Original Article

neurogenetics

, Volume 14, Issue 2, pp 123-132

First online:

Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland

  • Mari AuranenAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of HelsinkiDepartment of Neurology, Helsinki University Central Hospital
  • , Emil YlikallioAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki
  • , Jussi ToppilaAffiliated withHUS Medical Imaging Center, Department of Clinical Neurophysiology, Helsinki University Central Hospital
  • , Mirja SomerAffiliated withDepartment of Medical Genetics, Vaestoliitto, The Family Federation of Finland
  • , Sari Kiuru-EnariAffiliated withDepartment of Neurology, Helsinki University Central Hospital
  • , Henna TyynismaaAffiliated withResearch Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of HelsinkiDepartment of Medical Genetics, Haartman Institute, University of Helsinki Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.

Keywords

Charcot-Marie-Tooth disease Axonal neuropathy GDAP1 Founder mutation Exome sequencing