Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations

Abstract

■ Abstract Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal CharcotMarie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination.

Allicin Protects PC12 Cells Against 6-OHDA-Induced Oxidative Stress and Mitochondrial Dysfunction via Regulating Mitochondrial Dynamics

“…These dynamic processes are of particular importance in neuronal cells because of their post-mitotic state and long processes with higher energy requirements, and dis-regulation in both fission and fusion proteins have been associated with central nervous system diseases [41,42]. In vertebrates, high-molecular weight GTPases, such as Mfn-1, Opa-1, Drp-1 and Fis-1, are key components involved in regulating the mitochondrial morphologic dynamics, and these factors have been linked to the cellular death program of apoptosis through the caspase associated pathway [43].…”

Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction

“…[37][38] Predominantly periventricular white matter alterations at brain MRI have been described in MFN2-mutated patients. 10,39 While this study was under review, two independent patients with early onset CMT, also carrying a p.R104W Mfn2 amino acid change, were reported to present with optic atrophy, white matter MRI changes, and macrocephaly in one of them, although they did not show cognitive dysfunction at the ages of 16 and 7 years, respectively. 39 An impairment of brain mitochondrial function was suggested by the HEPs pattern at MRS in our patients.…”

“…10,39 While this study was under review, two independent patients with early onset CMT, also carrying a p.R104W Mfn2 amino acid change, were reported to present with optic atrophy, white matter MRI changes, and macrocephaly in one of them, although they did not show cognitive dysfunction at the ages of 16 and 7 years, respectively. 39 An impairment of brain mitochondrial function was suggested by the HEPs pattern at MRS in our patients. This data are in keeping with the observation, made using CMT2A cell cultures, that although the mitochondrial network appeared morphologically unaltered, there was a significant defect of mitochondrial coupling, associated with a reduction of membrane potential.…”

Early-onset Charcot-Marie-Tooth patients with mitofusin 2 mutations and brain involvement

“…To date, four patients have been described. Züchner et al 5 found a patient with cerebellar peduncle involvement, Brockmann et al 7 described two patients with thalami and parieto-occipital lobe involvements and Chung et al 3 reported a patient with a frontal lobe lesion.…”