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OFELIA (NCT05073133), a phase 4, open-label, multicenter study conducted in Latin America, assessed safety and efficacy of single-dose intravenous onasemnogene abeparvovec (OA) for patients with spinal muscular atrophy (SMA) weighing ≤17 kg and ≤24 months old over 18 months post-infusion. Primary endpoint was safety, measured by treatment-emergent adverse events (TEAEs), serious TEAEs, adverse events of special interest (AESI), and hematology/laboratory changes. Secondary endpoint was efficacy, measured by WHO MGRS motor milestone achievement. Data were summarized descriptively. Sixteen patients were enrolled; three (19%) were previously treated with nusinersen. At dosing, median (range) age was 17.88 (3.95–23.75) months and weight was 8.35 (6.10–12.10) kg. Most patients had SMA type 1 (n=10; 62.5%) and two (n=8; 50.0%) or three (n=8; 50.0%) SMN2 copies. Safety was consistent with previous studies with OA. Eleven patients (68.8%) experienced serious TEAEs. Twelve patients (75.0%) experienced AESI: 11 (91.7%) hepatotoxicity, 5 (41.7%) thrombocytopenia, and 2 (16.7%) thrombotic microangiopathy (TMA). Transaminase elevations (n=2/16; 12.5%) were asymptomatic; troponin elevations (n=6/8; 75.0%) were isolated and without clinical relevance. Two (12.5%) deaths occurred: one due to AESI of TMA (related to treatment per investigator); the second death was not related to treatment. Most patients achieved WHO MGRS motor milestones by 18 months of follow-up (up to 3 years old for most patients): sitting without support (n=10/12; 83.3%), crawling (n=3/12; 25.0%), standing with assistance (n=7/12; 58.3%), walking with assistance (n=2/12; 16.7%), standing alone (n=3/12; 25.0%), and walking alone (n=1/12; 8.3%). OFELIA confirms that OA is safe and efficacious for older, heavier patients with SMA and for patients from different geographic locations than previously studied. Most patients demonstrated maintenance or improvement of motor milestones up to 18 months post-treatment. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare disease characterized by progressive loss of motor neurons. The most common form of SMA (5q-SMA), classified into subtypes, according to the age of onset and the maximum motor function achieved. Nusinersen is a disease modifying treatment (DMT), incorporated free of charge into the Brazilian Unified National Health System (SUS) for the treatment of subtype 1 of the disease, in 2019. In 2021, the treatment was expanded to 5q-SMA subtype 2. This is a cross-sectional observational study aimed to characterize the clinical characteristics and access to DMT from patients with 5q-SMA types 2 and 3 in references centers from the SUS. Patients with 5q-SMA types 2 and 3, both sexes from 9 national reference centers were included between 2020 to 2021, independent of DMT treatment. A total of 155 patients were included, 76 of subtype 2 and 79 of subtype 3. For subtype 2, 45% sit stable, 11% stand with support, 78% have scoliosis and 39 have access to Nusinersen and 37 without access the DMT. As for subtype 3, 43% sit stably, 13% stand with support, 34% walk independently, 66% have scoliosis and 21 have access to Nusinersen and 58 without access to DMT. In the Brazilian Public Health System, the SMA patients has poorly access to DMT for 5q-SMA subtype treatment with relevant clinical impacts in long-term. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare disease characterized by progressive loss of motor neurons located in the anterior horn of the spinal cord and brainstem, leading to progressive muscle atrophy and weakness. The most common form of SMA (5q SMA) is caused by bi-allelic mutations in the SMN1 gene on chromosome 5q13.2, classified into subtypes, according to the age of onset and the maximum motor function achieved. The journey to diagnosis can last for years and have a wide and significant impact on patients' lives. This study aims to map the time interval between the appearance of the first signs and symptoms to lived achievement of the 5q-SMA diagnosis using a genetic report in Latin American patients with 5q-SMA. In this study the data analysis in a multicenter clinical registry for SMA disease include patients with SMA 5q types 1, 2, 3 and 4 of all ages and both sexes, treated in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico and Uruguay). Currently 361 participants were included, with an average age of 13.7 (years), with 59.3% females and 40.7% males. Results show subtype 2, 158 (43.8%) constitutes the largest number of participants in this study, followed by subtypes 3(38.0%) and 1, 114 (31.5%). To date, 245 (67.9%) use or have had access to disease modifying therapy for SMA and 116 (32.1%) have never had access to therapies. Knowing the reality of the patients' journey is relevant for greater assertiveness in the clinical management of the disease and management of access to treatments that modify the course of the disease. