Impact of Genomic Characterization in Patients with Non-5q Spinal Muscular Atrophy
Journal: Advances in Medicine and Engineering Interdisciplinary Research DOI: 10.32629/ameir.v3i1.3608
Abstract
Spinal Muscular Atrophy (SMA) is defined as a set of hereditary neurodegenerative disorders that cause phenotypic and genotypic variability, impacting the quality of life, psychosocial, emotional, and functional development of those affected. In Colombia, it is considered a rare disease due to its low prevalence, chronicity, and high complexity. The objective of this case report is to describe, characterize, and correlate phenotypically and genotypically a patient with clinical suspicion of neurodegenerative disease. The patient is a 32-year-old female with a clinical picture of equinus, varus, supination of the hindfoot, adduction of the right forefoot, and limitation in wrists with subsequent weakness and predominantly lower limb muscle atrophy, generalized areflexia, and positive Gowers sign. Given the suspicion of progressive degenerative neuromuscular disease, endocrine, neuromuscular, cardiovascular studies, sural nerve biopsy, and genetic testing are requested. The results show that sural nerve biopsy revealed axonal loss with little demyelination, and a genomic study using trio clinical exome sequencing performed with Illumina technology identified pathogenic variants in the Nod2 gene with heterozygous status and DYNC2H1 gene with homozygous status. Finally, a gene interaction network is created using the GeneMania program, determining gene associations. The conclusion of this study is that the diagnosis of SMA is a challenge due to its wide phenotypic-genotypic variability. Although most patients are due to variants in the SmN1 gene, there are other non-5q genes associated with this pathology. A specific diagnosis impacts treatment, prognosis, and attributed morbidity and mortality, establishing heritability risk and genetic counseling for the sake of preventive, predictive, personalized, and participatory medicine.
Keywords
spinal muscular atrophy; rare disease; neuromuscular; genetic characterization; preventive medicine
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[3] Bolaño Díaz CF, et al. The Difficult Path to Diagnosis of the Patient with Spinal Muscular Atrophy. Arch Argent Pediatr 2023 Apr 1;121(2):e202102542. English, Spanish. https://doi.org/10.5546/aap.2021-02542.eng
[4] Castellano IP, et al. Consenso Delphi de las recomendaciones para el tratamiento de los pacientes con atrofia muscular espinal en España (consenso RET-AME). Neurología. 2021:216-228. https://doi.org/10.1016/j.nrl.2021.07.008
[5] Madruga-Garrido M, et al. Design of a Non-Inter-ventional Study to Validate a set of Patient- and Caregiver-Oriented Measurements to Assess Health outcomes in Spinal Muscular Atrophy (SMA-TOOL study). Neurol Ther. 2021 Jun;10(1):361-373. https://doi.org/10.1007/s40120-020-00229-w
[6] Cardona N, et al. Caracterización clínica y funcional de pacientes con atrofia muscular espinal en el centro-occidente colombiano. Biomed. [Internet]. 2022 May 42(Suppl 1):89-99. https://doi.org/10.7705/biomedica.6178
[7] Instituto Nacional de Salud. Comportamiento de la notificación al Sivigila de las enfermedades huérfanas y raras, Colombia, 2021 hasta semana epidemiológica 20. Disponible en: https://www.ins.gov.co/buscador-eventos/BoletinEpidemiologico/2021_Bole-tin_epidemiologico_semana_24.pdf
[8] Instituto Nacional de Salud, Proporción de notificación de enfermedades huérfanas-raras, Colombia, 2016 hasta periodo epidemiológico I de 2021. Disponible en: https://www.ins.gov.co/BibliotecaDigital/informe-de-evento-enfermedades-huerfanas-raras-2020.pdf#search=hiperlipoproteinemia
[9] Peeters K, et al. Clinical and Genetic Diversity of SMN1-Negative Proximal Spinal Muscular Atrophies. Brain. 2014 Nov;137(Pt 11):2879-96. https://doi.org/10.1093/brain/awu169
[10] Tsurusaki Y, et al. A DYNC1H1 Mutation Causes a Dominant Spinal Muscular Atrophy with Lower Extremity Predominance. Neurogenetics. 2012 Nov;13(4):327-32. https://doi.org/10.1007/s10048-012-0337-6
[11] Darras BT. Non-5q Spinal Muscular Atrophies the Alphanumeric Soup Thickens. 2011 Jul 26;77(4):312-4. https://doi.org/10.1212/WNL.0b013e3182267bd8
