Ultrastructural lesions of axonal mitochondria in patients with childhood-onset

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Bull Acad Natl Med. 2009 Jan;193(1):151-60; discussion 160-1.

Ultrastructural lesions of axonal mitochondria in patients with childhood-onset

Charcot-Marie-Tooth disease due to MFN2 mutations

Funalot B, Magdelaine C, Sturtz F, Ouvrier R, Vallat JM.

Service de Neurologie et Centre de Référence des Neuropathies périphériques

rares, CHU Dupuytren, Limoges, France.

We present neuropathological findings based on sural nerve biopsy in six

children with mutations of the mitofusin 2 gene (MFN2). All six children had

severe axonal neuropathies (mild or severe hereditary motor and sensory

neuropathy, HMSN), with onset in early childhood. All had a marked decrease in

the density of mainly large myelinated fibers.

Although neurophysiological findings were suggestive of axonal degeneration,

some onion bulbs were present in each case. Unequivocal mitochondrial changes

were apparent only on longitudinal sections.

Many axonal mitochondria appeared smaller than normal and round or spherical

instead of tubular. These mitochondria were abnormally aggregated, accumulating

primarily at the axon periphery. This peripheral distribution was clearest in

residual large myelinated fibers. The inner and outer mitochondrial membranes

were irregular, and the cristae were quite often disrupted. These changes were

observed in both myelinated and unmyelinated fibers.

Mitofusin 2 is a large mitochondrial transmembrane GTPase, with two coiled coil

domains and two transmembrane spans. It is targeted to the outer mitochondrial

membrane, where it interacts with mitofusin 1 to regulate the mitochondrial

network architecture by stimulating mitochondrialfusion. The mitochondrial

changes we observed could thus result from abnormal mitochondrial fusion and

fission.

Neuropathologic abnormalities can be sufficiently characteristic to suggest the

genetic basis of some hereditary neuropathies such as those associated with

mutations in MPZ, GJB1, GDAP1, MTMR2, SH3TC2, PRX, FGD4 and LMNA. This may also

be true of MFN2-related neuropathies.