Brain Advance Access originally published online on July 10, 2006
Brain 2006 129(8):2103-2118; doi:10.1093/brain/awl174
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset severe and late-onset mild Charcot–Marie–Tooth disease with mitofusin 2 (MFN2) mutations
1 Department of Biological Science, Kongju National University Kongju 2 Department of Neurology, Kyung Hee University, College of Medicine, Gunpo, Korea 3 Departments of Neurology, Ewha Woman's University, College of Medicine Gunpo, Korea 4 Departments of Ophthalmology, Ewha Woman's University, College of Medicine Gunpo, Korea 5 Radiology and Ewha Medical Research Center, Ewha Woman's University, College of Medicine Gunpo, Korea 6 Division of Nanosciences, Ewha Woman's University, College of Medicine, Gunpo, Korea 7 Department of Neurology, Yonsei University College of Medicine Seoul, Korea 8 Department of Pathology, Yonsei University College of Medicine Seoul, Korea 9 Department of Neurology and INAM Neuroscience Research Center, Wonkwang University, College of Medicine Gunpo, Korea
Correspondence to: Prof. Byung-Ok Choi, MD, PhD, Department of Neurology and Ewha Medical Research Center, Ewha Woman's University, College of Medicine, Dongdaemun Hospital, 70 Jongno 6-ga, Jongno-gu, 110-783, Seoul, Korea E-mail: bochoi{at}ewha.ac.kr
 |
Summary |
|---|
 Top Summary IntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot–Marie–Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI). It is well known that HMSN VI is an axonal CMT neuropathy with optic atrophy. However, the differences between CMT2A and HMSN VI with MFN2 mutations remained to be clarified. Therefore, we studied the phenotypic characteristics of CMT patients with MFN2 mutations. Mutations in MFN2 were screened in 62 unrelated axonal CMT neuropathy families. We calculated CMT neuropathy scores (CMTNSs) and functional disability scales (FDSs) to quantify disease severity. Twenty-one patients with the MFN2 mutations were studied by brain MRI. Ten pathogenic mutations were identified in 26 patients from 15 families (24.2%). Six of these mutations had not been reported, and de novo mutations were observed in five families (33.3%). The electrophysiological patterns of affected individuals with the MFN2 mutations were typical of axonal CMT; however, the clinical and electrophysiological characteristics were markedly different in early (<10 years) and late disease-onset (
10 years) groups. All patients with an early onset had severe CMTNS (21) and FDS (6 or 7), whereas most patients with late onset had mild CMTNS (
10) and FDS (3). We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy. In addition, two early onset families with R94W mutations, previously reported for HMSN VI, did not have visual impairment. Interestingly, eight patients had periventricular and subcortical hyperintense lesions by brain MRI. In the late-onset group, three patients had sensorineural hearing loss and two had bilateral extensor plantar responses. We found that MFN2 mutations are the major cause of axonal CMT neuropathy, and that they are associated with variable CNS involvements. Phenotypes were significantly different in the early and late disease-onset groups. Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype.
Key Words: Charcot–Marie–Tooth disease; CMT2A; HMSN VI; mitofusin 2 (MFN2)
Abbreviations: CMAP, compound muscle action potential; CMT, Charcot–Marie–Tooth; CMTNS, CMT neuropathy score; FDS, functional disability scale; FLAIR, fluid-attenuated inversion recovery; HMSN, hereditary motor and sensory neuropathy; MCV, motor nerve conduction velocity; MFN2, mitofusin 2; MNF, myelinated nerve fibre; MRC, Medical Research Council; PCR, polymerase chain reaction; SCV, sensory nerve conduction velocity; SNAP, sensory nerve action potential; SNHL, sensorineural hearing loss; TLIs, terminal latency indices; VEP, visual evoked potential
Received April 12, 2006. Revised May 31, 2006. Accepted June 7, 2006.
|
Introduction |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Charcot–Marie–Tooth (CMT) disease is a genetically and clinically heterogeneous disorder, and many CMT-causative genes have been identified (Shy et al., 2004
). CMT is frequently classified as type 1, the demyelinating form (CMT1), or type 2, the axonal form (CMT2). The primary defect in CMT2 patients is neuronal, and CMT2 patients have slightly reduced (>38 m/s) or even normal nerve conduction velocities (NCVs) (Pareyson et al., 2004).
CMT2 has been divided into many subtypes by linkage analysis as follows: CMT2A (1p35–p36), 2B (3q21), 2D (7p15), 2E (8p21), 2F (7q11.23), 2G (12q12–q13.3), 2I (1q22), 2K (8q13–q21.1) and 2L (12q24). Several genes have been reported to be associated with CMT2 loci, namely, kinesin family member 1B-ß (KIF1B: MIM no. 605995
[OMIM]
) in CMT2A (Zhao et al., 2001), RAB7 (MIM no. 602298
[OMIM]
) in CMT2B (Verhoeven et al., 2003), GARS (MIM no. 600287
[OMIM]
) in CMT2D (Antonellis et al., 2003), NEFL (MIM no. 162280
[OMIM]
) in CMT2E (Mersiyanova et al., 2000; Choi et al., 2004), HSPB1 (MIM no. 602195
[OMIM]
) in CMT2F (Evgrafov et al., 2004), MPZ (MIM no. 159440
[OMIM]
) in CMT2I (Boerkoel et al., 2002) and HSPB8 (MIM no. 608014
[OMIM]
) in CMT2L (Tang et al., 2005).
