Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy / Consenso da Academia Brasileira de Neurologia para diagnóstico, aconselhamento genético e uso de terapias modificadoras na atrofia muscular espinhal 5q

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.

Brazilian version of the CHOP INTEND scale: cross-cultural adaptation and validation / Versão brasileira da escala CHOP INTEND: adaptação transcultural e validação

Abstract Background Spinal muscular atrophy (SMA) is a rare genetic disease that causes progressive muscle weakness and impacts motor function. The type I is the most severe presentation and affects infants before 6 months old. In addition, the instruments available for assessing motor function have limitations when applied to infants with neuromuscular diseases and significant muscle weakness. Objective To translate, cross-culturally adapt, and validate the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) to Brazilian Portuguese. Methods The present study comprised the translation, synthesis of translations, backtranslation, consolidation by a committee of experts, and test of the final version of the CHOP INTEND in 13 patients with SMA type I. We also assessed the content validity and reliability of the translated version. Results The scale was translated considering semantic, structural, idiomatic, and cultural aspects. All agreement rates were > 0.8, the overall content validity index of the instrument was 0.98, and inter-rater reliability using the intraclass correlation coefficient was 0.998. Conclusion The Brazilian version of the CHOP INTEND met semantic and technical equivalence criteria with the original version and was valid and reliable for patients with SMA type I.

Resumo Antecedentes A atrofia muscular espinhal (AME) é uma doença genética rara que provoca fraqueza muscular progressiva com impacto sobre a motricidade dos pacientes. A AME tipo I é considerada o tipo mais grave e acomete lactentes antes dos 6 meses de idade. As escalas disponíveis para avaliação das aquisições motoras mostram limitações para uso com crianças pequenas com doenças neuromusculares e fraqueza importante. Objetivo Realizar a tradução, adaptação transcultural e validação para a língua portuguesa do Brasil da Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND, na sigla em inglês). Métodos O presente estudo seguiu as etapas de tradução, síntese das traduções, retrotradução, consolidação por comitê de especialistas e teste com 13 pacientes com AME tipo 1. Foi avaliada a validade de conteúdo e a confiabilidade do instrumento. Resultados A escala foi traduzida considerando os aspectos semânticos, estruturais, idiomáticos e culturais. Todas as taxas de concordância foram > 0,8. O índice de validade de conteúdo geral do instrumento foi de 0,98. A confiabilidade interavaliadores analisada através do coeficiente de correlação intraclasse (ICC, na sigla em inglês) demonstrou um valor de ICC = 0,998. Conclusão A versão da CHOP INTEND em português atende aos critérios de equivalência semântica e técnica em relação à versão original e apresenta validade de conteúdo e confiabilidade para seu uso na população de pacientes com AME tipo I.

El difícil camino al diagnóstico del paciente con atrofia muscular espinal / The difficult path to diagnosis of the patient with spinal muscular atrophy

Introducción. Con las nuevas terapias, el diagnóstico temprano de la atrofia muscular espinal (AME) es esencial. El objetivo de este estudio es analizar los distintos componentes que influyen en el retraso diagnóstico. Población y métodos. Se incluyeron pacientes con un diagnóstico molecular de AME tipo I, II y III. Se estudiaron varios parámetros, como la edad al momento de la aparición del primer signo, qué signo fue y el intervalo entre este y el diagnóstico confirmado. Neurólogos especialistas realizaron entrevistas que se complementaron con la revisión de historias clínicas cuando fue necesario. Resultados. Se entrevistaron 112 pacientes. AME I n = 40, AME II n = 48, AME III n = 24. La mediana de edad en meses al momento del reporte del primer signo fue AME I: 1,5 (R 0-7), AME II: 9 (R 2-20), AME III: 18 (R 8-180). Los primeros signos fueron reconocidos por los padres en el 75 % al 85 % de las veces en todos los subtipos. La mediana del tiempo transcurrido entre el primer signo y la primera consulta médica fue menor a un mes en los tres tipos. La mediana de tiempo transcurrido en meses entre el primer signo y el diagnóstico molecular confirmado fue en AME I: 2 (R 0-11), en AME II: 10 (3-46) y en AME III: 31,5 (R 4-288). Conclusiones. Existe un significativo retraso en el diagnóstico de la AME relacionado fundamentalmente a la falta de sospecha clínica. La demora es menor en AME I y mayor en AME III. Otros factores incluyen deficiencias en el sistema de salud.

