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.

Gene-based therapies for neuromuscular disorders.

Neuromuscular diseases (NMD) include a broad group of medical conditions with both acquired and genetic causes. In recent years, important advances have been made in the treatment of genetically caused NMD, and most of these advances are due to the implementation of therapies aimed at gene regulation. Among these therapies, gene replacement, small interfering RNA (siRNA), and antisense antinucleotides are the most promising approaches. More importantly, some of these therapies have already gained regulatory approval or are in the final stages of approval. The review focuses on motor neuron diseases, neuropathies, and Duchenne muscular dystrophy, summarizing the most recent developments in gene-based therapies for these conditions.

Doenças neuromusculares (DNM) compõem um grupo amplo de doenças de causa tanto adquiridas quanto genéticas. Nos últimos anos, importantes avanços ocorreram quanto ao tratamento das DNM de causa genética e grande parte desses avanços se deve à implementação de terapias voltadas para a modificação gênica. Dentre essas terapias, destacam-se as terapias de reposição gênica, uso de RNA de interferência, uso de antinucleotídeos antisense, entre outras. E, mais importante, algumas dessas terapias já se tornaram realidade na prática médica e já foram aprovadas, ou estão a poucos passos da aprovação, por órgãos governamentais regulatórios. Esta revisão aborda aspectos mais recentes quanto ao uso das terapias genéticas avançadas para algumas das formas mais comuns de DNM, em especial para doenças do neurônio motor (esclerose lateral amiotrófica e atrofia muscular espinhal), neuropatias e distrofia muscular de Duchenne.

Unraveling the Genetic Tapestry of a Village Legend.

In the heart of the emerald expanse of rural Brazil, where I spent my childhood in a humble village, a chilling legend clung to the corners of every home, whispering of a blighted lineage. This unfortunate family bore a strange malady-a gradual forfeiture of their ability to walk-a lamentable curse that extended its icy fingers through 5 harrowed generations.

Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series.

The RASopathies are a group of genetic rare diseases caused by mutations affecting genes involved in the RAS/MAPK (RAS-mitogen activated protein kinase) pathway. Among them, PTPN11 pathogenic variants are responsible for approximately 50% of Noonan syndrome (NS) cases and, albeit to a lesser extent, of Leopard syndrome (LPRD1), which present a few overlapping clinical features, such as facial dysmorphism, developmental delay, cardiac defects, and skeletal deformities. Motor impairment and decreased muscle strength have been recently reported. The etiology of the muscle involvement in these disorders is still not clear but probably multifactorial, considering the role of the RAS/MAPK pathway in skeletal muscle development and Acetylcholine Receptors (AChR) clustering at the neuromuscular junction (NMJ). We report, herein, four unrelated children carrying three different heterozygous mutations in the PTPN11 gene. Intriguingly, their phenotypic features first led to a clinical suspicion of congenital myasthenic syndrome (CMS), due to exercise-induced fatigability with a variable degree of muscle weakness, and serum proteomic profiling compatible with a NMJ defect. Moreover, muscle fatigue improved after treatment with CMS-specific medication. Although the link between PTPN11 gene and neuromuscular transmission is unconfirmed, an increasing number of patients with RASopathies are affected by muscle weakness and fatigability. Hence, NS or LPDR1 should be considered in children with suspected CMS but negative genetic workup for known CMS genes or additional symptoms indicative of NS, such as facial dysmorphism or intellectual disability.

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.

Human skeletal myopathy myosin mutations disrupt myosin head sequestration.

Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. However, it is unclear how mutations in these genes disrupt myosin structure and function leading to skeletal muscle myopathies termed myosinopathies. Here, we used multiple approaches to analyze the effects of common MYH7 and MYH2 mutations in the light meromyosin (LMM) region of myosin. Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients and fluorescent ATP analog chase protocols to estimate the proportion of myosin heads that were super-relaxed, together with x-ray diffraction measurements to estimate myosin head order, we found that basal myosin ATP consumption was increased and the myosin super-relaxed state was decreased in vivo. In addition, myofiber mechanics experiments to investigate contractile function showed that myofiber contractility was not affected. These findings indicate that the structural remodeling associated with LMM mutations induces a pathogenic state in which formation of shutdown heads is impaired, thus increasing myosin head ATP demand in the filaments, rather than affecting contractility. These key findings will help design future therapies for myosinopathies.

Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.

Background and Objectives: Pathogenic variants in the valosin-containing protein (VCP) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel VCP variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized VCP variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study. Methods: A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0.5 to 5.5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis. Results: All variants were missense, except for one small deletion-insertion, 18 led to amino acid changes within the N and D1 domains, and 13 increased the enzymatic activity. The clinical score coincided with the functional studies in 17 of 19 variants and with the in silico analysis in 12 of 19. For 12 variants, the 3 predictive tools agreed, and for 7 variants, the predictive tools disagreed. The pooled data supported the pathogenicity of 13 of 19 novel VCP variants identified in the study. Discussion: This study provides data to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.

Abnormal myosin post-translational modifications and ATP turnover time associated with human congenital myopathy-related RYR1 mutations.

AIM: Conditions related to mutations in the gene encoding the skeletal muscle ryanodine receptor 1 (RYR1) are genetic muscle disorders and include congenital myopathies with permanent weakness, as well as episodic phenotypes such as rhabdomyolysis/myalgia. Although RYR1 dysfunction is the primary mechanism in RYR1-related disorders, other downstream pathogenic events are less well understood and may include a secondary remodeling of major contractile proteins. Hence, in the present study, we aimed to investigate whether congenital myopathy-related RYR1 mutations alter the regulation of the most abundant contractile protein, myosin. METHODS: We used skeletal muscle tissues from five patients with RYR1-related congenital myopathy and compared those with five controls and five patients with RYR1-related rhabdomyolysis/myalgia. We then defined post-translational modifications on myosin heavy chains (MyHCs) using LC/MS. In parallel, we determined myosin relaxed states using Mant-ATP chase experiments and performed molecular dynamics (MD) simulations. RESULTS: LC/MS revealed two additional phosphorylations (Thr1309-P and Ser1362-P) and one acetylation (Lys1410-Ac) on the ß/slow MyHC of patients with congenital myopathy. This method also identified six acetylations that were lacking on MyHC type IIa of these patients (Lys35-Ac, Lys663-Ac, Lys763-Ac, Lys1171-Ac, Lys1360-Ac, and Lys1733-Ac). MD simulations suggest that modifying myosin Ser1362 impacts the protein structure and dynamics. Finally, Mant-ATP chase experiments showed a faster ATP turnover time of myosin heads in the disordered-relaxed conformation. CONCLUSIONS: Altogether, our results suggest that RYR1 mutations have secondary negative consequences on myosin structure and function, likely contributing to the congenital myopathic phenotype.

Brain MRI Abnormalities, Epilepsy and Intellectual Disability in LAMA2 Related Dystrophy - a Genotype/Phenotype Correlation.

BACKGROUND: LAMA2-related muscular dystrophy is a disorder that causes muscle weakness and varies in severity, from a severe, congenital type to a milder, late-onset form. However, the disease does not only affect the muscles, but has systemic involvement and can lead to alterations such as brain malformation, epilepsy and intellectual disability. OBJECTIVE: Describe the frequency of cortical malformations, epilepsy and intellectual disability in LAMA2-RD in a Brazilian cohort and correlate the neurological findings to genetic and motor function. METHODS: This is an observational study of 52 LAMA2-RD patients, who were divided into motor function subgroups and compared based on brain MRI findings, epilepsy, intellectual disability, and type of variants and variant domains. RESULTS: 44 patients (84.6%) were only able to sit, and 8 patients (15.4%) were able to walk. 10 patients (19.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),10 patients (19.2%) presented with epilepsy, and 8 (15.4%) had intellectual disability. CNS manifestations correlated with a more severe motor phenotype and none of the patients able to walk presented with cortical malformation or epilepsy. There was a relation between gene variants affecting the laminin-α2 LG-domain and the presence of brain malformation (P = 0.016). There was also a relation between the presence of null variants and central nervous system involvement. A new brazilian possible founder variant was found in 11 patients (21,15%) (c.1255del; p. Ile419Leufs*4). CONCLUSION: Cortical malformations, epilepsy and intellectual disability are more frequent among LAMA2-RD patients than previously reported and correlate with motor function severity and the presence of variants affecting the laminin-α2 LG domain. This brings more insight fore phenotype-genotype correlations, shows the importance of reviewing the brain MRI of patients with LAMA2-RD and allows greater attention to the risk of brain malformation, epilepsy, and intellectual disability in those patients with variants that affect the LG domain.