Following the mapping of CMT2A to the short arm of chromosome 1, 1p35–p36, a missense mutation was detected in KIF1B in a Japanese CMT2A family (Zhao et al., 2001). However, no other mutation has been identified in KIF1B, and, thus, it is believed that another gene is involved (Muglia et al., 2001; Bissar-Tadmouri et al., 2004). By linkage analysis and screening genes linked to the CMT2A locus, Züchner et al. (2004) first identified several mutations in the mitofusin 2 (MFN2) gene. Subsequently, additional MFN2 mutations were reported in CMT2A patients (Kijima et al., 2005; Lawson et al., 2005). Thus, today, mutations in MFN2 are considered to provide the genetic basis of the CMT2A phenotype. MFN2 encodes an outer mitochondrial membrane protein, which has important roles in the regulation of the fusion of mitochondria in cooperation with the Mfn1 isoform (Rojo et al., 2002; Chen et al., 2003; Koshiba et al., 2004). Mitochondrial fusion is essential for various biological functions in eukaryotic cells (Chen et al., 2005). It has also been suggested that MFN2 may be associated with the maintenance of mitochondrial membrane potentials (Honda et al., 2005). Moreover, MFN2-deficient mice die in mid-gestation and display fragmented mitochondria (Chen et al., 2003). In addition, it is believed, even in a few population-based studies, that MFN2 mutations are most common in CMT2 (Szigeti et al., 2006).
Recently, axonal CMT neuropathy with visual impairment due to optic atrophy designated as hereditary motor and sensory neuropathy type VI (HMSN VI) was also shown to be caused by mutations in the MFN2 gene (Züchner et al., 2006). After the vertical inheritance in HMSN VI from male to male was first documented by Vizioli (1889), other patterns of inheritance have been demonstrated, that is, autosomal dominant with incomplete penetrance (Voo et al., 2003; Züchner et al., 2006), autosomal recessive (Schneider and Abeles, 1937; Iwashita et al., 1970), X-linked recessive (Rosenberg and Chutorian, 1967) and sporadic (Krauss, 1906). These variable inheritance patterns of HMSN VI may be due to the incomplete penetrance of optic atrophy.
Because MFN2 mutation screening studies and examinations of the relationships between genotypes and clinical phenotypes have only been performed recently in CMT patients, mutation data in different ethnic groups are limited (Kijima et al., 2005; Lawson et al., 2005). Therefore, we screened for MFN2 mutations in 62 unrelated axonal CMT neuropathy families and identified 10 causative mutations in 15 families. We found that some affected individuals developed unusually severe phenotypes with an early onset and others a mild form of axonal neuropathy with a late age of onset. In addition, we detected two HMSN VI families with the R364W MFN2 mutation; however, the other two families with the same mutations did not show optic atrophy.
|
Patients and methods |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Patients
This study included a total of 218 patients from 62 families with distinct CMT type 2 phenotypes of Korean origin. Blood samples were collected from patients diagnosed as having CMT at Ewha Woman's University Hospital. The clinical guidelines of the European CMT consortium were used to diagnose CMT type 2 (De Jonghe et al., 1998
). In addition, 200 healthy controls for sequence variations were recruited from the neurological department, after careful clinical and electrophysiological examinations. In families with de novo mutation, paternity and maternity were confirmed in these families by genotyping 15 markers provided in AmpFLSTR identifier kits (Applied Biosystems, Foster City, CA, USA). All participants included in this study provided written informed consent according to the protocol approved by the Ethics Committee of Ewha Woman's University Hospital.
MFN2 mutation screening
DNA was extracted from blood samples using a genomic DNA isolation kit (SolGent, Daejeon, Korea). All exons of MFN2 were amplified using a standard polymerase chain reaction (PCR) method. Exons 7–8, 10–11 and 13–14 were amplified together, whereas the others were amplified separately. The primer sequences and PCR conditions used are available on request. PCR products were purified using PCR product purification kits (SolGent, Daejeon, Korea) and sequenced using an ABI 3100 automatic sequencer (Applied Biosystems-Hitachi, Tokyo, Japan). Sequence variations were confirmed by analysing both DNA strands.
Clinical assessment
Clinical information was obtained in a standardized manner and included assessments of motor and sensory impairments, deep tendon reflexes and muscle atrophy. Muscle strengths of flexor and extensor muscles were assessed manually using the standard Medical Research Council (MRC) scale. In order to determine physical disability, we used two scales, a functional disability scale (FDS) (Birouk et al., 1998) and a CMT neuropathy score (CMTNS) (Shy et al., 2005). Disease severity was determined for each patient using a nine-point FDS, which was based on the following criteria: 0 = normal; 1 = normal but with cramps and fatigability; 2 = an inability to run; 3 = walking difficulty but still possible unaided; 4 = walking with a cane; 5 = walking with crutches; 6 = walking with a walker; 7 = wheelchair-bound; and 8 = bedridden. In addition, we determined the recently created CMTNS, based on motor and sensory symptoms, and on pain and vibration, muscle strength and neurophysiological test results. Moreover, patients were divided into mild (CMTNS 10), moderate (CMTNS 11 and 20) and severe (CMTNS 21) categories. Sensory impairments were assessed in terms of the level and severity of pain, temperature, vibration and position, and pain and vibration sense were compared. Age at onset was determined by asking patients for their ages, when symptoms, that is, distal muscle weakness, foot deformity or sensory change, first appeared. Ophthalmological examination, done in all patients with MFN2 mutations, included best-corrected visual acuity, colour vision using Ishihara colour plates, pupillary reflex, automated visual field test, anterior segment and dilated fundus examination.
Electrophysiological study
Motor and sensory conduction velocities of median, ulnar, peroneal, tibial and sural nerves were determined in 26 patients. Recordings were obtained by standard methods using surface stimulation and recording electrodes. Motor conduction velocities (MCVs) of the median and ulnar nerves were determined by stimulating at the elbow and wrist while recording compound muscle action potentials (CMAPs) over the abductor pollicis brevis and abductor digiti quinti, respectively. In the same way, the MCVs of peroneal and tibial nerves were determined by stimulating at the knee and ankle, while recording CMAPs over the extensor digitorum brevis and abductor hallucis, respectively. CMAP amplitudes were measured from positive peak to negative peak values. Sensory conduction velocities (SCVs) were obtained over a finger-wrist segment from the median and ulnar nerves by orthodromic scoring and were also recorded for sural nerves. Sensory nerve action potential (SNAP) amplitudes were measured from positive peaks to negative peaks. Terminal latency indices (TLIs) were calculated for median nerves [TLI = terminal distance (mm)/MCV (m/s) x distal motor latency (ms)].