Introduction. News treatments, make early diagnosis of spinal muscular atrophy (SMA) critical. The objective of this study is to analyze the different factors that influence delay in diagnosis. Population and methods. Patients with a molecular diagnosis of types I, II, and III SMA were included. Several parameters were studied, such as age at onset of first sign, what sign it was, and the time from recognition of first sign to confirmed diagnosis. Neurologists specialized in SMA conducted interviews, supported by the review of medical records when deemed necessary. Results. A total of 112 patients were interviewed. SMA I n = 40, SMA II n = 48, SMA III n = 24. The median age in months at the time of reporting the first sign was SMA I: 1.5 (R: 0­7), SMA II: 9 (R: 2­20), SMA III: 18 (R: 8­180). In all subtypes, first signs were identified by parents from 75% to 85% of the times. The median time from first sign to first medical consultation was less than a month in all 3 types. The median time in months, from first sign to confirmed molecular diagnosis in SMA I was: 2 (R: 0­11), in SMA II: 10 (R: 3­46), in SMA III: 31.5 (R: 4­288). Conclusions. There is a significant delay in SMA diagnosis mainly related to the absence of clinical suspicion. The delay is shorter in SMA I and longer in SMA III. Other factors include deficiencies in the health care system.

Evaluation of the comparative effects of infrared and red laser photobiomodulation therapy on skeletal muscle atrophy in an immobilization model in rats

Introduction: Skeletal muscle atrophy leads to a reduction in muscle strength, functionality, and the quality of life of individuals. Objective: To explore the effects of two different wavelengths (red and infrared) of laser PBMT on muscle atrophy and its active ingredients on skeletal muscle atrophy using an in vivo model of muscle atrophy. Methods: Thirty-two Wistar rats were randomly divided into four experimental groups: control (CG) animals were not immobilized and did not receive any type of treatment; immobilized animals with no treatment (ImC); immobilized animals submitted to red laser with wavelength of 660 nm (ImR) and near-infrared laser with wavelength of 808 nm (ImIR) treatments. The treatments were applied daily, at 2 points in the right gastrocnemius muscle (cranial and caudal), through the punctual contact technique, for 9 sessions, with the first application immediately after removing the cast. Results: The histological results demonstrated that in both treated groups (red and infrared wavelengths) a reduction of the inflammatory infiltrate and less connective tissue thickening when compared to the ImC. However, only infrared light was observed regenerating muscle fibers and an increase in the number of oxidative fibers (type I). Conclusion: These results suggest that red and infrared wavelength laser PBMT were able to promote changes in the morphology of the gastrocnemius muscle submitted to atrophy in an experimental immobilization model, reducing the inflammatory infiltrate and the formation of intramuscular connective tissue. However, infrared laser PBMT promoted more evident positive effects by increasing regenerating muscle fibers and the number of oxidative fibers.

Disease-modifying therapy for spinal muscular atrophy / 中华实用儿科临床杂志

Spinal muscular atrophy (SMA) was a severe inherited neuromuscular disease caused by the deficiency of the survival motor neuron (SMN) protein encoded by SMN1 gene with pathogenic variants.According to the age of onset and maximal achievement of motor function, SMA was classified into 4 subtypes.The most common and severe subtype was SMA type 1.During the natural course, most of patients with SMA type 1 die of respiratory failure within 2 years of age if not treated.Patients with other subtypes have progressive muscle weakness and atrophy at varying degrees.Before the emergence of disease-modifying therapy, a multidisciplinary management, including physical therapy, respiratory and nutritional support, has been the only approach to delay the disease progression and enhance the survival rate of SMA.However, motor milestone progress is unable to achieve by SMA patients, because the lack of SMN protein has not been solved.In the past 5 years, 3 drugs have been approved for the treatment of SMA.Clinical trials and a growing number of real-world study data have shown that medications of disease-modifying agents contribute to effectively improve motor function in SMA patients with different subtypes, and promote the motor milestone progress in some patients, which significantly reduce the mortality.However, treatment response of disease-modifying agents to SMA varies with the subtypes of SMA, individualized conditions and courses of disease.Therefore, it is particularly important to choose an optimal treatment to ensure the quality of life of patients.This review focuses on recent advances and emerging challenges in the treatment of SMA.

Progress in the application of assessment scales associated with activities of daily living in the disease-modifying treatments of spinal muscular atrophy / 国际儿科学杂志

Spinal muscular atrophy(SMA) is a serious neuromuscular degenerative disease that severely impairs the quality of life for patients and entire families.The emergence of disease-modifying treatments such as nusinersen and risdiplam has gradually changed the natural course of SMA patients.It is particularly important to include the activities of daily living(ADL) ability reported by patients or caregivers in the comprehensive assessment of SMA patients.There are many ADL-related assessment tools, and studies have found that disease-modifying treatments can somewhat improve the ADL ability of SMA children.This article reviews the progress on the effect of disease-modifying treatments on ADL in SMA patients, which can provide a reference for exploring more comprehensive and effective assessment tools and treatment decision-making in subsequent clinical practice.

