title: A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations.
abstract: Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1 encoding ganglioside-induced differentiation associated protein 1 may be associated with mild neuropathy. The proband, a 41-year-old woman, and her daughter present a severe axonal form of Charcot-Marie-Tooth (CMT) disease. Both are heterozygous for the well-described mild variant p.R120W in GDAP1, which was transmitted by the pauci symptomatic proband's mother. Given that they had an early onset in the first decade and delayed walking acquisition, the other genes implicated in axonal forms of CMT disease were analyzed. A second mutation truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This mutation was transmitted by the proband's father who has normal neurological examination. The proband underwent two nerve biopsies which showed an axonal degeneration, myelin modifications, and intra-axonal mitochondria with distorted cristae. Such abnormal mitochondria have been reported in cases with autosomal dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1 mutation. Our two cases show that heterozygous truncation of MFN2, which is silent at least until the sixth decade, when combined with the mild p.R120W GDAP1 variant, leads to a severe neuropathy. This supports the emerging hypothesis of cumulative effects of MFN2 and GDAP1 mutation.
authors.affiliation: Institut des Maladies Neurodégénératives, CNRS UMR 5293, Univ. Bordeaux, Bordeaux, France. anne.vital@chu-bordeaux.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Vital
authors.forename: Philippe
authors.initials: P
authors.lastname: Latour
authors.forename: Guilhem
authors.initials: G
authors.lastname: Sole
authors.forename: Xavier
authors.initials: X
authors.lastname: Ferrer
authors.forename: Marie
authors.initials: M
authors.lastname: Rouanet
authors.forename: François
authors.initials: F
authors.lastname: Tison
authors.forename: Claude
authors.initials: C
authors.lastname: Vital
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D002607:Charcot-Marie-Tooth Disease / Q000208:ethnology* / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D005260:Female; D005602:France; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010543:Peroneal Nerve / Q000473:pathology; D010641:Phenotype
chemical_list: C118663:GDAP protein; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human