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a genetic rare disease characterized by progressive loss of motor neurons located in the anterior horn of the spinal cord and brainstem, leading to progressive muscle atrophy and weakness. The most common form of SMA (5q-SMA) classified into subtypes, according to the age of onset and the maximum motor function achieved. This study is an international multicenter clinical Registry for SMA diseases (LATAM RegistrAme study NCT05475691) that includes patients with 5q-SMA types 1, 2, 3 and 4 of all ages and both sexes, treated at reference centers in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, and Uruguay). The average time of appearance of the first signs and symptoms, the average time of illness, and the time interval between the appearance of the first signs and symptoms until obtaining the confirmatory genetic diagnosis of 5q-SMA and the clinical evolution over the course of the study will be analyzed. Currently, the study already has 361 patients included (Argentina: 63; Brazil: 180; Chile: 35; Colombia: 54; Mexico: 20 and Uruguay: 7). The SMA subtype 2 constitutes the largest number of participants included in the study, followed by subtypes 3 and 1. The mean time for first signs and symptoms was one month of life. The mean time to reach the confirmatory molecular report of 5q-SMA varies greatly across countries. Analyzing the reality of how long it takes for these patients to arrive at confirmation of the genetic diagnosis of 5q-SMA is of great relevance. Diagnostic confirmation is fundamental for greater assertiveness in the clinical management of the disease and access to treatments that modify the course of the disease (DMTs). Knowing the time profile of patients with 5q-SMA diagnosis in Latin America is scarce; however, the LATAM RegistrAME is the first Registry study to improve the knowledge of SMA clinical management in Latin-America. [ABSTRACT FROM AUTHOR]

Introduction – We present herein clinical, histological and magnetic resonance imaging (MRI) findings in a patient with Fukuyama-type congenital muscular dystrophy (FCMD). He is the first case report in the Japanese population living in Brazil. Case report – The child presented with neonatal hypotonia, delayed motor abilities and speech, seizures, cerebral and cerebellar gyrus abnormalities with signal intensity change in the white matter by MRI, high serum level of creatinephosphokinase (CK), and dystrophic skeletal muscle with normal merosin, α-sarcoglycan and dystrophin expression. The fukutin gene study showed one founder 3-kb retrotransposal insertion in the 3′-non-coding region, and in the other allele no mutation was detected after screening all exons and flanking introns by sequencing. Discussion – This case report emphasizes the importance to consider FCMD in Japanese people living in other countries. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XL-MTM) is a rare and often lethal congenital myopathy, clinically characterized by muscle weakness. Its underlying molecular mechanisms remain incompletely understood. As myosin has been implicated in the pathophysiology of other forms of congenital myopathies, in the present study, we aimed to define whether muscle myosin is dysfunctional in the context of XL-MTM. For that, we used muscle tissue from human patients and a canine model. We isolated individual muscle fibres from these two species and performed loaded Mant-ATP chase experiments. Our preliminary results indicate a shift of myosin metabolic/biochemical states towards highly energy-consuming conformations in human and canine XL-MTM. Subsequently, to reverse this alteration potentially contributing to muscle fatigue, we investigated the effects of an ATP-conserving drug targeting myosin, mavacamten, using a well-defined mouse model of XL-MTM lacking myotubularin. The results are currently being analysed and include histology as well as untargeted global proteomics. Potentially, taken together, these data will lead to a better understanding of XL-MTM and the potency of myosin as a drug target. [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre‑mRNA splicing modifier that has been widely approved for the treatment of spinal muscular atrophy (SMA). RAINBOWFISH (NCT03779334) is a global, open-label, single-arm, multicentre, Phase 2 study assessing the efficacy, safety and pharmacokinetics/pharmacodynamics of risdiplam in infants with genetically diagnosed and presymptomatic SMA from birth to 6 weeks of age (at first dose), regardless of SMN2 copy number. The