Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying MFN2 mutation

Brain Dev. 2016 May;38(5):498-506. doi: 10.1016/j.braindev.2015.11.006. Epub 2015 Dec 10.


Introduction: The Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2) with early onset. This gene is involved in typical CMT2A and in more atypical phenotypes as optic atrophy or spastic paraplegia. CMT2 refers to inherited axonal polyneuropathy, which associates progressive peripheral motor and sensory neuropathy, a family history consistent mainly with autosomal dominant inheritance, and normal nerve conduction velocities.

Subjects: Between 1999 and 2012, the genetic diagnosis of MFN2 mutation was made in 11 children who were treated in our department for different neurological symptoms. All data including family and personal history data, results of standardized clinical and electrophysiology testing, brain magnetic resonance imaging (MRI), neuro-ophthalmic evaluation, muscle biopsy histopathology and molecular diagnosis were retrospectively analyzed.

Results: Five different mutations were found in 6 unrelated families. Three of them have previously been described; the two remaining are new mutations: one of them related a new phenotype. Clinical signs appeared before the age of 6 years in more than half of the patients (54%). The motor deficit was predominant in 8 patients (72%). Two children presented an acute onset of disease that stabilized afterwards; the other children showed a more progressive deterioration that was managed symptomatically.

Conclusion: This large pediatric study describes a great interfamilial and intrafamilial phenotypic variability. We recommend screening this gene in pediatric patient with chronic neurologic symptoms such as motor deficit or optic atrophy but also in acute neurologic deficiencies such as subacute polyradiculoneuritis.

Keywords: Charcot–Marie–Tooth (CMT); Mitofusin 2 (MFN2); Neuropathy; Optic atrophy; Respiratory chain deficiency; Subacute polyneuropathy; White matter lesion.

Publication types

  • Case Reports

MeSH terms

  • Alleles
  • Charcot-Marie-Tooth Disease / genetics
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism
  • GTP Phosphohydrolases / physiology
  • Genetic Testing
  • Genotype
  • Humans
  • Infant
  • Male
  • Membrane Proteins / genetics
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Mitochondrial Proteins / physiology
  • Optic Atrophy / genetics
  • Pedigree
  • Phenotype


  • Membrane Proteins
  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • MFN2 protein, human