Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

Abstract

Spinal muscular atrophy linked to chromosome 5 (SMA-5q) is an autosomal recessive genetic disease caused by mutations in the SMN1. SMA-5q is characterized by progressive degeneration of the spinal cord and bulbar motor neurons, causing severe motor and respiratory impairment with reduced survival, especially in its more severe clinical forms. In recent years, highly effective disease-modifying therapies have emerged, either acting by regulating the splicing of exon 7 of the SMN2 gene or adding a copy of the SMN1 gene through gene therapy, providing a drastic change in the natural history of the disease. In this way, developing therapeutic guides and expert consensus becomes essential to direct the use of these therapies in clinical practice. This consensus, prepared by Brazilian experts, aimed to review the main available disease-modifying therapies, critically analyze the results of clinical studies, and provide recommendations for their use in clinical practice for patients with SMA-5q. This consensus also addresses aspects related to diagnosis, genetic counseling, and follow-up of patients under drug treatment. Thus, this consensus provides valuable information regarding the current management of SMA-5q, helping therapeutic decisions in clinical practice and promoting additional gains in outcomes.

Resumo

Atrofia muscular espinhal ligada ao cromossomo 5 (AME-5q) é uma doença genética de herança autossômica recessiva causada por mutações no gene SMN1. A AME-5q cursa com degeneração progressiva dos motoneurônios medulares e bulbares, acarretando grave comprometimento motor e respiratório com redução da sobrevida, especialmente nas suas formas clínicas mais graves. Nos últimos anos, terapias modificadoras da doença altamente eficazes, ou que atuam regulando o splicing do exon 7 do gene SMN2 ou adicionando uma cópia do gene SMN1 via terapia gênica, têm surgido, proporcionando uma mudança drástica na história natural da doença. Dessa forma, o desenvolvimento de guias terapêuticos e de consensos de especialistas torna-se importante no sentido de direcionar o uso dessas terapias na prática clínica. Este consenso, preparado por especialistas brasileiros, teve como objetivos revisar as principais terapias modificadoras de doença disponíveis, analisar criticamente os resultados dos estudos clínicos dessas terapias e prover recomendações para seu uso na prática clínica para pacientes com AME-5q. Aspectos relativos ao diagnóstico, aconselhamento genético e seguimento dos pacientes em uso das terapias também são abordados nesse consenso. Assim, esse consenso promove valiosas informações a respeito do manejo atual da AME-5q auxiliando decisões terapêuticas na prática clínica e promovendo ganhos adicionais nos desfechos finais.

Keywords

Spinal Muscular Atrophy - Survival of Motor Neuron 1 Protein - Oligonucleotides - Risdiplam - Genetic Therapy - Onasemnogene abeparvovec

Palavras-chave

Atrofia Muscular Espinhal - Proteína 1 de Sobrevivência do Neurônio Motor - Oligonucleotídeos - Risdiplam - Terapia Genética - Onasemnogene abeparvovec

Authors' Contributions

All authors: Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing-original draft, Writing-review & editing

Support

This study was supported by ABN (Academia Brasileira de Neurologia).

