Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations

K. W. Chung, S. B. Kim, K. D. Park, K. G. Choi, J. H. Lee, H. W. Eun, J. S. Suh, J. H. Hwang, Won-Ki Kim, B. C. Seo, S. H. Kim, I. H. Son, S. M. Kim, I. N. Sunwoo, B. O. Choi

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2103-2118
Number of pages16
JournalBrain
Volume129
Issue number8
DOIs
Publication statusPublished - 2006 Aug 1
Externally publishedYes

Fingerprint

Charcot-Marie-Tooth Disease
Mutation
Optic Atrophy
Tooth
Babinski's Reflex
Phenotype
Sensorineural Hearing Loss
GTP Phosphohydrolases
Vision Disorders
Brain
Hereditary Motor And Sensory Neuropathy VI

Keywords

  • Charcot-Marie-Tooth disease
  • CMT2A
  • HMSN VI
  • Mitofusin 2 (MFN2)

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chung, K. W., Kim, S. B., Park, K. D., Choi, K. G., Lee, J. H., Eun, H. W., ... Choi, B. O. (2006). Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain, 129(8), 2103-2118. https://doi.org/10.1093/brain/awl174

Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. / Chung, K. W.; Kim, S. B.; Park, K. D.; Choi, K. G.; Lee, J. H.; Eun, H. W.; Suh, J. S.; Hwang, J. H.; Kim, Won-Ki; Seo, B. C.; Kim, S. H.; Son, I. H.; Kim, S. M.; Sunwoo, I. N.; Choi, B. O.

In: Brain, Vol. 129, No. 8, 01.08.2006, p. 2103-2118.

Research output: Contribution to journalArticle

Chung, KW, Kim, SB, Park, KD, Choi, KG, Lee, JH, Eun, HW, Suh, JS, Hwang, JH, Kim, W-K, Seo, BC, Kim, SH, Son, IH, Kim, SM, Sunwoo, IN & Choi, BO 2006, 'Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations', Brain, vol. 129, no. 8, pp. 2103-2118. https://doi.org/10.1093/brain/awl174
Chung, K. W. ; Kim, S. B. ; Park, K. D. ; Choi, K. G. ; Lee, J. H. ; Eun, H. W. ; Suh, J. S. ; Hwang, J. H. ; Kim, Won-Ki ; Seo, B. C. ; Kim, S. H. ; Son, I. H. ; Kim, S. M. ; Sunwoo, I. N. ; Choi, B. O. / Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. In: Brain. 2006 ; Vol. 129, No. 8. pp. 2103-2118.
@article{d7870c95629f413893cd9a902ecd2de9,
title = "Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations",
abstract = "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.",
keywords = "Charcot-Marie-Tooth disease, CMT2A, HMSN VI, Mitofusin 2 (MFN2)",
author = "Chung, {K. W.} and Kim, {S. B.} and Park, {K. D.} and Choi, {K. G.} and Lee, {J. H.} and Eun, {H. W.} and Suh, {J. S.} and Hwang, {J. H.} and Won-Ki Kim and Seo, {B. C.} and Kim, {S. H.} and Son, {I. H.} and Kim, {S. M.} and Sunwoo, {I. N.} and Choi, {B. O.}",
year = "2006",
month = "8",
day = "1",
doi = "10.1093/brain/awl174",
language = "English",
volume = "129",
pages = "2103--2118",
journal = "Brain : a journal of neurology",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "8",

}

TY - JOUR

T1 - Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations

AU - Chung, K. W.

AU - Kim, S. B.

AU - Park, K. D.

AU - Choi, K. G.

AU - Lee, J. H.

AU - Eun, H. W.

AU - Suh, J. S.

AU - Hwang, J. H.

AU - Kim, Won-Ki

AU - Seo, B. C.

AU - Kim, S. H.

AU - Son, I. H.

AU - Kim, S. M.

AU - Sunwoo, I. N.

AU - Choi, B. O.

PY - 2006/8/1

Y1 - 2006/8/1

N2 - 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.

AB - 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.

KW - Charcot-Marie-Tooth disease

KW - CMT2A

KW - HMSN VI

KW - Mitofusin 2 (MFN2)

UR - http://www.scopus.com/inward/record.url?scp=33747872317&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33747872317&partnerID=8YFLogxK

U2 - 10.1093/brain/awl174

DO - 10.1093/brain/awl174

M3 - Article

C2 - 16835246

AN - SCOPUS:33747872317

VL - 129

SP - 2103

EP - 2118

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

SN - 0006-8950

IS - 8

ER -