The Genotype-Phenotype Correlation in Children with Duchenne Muscular Dystrophy: Single Center Experience

Abstract

Objective: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by mutations in the dystrophin gene. In this study, we aimed to investigate the relationship between different mutations in the dystrophin gene and motor functions in children with DMD.

Material and Methods: Children with DMD followed-up between January 2016 and January 2018 were evaluated. Demographic data, genetic mutations, duration of steroid treatment and 6-minute walk test results were recorded. The children were divided into three groups according to the mutation in the dystrophin gene as deletion, duplication and point mutation. The 6-minute walk test results were compared between the three groups.

Results: Thirty-three male patients with DMD at a mean age of 6.7 ± 2 years (4-11 years) were included in the study. Twenty-two patients (67%) had deletion, 6 patients (18%) had duplication and 5 patients (15%) had point mutations. The mean duration of steroid treatment was 1.6 ± 0.8 years (0.5 to 3 years) in 18 patients receiving steroid treatment. There were no significant differences between the three groups in terms of age and steroid use (p> 0.05). The mean 6-minute walk test result was 324 ± 51 meters (220-427 meters), 326 ± 77 meters (264-440 meters) and 285 ± 38 meters (250-326 meters) in children with deletion, duplication and point mutation of the dystrophin gene, respectively. Although the walking distance in 6-minute walk test was shorter in children with point mutation compared to the children with deletion and duplication, there was no statistically significant difference observed between the 3 groups (p> 0.05).

Conclusion: There is no significant relationship between the type of mutation in the dystrophin gene and clinical course in children with DMD. The progression rate of the DMD may show a difference.

Duchenne Musküler Distrofili Çocuklarda Genotip-Fenotip İlişkisi: Tek Merkez Deneyimi

Abstract

Amaç: Duchenne musküler distrofi (DMD), DMD genindeki mutasyonların neden olduğu ilerleyici kas güçsüzlüğü ile seyreden bir hastalıktır. Bu çalışmada, DMD tanılı çocuklarda DMD genindeki farklı mutasyonlar ile motor fonksiyonlar arasındaki ilişkiyi incelemeyi amaçladık.

Yöntem: Ocak 2016 ile Ocak 2018 tarihleri arasında DMD tanısı ile takip edilen, yürüyebilen ve ek hastalığı olmayan çocuklar çalışmaya dahil edildi. Demografik veriler, genetik mutasyon sonuçları, steroid kullanım süreleri ve 6 dakika yürüme testi sonuçları kaydedildi. Çocuklar DMD genindeki mutasyona göre delesyon, duplikasyon ve nokta mutasyona sahip olanlar olarak 3 gruba ayrıldı. Üç grup arasında 6 dakika yürüme testi sonuçları karşılaştırıldı.

Bulgular: DMD tanılı 33 erkek hasta çalışmaya dahil edildi, ortalama yaşları 6,7 ± 2 yıldı (4-11 yıl). Yirmi iki hastada (%67) delesyon, 6 hastada (%18) duplikasyon, 5 hastada (%15) nokta mutasyon mevcuttu. Steroid tedavisi alan 18 hastanın ortalama steroid kullanma süresi 1,6 ± 0,8 yıldı (0,5-3 yıl). Üç grup arasında yaş ve steroid kullanım süreleri açısından anlamlı farklılık saptanmadı (p> 0,05). DMD geninde delesyon, duplikasyon ve nokta mutasyon saptananların ortalama 6 dakika yürüme mesafesi sırasıyla 324 ± 51 metre (220-427 metre), 326 ± 77 metre (264-440 metre) ve 285 ± 38 metreydi (250-326 metre). Altı dakika yürüme testi açısından nokta mutasyon saptanan hastalarda delesyon ve duplikasyon saptanan hastalara göre yürüme mesafesi daha kısa olmakla birlikte istatiksel olarak 3 grup arasında anlamlı farklılık saptanmadı (p> 0,05).

Sonuç: DMD tanılı çocuklarda DMD genindeki mutasyonun tipi ile klinik gidiş arasında anlamlı ilişki bulunmamaktadır. Hastalığın ilerleme hızı benzer mutasyon tiplerinde dahi bireysel farklılıklar gösterebilmektedir. 

Keywords

• çocuk
• distrofi
• gen

References

1. [1] Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 2014;24:482-91.
2. [2] McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, Goemans N, et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1489-98.
3. [3] Shimizu-Motohashi Y, Murakami T, Kimura E, Komaki H, Watanabe N. Exon skipping for Duchenne muscular dystrophy: a systematic review and meta-analysis. Orphanet J Rare Dis 2018;13:93.
4. [4] D'Angelo MG, Lorusso ML, Civati F, Comi GP, Magri F, Del Bo R, et al. Neurocognitive profiles in Duchenne muscular dystrophy and gene mutation site. Pediatr Neurol 2011;45:292-9.
5. [5] McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, et al. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve 2010;41:500-10.
6. [6] McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Atkinson L, et al. The 6-minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations. Muscle Nerve 2010;42:966-74.
7. [7] McDonald CM, Henricson EK, Abresch RT, Florence J, Eagle M, Gappmaier E, et al. The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve 2013; 48:357-68.
8. [8] Pane M, Mazzone ES, Sormani MP, Messina S, Vita GL, Fanelli L, et al. 6 Minute walk test in Duchenne MD patients with different mutations: 12-month changes. PLoS One 2014;9:e83400.

9. [9] Pegoraro E, Hoffman EP, Piva L, Gavassini BF, Cagnin S, Ermani M, et al. SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. Neurology 2011;76:219-26.
10. [10] Flanigan KM, Ceco E, Lamar KM, Kaminoh Y, Dunn DM, Mendell JR, et al. LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Ann Neurol 2013;73:481-8.
11. [11] Vieitez I, Gallano P, González-Quereda L, Borrego S, Marcos I, Millán JM, et al. Mutational spectrum of Duchenne muscular dystrophy in Spain: Study of 284 cases. Neurologia 2017;32:377-85.
12. [12] Cunniff C, Andrews J, Meaney FJ, Mathews KD, Matthews D, Ciafaloni E, et al. Mutation analysis in a population-based cohort of boys with Duchenne or Becker muscular dystrophy. J Child Neurol 2009;24:425-30.
13. [13] Juan-Mateu J, Gonzalez-Quereda L, Rodriguez MJ, Baena M, Verdura E, Nascimento A, et al. DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PLoS One 2015;10:e0135189.
14. [14] Tuffery-Giraud S, Béroud C, Leturcq F, Yaou RB, Hamroun D, Michel-Calemard L, et al. Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase. Hum Mutat 2009;30:934-45.
15. [15] Takeshima Y, Yagi M, Okizuka Y, Awano H, Zhang Z, Yamauchi Y, et al. Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. J Hum Genet 2010;55:379-88.
16. [16] Bladen CL, Salgado D, Monges S, Foncuberta ME, Kekou K, Kosma K, et al. The TREAT NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat 2015;36:395-402.
17. [17] Vengalil S, Preethish-Kumar V, Polavarapu K, Mahadevappa M, Sekar D, Purushottam M, et al. Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort. J Clin Neurol 2017;13:91-7.
18. [18] Yang J, Li SY, Li YQ, Cao JQ, Feng SW, Wang YY, et al. MLPA-based genotype-phenotype analysis in 1053 Chinese patients with DMD/ BMD. BMC Med Genet 2013;14:29.
19. [19] White SJ, Aartsma-Rus A, Flanigan KM, Weiss RB, Kneppers AL, Lalic T, et al. Duplications in the DMD gene. Hum Mutat 2006;27:938-45.