UNASSIGNED: Spinal muscular atrophy (SMA) is caused by homozygous loss of the SMN1 gene with SMN2 gene copy number correlating with disease severity. Rarely SMA is caused by a deletion on one allele and a pathogenic variant on the other. The pathogenic missense variant c.5C>G (p.Ala2Gly) correlates with a mild disease phenotype that does not correlate with SMN2 copy number. In a mouse model the c.5C>G transgene produces SMN that is thought to form partially functional SMN complexes, but levels in humans have not yet been investigated.
UNASSIGNED: We identified two patients with mild SMA caused by a heterozygous deletion of SMN1 and the heterozygous variant, c.5C>G. Molecular findings were confirmed with deletion/duplication analysis and Sanger sequencing. Skin fibroblasts were collected and cultured, and SMN expression was analyzed using immunofluorescence.
UNASSIGNED: Two patients with slowly progressing mild weakness were confirmed to have heterozygous pathogenic missense variant c.5C>G and a heterozygous deletion of SMN1. Their clinical presentation revealed much milder disease progression than patients with matched SMN2 copy number. Analysis of the patients\' fibroblasts revealed much higher numbers of SMN nuclear complexes than a patient with a homozygous SMN1 deletion and matched SMN2 copy number.
UNASSIGNED: These case reports reinforce that the rare c.5C>G variant causes mild disease. Furthermore, the analysis of SMA nuclear gems in patient samples supports the theory that the p.Ala2Gly SMN can form partially functional SMN complexes that may carry out essential cellular functions and result in mild disease.

OBJECTIVE: Following the approval of risdiplam, there are more possibilities for disease-modifying therapy (DMT) in children with spinal muscular atrophy (SMA). Non-treatment-naïve subjects with SMA involved in the JEWELFISH study, designed to evaluate the safety and tolerability of risdiplam, were required to undergo a washout period before receiving risdiplam. This study aims to investigate the safety of administering risdiplam in patients within 90 days of receiving treatment with nusinersen.
METHODS: Data were collected on SMA patients who had undergone treatment with nusinersen, and who then received risdiplam within 90 days of their last dose of nusinersen, including demographic characteristics, information on treatment with nusinersen and risdiplam, adverse events, and laboratory assessments in a follow-up period of 90 days, presented as median (range).
RESULTS: A total of 15 children with SMA were reported, including 8 males and 7 females. The median number of doses of previous nusinersen treatment received was 8 (6-17) doses, and the median age at first risdiplam treatment was 4.3 (1.9-11.2) years. Specifically, 8 children received risdiplam 30 days or less after their most recent nusinersen treatment, 2 at 31-60 days after nusinersen, and 5 at 61-89 days post-nusinersen. Adverse events of pyrexia, pneumonia, vomiting and rash were reported in 4 patients.
CONCLUSIONS: Our study showed good safety data on patients who received risdiplam following nusinersen within the washout period of 90 days. This supplements the JEWELFISH study in the era of DMT, providing additional guidance for clinicians, but additional data from other centers is needed.

The nutritional implications of spinal muscular atrophy (SMA) are profound. Disease modifying therapies (DMT) have improved clinical outcomes. This review describes the impact of DMT on nutrition outcomes. A systematic search strategy was applied across seven databases until May 2023. Eligible studies measured nutrition outcomes in individuals with SMA on DMT (nusinersen, risdiplam or onasemnogene abeparvovec [OA]) compared to untreated comparators. Nutrition outcomes included anthropometry, feeding route, swallowing dysfunction, dietary intake, dietetic intervention, nutritional biochemistry, metabolism, gastrointestinal issues and energy expenditure. Articles retrieved were screened in duplicate, data were extracted and appraised systematically. Sixty three articles from 54 studies were included; 41% (n = 22) investigated nusinersen in pediatric participants with SMA type 1. Anthropometry (n = 18), feeding route (n = 39), and swallowing dysfunction (n = 18) were the most commonly reported outcomes. In combined pediatric and adult cohorts, BMI z-score remained stable post nusinersen therapy. The proportion of children with SMA requiring enteral nutrition was stable post nusinersen therapy. Ability to thrive at age 1.5 years was higher in children treated in early infancy with OA compared to historical controls. Significant heterogeneity existed across study population characteristics and outcome measures. Nusinersen may prevent deterioration in some nutrition outcomes; and OA in early infancy may be associated with improved nutrition outcomes. Timing of DMT initiation is an important consideration for future nutrition research. Studies investigating nutrition as a primary outcome of DMT, using consistent outcome measures are required for nutritional management strategies for this cohort to be appropriately tailored.

