Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.
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).


METHODS
Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations.


METHODS
Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies.


METHODS
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.


METHODS
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.
Calvo
Judith
J
Service de neurologie, Centre Hospitalier Universitaire (CHU) de Limoges, Limoges, France.
Funalot
Benoît
B
Ouvrier
Robert A
RA
Lazaro
Leila
L
Toutain
Annick
A
De Mas
Philippe
P
Bouche
Pierre
P
Gilbert-Dussardier
Brigitte
B
Arne-Bes
Marie-Christine
MC
Carrière
Jean-Pierre
JP
Journel
Hubert
H
Minot-Myhie
Marie-Christine
MC
Guillou
Claire
C
Ghorab
Karima
K
Magy
Laurent
L
Sturtz
Franck
F
Vallat
Jean-Michel
JM
Magdelaine
Corinne
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020558:GTP Phosphohydrolases; D005799:Genes, Dominant; D005808:Genes, Recessive; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012720:Severity of Illness Index; D055815:Young Adult
D005819:Genetic Markers; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human