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BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce. METHODS: A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up. RESULTS: Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1-12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients. CONCLUSIONS: Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.

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OBJECTIVE: To elucidate the clinical characteristics and standard of care (SoC) of spinal muscular atrophy (SMA) patients in Thailand, focusing on primary endpoints: age at death and a composite of death or tracheostomy need. DESIGN: Retrospective observational study. SETTING: Seven tertiary centres across Thailand. PATIENTS: Records of 110 patients with genetically confirmed SMA, spanning 2012-2021. INTERVENTIONS: Historical data review; no active interventions. MAIN OUTCOME MEASURES: Age at death and a composite measure of death or tracheostomy necessity. RESULTS: The cohort included 1 SMA0, 50 SMA1, 40 SMA2 and 19 SMA3 cases. Median ages at the onset and diagnosis of SMA1 were 3 and 6.2 months. Of SMA1 patients, 63% required ventilators, and eight received dimethyltryptamines (DMTs) at a median of 15 months (range 6.4-24.5 months). The median time from onset to DMT was 11 months (range 4.2-20.5 months). Among SMA1 patients, 73% died by the study's end. SMA2 and SMA3 patients' median onset ages were 11 and 24 months, respectively, with diagnosis at 24.8 and 68.7 months. Half of all types received physical therapy. CONCLUSIONS: Significant delays in diagnosis and SoC access, including DMTs, were observed, underscoring urgent needs for improved diagnostic and care strategies to enhance SMA patient outcomes in Thailand.

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Objective: To summarize the effects of disease-modifying drugs for spinal muscular atrophy (SMA) on the ventilation support of type 1 children after acute respiratory failure. Methods: A case-control study was conducted, including the data of clinical characteristics, medication and ventilation supports of 38 SMA patients of type 1 with pneumonia and acute respiratory failure hospitalized in Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2020 to July 2023. Children were divided into the treatment group and the untreated group based on whether they started and persisted in using Nusinersen or Risdiplam or not before hospitalization. The differences of ventilation support between the 2 groups were analyzed. The children of the treatment group were divided into the improved group and the unimproved group based on whether they could be avoid of prolonged dependence on continuous mechanical ventilation in the next six months after discharge. The differences in clinical characteristics between the two groups were analyzed. T-test and χ2 test were used for comparison. Results: Among the enrolled children, 19 were male and 19 were female. The age was 1.3 (0.6, 2.0) years at the time of hospitalization due to pneumonia. There were 26 cases in the treatment group and 12 cases in the untreated group. The treatment group had a higher proportion of patients without prolonged dependence on continuous mechanical ventilation in the next six months after discharge (69% (18/26) vs. 2/12, χ2=9.10, P<0.05). Eighteen children were improved among the treated group, while 8 children were not. The improved group had a larger age of first onset of acute respiratory failure (1.6 (0.4, 3.4) vs. 0.5 (0.3, 0.7) years, Z=2.07, P<0.05), a longer duration of medication taken before hospitalization (3.6 (2.4, 8.7) vs. 1.2 (1.2, 2.4) months, t=2.74, P<0.05), and a smaller proportion with underlying diseases (1/18 vs. 6/8, χ2=13.58, P<0.05). Conclusions: SMA disease-modifying drugs are useful for type 1 children to avoid of prolonged dependence on continuous mechanical ventilation after acute respiratory failure. The patients who take medication longer, or have acute respiratory failure for the first-time at an older age, or without underlying diseases are more likely to avoid of.

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In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and skeletal deformities. Recognizing the pre-symptomatic phases supported by screening and confirmatory genetic tests is crucial for early diagnosis. This work addresses key considerations in implementing 5q-SMA screening within the Brazilian National Newborn Screening Program and explores Brazil's unique challenges and opportunities, including genetic tests, time-to-patient referral to specialized centers, program follow-up, and treatment algorithms. We aim to guide healthcare professionals and policymakers, facilitating global discussions, including Latin American countries, and knowledge-sharing on this critical subject to improve the care for newborns identified with 5q SMA.

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Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival. Onasemnogene abeparvovec is the first gene replacement therapy (GT) approved to treat this condition. An observational retrospective study was conducted to assess adverse events and efficacy of GT in SMA patients. Forty-one patients with SMA (58.5% females and 80.1% SMA type 1) were included. The mean age at GT dosing was 18 (±6.4) months. Thirty-six patients (87.8%) were under previous treatment with nusinersen, and 10 (24.4%) continued nusinersen after GT. Mean CHOP-INTEND increased 13 points after 6 months and this finding did not differ between groups according to nusinersen maintenance after GT (p = 0.949). Among SMA type 1 patients, 14 (46.6%) reached the ability to sit alone. Liver transaminases elevation at least two times higher than the upper limit of normal value occurred in 29 (70.7%) patients. Thrombocytopenia occurred in 13 (31.7%) patients, and one presented thrombotic microangiopathy. Older age (>2 years) was associated with more prolonged use of corticosteroids (p = 0.021). GT is effective in SMA patients, combined nusinersen after GT did not appear to add gain in motor function and older age is associated with prolonged corticosteroid use.

