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Early-onset Charcot-Marie-Tooth patients with mitofusin 2 mutations and brain involvement
  1. K W Chung1,
  2. B C Suh2,
  3. S Y Cho3,
  4. S K Choi3,
  5. S H Kang1,
  6. J H Yoo4,
  7. J Y Hwang4,
  8. B O Choi3
  1. 1Department of Biological Science, Kongju National University, Gongju, Korea
  2. 2Department of Neurology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
  3. 3Department of Neurology, Ewha Medical Research Center, Ewha Womans University School of Medicine, Seoul, Korea
  4. 4Department of Radiology, Ewha Womans University School of Medicine, Seoul, Korea
  1. Correspondence to Dr Byung-Ok Choi, Department of Neurology, Ewha Womans University, School of Medicine, Mokdong Hospital, 911-1 Mokdong, Yangcheon-ku, Seoul 158-710, Korea; bochoi{at}


Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot-Marie-Tooth disease (CMT). A prospective brain MRI study was performed on 18 early-onset CMT patients with MFN2 mutations, and a high frequency (39%) of brain abnormalities was found. Early-onset patients showed multiple scattered or confluent brain lesions that involved gray matter as well as white matter. Patterns of brain involvement in early-onset patients differed from those of late-onset patients and other hereditary peripheral neuropathies. In addition, one CMT patient demonstrated a brain lesion before the development of peripheral neuropathy.

  • Charcot-Marie-Tooth disease
  • magnetic resonance image
  • mitofusin 2
  • neuropathy
  • genetics
  • HMSN (Charcot-Marie-Tooth)
  • MRI

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Charcot-Marie-Tooth disease (CMT) is a heterogeneous motor and sensory peripheral neuropathy, which is classically categorised into two major phenotypes; type 1 (CMT1), the demyelinating form, and type 2 (CMT2), the axonal form. The mitofusin 2 (MFN2) gene encodes an outer mitochondrial membrane protein that plays a central role in mitochondrial fusion, which causes axonal neuropathies in CMT2 and controls the efficiency of calcium ion uptake by mitochondria.1 More than 50 different MFN2 mutations have been reported to be associated with the axonal forms of CMT, and most of these are caused by single amino-acid substitutions within or adjacent to the GTPase domain.2 Axonal CMT patients with MFN2 mutations can be divided into two clinical subtypes; early-onset CMT (<10 years), which is associated with severe phenotypes, and late-onset CMT (≥10 years), which is associated with much milder clinical features.2 3

Altered mitochondrial transport has been suggested to be a pathomechanism of axonal CMT neuropathy in even the first study on MFN2 mutations. However, although clinical symptoms in most MFN2 patients include axonal peripheral neuropathies, some patients with MFN2 have a variety of additional central nervous system (CNS) symptoms, such as pyramidal signs,4 optic atrophy5 and cognitive impairments.6

Because brain MRI studies in early-onset MFN2 patients have only been performed recently, data on different phenotypes are limited. To date, four patients have been described. Züchner et al5 found a patient with cerebellar peduncle involvement, Brockmann et al7 described two patients with thalami and parieto-occipital lobe involvements and Chung et al3 reported a patient with a frontal lobe lesion.

This prospective brain MRI study was performed in 18 early-onset CMT patients with MFN2 mutations, and brain involvements were identified in seven patients. In addition, we encountered one CMT patient who presented with brain involvement before the development of peripheral neuropathy.

Patients and methods

Eighteen early-onset axonal CMT patients (male 6, female 12; aged 3–48 years) with MFN2 mutations were enrolled. Of them, 13 patients were previously reported for their MFN2 mutations and CMT phenotypes.3 8 All subjects provided written informed consent according to the guidelines issued by the ethics committee of Ewha Womans University Hospital.