MRI study
Twenty-one individuals with MFN2 mutations were evaluated using a 1.5-T system (Siemens Vision; Siemens, Erlangen, Germany). Whole brains were scanned using a slice thickness of 7 mm and a 2-mm interslice gap, to produce 16 axial images. The imaging protocol consisted of T2-weighted spin echo [repetition time (TR)/echo time (TE) = 4700/120 ms], T1-weighted spin echo (TR/TE = 550/12 ms) and fluid-attenuated inversion recovery (FLAIR) (TR/TE = 9000/119 ms, inversion time 2609 ms) images.
Histopathological study
Pathological examinations of affected individuals included the light and electron microscopic analyses of a sural nerve. One sural nerve fragment was fixed in 10% formalin, embedded in paraffin and stained with haematoxylin–eosin (H–E). Another fragment was immediately fixed by immersion in 5% buffered glutaraldehyde and post-fixed in 1% osmium tetroxide. Epon-embedded semi-thin and ultra-thin sections were prepared for light and ultra-structural examinations. In addition, a muscle biopsy was taken from the gastrocnemius under local anaesthesia. Cross-sections of biopsy tissue were stained with H–E, modified Gomori-trichrome and oxidative enzymes (NADH-TR, succinate dehydrogenase). Another biopsy fragment was examined by electron microscopy.
Statistical analysis
Percentages and means were compared using the 
2-test and the Student's t-test, respectively. Correlation studies were performed using Spearman's correlation coefficient (r), and strong correlations were considered significant when r-values were >0.7 and P-values were <0.05. Statistical significance was accepted for P-values exceeding 0.05. Statistical analyses were performed using SPSS for Windows, Ver. 11.0 (SPSS Inc., Chicago, IL, USA).
|
Results |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Identification of causative mutations
Mutation screening of MFN2 in 62 unrelated CMT2 families identified ten causative missense mutations in 15 families (24.2%). Details of the mutations are listed in Table 1. Most mutations were located within or close to the GTPase domain. Six mutations [c.275T
C (L92P), c.380GA (G127D), c.494AG (H165R), c.787TC (S263P), c.1085CT (T362M) and c.1127TC (M376T)] had not been reported previously, and were not detected in the 400 control chromosomes (Fig. 1A). Amino acid sequences are highly conserved in different species at most mutation sites (Fig. 1B). In the present study, CMT2A families with MFN2 mutations showed an autosomal dominant inheritance, even though there were de novo mutations. Five de novo mutations were proved in 5 families of the 15 CMT2A families (33.3%), which is a high rate.
|
|
The c.275T
C (L92P) de novo mutation at exon 4 was found in a patient with a severe CMT2 phenotype (FC34). This mutation was only detected in the proband (III-2), who was the only affected member of his family (Fig. 2A). The c.280CT (R94W) autosomal dominant mutation at exon 4 was detected in severely affected individuals of two CMT2 families. This mutation was transmitted from father (possible affected) to son in Family FC25 (Fig. 2B) and from mother to son in Family FC113 (Fig. 2C), respectively. Mutations at the 94th codon have been previously reported in several families (Züchner et al., 2004; Kijima et al., 2005). Two de novo mutations at exon 5, c.314CT (T105M) and c.380GA (G127D), were identified in CMT2 families with a mild phenotype, FC135 (Fig. 2D) and FC48 (Fig. 2E), respectively. The T105M mutation has been previously reported in two CMT2 families (Züchner et al., 2004; Lawson et al., 2005). The c.494AG (H165R) mutation at exon 6 was detected in two CMT2 families with a mild phenotype, FC81 (Fig. 2F) and FC111 (Fig. 2G). This mutation co-segregated to affected members in both pedigrees in an autosomal dominant mode. The exon 8 c.787TC (S263P) mutation was identified in a mild CMT2 family (FC52) and had been transmitted from mother to son (Fig. 2H), and c.839GA (R280H), an autosomal dominant mutation at exon 9, was also identified in a mild CMT2 family, FC169 (Fig. 2I). The R280H mutation has been previously reported in a CMT2 family (Züchner et al., 2004). A novel c.1085CT (T362M) mutation was observed in a late-onset CMT2 family with a mild phenotype (FC188). The proband (II-2) had received the mutation from her mother (I-2), who showed very mild phenotype (Fig. 2J). Four families with a severe phenotype were found to possess c.1090CT (R364W) at exon 11. In the FC1 pedigree (Fig. 2K), the proband (III-1) and her twin sister (III-2) had received the mutation from their mother (II-3), but II-3 was a de novo case. FC6 (Fig. 2L) and FC87 (Fig. 2N) showed autosomal dominant inheritance (mother to son), whereas FC55 (Fig. 2M) showed a de novo mutation. The c.1127TC (M376T) autosomal dominant mutation at exon 11 was identified in mild patients in a CMT2 pedigree (FC70; Fig. 2O). This mutation had been transmitted from mother (I-2) to the proband (II-5) and her brother (II-4).
|
We also found several polymorphic variants in the exon region: c.–212T
C (5'-UTR, exon 1), c.150CA (I150I), c.165CT (T55T), c.408AT (V136V), c.1569CT (S523S) and c.2332AG (3'-UTR at exon 19). These variants were also observed in controls, but no amino acid substitutions were involved; thus, they were not regarded as causative mutations. Some polymorphic sites (c.150CA, c.165CT, c.408AT and c.1569CT) have been reported previously (Kijima et al., 2005). A mutation at intron 5 near the 5'-splicing site, c.474+4AG, was also detected in two CMT2 families. However, this mutation did not co-segregate to affected individuals and was also found in controls at a frequency of 0.015, and, thus, was not considered a causative mutation.
