CMT 2: Mutated mitofusin 2 presents with intrafamilial variability and brain mit

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Neurology. 2008 Oct 22.

Mutated mitofusin 2 presents with intrafamilial variability and brain

mitochondrial dysfunction.

Del Bo R, Moggio M, Rango M, Bonato S, D'Angelo MG, Ghezzi S, Airoldi

G, Bassi MT, Guglieri M, Napoli L, Lamperti C, Corti S, Federico A,

Bresolin N, Comi GP.

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., 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.

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.