Inmaculada Pitarch-Castellano

Introduction/Aims To evaluate the usefulness of the Goal Attainment Scale (GAS) light for assessing response to risdiplam in patients with SMA aged ≥15 years. Methods In this population-based, longitudinal, ambispective study, patients were evaluated before and at 12 and 24 months after risdiplam initiation using motor scales (SMA Functional Composite Score Revised [SMA-FCR]), pinch strength (MyoPinch), functional scales (EK2, ALSFRS-R), patient and clinician global impression of change (PGIC and CGIC), and GAS light. Longitudinal changes were assessed using linear mixed-effects models. The minimal detectable change (MDC) and minimal clinically important change (MCIC) of GAS light were calculated. Results Forty-four patients (median age 32 years; 56.8% female) were included: 31.8% non-sitters, 56.8% sitters, and 11.4% walkers. GAS light priorities differed across functional subgroups, with patients prioritising moderately affected domains. After 24 months of risdiplam treatment, motor outcomes showed non-significant improvements in walkers, whereas functional scales improved significantly only in non-sitters. In contrast, GAS light detected significant, increasing improvements across all functional subgroups. The MCIC and MDC for GAS light were 6.5 and 10.65 points, respectively. According to the CGIC, 58% of patients improved slightly, 29% remained stable, and 13% worsened slightly at 24 months. Using the MCIC threshold, 64.5% achieved clinically meaningful goal improvement. Discussion GAS light is a feasible, sensitive, patient-centred tool that may complement standardised outcome measures when evaluating treatment response in adults with SMA. These findings further support risdiplam as a valuable therapeutic option in this population.

Background and objective: Nusinersen was the first disease-modifying treatment approved for spinal muscular atrophy (SMA). However, long-term results of broad unselected populations—particularly adolescents and adults—remain limited. We aimed to evaluate nusinersen long-term persistence and effectiveness in a population-based cohort. Methods: We conducted a population-based, ambispective observational study of all SMA patients in the Valencian community (Spain) between 2017 and 2022, with follow-up until December 2025 or censoring (due to death, clinical trial, or treatment switch). Demographic, clinical, and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. Nusinersen discontinuation risks and motor trajectories were evaluated using Bayesian linear and mixed linear models. Results: Of 72 patients included, 18 were < 12 years old (all treated with nusinersen) and 54 were ≥ 12 years (28 treated; 26 untreated) at the baseline visit. After a median follow-up of 4.6 years until censoring, all children were found responders, compared with 68% of those ≥ 12 years. Discontinuation rates were 11% in children compared to 75% in the older cohort. In patients ≥ 12 years, reasons for discontinuation included: treatment burden (71%), and loss (53%) or lack of benefit (43%). Lower baseline SMA-FCR (expEstimate = 0.84 [0.718,0.93],prob:1) and older age (expEstimate = 1.028 [1.011,1.055],prob:1) independently predicted higher discontinuation risk. Sustained treatment was associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration. Discussion: Nusinersen persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy although a 25% of adolescents and younger adults with higher baseline function experienced sustained benefit.

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder caused by biallelic SMN1 variants, partially modulated by SMN2 copy number. Risdiplam, an oral SMN2 splicing modifier, has demonstrated efficacy in SMA. However, long-term adherence and persistence are key to sustaining benefit. We evaluated real-world adherence, persistence, and safety of risdiplam in a population-based cohort. This was a retrospective observational study including all genetically confirmed SMA type 1-3 patients treated with risdiplam in Spain between January 2020 and October 2025. Adherence was assessed using the proportion of days covered (PDC) from pharmacy dispensing records and the Morisky-Green questionnaire. Persistence was defined as time to permanent discontinuation or switch. Adverse events (AEs) were extracted from clinical records, and Kaplan-Meier analysis was used to estimate persistence probabilities. Fifty-three patients were included (38 adults, 15 pediatric patients); 5.7% had SMA type 1, 52.8% type 2, and 41.5% type 3. One pediatric patient with SMA type 1 was presymptomatic at treatment initiation. Median age at risdiplam initiation was 29 years (interquartile range [IQR] 17-42), and 35.8% had prior nusinersen exposure. Adherence was high: median PDC was 100% (IQR 100-100) at 12 months and throughout follow-up; all patients assessed with the Morisky-Green questionnaire (35/53, 66%) were adherent. At 12 months, 92.5% (49/53) remained on treatment (Kaplan-Meier estimate 94.3%; 95% CI 88.3-100.0). Persistence at 24 and 36 months was 87.8% and 80.1%, respectively; later estimates should be interpreted cautiously because of the limited number of patients at risk. Median treatment duration was 28.1 months. Nine patients (17.0%) discontinued treatment. Treatment-related AEs occurred in 4/53 patients (7.5%), including one pediatric case of leukocytoclastic vasculitis requiring permanent discontinuation. In this real-world population-based cohort, risdiplam showed very high adherence, favorable short- to mid-term persistence, and a favorable safety profile, supporting the feasibility of oral therapy in both pediatric and adult patients with SMA.