study enrolled 26 infants: eight infants had two SMN2 copies, 13 infants had three SMN2 copies and five infants had ≥4 SMN2 copies. The primary efficacy (PE) population (n=5) had two SMN2 copies and baseline compound muscle action potential (CMAP) amplitudes ≥1.5mV. Drug dosage was adjusted to achieve a target exposure of approximately 2,000 ng∙ hr/mL. The primary endpoint was met after 12 months of risdiplam treatment with 4/5 (80%) infants in the PE population able to sit without support for ≥5 seconds (Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, third edition [BSID-III]). Irrespective of CMAP amplitude, 7/8 infants with two SMN2 copies were able to sit without support for ≥30 seconds (BSID‑III Item 26), including all infants with CMAP amplitude <1.5 mV (n=3). Out of 26 infants, 24 (92%) were able to sit without support, 13 (50%) were able to stand unaided and 12 (46%) were able to walk independently at Month 12, as assessed by the Hammersmith Infant Neurological Examination, Module 2. At Month 12, all infants were alive without permanent ventilation, maintained their swallowing and feeding abilities and no adverse events (AEs) led to withdrawal or treatment discontinuation. Most AEs were not considered treatment-related and resolved over time. One infant met the criteria for development of clinically manifested SMA. Here we report, for the first-time, the 2-year efficacy and safety data from RAINBOWFISH. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants at TK2 lead to a severe and progressive and specific myopathy (TK2d). In a scenario of a potential supplementation therapy that changes the natural history of the disease, it is urgent to increase suspicion and accelerate diagnosis. We described the clinical characterization of 31 TK2d patients from several centers across Brazil. Genotype-phenotype correlation was performed for recurrent and novel variants. Motor and respiratory assessments were systematically performed in 10 patients, three of whom were receiving the nucleosides reposition therapy. Eight patients with the infantile form, 18 with childhood form and 5 with late-onset form were described. Extramuscular features were present in 30% of the cohort. Neuropathy and encephalopathy were clinically predominant for some patients. Four variants were recurrent, and one was novel, allowing genotype-phenotype correlations. T108M patients presented a milder presentation compared to the H121N group. R183T was associated with peripheral nerve involvement and c.536_538+8del with encephalomyopathic involvement. A two-year follow-up of three patients showed decreased motor, bulbar, and respiratory function, compared to a dramatic improvement in treated patients. TK2d is a very debilitating disease. Early diagnosis is essential in order to change the natural history of the disease and reduce the high mortality and morbidity rates. High diagnostic suspicion is imperative, and extramuscular involvement might play an important role for diagnostic strategies, starting with the inclusion of the TK2d in the differential diagnosis for neuropathies and epilepsy. Despite the higher mortality rates among infantile-patients, childhood-onset disease is also a debilitating and progressive disease. And the nucleosides reposition was well tolerated and benefic for the patients presented here. [ABSTRACT FROM AUTHOR]

The Motor Unit Number Index (MUNIX) has emerged as a more sensitive biomarker for detecting motor unit loss in 5q-spinal muscular atrophy (SMA) compared to compound muscle action potential (CMAP). Recent studies have shown correlations between MUNIX values of various muscles and motor scales used to assess disease progression and treatment response. Objective: This study is an investigation of the feasibility of MUNIX as a biomarker for disease progression in SMA types 3 and 4 treated with nusinersen. A four-year study involved 20 patients diagnosed with SMA types 3 and 4, ten treated with nusinersen and ten non-treated. Patients underwent evaluations using the Hammersmith Functional Motor Scale Expanded (HFMSE), the 6-minute walk test (6MWT), and assessments of CMAP and MUNIX in the abductor policis brevis (APB), adductor digiti minimi (ADM), and tibialis anterior (TA) muscles. A significant change was observed between the first and fourth years in CMAP values of the ADM muscle (p=0.012) in treated patients. In contrast, untreated patients experienced a significant reduction in mean CMAP values of the TA (p=0.015). Significant decreases in mean MUNIX values were found only in untreated patients, in the ADM (p=0.022) and TA (p<0.001). Treated patients experienced an average increase of 24.9 points in the MUNIX of the ADM (p=0.024) compared to non-treated patients. CMAP and MUNIX values for the TA muscle correlated with HFMSE scale results. The MUNIX values of ADM and TA muscles are biomarkers for disease progression in 5q-SMA types 3 and 4 over a four-year follow-up period. Despite a significant increase in ADM CMAP values among treated patients, only ADM MUNIX could identify motor unit loss in untreated patients. Furthermore, MUNIX values remained stable among treated patients over the four-year follow-up period. [ABSTRACT FROM AUTHOR]

LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. Three individuals never achieved the ability to sit (2.6%), and 84 patients reached the maximum motor ability to sit without support (73.7%). Out of these 84 patients, two lost the ability to sit without support with eight and nine years old, respectively. 27 patients acquired the ability to walk without support (23.7%). Out of these 27 patients, 3 lost the ability to walk between the first and second decade of life. Ninety-one patients underwent brain MRI, with 13 (14.3%) displaying cortical malformations, while every patient exhibited hypersignals in the white matter. Fifteen (16.5%) patients had epilepsy, and 14 (15.4%) patients reported learning difficulties. Clinical outcome information, including loss of ambulation, use of NIV, necessity of gastrostomy, and survival length, was obtained in 75 patients. Six patients required gastrostomy, all during the first decade of life. Four patients of this cohort died, all due to pneumonia—2 within the first 2 years of life and 2 after the first decade of life. None of them were using regular noninvasive ventilation. Kaplan-Meier survival analysis revealed a progressive increase in the need for NIV according to age, regardless of whether the patient was ambulatory. The mean age for the use of NIV was 14.9 years (SD: +/- 1.71; CI 11.55% to 18.26%), with a median of 11 years (SD: +/- 0.94; CI 9.15% to 12.85%). By the age of 20, over 85% of the patients were using NIV (Figure 1). We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p<0.0001. Although no specific hotspot regions existed in the LAMA2 , 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population. [ABSTRACT FROM AUTHOR]

Recent literature has reported neurodevelopmental changes in spinal muscular atrophy (SMA) type 1, especially autism spectrum disorder (ASD). Furthermore, previous reports before the advent of disease-modifying therapies suggested brain involvement in 5q-SMA. In this work, we present five SMA type 1 and pre-symptomatic patients with two copies of SMN2 who presented neurodevelopmental disorders and were submitted to brain MRI with DTI (diffusion tensor imaging). These patients presented with abnormalities in the white matter of the frontal lobes on brain MRI, which correlates with less representation association fibers (superior longitudinal fasciculus) on DTI. Brain involvement in SMA type 1 may occur even in patients treated with new disease-modifying therapies, and its correlation with neurodevelopmental disorders remains an open question. [ABSTRACT FROM AUTHOR]

LAMA2-CMD is a rare autosomal recessive disease characterized by hypotonia, muscle weakness, and the inability to achieve independent gait. It imposes a considerable disease burden, including difficulty in weight gain and dysphagia. However, this disease burden has not been thoroughly assessed in the medical literature, and this study aims to address this gap. Patients with genetically confirmed LAMA2-CMD were cross-sectionally evaluated. Clinical assessments included analysis of dysphagia, NdSss scale, weight measurement, and the necessity of gastrostomy. Patients received ultrasound evaluations of tongue muscles, and the classification of the muscle abnormalities was based on the modified Heckmatt scale. The ultrasound M mode was used to assess the hyoid elevation movement during swallowing. Qualitative analysis of ultrasound findings and correlations with clinical presentations were conducted. 20 patients with LAMA2-CMD were evaluated, ranging from 3-27 years old (mean 7.7). 8/20 patients (40%) weighted below the 3rd percentile. All patients experienced some degree of dysphagia, with a maximum score of 7 on the NdSss scale. 17/20 patients (85%) reported taking more than 30 minutes to finish a meal. 4/20 patients (20%) had gastrostomy tubes. Among the three tongue muscles evaluated, the geniohyoid muscle was the most affected. 14/ 20 patients had markedly hyperechoic muscle. The genioglossus muscle was the second most affected, with 9/20 patients having markedly hyperechoic muscle. None of the patients had normal geniohyoid or genioglossus muscles. Lastly, the least affected muscle was the digastric, with 7/20 patients having markedly hyperechoic muscle. 