Clinical findings
The clinical features of the 26 patients (11 males, 15 females) from the 15 families are shown in Table 2. Muscle weakness and atrophy started and predominated in the distal portions of legs and were noted to a lesser extent distally in upper limbs. Paresis in the distal regions of lower limbs varied from asymptomatic or mild weakness to the complete paralysis of distal muscle groups.
|
Age at onset was earlier than 10 years (early onset group) in five males and seven females and occurred later (late-onset group) in six males and eight females. Mean age at onset was 3.9 ± 3.0 years (range: 1–9 years) in the early onset group and 23.9 ± 13.0 years (range: 10–50 years) in late-onset group (P < 0.001). Disease duration at the time of examination was 14.5 ± 9.8 years in the early onset group and 11.8 ± 8.5 years in the late-onset group, which was not significantly different. Clinical findings confirmed that patients in the early onset group were more severely affected than those in the late-onset group, and this was significant for several items, that is, severity of muscle weakness (P < 0.01), frequency of upper and lower limb areflexia (P < 0.01) and the presence of flat feet deformities (P < 0.01). Length-dependent sensory loss was found in 24 patients (92.3%). Vibration sense was reduced to a greater extent than pain in 8 of the 12 patients in the early onset group (66.7%). In the late-onset group, pain sense was reduced to a greater extent than vibration in 3 of 14 patients (21.4%), whilst in 10 patients (71.4%) those were reduced to a similar extent.
Functional disability was severe in patients with an early onset, but mild in patients with a late onset. Mean FDS was 6.6 ± 0.5 in the early onset group and 1.4 ± 0.8 in late-onset group (P < 0.001). CMTNS was 31.8 ± 5.2 in the early onset group and 7.1 ± 3.2 in the late-onset group, which was significantly different (P < 0.001). High FDSs (score = 6 or 7) were found only in the early onset group; however, the late-onset group members showed low FDSs (score 3). All 12 patients in the early onset group were in the severe (CMTNS 21) category. Except for one patient (III-3 in Family FC81; CMTNS = 15), who was in moderate category, 13 of the 14 late-onset patients were in mild (CNTNS 10) category. CMTNSs and FDSs showed a bimodal distribution in patients with MFN2 mutations (Fig. 3A and B).
|
Foot deformities were found in all patients. Pes cavus with flattening was more frequent in the early onset group, and, similarly, high arched foot deformities were more frequent in the late-onset group. Associated signs differed in the early and late-onset groups. Scoliosis (38.5%) and knee joint contracture (26.9%) was found only in patients with an early onset; however, postural hand tremor (30.8%), pain (19.2%) and sensorineural hearing loss (SNHL) (11.5%) were demonstrated by patients with a late onset. In addition, two affected males had bilateral extensor plantar responses with no explanation other than CMT.
Electrophysiological findings
Neurophysiological studies were carried out on 26 affected individuals (11 males and 15 females). MCVs of median, ulnar, peroneal and tibial nerves and SCVs of median, ulnar and sural nerves are shown in Table 3. Electrophysiological findings also confirmed that patients with an early onset were more severely affected than those with a late onset. In the early onset group, the amplitudes of evoked motor responses were often markedly reduced, and we were unable to record amplitudes in 8 of the 12 patients (67%). All patients, except those with absent NCVs, had at least one motor NCV > 38 m/s. However, in the late-onset group, NCVs were obtained for all patients, and some motor NCVs in upper limbs were normal without conduction block. In a patient (III-2 in Family FC34) with an early age at onset, we carried out three follow-up nerve conduction studies over a 10-year period and finally observed the absence of action potentials in all nerves tested (Table 3). Sensory and motor amplitudes changed at a much slower rate in patients with a late onset than in those with an early onset.
|
The distal and lower limb predominant motor involvement was common in patients with MFN2 mutations. Therefore, we studied correlations between CMAP and distal limb muscle strength. The amplitudes of the CMAPs of median, ulnar and posterior tibial nerves were found to be significantly correlated with corresponding distal muscle strengths in MFN2 patients (r = 0.80, P < 0.001; r = 0.79, P < 0.001; r = 0.78, P = 0.005, respectively). In contrast, the MCVs of median, ulnar and posterior tibial nerves did not correlate with distal muscle strength in MFN2 patients (r = 0.50, P > 0.05; r = 0.48, P > 0.05; r = 0.58, P > 0.05, respectively). These findings indicate that the weakness is the consequence of axonal loss as reflected in the reduced amplitudes in all motor nerves.
Mean median nerve TLIs in patients with MFN2 mutations (0.30 ± 0.06, range: 0.16–0.43) were not significantly different from those of 158 healthy controls (0.31 ± 0.04, range: 0.23–0.43). TLIs in the majority of patients in each group were distributed over a narrow range of values. In both early and late-onset groups, TLIs displayed similar distributions (0.30 ± 0.07, range: 0.22–0.43; 0.31 ± 0.06, range: 0.16–0.39, respectively). This finding was expected in CMT2 and supports the hypothesis that axonopathy in patients with MFN2 mutations is uniformly distributed along nerves.
Ophthalmological findings
Three patients (II-6 and III-1 in Family FC6, and II-3 in Family FC1) developed bilateral optic atrophy during the course of CMT. A patient (II-6 in Family FC6) showed visual impairment at 10 years and experienced a subacute deterioration of visual acuity as low as 20/130 bilaterally. Her son (III-1 in Family FC6) experienced visual deterioration from 13 years and subacute loss of visual acuity as low as 20/100 bilaterally. However, the other patient (II-3 in Family FC1) could not recall the exact age of visual impairment onset and experienced a prolonged decline of visual acuity to as low as 20/200 in the right eye and 20/400 in the left. A central scotoma was detected in all of the above patients. Also, these affected individuals had colour vision defects, and their Ishihara colour plate test results were low (2/21–9/21). Afferent pupillary defect was not found, and intraocular pressures were not increased. Fundus examination of three patients showed a white flat optic disc, attenuation of peripupillary blood vessels and thinning of the retinal nerve fibre layer. The macular, peripheral retina and blood vessels appeared normal, as were the anterior segments of the eye. In addition, one patient (III-1 in Family FC6) had the cup of optic disc showing concentric enlargement and an oval shape. Visual evoked potentials (VEPs) showed no amplitudes in one patient, and markedly reduced amplitudes and delayed patterns in the other patients (Fig. 4A and B). Over the course of several years, both patients in the FC6 family experienced visual acuity recovery to near-normal levels; however, another patient (II-3 in Family FC1) did not improve.
|
Two daughters of an HMSN VI patient (II-3 in Family FC1) did not have optic atrophy, but extremely severe axonal CMT phenotypes were expressed in both. They showed normal visual acuity (20/20 in both sides) and VEP patterns. Two families (FC55 and FC87) with R364W MFN2 mutations (like FC1 and FC6) showed normal VEP patterns without optic atrophy (Fig. 4C and D). In addition, two families with R94W, previously reported for HMSN VI, also displayed normal VEP patterns without optic atrophy (Fig. 4E). Moreover, a patient (III-2 in Family FC34) with an early onset with L92P, which showed a clinical course resembling those of R364W or R94W mutations, did not have optic atrophy and normal VEP findings (Fig. 4F). Retinitis pigmentosa was not found in any study subject.
