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Sci Rep. 2017 Jul 27;7(1):6677. doi: 10.1038/s41598-017-06894-6.

Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain.

Author information

1
Department of Neurology, Hospital Francesc de Borja, Gandía, Spain. rafasivera@gmail.com.
2
Department of Neurology, Hospital Universitari i Politécnic La Fe, Valencia, Spain.
3
Neuromuscular Research Unit, Instituto de Investigación Sanitaria la Fe (IIS La Fe), Valencia, Spain.
4
Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders and Service of Genomics and Traslational Geneticis, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
5
Department of Neurology, Hospital Clínico, Santiago de Compostela, Spain.
6
Neurogenetics Research Group, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
7
Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
8
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Intituto Carlos III, Ministry of Economy and Competitiviness, Madrid, Spain.
9
Neuromuscular Disorders Unit, Neurology Department, Hospital Donostia, San Sebastián, Spain.
10
The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
11
Neuroscience Area, Biodonostia Health Research Institute, San Sebastián, Spain.
12
Center for Biomedical Research in the Neurodegenerative Diseases (CIBERNED) Network, Instituto Carlos III, Ministry of Economy and Competitiviness, Madrid, Spain.
13
Department of Neurosciences, School of Medicine, University of the Basque Country (EHU-UPV), San Sebastián, Spain.
14
Department of Neurology and Neurophysiology, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
15
Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
16
Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
17
Neuropaediatrics Department, Hospital la Paz, Madrid, Spain.
18
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain.
19
Department of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", Santander, Spain.
20
University of Cantabria (UC), Santander, Spain.
21
Neuromuscular Diseases Unit, Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain.
22
Neuromuscular Diseases Unit, Department of Neurology, Hospital Universitari de Bellvitge - IDIBELL, Barcelona, Spain.
23
Child Neurology Unit, Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain.
24
Facultad de Medicina, Universidad Complutense, Madrid, Spain.
25
Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain.
26
Department of Neurology, Hospital Ruber Internacional, Madrid, Spain.
27
Department of Neurophysiology, Hospital Universitari I Politécnic La Fe, Valencia, Spain.
28
Department of Neurology, Hospital General de Alicante, Alicante, Spain.
29
Institut de Recerca Sant Joan de Déu and Hospital Sant Joan de Déu, Barcelona, Spain.
30
Hospital Clínic, Barcelona, Spain.
31
Division of Pediatrics, University of Barcelona School of Medicine and Health Sciences, Barcelona, Spain.
32
Department of Medicine, University of Valencia, Valencia, Spain.

Abstract

Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.

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