title: Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features.
abstract: OBJECTIVE
  Axonal Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous, with 11 genes identified. Axonal CMT has most frequently been associated with mutations in the MFN2 gene (CMT2A).
  
  
  OBJECTIVE
  To describe the clinical and molecular features of CMT2A, to delineate prognostic factors, to understand connections between a certain phenotype and more serious clinical consequences, and to identify interactions among the associated genes.
  
  
  METHODS
  We describe the clinical, molecular, electrophysiological, and additional features of 43 patients with CMT2A. The degree of physical disability was determined by the CMT neuropathy score and adapted to the CMT neuropathy score gradient to evaluate the clinical course. We evaluated all data within the context of the most recent and important publications concerning this issue.
  
  
  RESULTS
  Twenty-five patients had early-onset CMT2A and severe functional disability, with 9 being wheelchair bound, and 18 had late-onset disease and a milder phenotype. Optic atrophy, vocal cord palsy, and auditory impairment were observed in 5, 6, and 2 patients, respectively. Among the 24 patients who underwent magnetic resonance imaging of the spinal cord, 6 had evidence of spinal atrophy with or without hydromyelia. In 1 patient, magnetic resonance imaging revealed hydrocephalus. Twenty different MFN2 mutations were identified, and 14 were considered new variants. Their transmission was predominantly autosomal dominant, with vertical transmission in 8 and de novo occurrence in 3. However, we also identified rare types of transmission, especially a germinal mosaicism and an autosomal recessive inheritance. One patient carried a rare variant in the GDAP1 gene and another in the OPA1 gene in association with MFN2 mutation.
  
  
  CONCLUSIONS
  Charcot-Marie-Tooth disease type 2A associated with MFN2 mutations is clinically very heterogeneous. Ranging from a mild to a severe form, CMT2A exhibits various types of transmission. Optic atrophy and vocal cord palsy were observed in patients with severe disability and an early-onset form and also in patients with later onset. Hydromyelia and spinal cord atrophy support central nervous system involvement in CMT2A.
authors: Groupe Hospitalier (GH) Pitié-Salpêtrière, Centre de Référence des Maladies Neuromusculaires Paris Est, Institut de Myologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors: Francesco
authors: F
authors: Bombelli
authors: Groupe Hospitalier (GH) Pitié-Salpêtrière, Centre de Référence des Maladies Neuromusculaires Paris Est, Institut de Myologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors: Tanya
authors: T
authors: Stojkovic
authors: Groupe Hospitalier (GH) Pitié-Salpêtrière, Centre de Référence des Maladies Neuromusculaires Paris Est, Institut de Myologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors: Odile
authors: O
authors: Dubourg
authors: Département de Neurologie, Hôpitaux Universitaires, Centre Hospitalier Universitaire (CHU) de Strasbourg, Strasbourg, France.
authors: Andoni
authors: A
authors: Echaniz-Laguna
authors: Département de Génétique et de Cytogénétique, GH Pitié-Salpêtrière, AP-HP, Paris, France.
authors: Sandrine
authors: S
authors: Tardieu
authors: Département de Génétique et de Cytogénétique, GH Pitié-Salpêtrière, AP-HP, Paris, France.
authors: Kathy
authors: K
authors: Larcher
authors: Département de Biochimie et Génétique, CHU Angers, Angers, France.
authors: Patrizia
authors: P
authors: Amati-Bonneau
authors: Département de Biochimie, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France.
authors: Philippe
authors: P
authors: Latour
authors: Service d'Ophtalmologie, Fondation Rothschild, Paris, France.
authors: Odile
authors: O
authors: Vignal
authors: Département de Génétique et de Cytogénétique, GH Pitié-Salpêtrière, AP-HP, Paris, France7Institut National de la Santé et de la Recherche Médicale U 1127, Institut du Cerveau et de la Moelle Epiniere, Hôpital Pitié-Salpêtrière, Paris, France.
authors: Cécile
authors: C
authors: Cazeneuve
authors: Département de Génétique et de Cytogénétique, GH Pitié-Salpêtrière, AP-HP, Paris, France7Institut National de la Santé et de la Recherche Médicale U 1127, Institut du Cerveau et de la Moelle Epiniere, Hôpital Pitié-Salpêtrière, Paris, France8Université Pi.
authors: Alexis
authors: A
authors: Brice
authors: Département de Génétique et de Cytogénétique, GH Pitié-Salpêtrière, AP-HP, Paris, France7Institut National de la Santé et de la Recherche Médicale U 1127, Institut du Cerveau et de la Moelle Epiniere, Hôpital Pitié-Salpêtrière, Paris, France8Université Pi.
authors: Eric
authors: E
authors: Leguern
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human