Publikationsverlauf

Eingereicht: 29. September 2023

Angenommen: 14. Dezember 2023

Artikel online veröffentlicht:
05. Februar 2024

• References

• 1 Lefebvre S, Bürglen L, Reboullet S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80 (01) 155-165
• 2 Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol 2011; 68 (08) 979-984
• 3 Darras BT. Spinal muscular atrophies. Pediatr Clin North Am 2015; 62 (03) 743-766
• 4 Prior TW, Krainer AR, Hua Y. et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009; 85 (03) 408-413
• 5 Crawford TO, Paushkin SV, Kobayashi DT. et al; Pilot Study of Biomarkers for Spinal Muscular Atrophy Trial Group. Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One 2012; 7 (04) e33572
• 6 Wirth B, Karakaya M, Kye MJ, Mendoza-Ferreira N. Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next. Annu Rev Genomics Hum Genet 2020; 21: 231-261
• 7 Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008; 371 (9630): 2120-2133
• 8 Bueno KC, Gouvea SP, Genari AB. et al. Detection of spinal muscular atrophy carriers in a sample of the Brazilian population. Neuroepidemiology 2011; 36 (02) 105-108
• 9 Calucho M, Bernal S, Alías L. et al. Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord 2018; 28 (03) 208-215
• 10 Chen TH. New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?. Int J Mol Sci 2020; 21 (09) 3297
• 11 Murad MH, Asi N, Alsawas M, Alahdab F. New evidence pyramid. Evid Based Med 2016; 21 (04) 125-127
• 12 Steurer J. The Delphi method: an efficient procedure to generate knowledge. Skeletal Radiol 2011; 40 (08) 959-961
• 13 Mercuri E, Finkel RS, Muntoni F. et al; SMA Care Group. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord 2018; 28 (02) 103-115
• 14 Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 2002; 70 (02) 358-368
• 15 Arkblad EL, Darin N, Berg K. et al. Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy. Neuromuscul Disord 2006; 16 (12) 830-838
• 16 Prior TW, Nagan N. Spinal Muscular Atrophy: Overview of Molecular Diagnostic Approaches. Curr Protoc Hum Genet 2016; 88: 9.27.1-9.27.13
• 17 Mendonça RH, Matsui Jr C, Polido GJ. et al. Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy. Neurol Genet 2020; 6 (05) e505
• 18 Liu B, Lu Y, Wu B. et al. Survival Motor Neuron Gene Copy Number Analysis by Exome Sequencing: Assisting Spinal Muscular Atrophy Diagnosis and Carrier Screening. J Mol Diagn 2020; 22 (05) 619-628
• 19 van der Steege G, Grootscholten PM, van der Vlies P. et al. PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet 1995; 345 (8955): 985-986
• 20 Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [updated 2020 Dec 3]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH. et al. eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.
• 21 Kirwin SM, Vinette KM, Gonzalez IL, Abdulwahed HA, Al-Sannaa N, Funanage VL. A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA. Mol Genet Genomic Med 2013; 1 (02) 113-117
• 22 Chiriboga CA, Swoboda KJ, Darras BT. et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 2016; 86 (10) 890-897
• 23 Finkel RS, Chiriboga CA, Vajsar J. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016; 388 (10063): 3017-3026
• 24 Finkel RS, Mercuri E, Darras BT. et al; ENDEAR Study Group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017; 377 (18) 1723-1732
• 25 Messina S, Pane M, Sansone V. et al; Italian EAP working Group. Expanded access program with Nusinersen in SMA type I in Italy: Strengths and pitfalls of a successful experience. Neuromuscul Disord 2017; 27 (12) 1084-1086
• 26 Farrar MA, Teoh HL, Carey KA. et al. Nusinersen for SMA: expanded access programme. J Neurol Neurosurg Psychiatry 2018; 89 (09) 937-942
• 27 Pechmann A, Langer T, Schorling D. et al. Evaluation of children with SMA type 1 under treatment with nusinersen within the expanded access program in Germany. J Neuromuscul Dis 2018; 5 (02) 135-143
