Article ; Online: Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.
2009 Volume 66, Issue 12, Page(s) 1511–1516
Abstract: Background: Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features.: Objective: To describe MFN2 mutations and associated phenotypes ... ...
| Abstract | Background: Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. Objective: To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Design: Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations. Setting: Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies. Patients: One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Main outcome measures: Results of genetic analyses and phenotypic observations. Results: Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. Conclusions: MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy. |
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| MeSH term(s) | Adolescent ; Adult ; Aged ; Charcot-Marie-Tooth Disease/classification ; Charcot-Marie-Tooth Disease/genetics ; Charcot-Marie-Tooth Disease/pathology ; Child ; Child, Preschool ; Female ; GTP Phosphohydrolases ; Genes, Dominant ; Genes, Recessive ; Genetic Markers/genetics ; Genotype ; Humans ; Male ; Membrane Proteins/genetics ; Middle Aged ; Mitochondrial Proteins/genetics ; Mutation, Missense/genetics ; Phenotype ; Severity of Illness Index ; Young Adult |
| Chemical Substances | Genetic Markers ; Membrane Proteins ; Mitochondrial Proteins ; GTP Phosphohydrolases (EC 3.6.1.-) ; MFN2 protein, human (EC 3.6.1.-) |
| Language | English |
| Publishing date | 2009-12 |
| Publishing country | United States |
| Document type | Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 80049-1 |
| ISSN | 1538-3687 ; 0003-9942 |
| ISSN (online) | 1538-3687 |
| ISSN | 0003-9942 |
| DOI | 10.1001/archneurol.2009.284 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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