MRI findings
Twenty-one patients with MFN2 mutations were subjected to brain MRI studies. Eight affected individuals from four families had abnormal MRI findings, namely, T2 and FLAIR high-signal intensities in centrum semiovale, periventricular and subcortical white matters. The onset age of one patient (II-2 in Family FC55) was earlier than 10 years; however, those of the other seven patients were later. In eight affected individuals, neither hypertension nor diabetes was found.
One patient (II-2 in Family FC55) had confluent periventricular white matter high-signal lesions in right frontal lobe for her age without any other explanation than CMT (Fig. 5A). Moreover, follow-up T2-weighted MRI scans over 3 years showed no interval change (Fig. 5B). She was born at full period, and no evidence of epileptic seizure, loss of consciousness or behavioural disturbances was documented.
|
Two patients (III-4 and III-8 in Family FC169) had abnormal brain MRI results in association with transient dysarthria and migraine. Patient III-4 in Family FC169 showed a confluent lesion in the left parietal lobe and multiple non-specific but definitely pathogenic hyperintensities for age (Fig. 6A). She experienced repeated attacks of transient dysarthria persisting for between a few hours and 2 days at the longest. These symptoms recurred at irregular intervals. The other patient (III-8 in Family FC169), the cousin of FC169 (III-4), had similar symptoms. Both experienced migraine without aura.
|
A patient (II-2 in Family FC188) experienced a sudden attack of transient right upper limb and facial sensory loss for 1 month at 43 years, and, subsequently, experienced recurrent brief transient episodes of paraesthesia with a right upper limb predominance. Brain MRI showed T1 low, T2 and FLAIR high-signal intensities in left subcortical lesion without abnormal enhancement (Fig. 6B).
Three patients (III-12 in FC169, and II-5 and III-3 in FC81) harbouring SNHL showed multiple subcortical white matter lesions (Fig. 6C). One patient (II-3 in Family FC48) with bilateral extensor plantar responses also displayed multiple non-specific but pathogenic subcortical hyperintense lesions (Fig. 6D), but an MRI scan of the whole spinal code showed no abnormalities.
Histopathological findings
Sural nerve biopsies were performed in seven patients (see Table 2). On light microscopic examination, numbers of myelinated nerve fibres (MNFs) in the early onset group ranged from 2327/mm2 to 2837/mm2 (Fig. 7A); however, numbers in the late- onset group ranged from 7821/mm2 to 8356/mm2 (Fig. 7B). Semi-thin transverse section of the sural nerve showed a marked loss of large myelinated fibres in early onset patients (Fig. 8A), but relatively greater preservation in late-onset patient (Fig. 8B). In both groups, unmyelinated nerve fibres were more preserved than large MNFs; however, those were clustered and atrophied (Fig. 8A). These features are compatible with axonopathy, which is characteristic in CMT2. In one patient (II-3 in Family FC1), the mean number of MNFs was 2299/mm2, and unmyelinated nerve fibres were relatively better preserved than MNFs. In this patient, diverse features, like pseudo-onion bulb formations that contained more than one axon, were observed by electron microscopy (Fig. 9A and B). One gastrocnemius muscle biopsy was available for histopathological study, in a patient (III-4 in Family FC135) who carried the MFN2 mutation. This muscle biopsy showed many small grouped atrophic foci, which is characteristic of neurogenic muscle atrophy; however, no ragged-red fibres (RRFs) were observed.
|
|
|
|
Discussion |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
In the present study, we identified 10 causative MFN2 missense mutations in 15 CMT families (24.2%). In particular, six of these mutations were determined to be novel. Mutations observed in the present study involved regions highly conserved between species, for example, Candida elegans and Drosophila melanogaster (Fig. 1B). All of them cause amino acid substitutions with different properties.
The phenotypic descriptions of the 15 families concur with previous reports and suggest that MFN2 mutations cause an axonal CMT2 phenotype (Züchner et al., 2004; Kijima et al., 2005; Lawson et al., 2005). In affected individuals with MFN2 mutations, phenotypes were clearly differentiated into two subgroups. In the early onset group (<10 years), unusually severe phenotypes predominated, whereas in the late-onset group (10 years), most patients had mild phenotypes. Moreover, phenotype severity was also concordant among siblings in individual families, and the clinical courses of families with the same mutations were very similar, indicating that severe and mild phenotypes are determined mainly by the position of mutations in the MFN2 gene.
In semiological terms, all 12 cases with an early onset required a walker or a wheelchair and were categorized as severe by CMTNS. However, in the late-onset group, one exhibited no disability and the others showed either difficulty walking or an inability to run and were categorized as mild to moderate by CMTNS. Moreover, our electrophysiological findings showed a striking difference between the two subgroups (see Table 3). In the early onset group, CMAP amplitudes were markedly reduced, to the extent that CMAPs were not recordable in eight patients (67%). However, in the late-onset group, nerve conductions were recordable in all patients, and some patients presented nearly normal values. In addition, follow-up studies showed that axonal degeneration changes were more rapid in patients with an early onset. Therefore, genetically determined phenotypes were found to correspond well with electrophysiological findings.