• 28 Aragon-Gawinska K, Seferian AM, Daron A. et al. Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: A cohort study. Neurology 2018; 91 (14) e1312-e1318
• 29 Pane M, Palermo C, Messina S. et al; Italian EAP working group. Nusinersen in type 1 SMA infants, children and young adults: Preliminary results on motor function. Neuromuscul Disord 2018; 28 (07) 582-585
• 30 Pane M, Coratti G, Sansone VA. et al; Italian Expanded Access Program Working Group. Nusinersen in type 1 spinal muscular atrophy: Twelve-month real-world data. Ann Neurol 2019; 86 (03) 443-451
• 31 Sansone VA, Pirola A, Albamonte E. et al. Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen. J Pediatr 2020; 219: 223-228.e4
• 32 Chen KA, Widger J, Teng A, Fitzgerald DA, D'Silva A, Farrar M. Real-world respiratory and bulbar comorbidities of SMA type 1 children treated with nusinersen: 2-Year single centre Australian experience. Paediatr Respir Rev 2021; 39: 54-60
• 33 de Holanda Mendonça R, Jorge Polido G, Ciro M, Jorge Fontoura Solla D, Conti Reed U, Zanoteli E. Clinical Outcomes in Patients with Spinal Muscular Atrophy Type 1 Treated with Nusinersen. J Neuromuscul Dis 2021; 8 (02) 217-224
• 34 Scheijmans FEV, Cuppen I, van Eijk RPA. et al. Population-based assessment of nusinersen efficacy in children with spinal muscular atrophy: a 3-year follow-up study. Brain Commun 2022; 4 (06) fcac269
• 35 Belančić A, Strbad T, Kučan Štiglić M, Vitezić D. Effectiveness of Nusinersen in Type 1, 2 and 3 Spinal Muscular Atrophy: Croatian Real-World Data. J Clin Med 2023; 12 (08) 2839
• 36 Chacko A, Marshall J, Taylor O, McEniery J, Sly PD, Gauld LM. Dysphagia and Lung Disease in Children With Spinal Muscular Atrophy Treated With Disease-Modifying Agents. Neurology 2023; 100 (19) 914-920
• 37 Iwayama H, Kawahara K, Takagi M. et al. Long-term efficacy of nusinersen and its evaluation in adolescent and adult patients with spinal muscular atrophy types 1 and 2. Brain Dev 2023; 45 (02) 110-116
• 38 Łusakowska A, Wójcik A, Frączek A. et al. Long-term nusinersen treatment across a wide spectrum of spinal muscular atrophy severity: a real-world experience. Orphanet J Rare Dis 2023; 18 (01) 230
• 39 Pane M, Coratti G, Sansone VA. et al; Italian EAP Working Group. Type I spinal muscular atrophy patients treated with nusinersen: 4-year follow-up of motor, respiratory and bulbar function. Eur J Neurol 2023; 30 (06) 1755-1763
• 40 Tachibana Y, Sato R, Makioka H, Hoshino M, Jin M. Safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 524 patients: results from an interim analysis of post-marketing surveillance in Japan. Int J Neurosci 2023; •••: 1-13
• 41 Mercuri E, Darras BT, Chiriboga CA. et al; CHERISH Study Group. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 2018; 378 (07) 625-635
• 42 Dunaway Young S, Montes J, Glanzman AM. et al; SHINE Study Group. Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function. J Clin Med 2023; 12 (15) 4901
• 43 Montes J, Dunaway Young S, Mazzone ES. et al; CS2 and CS12 Study Groups. Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy. Muscle Nerve 2019; 60 (04) 409-414
• 44 Walter MC, Wenninger S, Thiele S. et al. Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3—a prospective observational study. J Neuromuscul Dis 2019; 6 (04) 453-465
• 45 Hagenacker T, Wurster CD, Günther R. et al. Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. Lancet Neurol 2020; 19 (04) 317-325
• 46 Jochmann E, Steinbach R, Jochmann T. et al. Experiences from treating seven adult 5q spinal muscular atrophy patients with Nusinersen. Ther Adv Neurol Disord 2020; 13: 17 56286420907803. Doi: 10.1177/1756286420907803
• 47 Moshe-Lilie O, Visser A, Chahin N, Ragole T, Dimitrova D, Karam C. Nusinersen in adult patients with spinal muscular atrophy: Observations from a single center. Neurology 2020; 95 (04) e413-e416
