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Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction

2008; Lippincott Williams & Wilkins; Volume: 71; Issue: 24 Linguagem: Inglês

10.1212/01.wnl.0000327095.32005.a4

1526-632X

Roberto Del Bo, Maurizio Moggio, Mario Rango, S. Bonato, Maria Grazia D’Angelo, Serena Ghezzi, Giovanni Airoldi, Maria Teresa Bassi, Michela Guglieri, Laura Napoli, C. Lamperti, Stefania Corti, Antonio Federico, Nereo Bresolin, Giacomo P. Comi,

Mitochondrial Function and Pathology

Background: The axonal forms of Charcot-Marie-Tooth (CMT2) disease are a clinically and genetically heterogeneous group of disorders. Mitofusin 2 gene ( MFN2 ) mutations are the most common cause of CMT2. Complex phenotypes have been described in association with MFN2 gene mutations, including CMT2 with pyramidal features (hereditary motor and sensory neuropathy [HSMN V]) and CMT2 with optic atrophy (HMSN VI). Objective: To report on the clinical, neurophysiologic, and neuropathologic features of an Italian family with a novel MFN2 gene mutation and investigate brain functional parameters using magnetic resonance spectroscopy (MRS). Methods: Three family members, a father and his two sons, were affected by peripheral neuropathy, cognitive impairment, and poor nocturnal vision (also optic neuropathy in one case). A member of this family also showed spastic paraparesis. The MFN2 gene sequence was analyzed. A sural nerve biopsy as well as brain 1 H-MRS and 31 P-MRS were evaluated in two patients. Results: Affected family members carried a novel MFN2 missense mutation, namely R104W, located within the critical GTPase domain of the protein which affects a highly conserved amino acid position. Sural nerve biopsies showed a normal mitochondrial network, particularly at the nodes of Ranvier, upon electron microscopy examination. A significant defect of high energy phosphates (HEPs) in the visual cortex was observed at rest by 31 P-MRS in the adult proband, while his son showed a defective recovery of HEPs after stimulation of the visual cortex. Conclusion: Cognitive impairment may be another feature of the MFN2 -related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2 -related and primary mitochondrial disorders.