Molecular pathological mechanism of liver metabolic disorder in mice with severe spinal muscular atrophy / 南方医科大学学报

OBJECTIVE@#To explore the molecular pathological mechanism of liver metabolic disorder in severe spinal muscular atrophy (SMA).@*METHODS@#The transgenic mice with type Ⅰ SMA (Smn-/- SMN20tg/2tg) and littermate control mice (Smn+/- SMN20tg/2tg) were observed for milk suckling behavior and body weight changes after birth. The mice with type Ⅰ SMA mice were given an intraperitoneal injection of 20% glucose solution or saline (15 μL/12 h), and their survival time was recorded. GO enrichment analysis was performed using the RNA-Seq data of the liver of type Ⅰ SMA and littermate control mice, and the results were verified using quantitative real-time PCR. Bisulfite sequencing was performed to examine CpG island methylation level in Fasn gene promoter region in the liver of the neonatal mice.@*RESULTS@#The neonatal mice with type Ⅰ SMA showed normal milk suckling behavior but had lower body weight than the littermate control mice on the second day after birth. Intraperitoneal injection of glucose solution every 12 h significantly improved the median survival time of type Ⅰ SMA mice from 9±1.3 to 11± 1.5 days (P < 0.05). Analysis of the RNA-Seq data of the liver showed that the expression of the target genes of PPARα related to lipid metabolism and mitochondrial β oxidation were down-regulated in the liver of type Ⅰ SMA mice. Type Ⅰ SMA mice had higher methylation level of the Fasn promoter region in the liver than the littermate control mice (76.44% vs 58.67%). In primary cultures of hepatocytes from type Ⅰ SMA mice, treatment with 5-AzaC significantly up-regulated the expressions of the genes related to lipid metabolism by over 1 fold (P < 0.01).@*CONCLUSION@#Type Ⅰ SMA mice have liver metabolic disorder, and the down-regulation of the target genes of PPARα related to lipid and glucose metabolism due to persistent DNA methylation contributes to the progression of SMA.

Improvement of Motor and Life Functions after Nusinersen Treatment in an Adult Patient with Spinal Muscular Atrophy Type II / The Japanese Journal of Rehabilitation Medicine

Spinal muscular atrophy is a neuromuscular disease characterized by muscle atrophy and progressive muscle weakness due to the degeneration of motor neurons in the anterior horn of the spinal cord. We report a case of an adult patient with spinal muscular atrophy type II and difficulty holding a sitting position. The patient was evaluated before and after Nusinersen treatment and thereafter periodically for up to 3 months for motor and daily living functions. At 3 months post-treatment, the Expanded version of the Hammersmith Functional Motor Scale and the Revised Upper Limb Module, which are motor function assessment tools for evaluating spinal muscular atrophy, showed an increase of 2 points. Evaluation of daily functioning using the Canadian occupational performance measure demonstrated improvements in eating and computer finger manipulation, and these improvements were considered important in daily lives by the patient. This report shows that the Nusinersen treatment improved motor and daily life functions in a patient with spinal muscular atrophy and low motor function. The report also concludes that rehabilitation evaluation for spinal muscular atrophy should include a disease-specific assessment of motor function, combined with an assessment focusing on physical symptoms and daily life functions to capture clinical changes that are responsive to individual patients with spinal muscular atrophy.

Reassessment of fatty infiltration by magnetic resonance ten years after rotator cuff injury repair / Reavaliação da infiltração gordurosa por ressonância magnética após dez anos de reparo de lesão do manguito rotador

ABSTRACT Quantitative assessments of rotator cuff muscle changes after successful tendon repair are scarce. On the other hand, semiquantitative and subjective assessments are more abundant, but their findings are controversial. One hypothesis about this divergence is that there is an immediate decrease in the proportion of fatty infiltration after surgical repair. Objective: Reassess fatty infiltration and muscle trophism of the rotator cuff after ten years of repair. Methods: Prospective comparison study. A total of 10 patients diagnosed with rotator cuff injury underwent repair of the lesion, and MRI of the affected shoulder was performed in the preoperative, immediate postoperative, and late postoperative periods (ten years). A comparative study was performed at every moment. Results: At 5% significance level, the mean of the immediate postoperative period was higher for the variable trophism and true muscle percentage. Fatty infiltration showed no difference in the three periods observed. Conclusion: Fatty infiltration does not change in the three periods evaluated and muscle trophism is greater in the immediate postoperative period. After ten years of rotator cuff repair, muscle trophism and fatty infiltration remain with statistically significantly equal results when compared to the preoperative period. Level of Evidence II, Prospective Comparison Study.