• 48 Szabó L, Gergely A, Jakus R. et al. Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: Real world data from Hungarian patients. Eur J Paediatr Neurol 2020; 27: 37-42
• 49 Veerapandiyan A, Eichinger K, Guntrum D. et al. Nusinersen for older patients with spinal muscular atrophy: A real-world clinical setting experience. Muscle Nerve 2020; 61 (02) 222-226
• 50 Yeo CJJ, Simeone SD, Townsend EL, Zhang RZ, Swoboda KJ. Prospective Cohort Study of Nusinersen Treatment in Adults with Spinal Muscular Atrophy. J Neuromuscul Dis 2020; 7 (03) 257-268
• 51 Mendonça RH, Polido GJ, Matsui C. et al. Real-World Data from Nusinersen Treatment for Patients with Later-Onset Spinal Muscular Atrophy: A Single Center Experience. J Neuromuscul Dis 2021; 8 (01) 101-108
• 52 Pera MC, Coratti G, Bovis F. et al; iSMAC group. Nusinersen in pediatric and adult patients with type III spinal muscular atrophy. Ann Clin Transl Neurol 2021; 8 (08) 1622-1634
• 53 Berti B, Fanelli L, Stanca G. et al. Oral and Swallowing Abilities Tool (OrSAT) in nusinersen treated patients. Arch Dis Child 2022;•••:archdischild-2022–323899. Doi: 10.1136/archdischild-2022-323899
• 54 Gallone A, Mazzi F, Bonanno S. et al. Muscle quantitative MRI in adult SMA patients on nusinersen treatment: a longitudinal study. Acta Myol 2022; 41 (02) 76-83
• 55 Arslan D, Inan B, Kilinc M, Bekircan-Kurt CE, Erdem-Ozdamar S, Tan E. Nusinersen for adults with spinal muscular atrophy. Neurol Sci 2023; 44 (07) 2393-2400
• 56 Bjelica B, Wohnrade C, Osmanovic A, Schreiber-Katz O, Petri S. An observational cohort study on pulmonary function in adult patients with 5q-spinal muscular atrophy under nusinersen therapy. J Neurol 2023; 270 (07) 3616-3622
• 57 Krosschell KJ, Brown L, Hoffman K. et al. Longitudinal Assessment of Timed Function Tests in Ambulatory Individuals with SMA Treated with Nusinersen. J Neuromuscul Dis 2023; 10 (03) 337-348
• 58 Pechmann A, Behrens M, Dörnbrack K. et al; SMArtCARE study group. Improvements in Walking Distance during Nusinersen Treatment - A Prospective 3-year SMArtCARE Registry Study. J Neuromuscul Dis 2023; 10 (01) 29-40
• 59 Schreiber-Katz O, Siegler HA, Wieselmann G. et al. Improvement of muscle strength in specific muscular regions in nusinersen-treated adult patients with 5q-spinal muscular atrophy. Sci Rep 2023; 13 (01) 6240
• 60 Shin HJ, Na JH, Lee H, Lee YM. Nusinersen for spinal muscular atrophy types II and III: a retrospective single-center study in South Korea. World J Pediatr 2023; 19 (05) 450-459
• 61 Yang H, Tao Q, Li D. et al. Assessment of motor function and nutritional status in children with spinal muscular atrophy treated with nusinersen after loading period in Western China: a retrospective study. BMC Neurol 2023; 23 (01) 35
• 62 Darras BT, Chiriboga CA, Iannaccone ST. et al; ISIS-396443-CS2/ISIS-396443-CS12 Study Groups. Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies. Neurology 2019; 92 (21) e2492-e2506
• 63 Finkel RS, Chiriboga CA, Vajsar J. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc Health 2021; 5 (07) 491-500
• 64 Coratti G, Cutrona C, Pera MC. et al. Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis. Orphanet J Rare Dis 2021; 16 (01) 430
• 65 Abbas KS, Eltaras MM, El-Shahat NA, Abdelazeem B, Shaqfeh M, Brašić JR. The Safety and Efficacy of Nusinersen in the Treatment of Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Medicina (Kaunas) 2022; 58 (02) 213
• 66 Gavriilaki M, Moschou M, Papaliagkas V. et al. Nusinersen in Adults with 5q Spinal Muscular Atrophy: a Systematic Review and Meta-analysis. Neurotherapeutics 2022; 19 (02) 464-475
• 67 Zhong ZJ, Zheng PM, Dou HH, Wang JG. Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis. Front Pediatr 2023; 11: 1152318