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Spinal muscular atrophy (SMA) is one of the most common genetic diseases and was, until recently, a leading genetic cause of infant mortality. Three disease-modifying treatments have dramatically changed the disease trajectories and outcome for severely affected infants (SMA type 1), especially when initiated in the presymptomatic phase. One of these treatments is the adeno-associated viral vector 9 (AAV9) based gene therapy onasemnogene abeparvovec (Zolgensma®), which is delivered systemically and has been approved by the European Medicine Agency for SMA patients with up to three copies of the SMN2 gene or with the clinical presentation of SMA type 1. While this broad indication provides flexibility in patient selection, it also raises concerns about the risk-benefit ratio for patients with limited or no evidence supporting treatment. In 2020, we convened a European neuromuscular expert working group to support the rational use of onasemnogene abeparvovec, employing a modified Delphi methodology. After three years, we have assembled a similar yet larger group of European experts who assessed the emerging evidence of onasemnogene abeparvovec's role in treating older and heavier SMA patients, integrating insights from recent clinical trials and real-world evidence. This effort resulted in 12 consensus statements, with strong consensus achieved on 9 and consensus on the remaining 3, reflecting the evolving role of onasemnogene abeparvovec in treating SMA.

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BACKGROUND: Gene replacement therapy (onasemnogene abeparvovec) is associated with an improvement of the prognosis of children with spinal muscular atrophy, but information on long-term respiratory outcome is scarce. The aim of this study was to report the polysomnography findings and respiratory muscle function of infants with treatment-naive spinal muscular atrophy type 1 and 2 up to 24 months after onasemnogene abeparvovec monotherapy. METHODS: A clinical and motor evaluation, respiratory muscle function testing, and polysomnography were performed repeatedly. RESULTS: Fifteen spinal muscular atrophy patients (1 presymptomatic, 7 type 1b, 6 type 1c, and 1 type 2) were included at a median age of 8.6 months (range 3.8-12.6) and followed for 24 months. The thoracic over head circumference ratio was close to normal at baseline (median 1.00 (range 0.90-1.05)) and increased significantly over time. All polysomnography and nocturnal gas exchange parameters were within normal ranges at baseline (median apnea-hypopnea index 2.5 events/hour (range 0.4-5.3)) and follow-up. The inspiratory muscle strength was normal at baseline but tended to slightly decrease over time and the expiratory muscle strength was low at any time especially for patients with recurrent respiratory infections (median (range) at baseline in cmH2O: crying esophageal pressure 54 (30-110), crying transdiaphragmatic pressure 65 (35-107), gastric pressure during maximal cough 26 (10-130), esophageal pressure during maximal cough 61 (38-150)). Only 3 patients required noninvasive ventilation. CONCLUSION: A continuous respiratory monitoring of spinal muscular atrophy patients during the first years of life following onasemnogene abeparvovec monotherapy seems recommended despite the normality of polysomnography parameters.

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BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease, causing progressive muscle weakness due to loss of lower motoneurons. Since 2017, three therapies, two modifying gene transcription and one adding the defective gene, have been approved with comparable efficacy on motor outcome. Data on cognitive outcomes of treated SMA type 1 patients is limited. The aim of this study was to evaluate cognitive function in symptomatic and presymptomatic SMA type 1 patients with two or three SMN2 copies who received SMN-modifying or gene-addition therapy in the first year of life. METHODS: Cognitive testing was performed in 20 patients, including 19 symptomatic SMA type 1 patients with up to three SMN2 copies and 1 pre-symptomatically treated patient. Children were tested using Bayley Scales of Infant Development (BSID-III) at the age of 2 or 3 years or the Wechsler Preschool and Primary Scale of Intelligence (WPSII-IV) at the of age of 5 years. RESULTS: 11/20 patients showed subnormal cognitive development. Boys had significantly lower cognitive scores. Patients requiring assisted ventilation or feeding support were more likely to have cognitive deficits. Achieving more motor milestones was associated with a better cognitive outcome. CONCLUSION: Treated patients with SMA type 1 have heterogeneous cognitive function with 55 % of patients showing deficits. Risk factors for cognitive impairment in our cohort were male gender and need for assisted ventilation or feeding support. Therefore, cognitive assessment should be included in the standard of care to allow early identification of deficits and potential therapeutic interventions.