[12] Chaytow H, et al. The Role of Survival Motor Neuron Protein (SMN) in Protein Homeostasis. Cell Mol Life Sci. 2018 Nov;75(21):3877-3894. https://doi.org/10.1007/s00018-018-2849-1
[13] Martínez-González JP, et al. DYNC1H1 de Novo Mutation, Spinal Muscular Atrophy and Attention Problems. Neurología. 2022;37:406-409. https://doi.org/10.1016/j.nrleng.2021.08.001
[14] Giménez G, et al. Cuidados respiratorios de los pacientes con atrofia muscular espinal. Neumología Pediátrica. 2022;16(1):23-29. https://doi.org/10.51451/np.v16i1.233
[15] Castiglionia C, Lozano-Arango A. Atrofias musculares espinales no asociadas a SMN1. Revista Médica Clínica Las Condes. 2018;29(6):643-653. https://doi.org/10.1016/j.rmclc.2018.10.002
[16] Aguilar C, et al. Cetoacidosis por estrés: caso clínico en paciente con atrofia muscular espinal. Rev Med Chile. 2020;148(6):875-880. http://dx.doi.org/10.4067/S0034-98872020000600875
[17] Specified Drug-Use Survey of Leuprorelin Acetate Injection Kit 11.25 mg. "All-Case Investigation: Spinal and Bulbar Muscular Atrophy (SBMA)" ClinicalTrias.gov. Disponible en: https://clinicaltrials.gov/ct2/show/NCT03555578?term=leuprorelina&cond=Spinal+-Muscular+Atrophy&draw=2&rank=2
[18] Quilagüy Camelo N, et al. Aspectos clínicos de la enfermedad de Kennedy. Artículo de Revisión. Ciencia Latina Revista Científica Multidisciplinar. 2022;6(4): 898-913. https://doi.org/10.37811/cl_rcm.vxix.xxx
[19] Gene Therapy for IGHMBP2-Related Diseases ClinicalTrials.gov. Disponible en: https://clinicaltrials.gov/ct2/show/NCT05152823?cond=IGHMBP2&-draw=2&rank=1
[20] Lee J, et al. Activation of PDGF Pathway Links LMNA Mutation to Dilated Cardiomyopathy. Nature. 2023;572(7769):335-340. https://doi.org/10.1038/s41586-019-1406-x
[21] Scoto M, et al. Novel Mutations Expand the Clinical Spectrum of DYNC1H1-Associated Spinal Muscular Atrophy. Neurology. 2015;84(7):668-79. https://doi.org/10.1212/WNL.0000000000001269
[22] Rivera EG, et al. SARS-CoV-2/COVID-19 and Its Relationship with NOD2 and Ubiquitination. Clin Immunol. 2022;238:109027. https://doi.org/10.1016/j.clim.2022.109027
[23] Keinath MC. Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance. Appl Clin Genet. 2021;14:11-25. https://doi.org/10.2147/TACG.S239603
[24] Febrer A, Meléndez M. Atrofia Muscular Espinal. Complicaciones y rehabilitación. Rehabilitación (Madr). 2001;35(5):307-311. https://doi.org/10.1016/S0048-7120(01)73196-9
[25] Harms MB, et al. Mutations in the Tail Domain of DY- NC1H1 Cause Dominant Spinal Muscular Atrophy. Neurology. 2012;78(22):1714-1720. https://doi.org/10.1212/WNL.0b013e3182556c05
[26] Weedon MN, et al. Exome Sequencing Identifies a DY- NC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease. Am J Hum Genet. 2011;89(2):308-312. https://doi.org/10.1016/j.ajhg.2011.07.002
[27] Qingping Yao, Jean Schils. Distal Lower Extremity Swelling as a Prominent Phenotype of NOD2-associated Autoinflammatory Disease. Rheumatology. 2013;52(11):2095-2097. https://doi.org/10.1093/rheu-matology/ket143
[28] Rubio S, et al. Secuenciación de nueva generación (NGS) de ADN: presente y futuro en la práctica clínica. Univ. Med. 2020;61(2). https://doi.org/doi.org/10.11144/Javeriana.umed61-2.sngs
[29] Lago Sampedro AM, García-Escobar E. Importance of Bioinformatics in Nowadays Medicine. Is it Really Necessary in Clinical Practice? Nutr Hosp. 2022;39(3):487-8. Disponible en: https://scielo.isciii.es/pdf/nh/v39n3/0212-1611-nh-39-3-487.pdf
[30] Instituto Nacional de Salud. Proporción de notificación de enfermedades huérfanas y raras, Colombia, 2022 hasta periodo epidemiológico VI. Disponible en: https://www.ins.gov.co/buscador-eventos/Informes-deevento/ENFERMEDADES%20HUERFANAS%20 PE%20VI%202022.pdf
[31] Del genotipo al fenotipo: estrategia de investigación [Internet]. Genotipia. 2023. Disponible en: https://genotipia.com/genetica_medica_news/la-investigacion-del-genotipo-al-fenotipo/?utm_source=NL%20Genotipia%202022&utm_medium=email&utm_campaign=Genotipia%20Hoy%2024%20Enero%202023%20%2801GQF8CP5R7YVKH13DJ59%29&_kx=G5f4ha6iy2_--vCEfJCsxoLcryft97m8xPNZaUc-nw7JkGMjlFPUsT_m42645P7OC.SLZegA
[32] Peeters K. Clinical and Genetic Diversity of SMN1-Negative Proximal Spinal Muscular Atrophies. Brain. 2014 Nov;137(Pt 11):2879-96. https://doi.org/10.1093/brain/awu169
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