Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland |
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Authors: | Mari Auranen Emil Ylikallio Jussi Toppila Mirja Somer Sari Kiuru-Enari Henna Tyynismaa |
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Affiliation: | 1. Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, r.C520b, Haartmaninkatu 8, 00290, Helsinki, Finland 2. Department of Neurology, Helsinki University Central Hospital, Helsinki, 00290, Finland 3. HUS Medical Imaging Center, Department of Clinical Neurophysiology, Helsinki University Central Hospital, Helsinki, Finland 4. Department of Medical Genetics, Vaestoliitto, The Family Federation of Finland, Helsinki, Finland 5. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
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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. |
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