• 68 Finkel RS, Day JW, Pascual Pascual SI. et al; DEVOTE Study Group. DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results. J Neuromuscul Dis 2023; 10 (05) 813-823
• 69 De Vivo DC, Bertini E, Swoboda KJ. et al; NURTURE Study Group. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord 2019; 29 (11) 842-856
• 70 Crawford TO, Swoboda KJ, De Vivo DC. et al; NURTURE Study Group. Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study. Muscle Nerve 2023; 68 (02) 157-170
• 71 Ratni H, Ebeling M, Baird J. et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem 2018; 61 (15) 6501-6517
• 72 Baranello G, Darras BT, Day JW. et al; FIREFISH Working Group. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med 2021; 384 (10) 915-923
• 73 Darras BT, Masson R, Mazurkiewicz-Bełdzińska M. et al; FIREFISH Working Group. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med 2021; 385 (05) 427-435
• 74 Masson R, Mazurkiewicz-Bełdzińska M, Rose K. et al; FIREFISH Study Group. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol 2022; 21 (12) 1110-1119
• 75 Baranello G, Boespflug-Tanguy O, Day JW. et al. FIREFISH Parts 1 and 2: 48-month safety and efficacy of risdiplamin Type 1 SMA. In: 2023 Annual SMA Research & Clinical Care Meeting, June 29–July 2. Orlando FL, USA:
• 76 Mercuri E, Baranello G, Boespflug-Tanguy O. et al. Risdiplam in types 2 and 3 spinal muscular atrophy: A randomized, placebo-controlled, dose-finding trial followed by 24 months of treatment. Eur J Neurol 2023; 30 (07) 1945-1956
• 77 Mercuri E, Deconinck N, Mazzone ES. et al; SUNFISH Study Group. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2022; 21 (01) 42-52
• 78 Oskoui M, Day JW, Deconinck N. et al; SUNFISH Working Group. Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA). J Neurol 2023; 270 (05) 2531-2546
• 79 Servais L, Day JW, Mazzone ES. et al. 188 SUNFISH 3-year efficacy and safety of risdiplam in types 2 and 3 SMA. J Neurol Neurosurg Psychiatry 2022; 93: e2.149
• 80 Chiriboga CA, Bruno C, Duong T. et al; JEWELFISH Study Group. Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study. Neurol Ther 2023; 12 (02) 543-557
• 81 Hahn A, Günther R, Ludolph A. et al; Risdiplam Compassionate Use Program Group. Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany. Orphanet J Rare Dis 2022; 17 (01) 276
• 82 Kwon JM, Arya K, Kuntz N. et al; US Expanded Access Program Working Group. An expanded access program of risdiplam for patients with Type 1 or 2 spinal muscular atrophy. Ann Clin Transl Neurol 2022; 9 (06) 810-818
• 83 Ñungo Garzón NC, Pitarch Castellano I, Sevilla T, Vázquez-Costa JF. Risdiplam in non-sitter patients aged 16 years and older with 5q spinal muscular atrophy. Muscle Nerve 2023; 67 (05) 407-411
• 84 McCluskey G, Lamb S, Mason S. et al. Risdiplam for the treatment of adults with spinal muscular atrophy: Experience of the Northern Ireland neuromuscular service. Muscle Nerve 2023; 67 (02) 157-161
• 85 Pascual-Morena C, Martínez-Vizcaíno V, Cavero-Redondo I. et al. Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta-analysis. Pharmacotherapy 2023; •••
• 86 Finkel RS, Farrar MA, Servais L. et al. RAINBOWFISH: Primary efficacy and safety data in risdiplam-treated infants with presymptomatic spinal muscular atrophy (SMA). In: 28th International Annual Congress of the World Muscle Society (WMS), Charleston, USA; October 3–7, 2023.
• 87 Sergott RC, Amorelli GM, Baranello G. et al; FIREFISH, SUNFISH, JEWELFISH Working Groups. Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy. Ann Clin Transl Neurol 2021; 8 (01) 54-65
• 88 Cleary Y, Gertz M, Grimsey P. et al. Model-Based Drug-Drug Interaction Extrapolation Strategy From Adults to Children: Risdiplam in Pediatric Patients With Spinal Muscular Atrophy. Clin Pharmacol Ther 2021; 110 (06) 1547-1557
• 89 Kletzl H, Ajmi H, Antys I. et al. Effect of mild or moderate hepatic impairment on the pharmacokinetics of risdiplam. Br J Clin Pharmacol 2022; 88 (08) 3749-3759