16/20 patients required an increased number of movements of hyoid elevation and had movements of low amplitude during swallowing. A correlation was observed between the patient's age and the severity of ultrasound abnormalities. The genioglossus and geniohyoid muscles appeared to be more preserved in patients under 5 years old compared to older patients (p=0.005 and p=0.017, respectively). Similarly, there was a correlation between extremely low weight (P<3) and markedly hyperechoic genioglossus muscle (p=0.0176). Patients with LAMA2-CMD experience greater difficulty in weight gain and exhibit some degree of dysphagia. Assessing tongue muscles via ultrasound serves as a valuable tool for comprehending functional abnormalities in these patients, aiding in clinical management, and potentially serving as a marker for disease progression. [ABSTRACT FROM AUTHOR]

To describe the changes found on ultrasound of the tongue muscles in patients with Nemaline myopathy. Early recognition of these changes is important for therapeutic guidance. Fourteen patients with a confirmed diagnosis of nemaline myopathy from a tertiary care center in Brazil were clinically evaluated and underwent ultrasound using muscle-specific setup with fixed gain (GE Logic E) with a 4 to 12 MHz transducer, evaluating the muscles of the tongue in coronal section with B-mode and M-mode, the latter being used with a plane on the digastric muscle to evaluate the number of movements performed during saliva swallowing. The muscles evaluated were the digastric, geniohyoid and genioglossus, and all ultrasound images were obtained by an experienced neurosonologist and graded on the modified Heckmatt scale (Grade 1 - normal muscle, with hypoechogenic muscle tissue and hyperechogenic connective tissue between the fibers; Grade 2 – uncertain, with increased echogenicity, but with identifiable tissue structure and no attenuation of deep tissues; Grade 3 – abnormal, with hyperechogenicity and alteration of tissue structure, with attenuation of deep tissues). Nine patients were male, aged between 1 and 54 years (median 17 years), 9 with pathogenic variants in the Nebulin gene, 4 in the ACTA1 gene and 1 inconclusive. Five patients had severe dysphagia with exclusive use of gastrostomy, five had mild dysphagia and four had normal swallowing. All patients showed involvement of the genioglossus muscle on ultrasound and seven patients had tongue atrophy on clinical examination. The geniohyoid was the least commonly affected muscle on ultrasound, being altered in only seven patients, the majority of which with tongue atrophy. The number of movements performed for swallowing was evaluated in eleven patients and was greater in patients with involvement of more than one muscle evaluated. Ultrasound of tongue muscles is capable of detecting changes in patients with nemaline myopathy even before the development of atrophy or dysphagia. The most frequently altered muscle is the genioglossus, and the other muscles and the number of movements performed for swallowing appear to be abnormal only in severe cases. [ABSTRACT FROM AUTHOR]

Abnormal dystrophin proteins (Dps) in Duchenne muscular dystrophy (DMD) are known to alter retinal electrophysiology, but their repercussion on visual functions have not been investigated in detail. In the present study we investigated whether different Dps influence vision by measuring psychophysical dark-adapted visual thresholds driven by cone and rod photoreceptors in DMD patients with different genetic backgrounds. Control group comprised 28 healthy volunteers (mean age=17.9±6.5 years). DMD groups were 29 patients (mean age=14.9±4.4 years) divided in three genetic groups depending on presumable affected Dps: group 1 (only Dp427 affected), group 2 (Dp427+Dp260+Dp140 affected) and group 3 (all Dps affected). Visual detection thresholds to 625-nm (red, cone-driven) and 527-nm (green, rod-dominated) flashes of 2° were measured during dark adaptation after 1-minute exposure to a bleaching light (3000 cd/m2). Initially, 8 minutes of interleaved 625-nm and 527-nm thresholds were measured. After an additional 5 minutes of dark-adaptation, a second set of threshold measurements to 527-nm stimuli was performed during the subsequent 6 minutes. Control thresholds were -1.7 ± 0.4 (cone) and -4.2 ± 0.2 (rod) log cd/m². Affected Dp427 alone (group 1) was not sufficient to alter visual thresholds (p = 0.28 cone and p = 0.48 rod) while affected Dp427+Dp260+Dp140 (group 2) caused elevated rod thresholds (-3.4 ± 0.9 log cd/m², p < 0.01). Interestingly, patients with presumable alteration of all retinal Dps (Dp427+Dp260+Dp140+Dp71, group 3) showed visual thresholds similar to controls (cone: -2.4 ± 1.4 and rod: -3.9 ± 0.4 log cd/m², p = 0.99). Affected retinal dystrophins are associated with alterations of the visual detection thresholds in DMD patients besides their well-known associations with retinal electrophysiology. It is worthy to highlight that the visual thresholds of the patients with all Dps affected (presumably) were similar to control thresholds despite the alteration of Dp260+Dp140. We speculate that compensatory mechanisms may be operating in the retina of DMD patients presumably lacking all Dps. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a genetic muscle disease caused by DMD gene mutations. Symptoms begin in early childhood with progressive muscle weakness and loss of walking, progressing to cardiac and respiratory failure. The muscle ultrasound (US) technique has been used to detect degrees of muscle involvement and disease progression in neuromuscular diseases. To correlate lung function with respiratory and non-respiratory muscles using muscle US in patients with DMD at different stages of the disease. This prospective observational study included DMD male patients between 5 and 18 years of age. Clinical data were collected, and muscle US was performed to evaluate 12 muscle types (respiratory, appendicular, and axial) and transformed into quantitative analysis using histograms. Pulmonary lung function evaluation comprised FVC (forced vital capacity) and peak cough flow (PCF). Motor function was assessed by applying the MFM-32 (Motor Function Measure). 42 DMD patients were included. All underwent muscle US, and 24 underwent pulmonary function testing and application of the MFM scale. The average age was 11 years. The average age at diagnosis was 6.3 years, and 35.7% had lost walking ability. The average FVC was 87.7%, and the PCF was 231.9 l/min. There was a statistically significant correlation between age and FVC with the US histograms of the 1st interosseous, biceps brachii, medial gastrocnemius, and digastric muscles. There was no statistical correlation between diaphragm thickness and FVC or age. On the motor scale, the variables D1, D2, and total D (MFM-32) were correlated with FVC, and D1 with age. Conclusion: Muscle US can be an important tool for evaluating respiratory muscles involvement and disease progression in patients with DMD and identifying indirect markers of pulmonary involvement. [ABSTRACT FROM AUTHOR]

BACKGROUND: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure. CONCLUSIONS: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482. opens in new tab.). [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre‑mRNA splicing modifier that has been approved in more than 90 countries worldwide. RAINBOWFISH (NCT03779334) is an open-label, single-arm, multicenter study assessing the efficacy, safety and pharmacokinetics/pharmacodynamics (PK/PD) of risdiplam in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA) from birth–6 weeks of age (at first dose), regardless of SMN2 copy number. The primary endpoint is the proportion of infants, with two SMN2 copies and baseline compound muscle action potential (CMAP) amplitude ≥1.5mV, who are able to sit without support for ≥5 seconds (assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, third edition). Secondary endpoints include: the development of clinically manifested SMA; survival and permanent ventilation; motor milestone achievement; motor function; growth measures; nutritional status; CMAP; PK/PD; and safety monitoring. The median age at first dose was 26.5 days (range: 16–40 days) for the first 18 enrolled infants (data cut-off: 1 July 2021). No treatment-related serious adverse events were reported in infants treated for ≤22.8 months. A preliminary analysis of seven infants treated for ≥12 months demonstrated that most reached near maximum scores on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale by 4–5 months of age and achieved motor milestones within World Health Organization windows for healthy children. All seven infants treated for ≥12 months were alive without permanent ventilation, maintained swallowing and feeding abilities, and had not required hospitalization. Here we report for the first-time results from the RAINBOWFISH primary analysis conducted at Month 12. [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 70 countries worldwide. RAINBOWFISH (NCT03779334) is an open-label, single-arm, multicenter study assessing the efficacy, safety and pharmacokinetics (PK)/pharmacodynamics (PD) of risdiplam. The study includes infants with genetically diagnosed, presymptomatic SMA from birth–6 weeks of age (at first dose), regardless of SMN2 copy number. The primary analysis will be conducted at Month 12 in infants with two SMN2 copies and baseline compound muscle action potential (CMAP) amplitude ≥1.5mV. The primary endpoint is the proportion of infants sitting without support for ≥5 seconds (assessed