Brain MRI scanning was performed on all patients using a 1.5-T system (Siemens Vision: Siemens, Erlangen, Germany). Twelve patients also underwent follow-up MRI scans. Axial and coronal T2-weighted spin echo (TR/TE, 4700/120), T1-weighted spin echo (TR/TE, 550/12), and fluid-attenuated inversion recovery (TR/TE, 9000/119) and images were obtained. Brain lesions were evaluated by location. We defined abnormal white matter hyperintensity (WMH) as a lesion diameter of >3 mm on T2-weighted images.9 Lesions in close proximity and groups of more than five lesions that were difficult to count are referred to as “confluent” lesions. All MR images were reviewed by two radiologists and two neurologists unaware of patient identities and clinical diagnoses.


The MRI study revealed brain abnormalities in 7 of the 18 early-onset CMT patients with MFN2 mutations (39%). Case 8 (family ID: FC55, R364W) was previously reported for the brain lesions.3 Details of the mutations and clinical phenotypes for each case are listed in table 1.

Table 1

Clinical and MRI features for early-onset CMT patients with MFN2 mutations

Of the seven patients with brain abnormalities, four patients showed only cerebral WMHs on T2-weighted and fluid-attenuated inversion recovery images. However, in three patients, the brainstem or cerebellum was involved; case 1 showed an increased T2 signal in both middle cerebellar peduncles (figure 1A), case 10 showed bilateral symmetric high signal intensities along dentate nuclei (figure 1B) and case 14 showed a small hyperintense lesion in the left pons (figure 1C). The characteristic MRI findings of early-onset patients were multiple and/or confluent hyperintensities (figure 1D). WMHs frequently involved the frontal or parietal lobes (table 1). Six (86%) of the seven patients with brain abnormalities had bilateral lesions.

Figure 1

Brain involvements in early-onset CMT patients with MFN2 mutations. (A) Case 1 with optic atrophy showed symmetric hyperintensities in both middle cerebellar peduncles on axial T2-weighted image. (B) Case 10 displayed bilateral symmetric hyperintensities along dentate nuclei on coronal T2-weighted image. (C, D) Case 14 experienced a sudden attack of transient sensory loss for 2 weeks at 33 years. She underwent brain MRI at 35 years and a small but definite hyperintensity in the left pons was revealed on coronal T2-weighted image (C). She also showed bilateral multiple temporal and parietal high signal intensities on axial fluid-attenuated inversion recovery image (D). (E, F) In case 9, axial T2-weighted brain MRI performed at 5 years of age showed small but definite pathogenic right (E) and left (F) frontal white matter hyperintensity lesions that could not be attributed to age. At 7 years, she was noticed to have a gait problem, and at 8 years, motor and sensory polyneuropathy was identified. (G, H) Follow-up study of case 9 with 4-year intervals revealed two newly developed lesions in right (G) and left (H) frontal white matters on axial fluid-attenuated inversion recovery images. None of the initial lesions disappeared during follow-up.

Of the eleven patients with the R364W mutation, only three had brain lesions, and of the three with a R94W mutation, two displayed brain lesions. Two of three patients with vocal cord paralysis displayed high T2 signals, and three of seven with optic atrophy showed white matter hyperintensities. In addition, a patient with a left pontine lesion (case 14) had transient right hemibody sensory impairment for 2 weeks.

When 5 years of age, case 9 showed right and left frontal periventricular WMHs (figure 1E,F). Nerve conduction studies and neurological examinations revealed no abnormality at this time. However, 2 years later, her parents began to notice a gait problem, and at 8 years, she had developed distal leg muscle weakness, mildly reduced median sensory nerve conduction velocities (NCVs) and sensory nerve action potentials, which indicated the presence of axonal polyneuropathy.

Follow-up MRI studies were performed on five brain-impaired patients. When initial and follow-up MR images were compared, no initial lesion was found to have disappeared in any patient. On the other hand, case 9 showed two newly developed lesions in right (figure 1g) and left (figure 1h) frontal white matters at 4-year intervals from 5 to 9 years.