• 90 Mendell JR, Al-Zaidy S, Shell R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017; 377 (18) 1713-1722
• 91 Mendell JR, Al-Zaidy SA, Lehman KJ. et al. Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy. JAMA Neurol 2021; 78 (07) 834-841
• 92 Day JW, Finkel RS, Chiriboga CA. et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol 2021; 20 (04) 284-293
• 93 Mercuri E, Muntoni F, Baranello G. et al; STR1VE-EU study group. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol 2021; 20 (10) 832-841
• 94 McGrattan KE, Shell RD, Hurst-Davis R. et al. Patients with Spinal Muscular Atrophy Type 1 Achieve and Maintain Bulbar Function Following Onasemnogene Abeparvovec Treatment. J Neuromuscul Dis 2023; 10 (04) 531-540
• 95 Waldrop MA, Karingada C, Storey MA. et al. Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes. Pediatrics 2020; 146 (03) e20200729
• 96 Ali HG, Ibrahim K, Elsaid MF. et al. Gene therapy for spinal muscular atrophy: the Qatari experience. Gene Ther 2021; 28 (10-11): 676-680
• 97 Friese J, Geitmann S, Holzwarth D. et al. Safety Monitoring of Gene Therapy for Spinal Muscular Atrophy with Onasemnogene Abeparvovec -A Single Centre Experience. J Neuromuscul Dis 2021; 8 (02) 209-216
• 98 Matesanz SE, Battista V, Flickinger J, Jones JN, Kichula EA. Clinical Experience With Gene Therapy in Older Patients With Spinal Muscular Atrophy. Pediatr Neurol 2021; 118: 1-5
• 99 Oechsel KF, Cartwright MS. Combination therapy with onasemnogene and risdiplam in spinal muscular atrophy type 1. Muscle Nerve 2021; 64 (04) 487-490
• 100 D'Silva AM, Holland S, Kariyawasam D. et al. Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy. Ann Clin Transl Neurol 2022; 9 (03) 339-350
• 101 Lee S, Lee YJ, Kong J. et al. Short-term clinical outcomes of onasemnogene abeparvovec treatment for spinal muscular atrophy. Brain Dev 2022; 44 (04) 287-293
• 102 Tosi M, Catteruccia M, Cherchi C, Mizzoni I, D'Amico A. Switching therapies: safety profile of Onasemnogene abeparvovec-xioi in a SMA1 patient previously treated with Risdiplam. Acta Myol 2022; 41 (03) 117-120
• 103 Weiß C, Ziegler A, Becker LL. et al. Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study. Lancet Child Adolesc Health 2022; 6 (01) 17-27
• 104 AlNaimi A, Hamad SG, Mohamed RBA. et al. A breakthrough effect of gene replacement therapy on respiratory outcomes in children with spinal muscular atrophy. Pediatr Pulmonol 2023; 58 (04) 1004-1011
• 105 Mendonça RH, Ortega AB, Matsui Jr C. et al. Real world safety and exploratory efficacy of gene therapy for patients with 5q-Spinal Muscular Atrophy in a Brazilian cohort. Gene Ther 2023 In press
• 106 Pane M, Berti B, Capasso A. et al; ITASMAc group. Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies. EClinicalMedicine 2023; 59: 101997
• 107 Tokatly Latzer I, Sagi L, Lavi R. et al. Real-Life Outcome After Gene Replacement Therapy for Spinal Muscular Atrophy: A Multicenter Experience. Pediatr Neurol 2023; 144: 60-68
• 108 Stettner GM, Hasselmann O, Tscherter A, Galiart E, Jacquier D, Klein A. Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study. BMC Neurol 2023; 23 (01) 88
• 109 Yang D, Ruan Y, Chen Y. Safety and efficacy of gene therapy with onasemnogene abeparvovec in the treatment of spinal muscular atrophy: A systematic review and meta-analysis. J Paediatr Child Health 2023; 59 (03) 431-438
• 110 Strauss KA, Farrar MA, Muntoni F. et al. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nat Med 2022; 28 (07) 1381-1389
• 111 Strauss KA, Farrar MA, Muntoni F. et al. Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nat Med 2022b; 28 (07) 1390-1397
• 112 Shell RD, McGrattan KE, Hurst-Davis R. et al. Onasemnogene abeparvovec preserves bulbar function in infants with presymptomatic spinal muscular atrophy: a post-hoc analysis of the SPR1NT trial. Neuromuscul Disord 2023; 33 (08) 670-676