RESUMO Avaliações quantitativas das mudanças musculares do manguito rotador após reparos bem-sucedidos são escassas. Em contrapartida, avaliações semiquantitativas e subjetivas são mais abundantes, porém com achados controversos. Uma hipótese sobre essa discrepância é que a diminuição imediata na proporção de gordura que ocorre logo após o reparo. Objetivo: Reavaliar a infiltração gordurosa e o trofismo muscular do manguito rotador passados dez anos do reparo. Métodos: Estudo prospectivo comparativo realizado com dez pacientes diagnosticados com lesão do manguito rotador que foram submetidos a reparo da lesão e exames de ressonância magnética do ombro acometido no pré-operatório, no pós-operatório imediato e no pós-operatório tardio (dez anos), a fim de comparar as mudanças musculares em cada momento. Resultados: Ao nível de significância de 5%, a média do pós-operatório imediato foi superior para as variáveis trofismo e porcentagem muscular verdadeira. A infiltração gordurosa não apresentou diferença nos três períodos observados. Conclusão: A infiltração gordurosa não se altera nos três períodos avaliados, e o trofismo muscular é maior no pós-operatório imediato. Após dez anos do reparo do manguito rotador, o trofismo muscular e a infiltração gordurosa se mantêm com resultados estatísticos significativamente iguais quando comparados com o pré-operatório. Nível de Evidência II, Estudo Prospectivo Comparativo.

Nusinersen treatment in patients with spinal muscular atrophy: A safety analysis of laboratory parameters / 西安交通大学学报(医学版)

【Objective】 To explore the changes of laboratory parameters and safety of nusinersen in the treatment of spinal muscular atrophy (SMA). 【Methods】 Retrospective analysis was made on the six SMA patients treated with nusinersen in the Department of Neurology at The First Affiliated Hospital of Xi’an Jiaotong University from December 2021 to December 2022. We summarized the patients’ clinical data, including genetic diagnosis results, disease classification, and clinical manifestations. Intrathecal injection of 5 mL/12 mg of nusinersen administered on the 1st, 14th, 28th, and 63rd days, followed by maintenance treatment every 4 months. After each administration, we compared and evaluated the patients’ cerebrospinal fluid, blood routine, liver function, kidney function, and coagulation function with baseline values. We regularly followed up the patients and recorded adverse reactions after administration to evaluate medication safety. 【Results】 A total of six patients were diagnosed with SMA, including four cases of SMA3 type and two cases of SMA4 type. The deletion of exon 7 of the survival motor neuron gene 1 (SMN1) in patients led to changes in motor neuron, most of which were caused by limb weakness; in severe cases, the patients were unable to stand. The baseline abnormal test indicators of patients included the increase of cerebrospinal fluid lactate dehydrogenase (CSF-LDH), the increase of creatine kinase (CK), and the decrease of creatinine (Cr). After four times of treatment, the patients’ CSF-WBC, CSF-Glu, CSF-Pro, CSF-LDH, WBC, PLT, RBC, ALT, AST, GGT, BUN, uric acid (UA), INR, aPTT, and D-dimer had no significant difference from the baseline (P>0 05). The patients had no other significant adverse reactions except headaches, dizziness, and back pain after puncture. 【Conclusion】 Nusinersen has good safety on SMA patients.

Clinical Practice Guideline for Adolescent & Adult Patients with Spinal Muscular Atrophy / 罕见病研究

@#In recent years, spinal muscular atrophy (SMA) has made progress in multidisciplinary treatment and disease-modifying therapeutic drugs, so that the progress has significantly improved the survival and quality of life of the patients. However, no clinical practice guideline has developed for the management of SMA in adults and adolescents patients. Experts of multidisciplinary from a number of tertiary medical centers in China who specialize in the diagnosis and treatment of SMA have come to an agreement based on the evidence-based medicine. This guideline serves as instrumental reference for the standardized care of the Chinese SMA patients.

Clinical Practice Guideline for Adolescent & Adult Patients with Spinal Muscular Atrophy / 罕见病研究

@#In recent years, spinal muscular atrophy (SMA) has made progress in multidisciplinary treatment and disease-modifying therapeutic drugs, so that the progress has significantly improved the survival and quality of life of the patients. However, no clinical practice guideline has developed for the management of SMA in adults and adolescents patients. Experts of multidisciplinary from a number of tertiary medical centers in China who specialize in the diagnosis and treatment of SMA have come to an agreement based on evidence-based medicine. This guideline serves as instrumental reference for the standardized care of the Chinese SMA patients.