It appears that mutational spots with high frequency might exist in MFN2, at the 94th, 105th, 280th and 364th codons. In particular, two different missense mutations at the 94th codon have been reported in seven unrelated CMT2A families (four cases of R94W and three cases of R94Q), including two cases in the present study (Züchner et al., 2004, 2006; Kijima et al., 2005). T105M has been detected in three families, once in the present study and once by Züchner et al. (2004) and Lawson et al. (2005); R280H has also been detected in three families, once in the present study and twice by Züchner et al. (2004); whereas R364W has been reported in five families, four unrelated families in the present study and once by Züchner et al. (2006).
Population data on MFN2 mutations by ethnicity are limited, because the relevance of the MFN2 mutation in CMT2 was reported for the first only recently (Züchner et al., 2004). In the present study, we identified MFN2 mutations in 24.2% of 62 axonal CMT2 families. Züchner et al. (2004) reported 7 (19.4%) mutations in 36 CMT2 families representing several ethnic groups, a Japanese group reported 7 (8.6%) mutations in 81 axonal or unclassified CMT patients (Kijima et al., 2005) and an American study reported 3 (23.1%) mutations in 13 CMT2 families (Lawson et al., 2005). The mutation frequency observed by the Japanese group was lower than those reported by other studies, which may be due to sampling or analytical differences or to different genetic backgrounds. We screened MFN2 mutations by directly sequencing all exons by PCR in CMT2 patients, whereas Kijima et al. (2005) performed denaturing high-performance liquid chromatography (DHPLC) before sequence analysis, which might have reduced the detection rate. In addition, Kijima et al. (2005) has reported a case of de novo mutation among 7 Japanese CMT2A families with MFN2 mutations (14.4%); however, we could prove de novo mutations in at least 5 out of 15 CMT2A families in this study (33.3%). Although additional evidence from other population studies is necessary, we suggest that the frequency of de novo mutations may be higher. And, even though a combined analysis of population-based studies on different ethnic groups is not yet available, we believe that MFN2 mutations are the most common mutation form in axonal CMT.
Electrophysiological evidence indicates that the predominant distal muscle weakness and atrophy of CMT is due to the evolving length-dependent degeneration of motor axons (Hattori et al., 2003). Distally accentuated muscle weakness was found to be strongly correlated with a reduction in the number of functioning large axons, as assessed by CMAPs, but not with nerve conduction slowing. TLI is usually used for determining differential motor conduction slowing between the distal and proximal segments of a nerve (Dubourg et al., 2001). In the present study, median nerve TLI was the same in controls and in patients with MFN2 mutations. Moreover, median nerve TLI varied little in controls, or in patients with either an early or late onset, suggesting that axonal degeneration occurring in patients with MFN2 mutations is homogeneous throughout a given nerve.
Optic atrophy, when noted at the examination of an axonal CMT patient with visual dysfunction, is demonstrated in HMSN VI (Voo et al., 2003). We identified three HMSN VI patients in two unrelated axonal CMT families with R364W mutation. Before molecular diagnosis of MFN2 gene, all of them were checked for mitochondrial mutations relevant to Leber's hereditary optic atrophy (MIM no. 535000
[OMIM]
); however, we could not find any mitochondrial mutations. In the FC1 family, children with axonal CMT phenotype did not have visual impairments. Another two families with R364W did not have optic atrophy and two families with R94W, previously reported for HMSN VI, also did not have visual impairments (Züchner et al., 2006). In addition, an early onset patient harbouring L92P mutation, with a clinical course that resembled those with R364W or R94W mutations, did not have optic atrophy. In fact, optic atrophy was only demonstrated by extremely severe axonal CMT patients with an early age at onset, and not by those with a late age at onset. In addition, it has been reported that HMSN VI had variant inherited patterns, and there has been reported an evidence of incomplete penetrance of optic atrophy, whereas the CMT phenotype was expressed in all mutation carriers (Voo et al., 2003; Züchner et al., 2006). Therefore, both the incomplete penetrance and the appearance of optic atrophy in unusually severe patients may be causes of reduced penetrance. On the basis of these findings, we suggest that axonal CMT with optic atrophy harbouring MFN2 mutation might be a variation of an early onset severe CMT2A phenotype.
The MRI findings of patients with MFN2 mutations are interesting. We identified a high incidence of CNS involvements in 8 of 21 patients (38%), by brain MRI. Comparing our findings with those of a previous report, which found an increased T2 signal in both cerebellar peduncles (Züchner et al., 2006), our MRI findings showed T2 and FLAIR high-signal intensities in centrum semiovale, periventricular and subcortical white matters without abnormal enhancement (see Figs 5 and 6). In addition, confluent T2 hyperintensities were detected in the periventricular white matter of frontal and parietal lobes, and the white matter lesions were considered definitive pathological lesions that could not be attributed to age. In a female patient (II-2 in Family FC55), the abnormalities observed in T2-weighted sequences showed no interval change between 3 and 6 years of age, which differs from the findings of cerebral lesions in unusual CMTX (CMT neuropathy type X) cases associated with transient CNS abnormalities, in which such changes are reversible over a relatively short period (Paulson et al., 2002; Hanemann et al., 2003). Subclinical CNS involvement in patients with Cx32 mutations has been previously reported (Nicholson et al., 1998; Bahr et al., 1999). We also found subclinical CNS involvements in patients with MFN2 mutations. In addition, abnormal MRI findings were more common in the late-onset group; therefore, we considered that these were not necessarily associated with age at onset or clinical severity. Moreover, it would be of interest to determine whether these non-specific but pathogenic findings are also found frequently in other populations with MFN2 mutations.
However, the relation between these abnormal brain MRI findings and mitochondrial dysfunction due to MFN2 mutations has not been established. The possible explanation for white matter changes in brain MRI findings of our patients is that MFN2 is highly abundant in brain, and it has been well known that mitochondria play a pivotal role in coordinating programmed cell death; therefore, while numerous cell death pathways are activated following an episode of brain ischaemia, mitochondrial dysfunction appears to be a crucial factor in the life or death decision (Fiskum et al., 2000; Zipfel et al., 2000; Bach et al., 2005; Korde et al., 2005). Whatever the exact pathomechanism turns out to be, it is important to remember that there are clinical examples of CNS involvements.