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Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

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BACKGROUND: Spinal muscular atrophy is a progressive neuromuscular disorder and among the most frequent genetic causes of infant mortality. While recent advancements in gene therapy provide the potential to ameliorate the disease severity, there is currently no modality in clinical use to visualize dynamic pathophysiological changes in disease progression and regression after therapy. METHODS: In this prospective diagnostic clinical study, ten pediatric patients with spinal muscular atrophy and ten age- and sex-matched controls have been examined with three-dimensional optoacoustic imaging and clinical standard examinations to compare the spectral profile of muscle tissue and correlate it with motor function (ClinicalTrials.gov: NCT04115475). FINDINGS: We observed a reduced optoacoustic signal in muscle tissue of pediatric patients with spinal muscular atrophy. The reduction in signal intensity correlated with disease severity as assessed by grayscale ultrasound and standard motor function tests. In a cohort of patients who received disease-modifying therapy prior to the study, the optoacoustic signal intensity was similar to healthy controls. CONCLUSIONS: This translational study provides early evidence that three-dimensional optoacoustic imaging could have clinical implications in monitoring disease activity in spinal muscular atrophy. By visualizing and quantifying molecular changes in muscle tissue, disease progression and effects of gene therapy can be assessed in real time. FUNDING: The project was funded by ELAN Fonds (P055) at the University Hospital of the Friedrich-Alexander-Universität (FAU) Erlangen-Nurnberg to A.P.R.

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ABSTRACT: Despite new effective medications, patients with spinal muscular atrophy types 1-3 can continue to have inadequate cough flows to prevent episodes of acute respiratory failure. Ventilator unweanable intubated patients are thought to require tracheostomy tubes. As a result, potentially beneficial medications may be discontinued and patients die despite receiving these medications. Three cases are presented of medically treated, physically strengthening children, with spinal muscular atrophy type 1. All three subsequently died or underwent tracheotomy. However, there is no evidence of extubation attempts to noninvasive ventilatory support settings or optimal mechanical insufflation-exsufflation despite this option being described to be over 98% successful for extubating unweanable medically untreated children with spinal muscular atrophy 1.

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BACKGROUND: Until recently, the treatment of spinal muscular atrophy (SMA) was limited to symptomatic treatment with no cure. Three innovative drugs, nusinersen, onasemnogene abeparvovec (OA), and risdiplam have been developed to treat SMA. Although the clinical trials for these drugs have demonstrated their efficacy, there is limited information on real world treatment strategies. In this study, we present a case of a male infant with SMA type 1 who underwent OA treatment after nusinersen treatment. CASE PRESENTATION: At 4 months of age, the patient was diagnosed with SMA type 1. At 6 months of age, nusinersen treatment was initiated. His motor function improved, but the effect was limited; therefore, his parents requested gene replacement therapy. During the preparation for OA treatment, anti-adeno-associated virus 9 (AAV9) antibody tests repeatedly showed non-specific reactions, which delayed initiation of treatment. The patient was put on ventilator management after he caught a common cold. During this management, the anti-AAV9 antibody test results were negative. Furthermore, the patient showed increased transaminase levels just before OA treatment; however, since these gradually decreased without signs of liver failure, we started OA treatment at 13 months of age. Four months later, the patient began to sit without support and was weaned from non-invasive positive pressure ventilation, although nasogastric tube feeding remained partially necessary. CONCLUSION: We believe that the management of unstable SMA type 1 symptoms, anti-AAV9 antibody testing, and changes in transaminase levels will be helpful for other patients with SMA who require treatment.

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OBJECTIVES: The aims of the study are to present noninvasive respiratory management outcomes using continuous noninvasive ventilatory support and mechanical in-exsufflation from infancy for spinal muscular atrophy type 1 and to consider bearing on new medical therapies. DESIGN: Noninvasive ventilatory support was begun for consecutively referred symptomatic infants with spinal muscular atrophy type 1 from 1 to 10 mos of age. Intercurrent episodes of respiratory failure were managed by intubation then extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation despite failing ventilator weaning and extubation attempts. Intubations, tracheotomies, and survival were monitored. RESULTS: Of 153 patients with spinal muscular atrophy 1 consecutively referred since 1995, 37 became continuous noninvasive ventilatory support dependent, almost half before 10 yrs of age. Of the 37, 18 required continuous noninvasive ventilatory support for a mean 18.6 ± 3.3 yrs to a mean 25.3 (range, 18-30) yrs of age, dependent from as young as 4 mos of age with 0 to 40 ml of vital capacity. One of the 18 died from COVID-19 acute respiratory distress syndrome at age 24 after 23 yrs of continuous noninvasive ventilatory support. Extubation success rate of 85% per attempt (150/176) resulted in only one undergoing tracheotomy. CONCLUSIONS: Medical treatments begun during the first 6 wks of age convert spinal muscular atrophy 1 into spinal muscular atrophy 2 or 3 but cough flows remain inadequate to avoid many pneumonias that, once resolved by a treatment paradigm of extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation, eliminates need to resort to tracheotomies.

