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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2023.tde-10052023-162255
Document
Author
Full name
Rodrigo de Holanda Mendonça
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2023
Supervisor
Committee
Zanoteli, Edmar (President)
Araujo, Alexandra Prufer de Queiroz Campos
Giannetti, Juliana Gurgel
Reed, Umbertina Conti
Title in Portuguese
Estudo clínico e funcional da atrofia muscular espinhal 5q: história natural e tratamento com nusinersena
Keywords in Portuguese
Atrofia muscular espinhal
Escoliose
Neurônios motores
Oligonucleotideos antisenso
Proteína 1 de sobrevivência do neurônio motor
Punção espinal
Respiração artificial
Abstract in Portuguese
Introdução: A atrofia muscular espinhal (AME) ligada ao cromossomo 5q relaciona-se a mutações bialélicas no gene SMN1. O número de cópias do gene SMN2 influencia o fenótipo. O Nusinersena, um oligonucleotídeo antisenso, atua modulando a expressão do gene SMN2, e tem se mostrado eficaz em modificar a história natural da AME com poucos efeitos adversos. Entretanto, faltam estudos na população brasileira. Objetivo: avaliar os aspectos clínicos e funcionais de pacientes com AME de acordo com a história natural e em tratamento com nusinersena. Métodos: estudo observacional retrospectivo em que foram incluídos pacientes com AME dos tipos 1, 2 e 3 em tratamento com nusinersena, e pacientes com AME dos tipos 2 e 3 sem tratamento modificador da doença, avaliados através de ganhos de marcos motores, tempo de suporte ventilatório e as escalas motoras The Childrens Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) e Hammersmith Functional Motor Scale Expanded (HFMSE). Resultados: foram incluídos 21 pacientes com AME do tipo 1 (52,4% homens) com duração de doença ao início do tratamento de 34,1 (±36,0) meses. O ganho médio na CHOP INTEND foi de 5,9 e 14 pontos após 12 e 24 meses de tratamento, respectivamente. Pacientes com menor tempo de doença e sem uso de ventilação invasiva obtiveram melhor resposta motora, e sete (33,3%) pacientes adquiriram algum marco motor. Foram incluídos 78 pacientes com AME tipos 2 e 3, sendo 30 em tratamento com nusinersena que foram avaliados pela HFMSE, e obtiveram ganho médio de +1,47 (±0,4) e +1,60 (±0,6) pontos após 12 e 24 meses de tratamento, respectivamente. Em comparação, 37 pacientes que não tiveram acesso ao tratamento (grupo controle), foram avaliados pela mesma escala, e apresentaram uma mudança média de -1,71 pontos (±0,02) e -3,93 pontos (±0,55) durante o mesmo período de seguimento. A duração da doença no início do tratamento foi o principal preditor de melhora motora, mas o tratamento não preveniu a progressão da escoliose. Uso de imagem (tomografia computadorizada ou fluoroscopia) foi necessário para realizar punção lombar em nove pacientes com cirurgia prévia de coluna, com baixa incidência de eventos adversos. O seguimento de longo prazo mostrou que 19 (90,5%) pacientes com AME do tipo 1 estavam vivos, e, do ponto de vista motor, mantiveram-se estáveis, sem ganhos de marcos motores adicionais no terceiro e quarto anos de seguimento. Dentre os pacientes com AME dos tipos 2 e 3, vinte e um (70%) permaneceram estáveis ou continuaram a ganhar pontos na HFMSE em quatro anos de seguimento, e nove pacientes (30%) perderam dois ou mais pontos, piora esta associada a escoliose grave ou cirurgia de coluna. Conclusão: Nusinersena modificou a história natural da AME, com efeitos benéficos nas funções motoras e respiratórias nos pacientes com AME do tipo 1, porém pacientes com longo tempo de doença e sob ventilação mecânica invasiva obtiveram menos benefícios. O uso de nusinersena no tratamento da AME de início tardio se mostrou eficaz e seguro, e os pacientes com menor tempo de doença ao início do tratamento demonstraram melhor resposta. Seguimento de longo prazo evidenciou que a escoliose e a cirurgia de coluna relaciona-se com piora funcional nestes pacientes
Title in English
Clinical and functional study of spinal muscular atrophy 5q: natural history and treatment with nusinersen
Keywords in English
Motor neuron survival protein 1
Motor neurons
Oligonucleotides antisense
Respiration artificial
Scoliosis
Spinal muscular atrophy
Spinal puncture
Abstract in English
Introduction: Spinal muscular atrophy (SMA) linked to chromosome 5q is related to biallelic mutations in the SMN1 gene. The number of copies of the SMN2 gene correlates with phenotype. Nusinersen, an antisense oligonucleotide, acts by modulating SMN2 gene expression, and has been shown to be effective in modifying the natural history course of the disease with few adverse effects. However, studies in the Brazilian population are lacking. Objective: to evaluate the clinical and functional aspects of patients with SMA according to the natural history of the disease and under nusinersen treatment. Methods: Retrospective observational study including patients with SMA types 1, 2 and 3 on nusinersen treatment, and patients with SMA types 2 and 3 without disease-modifying treatment, evaluated through gains in motor milestones, time of ventilatory support and by the motor scales The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders motor scales (CHOP INTEND) and Hammersmith Functional Motor Scale Expanded (HFMSE). Results: Twenty one patients with SMA type 1 (52.4% men) with a disease duration of 34.1 (±36.0) months were included. The mean gain on CHOP INTEND was 5.9 and 14 points after 12 and 24 months of treatment, respectively. Patients with a shorter disease duration and without the use of invasive ventilation had better motor response and seven (33.3%) acquired a motor milestone. A total of 78 patients with SMA types 2 and 3 were included, 30 of whom were undergoing treatment with nusinersen, and were evaluated by the HFMSE, and obtained a mean gain of +1.47 (±0.4) and +1.60 (±0.6) points after 12 and 24 months of treatment, respectively. In comparison, 37 patients who did not have access to treatment (control group), were evaluated using the same scale, and showed an average change of -1.71 points (±0.02) and -3.93 points (±0.55 ) during the same follow-up period. Disease duration at baseline was the main predictor of motor improvement, but treatment did not prevent scoliosis progression. Imaging (computed tomography or fluoroscopy) was required to perform lumbar puncture in nine patients with previous spinal surgery, with a low incidence of adverse events. Long-term follow-up showed that 19 (90.5%) patients with type 1 SMA are alive, and, from a motor point of view, the patients remained stable, with no additional motor milestones gains in the third and fourth years of follow-up. Among patients with SMA types 2 and 3, twenty-one (70%) remained stable or continued to gain points on the HFMSE in four years of follow-up, and nine patients (30%) lost two or more points, a worsening associated with severe scoliosis or spine surgery. Conclusion: Nusinersen modified the natural history of SMA, with beneficial effects on motor and respiratory functions in patients with type 1 SMA, but patients with a long disease duration and under invasive mechanical ventilation obtained less benefits. The use of nusinersen in the treatment of late-onset SMA proved to be effective and safe, and patients with a shorter disease duration at the beginning of treatment showed a better response. Long-term follow-up showed that scoliosis and spine surgery were related to functional worsening in these patients
 
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Publishing Date
2023-05-11
 
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