CMT 2:Genotype-phenotype correlations caused by mitofusin 2 mutations

December 17, 2009

Arch Neurol. 2009 Dec;66(12):1511-6.

Genotype-phenotype correlations in charcot-marie-tooth disease type 2 caused by

mitofusin 2 mutations.

Calvo J, Funalot B, Ouvrier RA, Lazaro L, Toutain A, De Mas P, Bouche P,

Gilbert-Dussardier B, Arne-Bes MC, Carrière JP, Journel H, Minot-Myhie MC,

Guillou C, Ghorab K, Magy L, Sturtz F, Vallat JM, Magdelaine C.

CHU de Limoges, Service de biochimie et génétique moléculaire, Hôpital

Universitaire Dupuytren, 2 avenue -Luther-King, 87000 Limoges, France.

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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