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|Year : 2014 | Volume
| Issue : 6 | Page : 635-639
Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy
Jianying Xi1, Gaelle Blandin2, Jiahong Lu1, Sushan Luo1, Wenhua Zhu1, Christophe Beroud3, Christophe Pecheux4, Veronique Labelle4, Nicolas Levy3, Jon Andoni Urtizberea5, Chongbo Zhao1, Martin Krahn3
1 Department of Neurology, Huashan Hospital, Fudan University; Fudan University, Institute of Neurology, 200040, Shanghai, China
2 Aix Marseille University, GMGF; Inserm, UMR_S 910, 13385, Marseille, France
3 Aix Marseille University, GMGF, 13385; Inserm, UMR_S 910, 13385; Department of Medical Genetics and Cell Biology, APHM, Children's Hospital La Timone, 13385, Marseille, France
4 Department of Medical Genetics and Cell Biology, APHM, Children's Hospital La Timone, 13385, Marseille, France
5 APHP, Marin Hospital, 64700, Hendaye, France
|Date of Submission||14-May-2014|
|Date of Decision||24-Aug-2014|
|Date of Acceptance||25-Sep-2014|
|Date of Web Publication||16-Jan-2015|
Source of Support: None, Conflict of Interest: None
Background and Aims: Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene. This study presents clinical features and the mutational spectrum in the largest cohort of Chinese patients analyzed to date. Patients and Methods: A total of 36 unrelated Chinese patients with diagnostic suspicion of dysferlinopathy were clinically and genetically characterized. Results: Patients were divided into five phenotypes: 19 patients with limb girdle muscular dystrophy (LGMD) type 2B, 10 with Miyoshi myopathy (MM), 1 with distal anterior compartment myopathy (DACM), 3 with exercise intolerance, and 3 with asymptomatic hypercreatine phosphokinasemia (hyperCPKemia). Thirty-one patients showed an absence or drastic reduction of dysferlin expression by Westernblot. Forty-three mutations were identified in DYSF, including 31 novel. Conclusion: Our study underlines clinical heterogeneity and a high proportion of novel mutations in Chinese patients affected with dysferlinopathy.
Keywords: Dysferlin, distal anterior compartment myopathy, limb girdle muscular dystrophy, Miyoshi myopathy, Mutation, Western-blot
|How to cite this article:|
Xi J, Blandin G, Lu J, Luo S, Zhu W, Beroud C, Pecheux C, Labelle V, Levy N, Urtizberea JA, Zhao C, Krahn M. Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy. Neurol India 2014;62:635-9
|How to cite this URL:|
Xi J, Blandin G, Lu J, Luo S, Zhu W, Beroud C, Pecheux C, Labelle V, Levy N, Urtizberea JA, Zhao C, Krahn M. Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy. Neurol India [serial online] 2014 [cited 2019 Sep 22];62:635-9. Available from: http://www.neurologyindia.com/text.asp?2014/62/6/635/149386
| » Introduction|| |
Mutations in DYSF (MIM#603009) cause dysferlinopathies, mainly presenting as limb girdle muscular dystrophy type 2B (LGMD2B; MIM#253601)  and Miyoshi myopathy (MM; MIM#254130). , Dysferlinopathies have been reported in different populations,  including 15 Chinese patients with genetic studies. ,, We report mutational data from the largest Chinese cohort to date, including 31 novel disease-causing mutations which point to a specific mutational spectrum.
| » Patients and Methods|| |
After approval by the Huashan Hospital (Fudan University) Institutional Review Board, 36 index patients (admitted to Huashan Hospital during 2005-2009) from the Han population were enrolled after informed consent, including one patient (C12-1-1-1) previously reported.  Dysferlin immunolabeling was negative in 30 patients and reduced in 4 by immunochemistry. Two additional patients without muscle biopsy were included based on clinical symptoms. Detailed clinical information was collected prospectively, including muscle strength (Medical Research Council scale) and functional status (Gardner-Medwin and Walton scales. . Single dysferlin Westernblot was performed in three patients and multi-Westernblot.  (dysferlin and calpain-3) in 28 patients. Genomic DYSF mutation screening was conducted as described. ,
| » Results|| |
All patients had normal motor milestones. Average age of onset was 23.7 ± 7.7 years (range 14-45 years) [Table 1]. The sex ratio was 4:5 (16 females versus 20 males). Nineteen patients (52.8%) presented as LGMD, 10 (27.8%) as MM, 1 (2.8%) as distal anterior compartment myopathy (DACM), 3 (8.3%) as exercise intolerance, and 3 (8.3%) as asymptomatic hypercreatine phosphokinasemia (hyperCPKemia). In this cohort weakness of the lower extremities occurred earlier and became more severe than that of the upper extremities. Two patients lost ambulation by age 40 and 47. No facial, pharyngeal, and respiratory muscles weakness and no abnormal electrocardiogram or echocardiogram was documented. All 36 patients had very high serum CPK levels (10-150N). Electromyography (EMG) showed a myopathic pattern in all patients.
