severe axonal neuropathy characterized by a major reduction of motor action potential in the left median nerve (0.1 mV) with a slightly reduced motor conduction velocity (43 m/s).Patient II-8, her 56-year-old brother, presented with a mild CMT2 clinical phenotype.Electrophysiologic examination showed a sensory axonal neuropathy (table e-1).His 2 daughters, aged 19 and 25 years, are currently asymptomatic.Patient II-2, who had a phenotype compatible with CMT, had died of respiratory failure. Results. Mutation analysis.Patient II-8 and his asymptomatic daughter (III-15) were found to be heterozygous for the pathogenic p.R468H mutation in MFN2, previously described.7 Individuals II-3, II-4, and II-7Genetic Diagnosis Center of Inherited Disease-IDIBELL (C.C., I.

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