MFN2 mutations have been associated with clinical findings suggesting CNS involvement. CMT with a pyramidal feature is an axonal form of CMT with variable pyramidal features but without frank spasticity (Vucic et al., 2003). In the present study, extensor plantar responses were found in one patient (II-3 in Family FC48) and brain and spine MRI findings were normal; however, the other patient (III-7 in Family FC169) with extensor plantar responses had an abnormal brain MRI. Both of these patients had flexor plantar weakness and increased knee and ankle reflexes but no frank spasticity, which is differentiated from spastic paraplegia. These findings are similar to the previous report by Zhu et al. (2005). In addition, SNHL was found in three patients with H165R and M376T mutations; all three cases had multiple subcortical hyperintense lesions on brain MRI. Although the additional evidences from in vivo or in vitro studies are necessary, we suggest that MFN2 mutations may cause variable CNS involvements.
Nerve biopsy findings in CMT2A patients showed typical evidence of axonopathy, such as axonal cluster formation, atrophy and loss of thick MNFs, as is found in CMT2 (Berciano et al., 1986; Thomas et al., 1996). The mean number of myelinated fibres in patients with an early onset was reduced by 70% compared with that in patients with a late onset. However, unmyelinated nerve fibres were similarly well preserved in both groups (see Figs 7 and 8). In a patient (II-3 from Family FC1), an electron microscopic examination showed some pseudo-onion bulb formations (see Fig. 9), and it would appear that this feature may have been caused by Schwann cell proliferation in clusters of regenerating nerve fibres.
Mutations in MFN2 gene are now viewed as the primary cause of axonal autosomal dominant CMT2A, and, thus, it has been suggested that MFN2 should be screened for in these patients. However, clinical and electrophysiological phenotypes of CMT patients with MFN2 mutations were significantly different in early and late disease-onset groups, and optic atrophy was found only in CMT2 patients with unusually severe phenotypes with an early age at onset. In addition, MFN2 mutations show variable CNS involvements. On the basis of prior evidence and the present study, it seems probable that MFN2 mutations affect the nervous system at various levels, and that HMSN VI might be a variant of an early onset severe CMT2A phenotype.
|
Acknowledgements |
|---|
We wish to thank Dr M. Shy for critical review of this manuscript. This work was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea (A05-0503-A20718-05N1-00010A), and in part by the Brain Korea 21 project, Ministry of Education.
|
REFERENCES |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionREFERENCES |
|---|
Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, et al. (2003) Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet 72:1293–9.[CrossRef][Web of Science][Medline]
Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, et al. (2005) Expression of MFN2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes 54:2685–93.
Bahr M, Anders F, Timmerman V, Nelis ME, Van Broeckhoven C, Dichgans J. (1999) Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. J Neurol Neurosurg Psychiatry 66:202–6.
Berciano J, Combarros O, Figols J, Calleja J, Cabello A, Silos I, et al. (1986) Hereditary motor and sensory neuropathy type II. Clinicopathological study of a family. Brain 109:897–914.
Birouk N, LeGuern E, Maisonobe T, Rouger H, Gouider R, Tardieu S, et al. (1998) X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study. Neurology 50:1074–82.
Bissar-Tadmouri N, Nelis E, Züchner S, Parman Y, Deymeer F, Serdaroglu P, et al. (2004) Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene. Neurology 62:1522–5.
Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, et al. (2002) Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol 51:190–201.[CrossRef][Web of Science][Medline]
Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200.
Chen H, Chomyn A, Chan DC. (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–92.
Choi BO, Lee MS, Shin SH, Hwang JH, Choi KG, Kim WK, et al. (2004) Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients. Hum Mutat 24:185–6.[Medline]
De Jonghe P, Timmerman V, Broeckhoven CV. (1998) Workshop Participants. 2nd Workshop of the European CMT Consortium: 53rd ENMC International Workshop on Classification and Diagnostic Guidelines for Charcot-Marie-Tooth Type 2 (CMT2HMSN II) and Distal Hereditary Motor Neuropathy (Distal HMNSpinal CMT): 26-28 September 1997, Naarden, The Netherlands. Neuromusc Disord 8:426–31.[CrossRef][Medline]
Dubourg O, Tardieu S, Birouk N, Gouider R, Leger JM, Maisonobe T, et al. (2001) Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain 124:1958–67.
Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, et al. (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 36:602–6.[CrossRef][Web of Science][Medline]
Fiskum G. (2000) Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma 17:843–55.[Web of Science][Medline]
Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD. (2003) Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation. Arch Neurol 60:605–9.
Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, et al. (2003) Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 126:134–51.
Honda S, Aihara T, Hontani M, Okubo K, Hirose S. (2005) Mutational analysis of action of mitochondrial fusion factor mitofusin-2. J Cell Sci 118:3153–61.
Iwashita H, Inoue N, Araki S, Kuroiwa Y. (1970) Optic atrophy, neural deafness, and distal neurogenic amyotrophy. Arch Neurol 22:357–64.
Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, et al. (2005) Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 116:23–7.[CrossRef][Web of Science][Medline]
Korde AS, Pettigrew LC, Craddock SD, Maragos WF. (2005) The mitochondrial uncoupler 2,4–dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia. J Neurochem 94:1676–84.[CrossRef][Web of Science][Medline]
Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC. (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858–62.
Krauss W. (1906) Atrophia nervi optici and neurotische Muskelartophie. Z Augenheilk 16:503–16.
Lawson VH, Graham BV, Flanigan KM. (2005) Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 65:197–204.
Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, et al. (2000) A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet 67:37–46.[Medline]
Muglia M, Zappia M, Timmerman V, Valentino P, Gabriele AL, Conforti FL, et al. (2001) Clinical and genetic study of a large Charcot-Marie-Tooth type 2A family from Southern Italy. Neurology 56:100–3.
Nicholson GA, Young I, Corbett A. (1998) Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations. Neurology 51:1412–6.