Muscle Ultrasound Changes Correlate With Functional Impairment in Spinal Muscular Atrophy.

OBJECTIVE: We investigated ultrasound patterns of muscle involvement in different types of spinal muscular atrophy (SMA) and their correlation with functional status to determine the pattern of muscle compromise in patients with SMA and the potential role of ultrasound to evaluate disease progression. METHODS: We examined muscles (biceps brachii, rectus femoris, diaphragm, intercostals and thoracic multifidus) of 41 patients with SMA (types 1 to 4) and 46 healthy age- and sex-matched control individuals using B-mode ultrasound for gray-scale analysis (GSA), area (biceps brachii and rectus femoris) and diaphragm thickening ratio. Functional scales were applied to patients only. We analyzed ultrasound abnormalities in specific clinical subtypes and correlated findings with functional status. RESULTS: Compared with controls, patients had reduced muscle area and increased mean GSA for all muscles (p < 0.001), with an established correlation between the increase in GSA and the severity of SMA for biceps brachii, rectus femoris and intercostals (p = 0.03, 0.01 and 0.004 respectively) when using the Hammersmith Functional Motor Scale Expanded. Diaphragm thickening ratio was normal in the majority of patients, and intercostal muscles had higher GSA than diaphragm in relation to the controls. CONCLUSION: Ultrasound is useful for quantifying muscular changes in SMA and correlates with functional status. Diaphragm thickening ratio can be normal even with severe compromise of respiratory muscles in quantitative analysis, and intercostal muscles were more affected than diaphragm.

Hypoglycemia in Patients With LAMA2-CMD.

BACKGROUND: Hypoglycemia has been reported in patients with LAMA2-CMD, but the frequency, risk factors, and correlation to genotype/phenotype have not been systematically assessed to date. METHODS: A retrospective cohort study was performed on 48 patients with LAMA2-CMD. Patients were divided into two groups: a hypoglycemic group, with at least one episode of hypoglycemia, and a nonhypoglycemic group. The groups were compared according to gait function, epilepsy, intellectual disability, constipation, gastroesophageal reflux, gastrostomy, weight percentile, scoliosis, the use of a ventilator device, the use of a feeding device, neuromuscular disease swallowing status scale, and type of mutation. RESULTS: Fifteen patients (31.2%) presented with at least one episode of symptomatic hypoglycemia and eight (16.6% of the cohort) had two or more episodes. All patients who had hypoglycemia were in the nonambulant group. We observed a correlation between gait, the use of ventilator and feeding devices, and swallow function with hypoglycemia. Patients with extremely low weight were five times more likely to have recurrent episodes of hypoglycemia. The presence of at least one missense variant appears to be associated with a lower risk of hypoglycemia. CONCLUSION: Patients with LAMA2-CMD are at risk of hypoglycemia. The risk is more relevant in patients with severe phenotype and patients with loss-of-function variants. For patients with extremely low weight, the risk is higher. Blood glucose should be actively measured in patients who are fasting or have infections, and health care providers should be prepared to identify and treat these patients.

Challenges and recommendations to increasing the use of exome sequencing and whole genome sequencing for diagnosing rare diseases in Brazil: an expert perspective.

Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10-13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing.

Clinical Manifestation of Nebulin-Associated Nemaline Myopathy.

Background and Objectives: Nemaline myopathy (NM) is a genetically heterogeneous inherited myopathy related with at least 12 genes, whereas pathogenic variants in NEB gene are the most common genetic cause. The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement. There is currently not enough data regarding the progression of the disease. In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-NEB) classified according to age groups and the use of ventilatory support. We focused on interventional support, genotype-phenotype correlation, and association between respiratory, bulbar, and motor systems in groups of patients stratified by age and by the use of ventilatory support (VS). Methods: Clinical and genetic data from patients with NM-NEB followed up in one specialized center were collected through regular consultations. Patients were evaluated regarding motor, bulbar, and respiratory functions. Results: Thirty-three patients with NM-NEB were evaluated consisting of 15 females and 18 males with an average age of 18 (±12) years and a median of 17 (±11) years. 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. Scoliosis and dysphagia were more common among patients who used VS. Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia. Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. In addition to that, we showed that VS use was associated with scoliosis and dysphagia. Discussion: NM-NEB is a very debilitating disease. There is an association between scoliosis and respiratory dysfunction while patients using VS have more often scoliosis than the no-VS group. Triple furrow tongue atrophy is a novel and frequent finding, which is directly associated with dysphagia. Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. All observations are relevant in the management care of patients with NM.

NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy.

Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients' muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin-deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin-deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.

Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization.

Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in ACTA1, two (8%) in KLHL40, and one in TPM2 (4%) and TPM3 (4%). In the NEB-related families, 25 different variants, 11 of them novel, were identified; splice site (10/25) and frame shift (9/25) mutations were the most common. Mutation c.24579 G>C was recurrent in three unrelated patients from the same region, suggesting a common ancestor. Clinically, the "typical" form was the more frequent and caused by mutations in the different NM genes. Phenotypic heterogeneity was observed among patients with mutations in the same gene. Respiratory involvement was very common and often out of proportion with limb weakness. Muscle MRI patterns showed variability within the forms and genes, which was related to the severity of the weakness. Considering the high frequency of NEB mutations and the complexity of this gene, NGS tools should be combined with CNV identification, especially in patients with a likely non-identified second mutation.

Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial.

BACKGROUND: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. METHODS: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. FINDINGS: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%). INTERPRETATION: Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam. FUNDING: F Hoffmann-La Roche.

Inflammatory myopathies: an update for neurologists.

Idiopathic inflammatory myopathies (IIM) are a heterogenous group of treatable myopathies. Patients present mainly to the rheumatologist and neurologists, complaining of acute or subacute onset of proximal weakness. Extramuscular manifestations may occur, including involvement of the lungs, skin, and joints. Classically, the diagnosis used to be made based on the creatine kinase level increase, abnormalities in electroneuromyography and presence of inflammatory infiltrates in the muscle biopsy. Recently, the importance of autoantibodies has increased, and now they may be identified in more than half of IIM patients. The continuous clinicoseropathological improvement in IIM knowledge has changed the way we see these patients and how we classify them. In the past, only polymyositis, dermatomyositis and inclusion body myopathy were described. Currently, immune-mediated necrotizing myopathy, overlap myositis and antisynthetase syndrome have been considered the most common forms of IIM in clinical practice, increasing the spectrum of classification. Patients previously considered to have polymyositis, in fact have these other forms of seropositive IIM. In this article, we reviewed the new concepts of classification, a practical way to make the diagnosis and how to plan the treatment of patients suffering from IIM.

Gene therapy in neuromuscular disorders.

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.

Effect of the COVID-19 pandemic on patients with inherited neuromuscular disorders.

BACKGROUND: The COVID-19 pandemic has brought substantial challenges for current practices in treating hereditary neuromuscular disorders (hNMDs). However, this infection has not been the only concern for these patients. Social distancing has compromised multidisciplinary assistance and physical activity, and has brought about several mental health issues. We presented a follow-up on 363 patients with hNMDs at a Brazilian tertiary center during the peak of the COVID-19 pandemic. OBJECTIVE: We aimed to show the frequency and severity of SARS-CoV-2 infection among hNMD patients and to demonstrate the effects of the pandemic on life habits, disease progression and multidisciplinary supportive care status. METHODS: Three hundred and sixty-three patients (58% male and 42% female) were followed for three months through three teleconsultations during the peak of the COVID-19 pandemic in Brazil. RESULTS: There were decreases in the numbers of patients who underwent physical, respiratory and speech therapies. For several patients, their appetite (33%) and sleep habits (25%) changed. Physical exercises and therapies were interrupted for most of the patients. They reported new onset/worsening of fatigue (17%), pain (17%), contractions (14%) and scoliosis (7%). Irritability and sleep, weight and appetite changes, and especially diminished appetite and weight loss, were more frequent in the group that reported disease worsening. There was a low COVID-19 contamination rate (0.8%), and all infected patients had a mild presentation. CONCLUSION: The isolation by itself was protective from a COVID-19 infection perspective. However, this isolation might also trigger a complex scenario with life habit changes that are associated with an unfavorable course for the NMD.