ABSTRACT Objective Onasemnogene abeparvovec (OA) is an AAV9‐based gene therapy for spinal muscular atrophy type I (SMA I). Real‐world outcomes show increased response variability compared to clinical trials, and follow‐up data beyond 12–18 months are limited. The aim of this 24‐month prospective observational study is to comprehensively describe the clinical outcomes of an Italian cohort of SMA I patients treated with OA. Methods Based on recent literature, patients' treatment status was categorized as: monotherapy (OA only), bridge therapy (transition to OA within 3 months of starting nusinersen or risdiplam), or switch therapy (transition to OA after > 3 months of 1st treatment). Linear mixed‐effects models examined predictors of improvement (CHOP‐INTEND), adjusting for baseline motor function, SMN2 copy number, age, and prior treatment. Descriptive analyses were used to show changes in motor, respiratory, and nutritional milestones. Results The cohort included 64 patients: 27 monotherapy, 9 bridge, and 28 switch. All patients showed significant improvement over 24 months (β = 20.40 points/year, p < 0.001). Patients who switched showed slower improvement (β = −3.76, p = 0.038) compared to monotherapy, while those who bridged showed no difference. Older age at treatment was associated with slower improvement (β = −1.48 points/year per month, p = 0.002). Of 49 non‐sitters at baseline, 39 (80%) achieved sitting and 5 (10%) achieved walking. No new safety signals emerged in the second year of follow‐up. Interpretation Age and baseline motor functional status significantly influence outcomes; however, substantial confounding, particularly the initial treatment, limits the ability to isolate individual effects. Longer follow‐up is essential for evaluating therapeutic responses in heterogeneous SMA I populations.

Brief rationale: To investigate vertebral fracture and risk factors in DMD. Main results: Vertebral fractures were found in 42

Background/Objectives: The advent of disease modifying therapies (DMTs) for Spinal Muscular Atrophy (SMA) has highlighted the need for reliable tools to assess bulbar function in type I individuals. The Oral and Swallowing Abilities Tool (OrSAT) was originally developed to evaluate swallowing and feeding abilities in infants with SMA type I during the first two years of life. This study aimed to assess the applicability of the OrSAT in a cohort of children with SMA type I older than 2 years. Methods: Fifty-two children with genetically confirmed SMA type I, aged 2 to 12.6 years, were included. All participants had received at least one DMT, administered either soon after diagnosis or when treatment became available. Bulbar and feeding abilities were assessed using the OrSAT and results were grouped according to clinical subtype and feeding modality. Given the small sample size of the subgroups and the ordinal nature of OrSAT scores, comparisons between groups were performed using the non-parametric Kruskal-Wallis test. Results: At follow-up, 27 children were orally fed, 19 were exclusively tube-fed, and 6 were tube-fed but were also able to eat some food by mouth. The OrSAT scores reflect a wide spectrum of bulbar function from severe to no impairment. Most children who required exclusive tube-feeding at follow-up had already been tube-fed at treatment initiation, while a small number showed improvement in swallowing abilities and the partial recovery of oral feeding during follow-up. Conclusions: Our results suggest that the OrSAT, previously used only in the first two years of life, may also be applicable in older children to describe bulbar involvement and monitor changes over time. However, further studies are needed to refine the tool for this age group and to formally validate its use in older children with SMA type I. Its use may contribute to the longitudinal assessment of swallowing abilities and support rehabilitative management.