Clinical Practice Guideline for Adolescent & Adult Patients with Spinal Muscular Atrophy / 罕见病研究

In recent years, spinal muscular atrophy (SMA) has made progress in multidisciplinary treatment and disease-modifying therapeutic drugs, so that the progress has significantly improved the survival and quality of life of the patients. However, no clinical practice guideline has developed for the management of SMA in adults and adolescents patients. Experts of multidisciplinary from a number of tertiary medical centers in China who specialize in the diagnosis and treatment of SMA have come to an agreement based on the evidence-based medicine. This guideline serves as instrumental reference for the standardized care of the Chinese SMA patients.

Study on the value of pharmaceutical service related to risdiplam based on follow-up data of DTP pharmacy / 中国药房

OBJECTIVE To explore the value of providing pharmaceutical service related to risdiplam in direct-to-patient （DTP） pharmacies. METHODS The follow-up data of spinal muscular atrophy （SMA） patients who purchased and used risdiplam from Shangyao Yunjiankang Yiyao Pharmacy （Shanghai） Co.， Ltd. from May 2021 to January 2023 were collected. The medication information， therapeutic efficacy and the occurrence of adverse events were retrospectively analyzed. RESULTS A total of 42 prescriptions were checked by pharmacists in the DTP pharmacies， and 7 prescriptions were found to be unreasonable （16.7%， 7/42）， which were corrected after the timely intervention. During the follow-up management， pharmacists replied to 4 patients （9.5%， 4/42） regarding medication consultation about medication requirements and adverse events. Two patients with type Ⅰ SMA experienced adverse events： one of them presented with fever and the other presented with skin dryness with darkening. Both of them were grade Ⅰ toxic reactions and generally did not require clinical treatment. Considering that the patient sustained low-grade fever for a long time， the pharmacist suggested symptomatic treatment under the guidance of the doctor. CONCLUSIONS Pharmacists in DTP pharmacies conducting follow-up management of risdiplam use for rare disease SMA patients can help promote rational， standardized medication for patients.

Acompanhamento das funções respiratória e motora de crianças com atrofia muscular espinhal e distrofia muscular de Duchenne: um estudo longitudinal / Monitoring of respiratory and motor functions on children with spinal muscular atrophy and Duchenne muscular dystrophy: a longitudinal study

Objetivo: Realizar o acompanhamento de crianças e adolescentes com Atrofia Muscular Espinhal (AME) e Distrofia Muscular de Duchenne (DMD) em um centro de referência, por meio de avaliações de parâmetros respiratórios e motores. Métodos: Conduziu-se 3 avaliações em um período de 24 meses, em pacientes até 15 anos, com DMD e AME. Avaliações respiratórias incluíram: parâmetros cardiorrespiratórios, força muscular respiratória, pico de fluxo de tosse e espirometria. Analisou-se a função motora por meio de escalas especificas: 1) Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) para crianças até 2 anos; 2) Medida da Função Motora (MFM-32) acima de 6 anos; 3) versão reduzida (MFM-20) para 2 a 6 anos. A análise estatística incluiu o teste de Shapiro-Wilk e utilizou-se ANOVA com Post Hoc de Bonferroni ou Friedman, e aplicou-se os coeficientes de Spearman ou Pearson. Resultados: Participaram 16 pacientes com mediana de idade de 6,5 anos, 12 com AME e 4 DMD. Houve diferença entre dados antropométricos, a frequência de crianças que não realizava fisioterapia reduziu (12,5%X6,3%) e houve aumento na adesão para técnica de empilhamento de ar (37,5%X43,8%). Uso de ventilação não invasiva se manteve igual, assim como parâmetros respiratórios e escalas motoras. Verificou-se forte correlação entre valor predito da capacidade vital forçada e escores MFM-20 e MFM-32. Conclusão: O acompanhamento ambulatorial de crianças com AME e DMD evidenciou relativa manutenção em parâmetros respiratórios e de função motora, o que pode ser atribuído a melhora na adesão de rotinas terapêuticas e aos cuidados em um centro de referência.

