8
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain

      research-article
      1 , , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 5 , 9 , 10 , 11 , 12 , 9 , 11 , 12 , 13 , 14 , 14 , 14 , 8 , 15 , 8 , 8 , 15 , 16 , 8 , 16 , 8 , 16 , 17 , 17 , 18 , 12 , 19 , 20 , 12 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 3 , 28 , 8 , 29 , 30 , 31 , 2 , 3 , 8 , 32 , 4 , 2 , 3 , 8 , 32
      Scientific Reports
      Nature Publishing Group UK

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references33

          • Record: found
          • Abstract: found
          • Article: not found

          Charcot-Marie-Tooth disease subtypes and genetic testing strategies.

          Charcot-Marie-Tooth disease (CMT) affects 1 in 2,500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, natural history studies, and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians. We analyzed data from 1,024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT. Of 1,024 patients evaluated, 787 received CMT diagnoses. A total of 527 patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies (HNPP), CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had >1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT, illustrated in a series of flow diagrams created as testing guides. Copyright © 2010 American Neurological Association.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

            Summary Background A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. Methods We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11·2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes—fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)—were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. Findings Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1·2%, 95% CI 0·5–1·9, p=0·002) but not thigh level (0·2%, −0·2 to 0·6, p=0·38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2·6%, 1·3–4·0, p=0·002) and thigh level (3·3%, 1·8–4·9, p=0·0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=–0·64, p=0·002) and the Charcot-Marie-Tooth examination score (ρ=0·63, p=0·003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4·0 ms [SE 0·5], calf 3·5 ms [0·6]; Charcot-Marie-Tooth 1A thigh 1·0 ms [0·3], calf 2·0 ms [0·3]) and MTR reduced compared with controls (inclusion body myositis thigh −1·5 percentage units [pu; 0·2], calf −1·1 pu [0·2]; Charcot-Marie-Tooth 1A thigh −0·3 pu [0·1], calf −0·7 pu [0·1]). Interpretation MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. Funding Medical Research Council UK.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

              Background The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. Methods We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). Results 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. Conclusions Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. Clinical trial registration ID number NCT01193075.
                Bookmark

