Molecular characterization of dystrophinopathies at the children's hospital “Dr. Francisco De Icaza Bustamante”, Guayaquil-Ecuador

Authors

Byron Heberth Sancan-Jalca Instituto de Posgrado, Maestría en Biomedicina, Universidad Técnica de Manabí, Portoviejo, Ecuador. Hospital del Niño "Dr. Francisco de Icaza Bustamante", Ecuador https://orcid.org/0000-0003-3265-6795
Liset Betancourt-Castellanos Facultad de Ciencias de la Salud, Universidad Técnica de Manabí, Portoviejo, Manabí, Ecuador https://orcid.org/0000-0002-4628-7698
Juan Elí Galarza-Brito Servicio de Pediatría, Hospital General “Teófilo Dávila”, Machala, Ecuador https://orcid.org/0000-0002-8725-741X

DOI:

https://doi.org/10.33936/qkrcs.v7i1.5204

Keywords:

dystrophin, muscular dystrophies, duchenne muscular dystrophy, molecular pathology

Abstract

Dystrophinopathies are muscular diseases caused by pathogenic variants in the DMD gene. The aim of this study was to collect and analyze the genetic variants presented by patients diagnosed with dystrophinopathies at the children's hospital "Dr. Francisco De Icaza Bustamante". An observational, descriptive and retrospective study was carried out; the population consisted of 20 patients who met the inclusion and exclusion criteria. The average age of diagnosis of molecular DMD/BMD was 8 years and 6 months, the male sex predominated, 95% of the cases. The most frequent city of residence was Guayaquil, representing 80% of the cases. The most frequent clinical manifestations were: gait disorder (94.7%) and muscle weakness (78.9%). In 9 patient’s deletions were found (45%) and in 3 patient’s duplications (15%), in 8 patients point pathogenic variants (40%), of which 6 corresponded to nonsense variants (75%) and 2 probands to pathogenic variants in the cut and splice site (25%). Deletions/duplications were the most frequent pathogenic variants found by MLPA technique. Sequencing is an indispensable technique in the diagnosis of point pathogenic variants and new therapies improve the quality of life and decrease morbidity and mortality in dystrophinopathies.

Author Biography

Byron Heberth Sancan-Jalca, Instituto de Posgrado, Maestría en Biomedicina, Universidad Técnica de Manabí, Portoviejo, Ecuador. Hospital del Niño "Dr. Francisco de Icaza Bustamante", Ecuador

Médico genetista enfocado en las enfermedades raras en pediatría.

References

Domingos J, Sarkozy A, Scoto M, Muntoni F. Dystrophinopathies and Limb-Girdle Muscular Dystrophies. Neuropediatrics [Internet]. 2017;48(4):262-72. Disponible en: http://doi.org/10.1055/s-0037-1601860

Lanza G, Pino M, Fisicaro F, Vagli C, Cantone M, Pennisi M, et al. Motor activity and Becker’s muscular dystrophy: lights and shadows. The Physician and Sportsmedicine [Internet]. 2020;48(2):151-60. Disponible en: http://doi.org/10.1080/00913847.2019.1684810

Rivas MM, Leones SMC, Ospina ER, Ruiz DMC, Echeverri RC, Arango MEM, et al. Consenso colombiano para el seguimiento de pacientes con Distrofia muscular de Duchenne. Pediatría [Internet]. 2019;52(3):75-84. Disponible en: http://doi.org/10.14295/p.v52i3.153

Flanigan KM. Duchenne and Becker Muscular Dystrophies. Neurologic Clinics [Internet]. 2014;32(3):671-88. Disponible en: http://doi.org/10.1016/j.ncl.2014.05.002

Waldrop MA, Flanigan KM. Update in Duchenne and Becker muscular dystrophy: Current Opinion in Neurology [Internet]. 2019;32(5):722–7. Disponible en: http://doi.org/10.1097/WCO.0000000000000739