Objective: The aim of this study was to monitor children and adolescents with Spinal Muscular Atrophy(SMA) and Duchenne Muscular Dystrophy (DMD) at a referral center, through assessments of respiratory and motor parameters. Methods: 3 evaluations were conducted over a period of 24 months, in patients up to 15 years old, with DMD and SMA. Respiratory assessments included: cardiorespiratory parameters, respiratory muscle strength, peak cough flow and spirometry. Motor function was analyzed using specific scales: 1) Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) for children up to 2 years old; 2) Measurement of Motor Function (MFM-32) over 6 years; 3) reduced version (MFM-20) for 2 to 6 years. The statistical analysis included the Shapiro-Wilk test and ANOVA with Bonferroni or Friedman's Post Hoc was used, and the Spearman or Pearson coefficients were applied. Results: 16 patients with a median age of 6.5 years, 12 with SMA and 4 DMD participated. There was a difference between anthropometric data, the frequency of children who did not undergo physical therapy decreased (12.5%X6.3%) and there was an increase in adherence to the air stacking technique (37.5%X43.8%). Use of non-invasive ventilation remained the same, as did respiratory parameters and motor scales. There was a strong correlation between the predicted value of forced vital capacity and scores MFM-20 and MFM-32. Conclusion: Outpatient follow-up of children with SMA and DMD showed a relative maintenance of respiratory and motor function parameters, which can be attributed to the improvement in adherence to therapeutic routines and care in a reference center.

Diagnóstico tardío de atrofia muscular espinal en paciente con síndrome de Down / Late diagnosis of spinal muscular atrophy in a patient with Down syndrome

El síndrome de Down (SD) es la anomalía cromosómica más frecuente entre los recién nacidos vivos. La atrofia muscular espinal (AME), por su parte, es una enfermedad neuromuscular caracterizada por la degeneración progresiva de las motoneuronas del asta anterior de la médula espinal que produce atrofia muscular, debilidad y parálisis. Presentamos el caso de una niña de 6 años con síndrome de Down derivada a nuestro centro para estudio por cuadro de debilidad muscular generalizada de evolución crónica con falta de adquisición de la marcha. Realizamos una revisión bibliográfica enfocándonos en el compromiso neurológico esperable en el síndrome de Down, la evolución de los hitos del desarrollo motor grueso estipulado para este grupo de pacientes y en los hallazgos que deben sugerir la presencia de una enfermedad neuromuscular.

A case of a 6-year-old girl with Down's syndrome is presented. She was referred to our center due to a history of generalized muscle weakness of chronic evolution, associated to her inability to walk. Her mother claimed that the girl's muscle weakness always called her attention as well as the difficulties to the development of motor skills shown by her daughter compared to other children, whether they were healthy or with Down's syndrome. There was information in her medical record and physical exam that strongly suggested the possibility of suffering a neuromuscular disorder. We asked for a molecular study that confirmed the spinal muscular atrophy diagnosis. We carried out a bibliographical revision focusing on the expected neurological impairment in Down's syndrome, the retardation of the gross motor skills development determined for this kind of patients and on the findings that must suggest a neuromuscular disorder.

Associação entre área de secção transversa do reto femoral e excursão diafragmática com o desmame de pacientes com traqueostomia na unidade de terapia intensiva / Association between rectus femoris cross-sectional area and diaphragmatic excursion with weaning of tracheostomized patients in the intensive care unit

RESUMO Objetivo: Verificar a relação entre área de secção transversa do reto femoral e excursão diafragmática com sucesso no desmame da ventilação mecânica em pacientes críticos crônicos com traqueostomia. Métodos: Este foi um estudo de coorte observacional prospectivo. Incluímos pacientes críticos crônicos (aqueles submetidos à colocação de traqueostomia após 10 dias de ventilação mecânica). A área de secção transversa do reto femoral e a excursão diafragmática foram obtidas por ultrassonografia realizada dentro das primeiras 48 horas após a traqueostomia. Medimos a área de secção transversa do reto femoral e a excursão diafragmática para avaliar sua associação com o desmame da ventilação mecânica, incluindo sua capacidade de prever o sucesso no desmame e a sobrevida durante toda a internação na unidade de terapia intensiva. Resultados: Foram incluídos 81 pacientes. Quarenta e cinco pacientes (55%) foram desmamados da ventilação mecânica. A mortalidade foi de 42% e 61,7% na unidade de terapia intensiva e hospitalar, respectivamente. O grupo que falhou em relação ao grupo que obteve sucesso no desmame apresentou menor área transversa do reto femoral (1,4 [0,8] versus 1,84 [0,76]cm2, p = 0,014) e menor excursão diafragmática (1,29 ± 0,62 versus 1,62 ± 0,51cm, p = 0,019). Quando a área de secção transversa do reto femoral ≥ 1,80cm2 e a excursão diafragmática ≥ 1,25cm era uma condição combinada, apresentava forte associação com sucesso no desmame (RC ajustada de 20,81; IC95% 2,38 - 182,28; p = 0,006), mas não com sobrevida na unidade de terapia intensiva (RC ajustada de 0,19; IC95% 0,03 - 1,08; p = 0,061). Conclusão: O sucesso no desmame da ventilação mecânica em pacientes críticos crônicos foi associado a medidas maiores de área de secção transversa do reto femoral e da excursão diafragmática.