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Hirayama disease is a self-limiting cervical motor neuron disease, usually affecting the spinal cord at level C7-T1. We share an unusual case of Hirayama disease in a young man affecting roots C4-C6. He presented in coma due to diaphragm weakness and hypercapnic respiratory failure. Diagnosis was achieved via clinical presentation, neurophysiological examination, ultrasonography of the diaphragm and dynamic MR-imaging. Conservative treatment with a cervical collar resulted in remarkable improvement in respiratory and motor function.

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Children with spinal muscular atrophy (SMA) frequently experience feeding intolerance and diminished growth. Although splicing modulators to prevent symptoms are available worldwide, adequate nutrition to support growth, development, and improved quality of life remains essential. We present a case study of a one-year-old malnourished male with SMA type I who achieved improved growth and feeding tolerance with a human milk (HM)-derived nutrition intervention. Despite feeding with appropriately balanced semielemental formula, he remained severely malnourished after two months of hospitalization. Feeds were partially replaced with HM-based diet plus a HM-based fat modular. Feeding tolerance, fecal calprotectin levels, and z scores for weight and length improved while receiving the HM-based intervention. We hypothesize that the HM-based feeding reduced intestinal inflammation by diminishing pathogenic elements of his microbiome. Owing to their aberrant fatty acid metabolism, patients with SMA are uniquely positioned to benefit from HM-based nutrient acquisition even while receiving splicing modulators to stabilize the disease process.

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Many women with spinal muscular atrophy (SMA) types II, III, and IV reach fertile age, and some of them may consider pregnancy. However, limited data are available about the potential effects of pregnancy on the course of SMA and the outcomes of pregnancies in these patients. Furthermore, the use of several disease-modifying therapies for the treatment of all types of SMA is expected to increase the number of female SMA patients considering pregnancy in the coming years. The aim of this report is to provide clinicians with an overview of the patients in our cohort who have experienced pregnancies. We conducted a retrospective analysis on these women, through the administration of a questionnaire, which investigated how they experienced the different stages of the pregnancy. Ten patients (3 SMAII; 7 SMA III) participated in the survey; 40% had pregnancies for a total of nine, six of which were term-pregnancies. The mean age of first pregnancy was 32.5 ± 7.8 years for SMA II patients, and 30.5 ± 2.1 years for SMA III. All pregnancies ended in cesarean sections. Interestingly, the sitters had more frequent complications in pre-term labor and delivery, but the newborns were all healthy. This report shows that a successful pregnancy is possible in female patients with SMA. However, the ideal approach should involve a standardized multidisciplinary team capable of effectively addressing every possible scenario. For this reason, it is critically important that clinicians working with SMA patients gain more in-dept knowledge about this topic.

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BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder that may result in neuromuscular weakness and respiratory insufficiency. Gene replacement therapy has changed the trajectory of this condition, but long-term outcomes related to sleep disordered breathing are not known. METHODS: This was a retrospective review of infants with SMA identified via newborn screening who subsequently received onasemnogene abeparvovec at the Hospital for Sick Children (Ontario, Canada). Polysomnograms were conducted at the time of confirmed diagnosis as well as regularly thereafter. RESULTS: Eleven children (4 female) were identified via newborn screen (7 with 2 copies of the SMN2 gene and 4 with 3 copies of the SMN2 gene) and received onasemnogene abeparvovec at a median age of 3.6 weeks. All eleven infants met criteria for sleep disordered breathing based on their first completed polysomnograms but improved over time. Three infants required respiratory technology, including a premature infant who was prescribed nocturnal supplemental oxygen therapy for central sleep apnea and two symptomatic infants with neuromuscular weakness who required nocturnal noninvasive ventilation. We did not find a correlation between motor scores and polysomnogram parameters. CONCLUSION: Children treated with onasemnogene abeparvovec have reduced sleep disordered breathing over time. Polysomnograms revealed abnormal parameters in all children, but the clinical significance of these findings was unclear for children who were asymptomatic for sleep disordered breathing or neuromuscular weakness. These results highlight the need to evaluate both motor scores and respiratory symptoms to ensure a holistic evaluation of clinical status.

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