• 113 Kay DM, Stevens CF, Parker A. et al. Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy. Genet Med 2020; 22 (08) 1296-1302
• 114 Boemer F, Caberg JH, Beckers P. et al. Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium. Sci Rep 2021; 11 (01) 19922
• 115 Elkins K, Wittenauer A, Hagar AF. et al. Georgia state spinal muscular atrophy newborn screening experience: Screening assay performance and early clinical outcomes. Am J Med Genet C Semin Med Genet 2022; 190 (02) 187-196
• 116 Shih ST, Farrar MA, Wiley V, Chambers G. Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis. J Neurol Neurosurg Psychiatry 2021; 92 (12) 1296-1304
• 117 Day JW, Howell K, Place A. et al. Advances and limitations for the treatment of spinal muscular atrophy. BMC Pediatr 2022; 22 (01) 632
• 118 Ogbonmide T, Rathore R, Rangrej SB. et al. Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Current Challenges and Safety Considerations for Onasemnogene Abeparvovec (Zolgensma). Cureus 2023; 15 (03) e36197
• 119 Guillou J, de Pellegars A, Porcheret F. et al. Fatal thrombotic microangiopathy case following adeno-associated viral SMN gene therapy. Blood Adv 2022; 6 (14) 4266-4270
• 120 Philippidis A. Novartis Confirms Deaths of Two Patients Treated with Gene Therapy Zolgensma. Hum Gene Ther 2022; 33 (17-18): 842-844
• 121 Galletta F, Cucinotta U, Marseglia L. et al. Hemophagocytic lymphohistiocytosis following gene replacement therapy in a child with type 1 spinal muscular atrophy. J Clin Pharm Ther 2022; 47 (09) 1478-1481
• 122 Gaillard J, Gu AR, Neil Knierbein EE. Necrotizing Enterocolitis following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series. J Pediatr 2023; 260: 113493
• 123 Day JW, Finkel RS, Mercuri E. et al. Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec. Mol Ther Methods Clin Dev 2021; 21: 76-82
• 124 Finkel RS, Darras BT, Mendell JR. et al. Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG). J Neuromuscul Dis 2023; 10 (03) 389-404
• 125 Davidson JE, Farrar MA. The changing therapeutic landscape of spinal muscular atrophy. Aust J Gen Pract 2022; 51 (1-2): 38-42
• 126 Slayter J, Hodgkinson V, Lounsberry J. et al. A Canadian Adult Spinal Muscular Atrophy Outcome Measures Toolkit: Results of a National Consensus using a Modified Delphi Method. J Neuromuscul Dis 2021; 8 (04) 579-588
• 127 Pechmann A, König K, Bernert G. et al. SMArtCARE - A platform to collect real-life outcome data of patients with spinal muscular atrophy. Orphanet J Rare Dis 2019; 14 (01) 18
• 128 Sansone VA, Walter MC, Attarian S. et al. Measuring Outcomes in Adults with Spinal Muscular Atrophy - Challenges and Future Directions - Meeting Report. J Neuromuscul Dis 2020; 7 (04) 523-534
• 129 Merlini L, Bertini E, Minetti C. et al. Motor function-muscle strength relationship in spinal muscular atrophy. Muscle Nerve 2004; 29 (04) 548-552
• 130 Edel L, Grime C, Robinson V. et al. A new respiratory scoring system for evaluation of respiratory outcomes in children with spinal muscular atrophy type1 (SMA1) on SMN enhancing drugs. Neuromuscul Disord 2021; 31 (04) 300-309
• 131 Pitarch Castellano I, Cabrera-Serrano M, Calvo Medina R. et al. Delphi consensus on recommendations for the treatment of spinal muscular atrophy in Spain (RET-AME consensus). Neurología (Engl Ed) 2022; 37 (03) 216-228
• 132 Leon-Astudillo C, Wagner M, Salabarria SM. et al. Polysomnography findings in children with spinal muscular atrophy after onasemnogene-abeparvovec. Sleep Med 2023; 101: 234-237
• 133 Xiao L, Chiang J, Castro-Codesal M. et al; SickKids SMA Group. Respiratory characteristics in children with spinal muscular atrophy type 1 receiving nusinersen. Pediatr Pulmonol 2023; 58 (01) 161-170
• 134 Kluger BM, Krupp LB, Enoka RM. Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. Neurology 2013; 80 (04) 409-416