ABSTRACT Objective: To verify the relationship between the rectus femoris cross-sectional area and diaphragmatic excursion with successful weaning from mechanical ventilation in chronic critically tracheostomized patients. Methods: This was a prospective observational cohort study. We included chronic critically ill patients (those who underwent tracheostomy placement after 10 days under mechanical ventilation). The rectus femoris cross-sectional area and diaphragmatic excursion were obtained by ultrasonography performed within the first 48 hours after tracheostomy. We measured rectus femoris cross-sectional area and diaphragmatic excursion to assess their association with weaning from mechanical ventilation, including their potential to predict successful weaning and survival throughout the intensive care unit stay. Results: Eighty-one patients were included. Forty-five patients (55%) were weaned from mechanical ventilation. The mortality rates were 42% and 61.7% in the intensive care unit and hospital, respectively. The fail group in relation to the success group at weaning presented a lower rectus femoris cross-sectional area (1.4 [0.8] versus 1.84 [0.76]cm2, p = 0.014) and lower diaphragmatic excursion (1.29 ± 0.62 versus 1.62 ± 0.51cm, p = 0.019). When rectus femoris cross-sectional area ≥ 1.80cm2 and diaphragmatic excursion ≥ 1.25cm was a combined condition, it had a strong association with successful weaning (adjusted OR = 20.81, 95%CI 2.38 - 182.28; p = 0.006) but not with intensive care unit survival (adjusted OR = 0.19, 95%CI 0.03 - 1.08; p = 0.061). Conclusion: Successful weaning from mechanical ventilation in chronic critically ill patients was associated with higher measurements of rectus femoris cross-sectional area and diaphragmatic excursion.

Hirayama Disease: Case Report / Doença de Hirayama: Relato de caso

Abstract A 26-year-old previously healthy patient who, at the age of 18 years, began progressive loss of distal strength, rest tremor, and muscle atrophy in the left upper limb. Upon examination, the patient presented moderate distal atrophy, degree 4 in muscular strength, and minipolymioclonus. Electromyoneurography revealed (EMNG) chronic preganglionic bilateral involvement of bilateral C7/C8/T1, worse on the left, with signs of active C8/T1 denervation. A cervical spine magnetic resonance imaging (MRI) scan showed spondylodiscal degenerative changes with central protrusions in C4-C5, C6-C7, and right central in C5-C6, which touched the dural sac. The anteroposterior diameter of the medulla in neutral position, in the C5-C6 plane, was of 5.1 mm. There was a reduction of the spinal cord caliber to 4.0 mm after the dynamic maneuver of forced flexion of the spine, as well as signal increase in the anterior horns. The clinical findings and those of the complementary tests were compatible with Hirayama disease (HD), a rare benign motor neuron disease that affects cervical spinal segments and is most prevalent in men, with onset in the early 20s. Unilateral and slowly progressive weakness is typical, but self-limited. Sensory disturbances, and autonomic and upper motor neuron signals are rare. Management is usually conservative, with the use of a soft cervical collar. Although rare, HD should be considered in young patients with focal asymmetric atrophy in the upper limbs. The early diagnosis of HD depends on the degree of suspicion, as well as on the cooperation and communication among the various specialties involved in the investigation.

Resumo Paciente de 26 anos, previamente hígido, que, aos 18 anos, iniciou perda progressiva de força distal, tremor de repouso, e atrofia muscular no membro superior esquerdo. Ao exame, apresentou atrofia moderada, distal, força muscular de grau 4, e minipolimioclonus. A eletroneuromiografia (ENMG) revelou comprometimento pré-ganglionar crônico de C7/C8/T1 bilateral pior à esquerda, com sinais de desnervação ativa em C8/T1. A ressonância magnética (RM) de coluna cervical mostrou alterações degenerativas espondilodiscais com protrusões centrais em C4-C5, C6-C7, e central direita em C5-C6, que tocavam o saco dural. O diâmetro anteroposterior da medula na posição neutra, no plano de C5-C6, era de 5,1 mm. Houve redução do calibre da medula para 4,0 mm após a manobra dinâmica de flexão forçada da coluna, e aumento de sinal nos cornos anteriores. Os achados clínicos e os dos exames complementares eram compatíveis com doença de Hirayama (DH), uma doença benigna rara dos neurônios motores, que afeta os segmentos espinhais cervicais e é mais prevalente em homens e de início próximo aos 20 anos. É típica a fraqueza unilateral e lentamente progressiva, porém autolimitada. Perturbações sensoriais, sinais autonômicos e do neurônio motor superior são raras. O manejo geralmente é conservador, com uso de colar cervical macio. Apesar de rara, a DH deve ser considerada em pacientes jovens que apresentam atrofias assimétricas focais de membros superiores. O diagnóstico precoce de DH depende do grau de suspeição, e da cooperação e comunicação entre as diversas especialidades envolvidas na investigação.