by item 22 of the gross motor scale of the Bayley scales of Infant and Toddler development, third edition). Secondary endpoints include: development of clinically manifested SMA; survival and permanent ventilation; motor milestone achievement; motor function; growth measures; nutritional status; CMAP; PK/PD; and safety monitoring. The median age at first dose was 26.5 days (range: 16–40 days) for the first 18 enrolled infants (data cut-off: 1 July 2021). No treatment-related serious adverse events were reported in infants treated for ≤22.8 months. Seven infants have been treated for ≥12 months; preliminary efficacy data demonstrated that most reached near maximum score organization windows for healthy children. All infants treated for ≥12 months were alive without permanent ventilation, maintained swallowing and feeding abilities, and had not required hospitalization. RAINBOWFISH will provide information about presymptomatic risdiplam administration and will help determine the dose for infants aged <2 months. [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 70 countries worldwide. FIREFISH (NCT02913482) is a multicenter, open-label, two-part study of risdiplam in infants with Type 1 SMA and two SMN2 gene copies (inclusion criteria: 1–7 months old at enrollment). FIREFISH Part 1 assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam doses. Pivotal Part 2 assessed the safety and efficacy of risdiplam over 24 months at the dose selected from Part 1. Thereafter, infants entered a 3-year open-label extension phase and continue to receive risdiplam at the pivotal dose. Pooled safety and efficacy data were available from 58 enrolled infants who received risdiplam treatment (Part 1 high-dose cohort, n=17; and Part 2, N=41). As of the cut-off date (23 November 2021), there were no treatment-related adverse events leading to withdrawal, no additional deaths and no additional infants meeting the definition of permanent ventilation since Month 24. At Month 36, 84% of infants were alive and did not require permanent ventilation. In FIREFISH, infants have achieved motor milestones not observed in the natural history of Type 1 SMA. Overall, infants have maintained or improved their motor skills in terms of developmental milestones and motor function between Month 24 and Month 36. Here we present longer-term pooled safety and efficacy data from infants who have received risdiplam at the pivotal dose for ≥36 months. FIREFISH Parts 1 and 2 are ongoing globally and will provide further safety and efficacy data of risdiplam in Type 1 SMA. [ABSTRACT FROM AUTHOR]

Nemaline myopathy (NM) is one of the most common congenital myopathies. NM is often related to pathogenic variants in the NEB, ACTA1, TPM2 and TPM3 genes. Even though the exact disease mechanisms remain to be elucidated, histological analyses of NM patients' muscle biopsies may reveal unexplained accumulation of glycogen and abnormal mitochondria. Thus, the aim of the present work was to identify what could cause such change in muscle energetics. For that, we applied mant-ATP chase experiments on skeletal muscle fibres from patients diagnosed with NM. We observed that the myosin-stabilising conformational state, known as the super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting patient muscle fibres expressing NEB and ACTA1 mutations. Such alteration was linked to hyper-phosphorylation of myosin-binding protein C, a protein linking myosin molecules to the thin filaments. Hence, our results may indicate a contribution of myosin to some of the histopathological aberrations related to NM. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to demonstrate the benefit of whole-body magnetic resonance imaging (WBMRI) as a diagnostic modality in the detection of muscle activity in juvenile dermatomyositis (JDM)/polymyositis (JPM) patients and to correlate these findings with clinical evaluation, laboratory examinations, nailfold capillaroscopy (NFC), and muscle biopsy. Method: Thirty-four patients aged 5.5 to 18.9 years with a diagnosis of JDM/JPM were prospectively evaluated using clinical examination, muscle enzyme determination, the Childhood Myositis Assessment Scale (CMAS), Disease Activity Score (DAS), Manual Muscle Testing (MMT), NFC, and WBMRI. An open muscle biopsy was performed if muscle disease activity was detected on WBMRI. Results: Disease activity was detected in WBMRI in four (11.7%) patients and confirmed by muscle biopsy. All four patients had elevation of at least one muscle enzyme and NFC showed scleroderma patterns in these patients. Conclusions: WBMRI allows us to evaluate the extent and symmetry of muscle disease and inflammatory activity. NFC is an important additional examination to assess disease activity. [ABSTRACT FROM AUTHOR]