In the present study, the frequency of brain involvements in early-onset CMT patients with MFN2 mutations was found to be high (39%), which indicates brain involvement is not uncommon, and that it is probably an under-recognised feature of this disorder. In addition, brain lesions were found in gray as well as in white matter. Regardless of the precise pathomechanisms involved, our findings suggest that early-onset MFN2 patients frequently have CNS and peripheral nervous system involvement.

Four MFN2 mutations were detected in early-onset CMT patients with brain lesions located within or near the GTPase domain (R94W and H165R), and between the GTPase and coil-to-coil domains (S350P and R364W). Thus, it is not considered that mutations within a particular region of the MFN2 gene are related to brain abnormalities. Furthermore, brain lesions were not always detected in patients with R94W or R364W mutations, and patterns of brain lesions were different even among patients with the same mutation. Therefore, it appears that phenotypic heterogeneity of brain involvement is a feature of early-onset CMT patients with MFN2 mutations.

Complex phenotypes are characteristics of CMT patients with MFN2 mutations.4–7 Case 9 had brain involvement before the onset of peripheral neuropathy. At 5 years of age, we found small but definite pathogenic bilateral frontal lobe WMHs without any explanation other than a MFN2 mutation; however, neurological examinations and nerve conduction studies were normal. At 8 years of age, nerve conduction studies revealed the presence of peripheral polyneuropathies. To the best of our knowledge, this is the first report of a CMT patient with brain lesions present before the onset of peripheral neuropathy. Furthermore, in a previous report, we described a MFN2 patient harbouring a cerebellar infarction without peripheral neuropathy.10 In addition, Del Bo et al6 reported a 10-year-old MFN2 patient with normal brain MRI findings, but various CNS phenotypes, including cognitive impairment, and a brain magnetic resonance spectroscopy finding of mitochondrial dysfunction. Therefore, it is possible that the clinical spectrum of the MFN2 mutation is much broader than previously believed.

In CMT patients with MFN2 mutations, phenotypes have been classified to two subgroups; an early-onset group with unusually severe phenotypes and a late-onset group with much milder clinical features.2 3 Our early-onset patients also experienced rapid disease progression and usually unrecordable compound muscle action potentials in upper and lower limbs. However, late-onset patients showed mild neuropathies and much slower disease progression.3 Early-onset patients had confluent white matter brain lesions, which tended to involve larger areas than those of late-onset patients, and brainstem and cerebellar involvement were confined to the early-onset group. In contrast, late-onset MFN2 patients did not have any confluent brain lesions. Accordingly, these findings indicate that patterns of brain involvement in early- and late-onset CMT patients differ with respect to clinical phenotype.

A few patients with hereditary peripheral neuropathies, such as CMTX, CMT4D and hereditary neuropathy with liability to pressure palsy, have been reported to show brain involvement.11–13 However, early-onset CMT patients with MFN2 mutations differ from these patients as follows: (1) the frequency of brain involvement in early-onset MFN2 patients is very high; (2) CMTX patients with GJB1 mutations have transient and reversible white matter lesions by MRI,11 although in the present study, it was found that observed lesions did not disappear in early-onset MFN2 patients; (3) all brain involvements in CMTX, CMT4D, and hereditary neuropathy with liability to pressure palsy patients are confined to white matter,11–13 although early-onset MFN2 patients exhibited gray matter as well as white matter involvements.7

The molecular pathomechanisms of brain abnormalities due to MFN2 mutations has not been established. One possible explanation is that Mfn2 protein is involved in the regulation of neuronal cell apoptosis, which underlies nerve degeneration and mitochondrial function.14 15 Furthermore, Mfn2 may function to protect cerebellar granules from injury induced by cell death,14 and it also appears that diminished mitochondrial fusion and activated fission caused by MFN2 mutations derive cerebellar neuron defects.15 Although further studies are required to understand the pathomechanisms involved, it appears that MFN2 mutations exhibit heterogeneous patterns of brain involvement, which differ from those of other hereditary peripheral neuropathies.



  • Funding This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MEST) (KRF-2008-313-C00750), the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A090500), and the Life Insurance Philanthropy Foundation.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the ethics committee of the Ewha Womans University Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.