Physical therapy protocols to attenuate skeletal muscle atrophy in critically ill patients: narrative review / Protocolos de terapia física para atenuar la atrofia del músculo esquelético en pacientes críticos: revisión narrativa

SUMMARY: To describe the physical therapy protocols used in critically ill patients to attenuate skeletal muscle atrophy. We conducted a search in PubMed and Embase from inception to November 2020. Observational or experimental studies published in English or Spanish that evaluated the effect of physical therapy protocols on the attenuation of skeletal muscle atrophy in critically ill patients through muscle strength or mass measurement were considered eligible. Studies were only included if they reported a detailed description of the dosing of the interventions. Seventeen studies met the eligibility criteria. We included randomised clinical trials (n = 16) and observational studies (n = 1). The total population of the included studies was 872 critically ill patients. The studies aimed to evaluate the reliability, safety or effectiveness of neuromuscular electrical stimulation (n = 10) protocols, early mobilisation (n = 3), ergometer training (n = 2), transfers in tilt table (n = 1), and blood flow restriction (n = 1). Physical therapy protocols are part of the critically ill patient's integral management. Strategies such as passive mobilisation, in-bed and out-of-bed transfers, gait training, ergometer training, and neuromuscular electrical stimulation substantially impact critically ill patients' prognoses and quality of life after hospital discharge.

RESUMEN: Describir los protocolos de terapia física usados en pacientes críticos para atenuar la atrofia muscular esquelética. Realizamos una búsqueda en PubMed y Embase desde el inicio hasta noviembre de 2020. Se consideraron los estudios observacionales o experimentales publicados en inglés o español que evaluaron el efecto de los protocolos de terapia física en la atenuación de la atrofia del músculo esquelético en pacientes críticos a través de la medición de la fuerza o la masa muscular. Los estudios solo se incluyeron si informaron una descripción detallada de la dosificación de las intervenciones. Diecisiete estudios cumplieron los criterios de elegibilidad. Se incluyeron ensayos clínicos aleatorizados (n = 16) y estudios observacionales (n = 1). La población total de los estudios incluidos fue de 872 pacientes en estado crítico. Los estudios tuvieron como objetivo evaluar la confiabilidad, seguridad o efectividad de los protocolos de estimulación eléctrica neuromuscular (n = 10), movilización temprana (n = 3), entrenamiento con ergómetro (n = 2), transferencias en mesa basculante (n = 1) y restricción del flujo sanguíneo (n = 1). Los protocolos de terapia física forman parte del manejo integral del paciente crítico. Es- trategias como la movilización pasiva, los traslados dentro y fuera de la cama, el entrenamiento de la marcha, el entrenamiento con ergómetro y la estimulación eléctrica neuromuscular tienen un impacto sustancial en el pronóstico y la calidad de vida de los pacientes críticos después del alta hospitalaria.

Gene therapy in neuromuscular disorders / Terapia gênica nas doenças neuromusculares

Abstract Monogenic neuromuscular disorders are potentially treatable through gene therapy. Using viral vectors, a therapeutic transgene aims to restore normal levels of a protein not produced by the defective gene, or to silence a gene whose expression leads to toxic effects. Spinal Muscular Atrophy (SMA) is a good example of a monogenic disease that currently has an AAV9-based vector gene therapy as a therapeutic option. In this review, we intend to discuss the viral vectors and their mechanisms of action, in addition to reviewing the clinical trials that supported the approval of gene therapy (AVXS-101) for SMA as well as neuromuscular diseases that are potentially treatable with gene replacement therapy.

Resumo Doenças neuromusculares monogênicas são potencialmente tratáveis através de terapia gênica. Utilizando-se de vetores virais, um transgene terapêutico objetiva repor os níveis normais de uma proteina não produzida pelo gene defeituoso ou silenciar um gene cuja expressão leva a efeitos tóxicos. A Atrofia Muscular Espinhal (AME) é um bom exemplo de doença monogenica que atualmente tem uma terapia gênica com vetor viral AAV9 como opção terapêutica. Nesta revisão, pretendemos discutir os vetores virais e macanismos de ação utilizados, além de revisar os ensaios clínicos que embasaram a aprovação da terapia gênica (AVXS-101) para AME, assim como doenças neuromusculares potencialmente tratáveis com terapia de reposição gênica.