|Table 1: Clinical, pathological, and protein and mutational data obtained in the cohort|
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The ~ 230kDa dysferlin band was absent in 28/31 (90.3%) patients and markedly reduced in 3/31 (9.7%). Absence or reduction of the ~90 kDa calpain-3-band was evidenced in 22/28 (78.6%) patients (11 absence and 11 reduction). However, only 6/28 (21%) showed secondary reduction for the ~60 kDa band [Table 1].
Mutational analyses evidenced 43 different disease-causing mutations (including 31 not previously reported) in 34 patients, including [Table 1]: 17 missense (11 novel; pathogenic effect predicted using UMD-predictor), 4 nonsense (3 novel), 17 exonic-frame shifting mutations (insertions or deletions, 15 novel), and 5 intronic mutations (2 novel; pathogenic effect predicted using UMD-Predictor). Twenty-one exonic mutations are predicted to disrupt the open reading frame and/or to lead to a premature stop codon. Five variants are predicted to promote abnormal splicing causing a frame shift at the messenger level, either by disrupting a canonical 5'splice-donor-site (c. 937 + 1G > A, c. 1284 + 2T > C, c. 4886 + 2T > C, c. 5057 + 1G > A) or by creating a novel 3'splice-acceptor-site (c. 5668 − 7G > A). In total, 58 different disease-causing alleles were identified, with 48 and 5 at the heterozygous and homozygous state, respectively.
Molecular diagnosis of dysferlinopathy was confirmed in 26/36 (72.2%) patients, including 21 compound heterozygotes and 5 homozygotes (4 with known consanguinity). Based on protein analysis, the diagnosis of dysferlinopathy in the other 10 patients was retained, but could not yet be confirmed at the genetics level.
| » Discussion|| |
Dysferlinopathy is the second most frequent type of LGMD in Europe and Japan, , but is under diagnosed in China. Here we present the data from the largest Chinese cohort characterized to date. Patients with LGMD2B, MM, and DACM initially had weakness of lower extremities, either with proximal or distal involvement; but distal weakness, especially progressive loss of the ability to stand on tiptoe was an important clue leading to the diagnosis. Atypical patients who showed exercise intolerance or asymptomatic hyper CPKemia without muscle weakness were reported before, ,, and they may be misdiagnosed as metabolic myopathy. However, the CPK level was constantly very high in patients with dysferlinopathies, while it was fluctuating in patients with metabolic myopathies. Thus, various phenotypes in our cohort further emphasized the clinical heterogeneity in Chinese patients with dysferlinopathies.
Mutational data analysis in this cohort evidenced a large mutational spectrum. Interestingly, most of the identified disease-causing mutations (31, 72%) had not been reported to date. Comparison of the mutational spectrum to a large French cohort  points to a possible difference, with a lower proportion of null mutations in the Chinese cohort (62 vs 76%) and accordingly more missense mutations (38 vs 24%). When compared only to patients from Japan (56 index cases in UMD-DYSF v1.1 (www.umd.be/DYSF/)), no difference in the proportion of mutation types were observed. Two mutations were recurrent (c. 965T > C and c. 3220_3221delCT, both identified in three unrelated patients). Two mutations previously identified in Chinese patients were retrieved in our cohort: c. 937 + 1G > A 6 and c. 3112C > T. 7
Altogether, our study underlines the clinical heterogeneity and reports a high proportion of novel mutations in Chinese patients with dysferlinopathy, outlining the importance of further characterization of this disease in China.
| » Acknowledgments|| |
We sincerely thank the patients for their participation. We sincerely thank the Association Française contre les Myopathies, the Jain Foundation, the APHM, Inserm, and Aix-Marseille Université for funding this work.
| » References|| |
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