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

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.

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.

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.

Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy.

OBJECTIVE: The aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number. METHODS: Four hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing. RESULTS: Four hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies. CONCLUSIONS: Patients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

Desempenho cognitivo através do mini-exame do estado mental na distrofia muscular de Duchenne / Cognitive performance by mini mental state examination in Duchenne muscular dystrophy

OBJETIVO: A distrofia muscular de Duchenne (DMD) é frequentemente associada à deficiência intelectual (DI) e ao prejuízo de funções superiores como leitura, raciocínio, lógica, e memória. O objetivo do estudo foi avaliar o desempenho cognitivo de pacientes com DMD através do Mini-Exame do Estado Mental (MEEM), um teste simples e rápido, usado como primeiro rastreio intelectual, principalmente quando baterias psicométricas complexas, dependentes de psicólogos especializados, não estão disponíveis. MÉTODO: Foi realizado um estudo observacional de trinta e quatro meninos com DMD, com idades entre 8 e 22 anos, separados em dois grupos de acordo com a presença de DI moderada-grave, conforme a definição clínica do funcionamento adaptativo do Manual Estatístico e Diagnóstico de Desordens Mentais 5º edição (DSM-5). Foram avaliados a pontuação no MEEM, marcos do desenvolvimento, independência nas atividades de vida cotidiana e capacidade de alfabetização. RESULTADOS: Os marcos motores e de linguagem estavam atrasados (16 meses), e a média no MEEM foi 21, ponto de corte mais baixo do que verificado em pares da mesma idade. O grupo com DI moderada-grave apresentou uma média de 12 no MEEM, e os subtestes de orientação, atenção e cálculo e linguagem foram os que demonstraram piores desempenhos. O ponto de corte de maior acurácia para distinguir DI moderada-grave nos pacientes com DMD foi 21. CONCLUSÃO: O MEEM apresentou adequada sensibilidade (100%) e especificidade (90%) para o ponto de corte de 21, revelando-se um bom método de triagem cognitiva para DI moderada-grave na DMD.

BACKGROUND: Duchenne muscular dystrophy (DMD) is often associated with intellectual disability (ID) and with impairment of higher mental functions as reading, learning, logical thinking and memory. The goal of this study was evaluate the cognitive performance of DMD patients by Mini-Mental State Examination (MMSE), first bedside screening test, widely used in pediatrics, when neuropsychologic batteries, dependent on specialized psychologists, are not easily available in public health system. METHODS: An observational study of thirty-four boys with DMD, aged 8-22 years, was performed, spliting this group into two sub-groups, according to the presence of moderate-severe, defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-5) adaptative functioning clinical criteria. The MMSE scores, developmental milestones, independence in daily life activities and literacy skills were evaluated. RESULTS: Motor and language milestones were reached with 16 months, later than usual and mean on MMSE was 21, lower than in healthy pairs. In assessment by groups, patients with moderate-severe intellectual disability presented a performance in total MMSE (12) and orientation, attention/calculation and language MMSE subtests lower than patients without ID. The most accurate cutoff value on MMSE to distinguish moderate-severe intellectual disability in DMD patients was 21. CONCLUSION: This study has shown adequate sensitivity and specificity of the MMSE for detection of moderate-severe intellectual disability, with almost 100% sensitivity and 90% specificity for cutoff values of 21 points in DMD.

Brazilian consensus on Duchenne muscular dystrophy. Part 2: rehabilitation and systemic care.

Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) have occurred since the publication of international guidelines for DMD care in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations for the guideline. Our recommendations were divided in two parts. Guideline methodology and overall disease concept descriptions are found in Part 1. Here we present Part 2, where we provide the results and recommendations on rehabilitation and systemic care for DMD.

Brazilian consensus on Duchenne muscular dystrophy. Part 2: rehabilitation and systemic care / Consenso brasileiro para distrofia muscular de Duchenne. Parte 2: reabilitação e cuidados sistêmicos

ABSTRACT Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) have occurred since the publication of international guidelines for DMD care in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations for the guideline. Our recommendations were divided in two parts. Guideline methodology and overall disease concept descriptions are found in Part 1. Here we present Part 2, where we provide the results and recommendations on rehabilitation and systemic care for DMD.

RESUMO Avanços significativos na compreensão e no manejo da Distrofia Muscular de Duchenne (DMD) ocorreram desde a publicação de diretrizes internacionais para o cuidado destes pacientes em 2010. Nosso objetivo foi elaborar um consenso nacional baseado em evidências para o cuidado multidisciplinar dos pacientes com DMD no Brasil. Utilizamos uma combinação da técnica de Delphi com uma revisão sistemática da literatura de 2010 a 2016 para classificarmos os níveis de evidência e graus de recomendação para o consenso. Nossas recomendações foram divididas em duas partes. A metodologia utilizada na elaboração do consenso e conceitos gerais da doença encontram-se na parte 1. Neste artigo fornecemos os resultados e recomendações sobre reabilitação e cuidados sistêmicos para DMD.

Mental retardation in Duchenne muscular dystrophy.

OBJECTIVE: To survey the medical literature directed to the study of cognitive dysfunction in patients with Duchenne muscular dystrophy through description of the milestones of neurological development and psychometric tests for quantifying intelligence. SOURCES: Non-systematic review of aspects of cognition in Duchenne muscular dystrophy in the major medical scientific bases: MEDLINE, LILACS, SciELO and Cochrane Library. SUMMARY OF THE FINDINGS: Patients with Duchenne muscular dystrophy exhibited delay in walking and language development, which correlated with lower scores on future intelligence tests. There is marked impairment in the verbal subtests. CONCLUSIONS: Average IQ has standard deviation below the average of the population. The greater the cognitive impairment, the worse aspects related to morbidity and mortality in the disease will be.