Background and objectives: Anoctamin-5 gene (ANO5)-related myopathies are clinically heterogeneous, and predictors of progression remain poorly defined. This study aims to characterize their long-term clinical and radiological evolution and identify factors influencing disease severity. Methods: We conducted a retrospective observational study of patients with anoctaminopathies in the Valencian Community (Spain). Demographic, clinical, genetic, ancillary tests, and serial muscle MRI data were analyzed using univariate and Bayesian multivariate models. Results: Thirty patients (21 males) from 23 families were included. Median disease duration was 13.5 years, and follow-up was 7 years (range 3–31). Median age at first assessment was 43.5 years (range 9–78). Most patients presented with pseudometabolic myopathy (47%) or asymptomatic hyperCKemia (37%), while 16% had LGMD-R12/MMD3. Nearly one-third of symptomatic patients had a documented asymptomatic hyperCKemia period (median 5.5 years). At last assessment, 27% had LGMD-R12/MMD3, 43% had pseudometabolic myopathy, and 30% remained asymptomatic. The most frequent variants were c.191dupA (35%) and c.692G > T (22%). CK levels, biopsy and EMG findings did not distinguish phenotypes. Baseline MRI revealed fat infiltration and STIR hyperintensities in most patients across all phenotypes. Muscle involvement progressed in 95% of serial scans. STIR hyperintensities preceded fat replacement in approximately 50% of muscles. More severe phenotypes correlated with older age, loss-of-function variants, and higher MRI T1 scores. Estimated prevalence was 1.8/100,000 in our region. Discussion: ANO5 -related myopathies show progressive muscle involvement regardless of phenotype. Muscle MRI analysis provides valuable outcome measures for monitoring and future clinical trials, with STIR hyperintensities as a sensitive biomarker of disease activity.

Nusinersen was the first disease modifying treatment approved for 5q spinal muscular atrophy (SMA). Long-term results of broad populations, particularly for adolescents and adults, remain limited. We conducted a population-based, ambispective observational study of all SMA patients living in the Valencian Community (Spain) between September 2017 and December 2022 and follow-up until December 2025. Demographic, clinical and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. The risk for nusinersen discontinuation was assessed with a Bayesian model, and SMA-FCR trajectories with mixed linear regression. Of 72 patients included, 18 were <12 years old (all treated with nusinersen) and 54 were ≥12 years (28 treated; 26 untreated) at the baseline visit. After a median of 7 years, all patients <12 years were classified as responders versus 68% of patients ≥12 years. Discontinuation rates were 11% in children compared to75% in the older cohort. In patients ≥12 years, reasons for discontinuation included: treatment burden (71%), and loss(53%) or lack of benefit (43 %). Lower baseline SMA-FCR (expEstimate= 0.84 [0.718,0.93], prob:1) and older age (expEstimate=1.028 [1.011,1.055], prob:1) independently predicted higher discontinuation risk. Sustained nusinersen treatment was independently associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration over time. In this long-term population-based study, nusinersen use and persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy. However, a proportion of adolescents and adults (those younger and with higher baseline function) experienced sustained benefit.