Quesada Vargas M, Esquivel Rodríguez N, Rosales Gutiérrez JM. Distrofia muscular de Duchene: diagnóstico y tratamiento. Rev.méd.sinerg [Internet]. 2019;4(12):e315. Disponible en: http://doi.org/10.31434/rms.v4i12.315

Guerra-Torres M, Suárez-Obando F, García-Roblesa R, Ayala-Ramírez P. Distrofia Muscular de Duchenne/Becker. Pediatria [Internet]. 2019;52(1):8-14. Disponible en: http://doi.org/10.14295/p.v52i1.112

García-Acero M, Pineda T, Guerra-Torres M, García-Robles R, Ayala-Ramírez P, Buitrago T, et al. Análisis del espectro mutacional de la distrofia muscular de Duchenne en un grupo de pacientes colombianos. Neurología Argentina [Internet]. 2018;10(3):137–46. Disponible en: http://doi.org/10.1016/j.neuarg.2018.05.001

Vieitez I, Gallano P, González-Quereda L, Borrego S, Marcos I, Millán JM, et al. Espectro mutacional de la distrofia muscular de Duchenne en España: estudio de 284 casos. Neurología [Internet]. 2017;32(6):377-85. Disponible en: http://doi.org/10.1016/j.nrl.2015.12.009

de Almeida P a. D, Machado-Costa MC, Manzoli GN, Ferreira LS, Rodrigues MCS, Bueno LSM, et al. Genetic profile of Brazilian patients with dystrophinopathies. Clin Genet [Internet]. 2017;92(2):199-203. Disponible en: http://doi.org/10.1111/cge.12975

Ma P, Zhang S, Zhang H, Fang S, Dong Y, Zhang Y, et al. Comprehensive genetic characteristics of dystrophinopathies in China. Orphanet J Rare Dis [Internet]. 2018;13(1):109. Disponible en: http://doi.org/10.1186/s13023-018-0853-z

Mah JK, Selby K, Campbell C, Nadeau A, Tarnopolsky M, McCormick A, et al. A Population-Based Study of Dystrophin Mutations in Canada. Canadian Journal of Neurological Sciences [Internet]. 2011;38(3):465-74. Disponible en: http://doi.org/10.1017/S0317167100011896

Okubo M, Goto K, Komaki H, Nakamura H, Mori-Yoshimura M, Hayashi YK, et al. Comprehensive analysis for genetic diagnosis of Dystrophinopathies in Japan. Orphanet J Rare Dis [Internet]. 2017;12(1):149. Disponible en: http://doi.org/10.1186/s13023-017-0703-4

Moreta G, Vinueza R, Carrera González A, Motúfar Armendariz S, Villegas F, Chiriboga A, et al. The importance of early clinical diagnosis in Duchenne muscular distrophy: mutations found in seven Ecuadorians patients. VozAndes [Internet]. 2016;7-14. Disponible en: Disponible en: http://docs.bvsalud.org/biblioref/2019/06/999421/01_2016_a01_089.pdf

Paz y Miño C, Saltos JC, Sánchez ME, Burgos R, Pérez C, Dávalos V, et al. Distrofia muscular de duchenne: detección de mutaciones del gen de la distrofia a través de la utilización de la PCR-multiplex. Metro cienc [Internet]. 1999;5-8. Disponible en: https://pesquisa.bvsalud.org/portal/resource/pt/lil-278945

Crisafulli S, Sultana J, Fontana A, Salvo F, Messina S, Trifirò G. Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. Orphanet J Rare Dis [Internet]. 2020;15(1):141. Disponible en: http://doi.org/10.1186/s13023-020-01430-8

Ebrahimzadeh-Vesal R, Teymoori A, Azimi-Nezhad M, Hosseini FS. Next Generation Sequencing approach to molecular diagnosis of Duchenne muscular dystrophy; identification of a novel mutation. Gene [Internet]. 2018;644:1-3. Disponible en: http://doi.org/10.1016/j.gene.2017.12.009