Pareyson D. (2004) Differential diagnosis of Charcot-Marie-Tooth disease and related neuropathies. Neurol Sci 25:72–82.[Web of Science][Medline]
Paulson HL, Garbern JY, Hoban TF, Krajewski KM, Lewis RA, Fischbeck KH, et al. (2002) Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease. Ann Neurol 52:429–34.[CrossRef][Web of Science][Medline]
Rojo M, Legros F, Chateau D, Lombes A. (2002) Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 115:1663–74.
Rosenberg RN and Chutorian A. (1967) Familial opticoacoustic nerve degeneration and polyneuropathy. Neurology 17:827–32.
Schneider DE and Abeles MM. (1937) Charcot-Marie-Tooth disease with primary optic atrophy: report of two cases occurring in two brothers. J Nervous Mental Dis 85:541–7.[Web of Science]
Shy ME. (2004) Charcot-Marie-Tooth disease: an update. Curr Opin Neurol 17:579–85.[CrossRef][Web of Science][Medline]
Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, et al. (2005) Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 64:1209–14.
Szigeti K, Garcia CA, Lupski JR. (2006) Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet Med 8:86–92.[Web of Science][Medline]
Tang BS, Zhao GH, Luo W, Xia K, Cai F, Pan Q, et al. (2005) Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet 116:222–4.[CrossRef][Web of Science][Medline]
Thomas PK, King RH, Small JR, Robertson AM. (1996) The pathology of Charcot-Marie-Tooth disease and related disorders. Neuropathol Appl Neurobiol 22:269–84.[Web of Science][Medline]
Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, et al. (2003) Mutations in the small GTPase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet 72:722–7.[CrossRef][Web of Science][Medline]
Vizioli F. (1889) Dell's atrofia muscolare progressive nervrotica. Boll de la R Accad Med-Chir.
Voo I, Allf BE, Udar N, Silva-Garcia R, Vance J, Small KW. (2003) Hereditary motor and sensory neuropathy type VI with optic atrophy. Am J Ophthalmol 136:670–7.[CrossRef][Web of Science][Medline]
Vucic S, Kennerson M, Zhu D, Miedema E, Kok C, Nicholson GA. (2003) CMT with pyramidal features. Charcot-Marie-Tooth. Neurology 60:696–9.
Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, et al. (2001) Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1B beta. Cell 105:587–97.[CrossRef][Web of Science][Medline]
Zhu D, Kennerson ML, Walizada G, Zuchner S, Vance JM, Nicholson GA. (2005) Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology 65:496–7.
Zipfel GJ, Babcock DJ, Lee JM, Choi DW. (2000) Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma 17:857–69.[Web of Science][Medline]
Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, et al. (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–51.[CrossRef][Web of Science][Medline]
Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, et al. (2006) Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 59:276–81.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Chen and D. C. Chan Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases Hum. Mol. Genet., October 15, 2009; 18(R2): R169 - R176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Liesa, M. Palacin, and A. Zorzano Mitochondrial Dynamics in Mammalian Health and Disease Physiol Rev, July 1, 2009; 89(3): 799 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Muglia, G. Vazza, A. Patitucci, M. Milani, D. Pareyson, F. Taroni, A. Quattrone, and M. L. Mostacciuolo A novel founder mutation in the MFN2 gene associated with variable Charcot-Marie-Tooth type 2 phenotype in two families from Southern Italy BMJ Case Reports, January 22, 2009; 2009(jan21_1): bcr0820080652 - bcr0820080652. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. D. Bo, M. Moggio, M. Rango, S. Bonato, M. G. D'Angelo, S. Ghezzi, G. Airoldi, M. T. Bassi, M. Guglieri, L. Napoli, et al. Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction Neurology, December 9, 2008; 71(24): 1959 - 1966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Casasnovas, L. M. Cano, A. Alberti, M. Cespedes, and G. Rigo Charcot-Marie-Tooth Disease Foot & Ankle Specialist, December 1, 2008; 1(6): 350 - 354. [Abstract] [PDF]
|
|
|
|
|
|
C. L. Bennett, V. H. Lawson, K. L. Brickell, K. Isaacs, W. Seltzer, H. P. Lipe, M. D. Weiss, G. T. Carter, K. M. Flanigan, P. F. Chance, et al. Late-onset hereditary axonal neuropathies Neurology, July 1, 2008; 71(1): 14 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Chung, S. Y. Cho, S. J. Hwang, K. H. Kim, J. H. Yoo, O. Kwon, S. M. Kim, I. N. Sunwoo, S. Zuchner, and B. O. Choi EARLY-ONSET STROKE ASSOCIATED WITH A MUTATION IN MITOFUSIN 2 Neurology, May 20, 2008; 70(21): 2010 - 2011. [Full Text] [PDF]
|
|
|
|
|
|
G. A. Nicholson, C. Magdelaine, D. Zhu, S. Grew, M. M. Ryan, F. Sturtz, J. -M. Vallat, and R. A. Ouvrier Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations Neurology, May 6, 2008; 70(19): 1678 - 1681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Carelli and M. Bellan Myelin, mitochondria, and autoimmunity: What's the connection? Neurology, March 25, 2008; 70(13_Part_2): 1075 - 1076. [Full Text] [PDF]
|
|
|
|
|
|
S. A. Detmer, C. V. Velde, D. W. Cleveland, and D. C. Chan Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A Hum. Mol. Genet., February 1, 2008; 17(3): 367 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Muglia, G Vazza, A Patitucci, M Milani, D Pareyson, F Taroni, A Quattrone, and M L Mostacciuolo A novel founder mutation in the MFN2 gene associated with variable Charcot Marie Tooth type 2 phenotype in two families from Southern Italy J. Neurol. Neurosurg. Psychiatry, November 1, 2007; 78(11): 1286 - 1287. [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Detmer and D. C. Chan Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations J. Cell Biol., February 12, 2007; 176(4): 405 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Baloh, R. E. Schmidt, A. Pestronk, and J. Milbrandt Altered Axonal Mitochondrial Transport in the Pathogenesis of Charcot-Marie-Tooth Disease from Mitofusin 2 Mutations J. Neurosci., January 10, 2007; 27(2): 422 - 430. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||