                Author and article information

                Contributors
                rafasivera@gmail.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                27 July 2017
                27 July 2017
                2017
                : 7
                : 6677
                Affiliations
                [1 ]Department of Neurology, Hospital Francesc de Borja, Gandía, Spain
                [2 ]ISNI 0000 0001 0360 9602, GRID grid.84393.35, Department of Neurology, , Hospital Universitari i Politécnic La Fe, ; Valencia, Spain
                [3 ]ISNI 0000 0001 0360 9602, GRID grid.84393.35, Neuromuscular Research Unit, , Instituto de Investigación Sanitaria la Fe (IIS La Fe), ; Valencia, Spain
                [4 ]ISNI 0000 0004 0399 600X, GRID grid.418274.c, 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 ]ISNI 0000 0000 8816 6945, GRID grid.411048.8, Department of Neurology, , Hospital Clínico, ; Santiago de Compostela, Spain
                [6 ]Neurogenetics Research Group, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain
                [7 ]ISNI 0000 0004 4688 8850, GRID grid.443929.1, , Fundación Pública Galega de Medicina Xenómica, ; Santiago de Compostela, Spain
                [8 ]ISNI 0000 0004 1791 1185, GRID grid.452372.5, , Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Intituto Carlos III, Ministry of Economy and Competitiviness, ; Madrid, Spain
                [9 ]GRID grid.414651.3, Neuromuscular Disorders Unit, , Neurology Department, Hospital Donostia, ; San Sebastián, Spain
                [10 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, The John Walton Muscular Dystrophy Research Centre, , Institute of Genetic Medicine, Newcastle University, ; Newcastle upon Tyne, UK
                [11 ]GRID grid.428061.9, Neuroscience Area, , Biodonostia Health Research Institute, ; San Sebastián, Spain
                [12 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, , Center for Biomedical Research in the Neurodegenerative Diseases (CIBERNED) Network, Instituto Carlos III, Ministry of Economy and Competitiviness, ; Madrid, Spain
                [13 ]ISNI 0000000121671098, GRID grid.11480.3c, Department of Neurosciences, , School of Medicine, University of the Basque Country (EHU-UPV), ; San Sebastián, Spain
                [14 ]ISNI 0000 0000 9542 1158, GRID grid.411109.c, 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 ]ISNI 0000 0001 0663 8628, GRID grid.411160.3, Neuromuscular Unit, Neuropaediatrics Department, , Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, ; Barcelona, Spain
                [17 ]ISNI 0000 0000 8970 9163, GRID grid.81821.32, Neuropaediatrics Department, , Hospital la Paz, ; Madrid, Spain
                [18 ]ISNI 0000000119578126, GRID grid.5515.4, Department of Pediatrics, , Universidad Autónoma de Madrid, ; Madrid, Spain
                [19 ]ISNI 0000 0001 0627 4262, GRID grid.411325.0, Department of Neurology, , University Hospital “Marqués de Valdecilla (IDIVAL)”, ; Santander, Spain
                [20 ]ISNI 0000 0004 1770 272X, GRID grid.7821.c, , University of Cantabria (UC), ; Santander, Spain
                [21 ]ISNI 0000 0001 0671 5785, GRID grid.411068.a, Neuromuscular Diseases Unit, , Department of Neurology, Hospital Clínico San Carlos, ; Madrid, Spain
                [22 ]ISNI 0000 0000 8836 0780, GRID grid.411129.e, Neuromuscular Diseases Unit, , Department of Neurology, Hospital Universitari de Bellvitge – IDIBELL, ; Barcelona, Spain
                [23 ]ISNI 0000 0001 1945 5329, GRID grid.144756.5, Child Neurology Unit, , Department of Neurology, Hospital Universitario 12 de Octubre, ; Madrid, Spain
                [24 ]ISNI 0000 0001 2157 7667, GRID grid.4795.f, Facultad de Medicina, , Universidad Complutense, ; Madrid, Spain
                [25 ]ISNI 0000 0001 1945 5329, GRID grid.144756.5, Department of Neurology, , Hospital Universitario 12 de Octubre, ; Madrid, Spain
                [26 ]ISNI 0000 0004 1768 8622, GRID grid.413297.a, Department of Neurology, , Hospital Ruber Internacional, ; Madrid, Spain
                [27 ]ISNI 0000 0001 0360 9602, GRID grid.84393.35, Department of Neurophysiology, , Hospital Universitari I Politécnic La Fe, ; Valencia, Spain
                [28 ]ISNI 0000 0000 8875 8879, GRID grid.411086.a, Department of Neurology, , Hospital General de Alicante, ; Alicante, Spain
                [29 ]ISNI 0000 0001 0663 8628, GRID grid.411160.3, , Institut de Recerca Sant Joan de Déu and Hospital Sant Joan de Déu, ; Barcelona, Spain
                [30 ]ISNI 0000 0000 9635 9413, GRID grid.410458.c, , Hospital Clínic, ; Barcelona, Spain
                [31 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Division of Pediatrics, , University of Barcelona School of Medicine and Health Sciences, ; Barcelona, Spain
                [32 ]ISNI 0000 0001 2173 938X, GRID grid.5338.d, Department of Medicine, , University of Valencia, ; Valencia, Spain
                Author information
                http://orcid.org/0000-0002-0532-2872
                http://orcid.org/0000-0003-4716-2667
                Article
                6894
                10.1038/s41598-017-06894-6
                5532232
                28751717
                cf8a25b5-1a65-44bd-8740-1c4df733b482
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 12 April 2017
                : 19 June 2017
                Categories
                Article
                Custom metadata
                © The Author(s) 2017

                Uncategorized
                Uncategorized

                Comments

                Comment on this article