Zhang K, Yang X, Lin G, Han Y, Li J. Molecular genetic testing and diagnosis strategies for dystrophinopathies in the era of next generation sequencing. Clin Chim Acta [Internet]. 2019;491:66-73. Disponible en: http://doi.org/10.1016/j.cca.2019.01.014

Reinig AM, Mirzaei S, Berlau DJ. Advances in the Treatment of Duchenne Muscular Dystrophy: New and Emerging Pharmacotherapies. Pharmacotherapy [Internet]. 2017;37(4):492-9. Disponible en: http://doi.org/10.1002/phar.1909

Garegnani L, Hyland M, Roson Rodriguez P, Escobar Liquitay CME, Franco JV. Antioxidants to prevent respiratory decline in people with Duchenne muscular dystrophy and progressive respiratory decline. Cochrane Database Syst Rev [Internet]. 2021;11:CD013720. Disponible en: http://doi.org/10.1002/14651858.CD013720.pub2

Cabezudo García P, Moreno Medinilla E, Calvo Medina R, Mora Ramírez MD, Martínez Antón J. Distrofia muscular de Duchenne: Presentación atípica y diagnóstico precoz. Arch argent pediatr [Internet]. 2015;113(3):e149-52. Disponible en: http://doi.org/10.5546/aap.2015.e149

Taheri F, Taghizadeh E, Pour MJR, Rostami D, Renani PG, Rastgar-Moghadam A, et al. Limb-girdle Muscular Dystrophy and Therapy: Insights into Cell and Gene-based Approaches. Curr Gene Ther [Internet]. 2020;19(6):386-94. Disponible en: http://doi.org/10.2174/1566523220666200218113526

Basta M, Pandya AM. Genetics, X-Linked Inheritance. StatPearls [Internet]. StatPearls Publishing; 2022. Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK557383/

Censos INEC. Proyecciones Poblacionales. Instituto Nacional de Estadística y Censos [Internet]. Disponible en: https://www.ecuadorencifras.gob.ec/proyecciones-poblacionales/ 2022 [consultada 2022.06.21]

Thangarajh M, Hendriksen J, McDermott MP, Martens W, Hart KA, Griggs RC, et al. Relationships between DMD mutations and neurodevelopment in dystrophinopathy. Neurology [Internet]. 2019;93(17):e1597–604. Disponible en: http://doi.org/10.1212/WNL.0000000000008363

Pupo JMR, Leyva LS, Silva DO, Rodríguez YR, Abreu YC. Caracterización clínica, genética y electrofisiológica de la distrofia muscular de Duchenne/Becker en Holguín: 2017-2019. Correo Científico Médico [Internet]. 2021;25(3). Disponible en: http://www.revcocmed.sld.cu/index.php/cocmed/article/view/3851

Yao S, Chen Z, Yu Y, Zhang N, Jiang H, Zhang G, Zhang Z and Zhang B. Current Pharmacological Strategies for Duchenne Muscular Dystrophy. Front Cell Dev Biol [Internet]. 2021;9:689533. Disponible en: http://doi.org/10.3389/fcell.2021.689533

Falzarano MS, Scotton C, Passarelli C, Ferlini A. Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules [Internet]. 2015;20(10):18168-84. Disponible en: http://doi.org/10.3390/molecules201018168

Lim KRQ, Nguyen Q, Yokota T. Genotype-Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry. J Pers Med [Internet]. 2020;10(4):E241. Disponible en: http://doi.org/10.3390/jpm10040241

Sheikh O, Yokota T. Advances in Genetic Characterization and Genotype-Phenotype Correlation of Duchenne and Becker Muscular Dystrophy in the Personalized Medicine Era. J Pers Med [Internet]. 2020;10(3):E111. Disponible en: http://doi.org/10.3390/jpm10030111

Takeda S, Clemens PR, Hoffman EP. Exon-Skipping in Duchenne Muscular Dystrophy. J Neuromuscular Diseases [Internet]. 2021;8(s2):S343-58. Disponible en: https://doi.org/10.3233/JND-210682