Risdiplam is an orally administered small molecule that modifies the mRNA splicing of SMN2 for the treatment of spinal muscular atrophy (SMA). Its use is approved in presymptomatic patients diagnosed by neonatal screening with early and severe forms with two copies of SMN2, but we do not have real data on the evolution of oral treatment in this early phenotype of SMA. We present two cases treated at one month of life with a follow-up of 12 months and discuss their different evolutions and the causes of this. Familial adherence to treatment is important, as discontinuation can convert an early form of presymptomatic SMA to symptomatic. Molecular biomarkers such as plasma monitoring of neurofilament light chain (pNf-L) should be considered in the follow-up of early forms of SMA and may support the decision to change treatment in infants with SMA.

Spinal muscular atrophy (SMA) is a degenerative neuromuscular condition resulting from a homozygous deletion of the survival motor neuron 1 (SMN1) gene in 95% of patients. A timely diagnosis via newborn screening (NBS) and initiating treatment before the onset of symptoms are critical for improving health outcomes in affected individuals. We carried out a screening test by quantitative PCR (qPCR) to amplify the exon seven of SMN1 using dried blood spot (DBS) samples. From October 2021 to August 2024, a total of 31,560 samples were tested in the Valencian Community (Spain) and 4 of them were positive for SMA, indicating an incidence of 1/7890. Genetic confirmation was performed using multiplex ligation-dependent probe amplification (MLPA) and AmplideX PCR/CE SMN1/2 Plus kit, in parallel obtaining concordant results in survival motor neuron 2 (SMN2) gene copy number. Within the first few weeks of their lives, two of the four patients detected by NBS showed signs of severe hypotonia, becoming ineligible for treatment. The other two patients were the first presymptomatic patients with two copies of SMN2 to receive treatment with Risdiplam in Spain. In order to treat positive cases in their early stages, we conclude that the official deployment of SMA newborn screening is necessary.

Persistent elevation of serum creatine kinase levels (hyperCKemia) as an isolated manifestation presents a diagnostic challenge. Genetic myopathies are frequently involved; however, studies using next-generation sequencing (NGS) in pediatric patients are lacking, and the significance of genetic aberrations remains poorly understood. This study, therefore, aimed to investigate the relevance of NGS and the support of contemporary diagnostic tools in the diagnosis of pediatric asymptomatic hyperCKemia. This was a prospective cohort study enrolling pediatric (0-18 years old) patients meeting the predefined criteria for asymptomatic/paucisymptomatic hyperCKemia, excluding DMD gene deletion/duplication, recruited from a referral center. NGS, muscle MRI, EMG, and muscle biopsies with immunolabeling and inflammatory markers were performed according to a prespecified protocol. Data analysis was performed using descriptive/univariate statistics and Bayesian logistic regression. The series comprised 65 patients (78% male). NGS diagnosis was achieved in 55% of the cohort, with 70% of the pathogenic variants involving 7 genes (DMD, CAPN3, ANO5, DYSF, RYR1, GAA, and CAV3). The diagnostic rate was similar across all age groups; however, the gene profiles varied between the childhood and juvenile groups. EMG yielded myopathic features in 48% of the investigated cases, being predictive for diagnosis (p < 0.05; odds ratio [OR] 13.484, 95% CI 1.358-705.297). MRI showed normal (64%), focal fatty change (26%), or short-tau inversion recovery hyperintensity (10%) profiles, which were not predictive of diagnosis but supported muscle biopsy indications. Muscle biopsy provided a significant diagnostic effect (p < 0.05; OR 0.028, 95% CI 0.001-0.238), contributing to myopathologic features clarifying the variant pathogenicity and identifying inflammatory myopathies. The diagnoses remained inconclusive and unresolved in 14% and 29% of the cohorts, respectively. The diagnostic rate for patients with CK levels below the threshold of 3× was 42%. In multivariate analysis, NGS was the only variable achieving a significant diagnostic effect (β = 9.85, 95% CI 4.65-16.09). NGS, as the primary diagnostic tool for investigating hyperCKemia in the pediatric population, yielded a higher diagnostic rate. However, muscle biopsies are necessary to define variants of uncertain pathogenicity and aid in identifying inflammatory myopathies. EMG and MRI may play a role in hyperCKemia characterization, guiding the decision to perform muscle biopsy. The primary limitation of this study was that not all ancillary tests were performed in all recruited patients owing to ethical restrictions, which lowered the power of the predictive analysis.