• 135 Fainmesser Y, Drory VE, Ben-Shushan S. et al. Longer-term follow-up of nusinersen efficacy and safety in adult patients with spinal muscular atrophy types 2 and 3. Neuromuscul Disord 2022; 32 (06) 451-459
• 136 Osmanovic A, Ranxha G, Kumpe M. et al. Treatment satisfaction in 5q-spinal muscular atrophy under nusinersen therapy. Ther Adv Neurol Disord 2021; 14: 17 56286421998902. Doi: 10.1177/1756286421998902
• 137 Protocolos clínicos e diretrizes terapêuticas (PCDT) – Atrofia Muscular Espinhal Tipo I e tipo II. CONITEC, Ministério da Saúde, Brasil, Maio de 2023. https://www.gov.br/conitec/pt-br/midias/protocolos/20230522_portariaconjuntano6atrofiamuscularespinhal5qtipos1e2.pdf
• 138 Ramos-Platt L, Elman L, Shieh PB. Experience and perspectives in the US on the evolving treatment landscape in Spinal Muscular Atrophy. Int J Gen Med 2022; 15: 7341-7353
• 139 McMillan HJ, Gerber B, Cowling T. et al. Burden of Spinal Muscular Atrophy (SMA) on Patients and Caregivers in Canada. J Neuromuscul Dis 2021; 8 (04) 553-568
• 140 Kichula EA, Proud CM, Farrar MA. et al. Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy. Muscle Nerve 2021; 64 (04) 413-427
• 141 Mirea A, Shelby ES, Axente M. et al. Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy Type I. J Clin Med 2021; 10 (23) 5540
• 142 Sugarman EA, Nagan N, Zhu H. et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet 2012; 20 (01) 27-32
• 143 Serra-Juhe C, Tizzano EF. Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors. Eur J Hum Genet 2019; 27 (12) 1774-1782
• 144 Alías L, Bernal S, Calucho M. et al. Utility of two SMN1 variants to improve spinal muscular atrophy carrier diagnosis and genetic counselling. Eur J Hum Genet 2018; 26 (10) 1554-1557
• 145 Rouzier C, Chaussenot A, Paquis-Flucklinger V. Molecular diagnosis and genetic counseling for spinal muscular atrophy (SMA). Arch Pediatr 2020; 27 (7S): 7S9-7S14
• 146 Aragon-Gawinska K, Mouraux C, Dangouloff T, Servais L. Spinal Muscular Atrophy Treatment in Patients Identified by Newborn Screening-A Systematic Review. Genes (Basel) 2023; 14 (07) 1377
• 147 Antonaci L, Pera MC, Mercuri E. New therapies for spinal muscular atrophy: where we stand and what is next. Eur J Pediatr 2023; 182 (07) 2935-2942
• 148 Pechmann A, Baumann M, Bernert G. et al. Treatment with Nusinersen - Challenges Regarding the Indication for Children with SMA Type 1. J Neuromuscul Dis 2020; 7 (01) 41-46
• 149 Glascock J, Sampson J, Connolly AM. et al. Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. J Neuromuscul Dis 2020; 7 (02) 97-100
• 150 Ricci M, Cicala G, Capasso A. et al; ITASMAC Working Group. Clinical phenotype of paediatric and adult patients with spinal muscular atrophy with 4 SMN2 copies: are they really all stable?. Ann Neurol 2023; 94 (06) 1126-1135
• 151 Madan E, Carrié S, Donado C. et al. Nusinersen for Patients With Spinal Muscular Atrophy: 1415 Doses via an Interdisciplinary Institutional Approach. Pediatr Neurol 2022; 132: 33-40
• 152 MacCannell D, Berger Z, Kirschner J. et al. Restoration of Nusinersen Levels Following Treatment Interruption in People With Spinal Muscular Atrophy: Simulations Based on a Population Pharmacokinetic Model. CNS Drugs 2022; 36 (02) 181-190
• 153 EVRYSDI® (risdiplam). https://www.gov.br/anvisa/pt-br/assuntos/medicamentos/novos-medicamentos-e-indicacoes/evrysdi-r-risdiplam-novo-registro
• 154 Chand DH, Mitchell S, Sun R, LaMarca N, Reyna SP, Sutter T. Safety of Onasemnogene Abeparvovec for Patients With Spinal Muscular Atrophy 8.5 kg or Heavier in a Global Managed Access Program. Pediatr Neurol 2022; 132: 27-32
• 155 Matsumura-Kimoto Y, Inamoto Y, Tajima K. et al. Association of Cumulative Steroid Dose with Risk of Infection after Treatment for Severe Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 2016; 22 (06) 1102-1107