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Published online before print October 22, 2008, doi:10.1212/01.wnl.0000327095.32005.a4)
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NEUROLOGY 2008;71:1959-1966
© 2008 American Academy of Neurology

Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction

R. Del Bo, PhD, M. Moggio, MD, M. Rango, MD, S. Bonato, MD, M. G. D’Angelo, MD, S. Ghezzi, PhD, G. Airoldi, PhD, M. T. Bassi, PhD, M. Guglieri, MD, L. Napoli, PhD, C. Lamperti, MD, PhD, S. Corti, MD, PhD, A. Federico, MD, N. Bresolin, MD and G. P. Comi, MD

From Dino Ferrari Centre (R.D.B., M.M., M.R., S.G., M.G., L.N., C.L., S.C., N.B., G.P.C.), Department of Neurological Sciences, University of Milan, I.R.C.C.S. Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan; Neuromuscular and Neurorehabilitation Unit (S.B., M.G.D.) and Laboratory of Molecular Biology (G.A., M.T.B., N.B), Scientific Institute E. Medea, Bosisio Parini, Lecco; Department of Neurological and Behavioural Science (A.F.), University of Siena; and Centre of Excellence for Neurodegenerative Diseases (N.B., G.P.C.), University of Milan, Italy.

Address correspondence and reprint requests to Prof. Giacomo P. Comi, Dipartimento di Scienze Neurologiche, Università di Milano, Padiglione, Ponti, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy giacomo.comi{at}unimi.it

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 1H-MRS and 31P-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 31P-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.

Abbreviations: CMAP = compound muscle action potential; CMT = Charcot-Marie-Tooth disease; EM = electron microscopy; MRC = Medical Research Council; NCS = nerve conduction studies; NCV = nerve conduction velocities; SNAP = sensory nerve action potential; VEP = visual evoked potential

e-Pub ahead of print on October 22, 2008, at www.neurology.org.

Supported by the "Associazione Amici del Centro Dino Ferrari," by a Research Grant from Italian Ministry of University and Research "PRIN 2006" to N.B and G.P.C., and by a Ministry of Health grant, Ricerca Finalizzata 2006 "Malattie del primo motoneurone: integrazione di approccio genetico–molecolare, clinico e strumentale." The Telethon "Bank of DNA, Nerve and Muscle Tissues" (no. GTF02008) was the source of the DNA used in this study. The Eurobiobank project QLTR-2001-02769 is also acknowledged.

Disclosure: The authors report no disclosures.

Received March 31, 2008. Accepted in final form June 23, 2008.




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