The most prevalent rare genetic disease affecting young individuals is spinal muscular atrophy (SMA), which is caused by a loss-of-function mutation in the telomeric gene survival motor neuron (SMN) 1. The high heterogeneity of the SMA pathophysiology is determined by the number of copies of SMN2, a separate centromeric gene that can transcribe for the same protein, although it is expressed at a slower rate. SMA affects motor neurons. However, a variety of different tissues and organs may also be affected depending on the severity of the condition. Novel pharmacological treatments, such as Spinraza, Onasemnogene abeparvovec-xioi, and Evrysdi, are considered to be disease modifiers because their use can change the phenotypes of the patients. Since oxidative stress has been reported in SMA-affected cells, we studied the impact of antioxidant therapy on neural stem cells (NSCs) that have the potential to differentiate into motor neurons. Antioxidants can act through various pathways; for example, some of them exert their function through nuclear factor (erythroid-derived 2)-like 2 (NRF2). We found that curcumin is able to induce positive effects in healthy and SMA-affected NSCs by activating the nuclear translocation of NRF2, which may use a different mechanism than canonical redox regulation through the antioxidant-response elements and the production of antioxidant molecules.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with progressive muscle atrophy and weakness, caused by biallelic mutations in the survival motor neuron 1 (SNM1) gene. Onasemnogene abeparvovec (OA) is an approved gene replacement therapy for patients with SMA. We report on two patients with SMA type 1, weighing 20 kg, previously treated with Nusinersen, who received OA infusion at 7 years of age. To our knowledge, these two patients are the heaviest treated in the real-world and we describe their different courses after gene therapy, including liver impairment requiring long-term steroid treatment and additional immunosuppression, with only transitory improvement in functional outcomes. Our cases illustrate how careful risk-benefit consideration is required in treating older and heavier SMA patients with OA, especially in view of the multiple treatment choices available for older patients with SMA.

UNASSIGNED: At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months.
UNASSIGNED: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire.
UNASSIGNED: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%).
UNASSIGNED: The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings.

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are neuromuscular disorders that affect muscular function. The most common causes of morbidity and mortality are respiratory complications, including restrictive lung disease, ineffective cough, and sleep-disordered breathing. The paradigm of care is changing as new disease-modifying therapies are altering disease trajectory, outcomes, expectations, as well as patient and caregiver experiences. This article provides an overview on therapeutic advances for SMA and DMD in the last 10 years, with a focus on the effects of disease-modifying therapies on respiratory function.

OBJECTIVE: Spinal muscular atrophy (SMA) manifests with progressive motor neuron degeneration, leading to muscle weakness. Onasemnogene abeparvovec is a US Food and Drug Administration-approved gene replacement therapy for SMA. This study aimed to present short-term data of children in the United Arab Emirates (UAE) treated with onasemnogene abeparvovec, particularly in the context of children requiring invasive ventilatory support via tracheostomy.
METHODS: A retrospective analysis was performed on 60 children who received onasemnogene abeparvovec. All these children received corticosteroids. They were followed up for up to 3 months. Motor function assessments were performed before and after the gene therapy. Comprehensive clinical evaluations, including pulmonary functions, were performed at baseline and the 3-month mark.
RESULTS: Forty-three percent were male, and the mean age at the time of infusion was 29.6 months (SD ± 17.2). The mean weight was 10.1 kg (SD 2.6). All children demonstrated marked improvements in motor function within 3 months of gene therapy administration. No adverse effects attributable to corticosteroid therapy were observed. Positive clinical outcomes, including increased ventilator-free intervals, reduced antibiotic dependency, and fewer hospital admissions, were reported among children with invasive ventilation via tracheostomy.
CONCLUSIONS: This study demonstrates the favorable tolerability and promising responses to onasemnogene abeparvovec in invasively ventilated pediatric patients. Early improvements in motor function, as observed within 3 months post-treatment, suggest its potential as a viable therapeutic option for this vulnerable patient population.

UNASSIGNED: Spinal muscular atrophy (SMA) is a genetic progressive neuromuscular disease. Nusinersen is the first disease modifying drug approved to treat patients with SMA. Our study aimed to evaluate the efficacy of nusinersen treatment on motor function in children with SMA.
UNASSIGNED: A retrospective analysis was conducted on the data of 52 genetically confirmed SMA patients from November 2020 to September 2023. Motor function was assessed based on standardized scales from baseline to 14 months of follow-up.
UNASSIGNED: Of patients in this study, the majority had SMA type 2 (40/52, 76.9%), 5 (9.6%) and 7 (13.5%) patients had SMA types 1 and 3, respectively. The median disease duration was 11 months (range 0-52), and the median age at initiation of treatment was 44.5 months (range 5-192). Motor function of all the patients with SMA improved from baseline to 14 months of follow-up. Mean increases of 4.6-point (p = 0.173), 4.7-point (p = 0.021) and 2.7-point (p = 0.013) were observed from baseline to 14 months of follow-up for the Children\'s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores, the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM), respectively. Increased disease duration and age of treatment initiation were negatively correlated with the changes in HFMSE scores (r = -0.567, p = 0.043; r = -0.771 and p = 0.002, respectively). Similar results were observed for the RULM scores (r = -0.714, p = 0.014; r = -0.638 and p = 0.035, respectively).
UNASSIGNED: Our study suggested that 14 months of treatment with nusinersen was effective and improved the motor function of children with SMA types 1, 2, or 3. In addition, disease duration and age at treatment initiation were negatively correlated with treatment outcome in the patients.

Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic target to treat neurodegenerative diseases.