Becker Muscular Dystrophy (BMD) is a genetic disorder, caused by mutations in the dystrophin gene. Cardiac involvement is a common feature in this condition, often manifesting as dilated cardiomyopathy (DCM) or arrhythmias. In patients with BMD, ventricular dysfunction is frequently attributed to non–ischemic mechanisms, given the known pathophysiology of dystrophinopathy. However, overlooking coexisting ischemic heart disease, particularly in older patients with cardiovascular risk factors, can result in suboptimal management. A 57–year–old patient, hypertensive, with high cholesterol and with a family history of idiopathic dilated cardiomyopathy, affected by BMD, presented for a cardiological evaluation as part of follow–up for his dystrophinopathy, asymptomatic for cardiac symptoms. The echocardiogram showed a worsening of left ventricular contractile function compared to the previous year’s check–up left ventricular ejection fraction (LVEF) was 42% vs 55%, with hypokinesia of the mid–basal lateral wall. Considering these findings, cardiac magnetic resonance (MRI) was recommended. The MRI confirmed left ventricular contractile dysfunction: LVEF 36%, with intramural late gadolinium enhancement (LGE) in the basal lateral, inferior, and septal segments, as well as the mid–inferolateral segment. Due to these findings, and despite the highly likely nature of the LV dysfunction related to the known muscular dystrophy, the patient underwent CT angiography to rule out coronary disease. The coronary CT angiography revealed bivasal coronary artery disease. Therefore, coronary angiography was performed and percutaneous coronary intervention (PCI) was performed on proximal and mid–RCA, distal LAD, and proximal D1 that had critical stenoses. DISCUSSION: This case demonstrates that cardiomyopathy secondary to coronary artery disease can coexist with dystrophin–related cardiomyopathy, especially in older patients with traditional cardiovascular risk factors. This case underscores the need to maintain a broad differential diagnosis when evaluating left ventricular dysfunction in BMD patients. The findings highlight the need for a comprehensive cardiovascular assessment. The importance of multimodal imaging: LGE patterns in cardiac MRI, while suggestive of fibrosis, may overlap with ischemic scarring, necessitating further evaluation with coronary imaging.

The advent of disease modifying therapies in spinal muscular atrophy (SMA) has increased life expectancy but also raising new challenges. We aimed to explore the neurobehavioral profile in SMA type I subjects and in those identified by newborn screening (NBS). Behavioral assessment included screening questionnaires (strengths and difficulties questionnaire (SDQ), social communication questionnaire (SCQ), and sensory profile 2 (SP2)), neurobehavioral observation, CARS2 and DSM-5 criteria. The cohort included thirty-one children (25 type I and 6 NBS) aged 2-10 years. On SDQ prosocial scale, 14/31 showed borderline or abnormal results. 6/14 had borderline scores at the SCQ questionnaire, while none had abnormal scores. Neurobehavioral observation suggested the presence of ASD in 3/31, confirmed by CARS2 and DSM-5 criteria. 5/31 showed other behavioral disorders. Our findings suggest that autism is present in SMA infants in a percentage slightly higher than in the general population. Other neurobehavioral difficulties are less frequent. Our study highlighted the challenges to select appropriate tools in infants with limited mobility and the need for a clear diagnostic pathway, starting with screening questionnaires followed by more appropriate diagnostic tools to reduce the number of false positive results.

ABSTRACT Objective This study investigated myostatin levels in SMA patients receiving disease‐modifying therapies (DMTs) to understand their relationship with treatment duration and functional status. Methods Our study includes both cross‐sectional and longitudinal analyses of myostatin levels in treated SMA patients. The longitudinal cohort included 46 treatment‐naive patients assessed at baseline and 12 months post‐treatment. Myostatin levels were measured using ELISA. Age‐matched controls (n = 89) were included for comparison. The cross‐sectional study included 128 patients with variable durations of treatment (from 0.4 to 7.2 years). In both cohorts, myostatin levels were correlated with SMA type, functional status, and clinical outcomes. Results Baseline myostatin levels were significantly lower than controls (p < 0.001), except during the neonatal period in presymptomatic patients. After 12 months of treatment, there were no significant changes compared to baseline levels (p = 0.1652). The only substantial changes were observed in presymptomatic neonates, who showed a reduction of myostatin despite treatment intervention. There was a significant correlation between myostatin levels, functional status, and SMA type both in the cross‐sectional and longitudinal groups. Interpretation This study demonstrates lower myostatin levels in SMA patients compared to controls. The association between myostatin levels, functional status, and SMA type suggests its possible role as a disease severity biomarker. The utility of myostatin as a biomarker for DMT response remains controversial; while we observed no significant increase in myostatin levels following treatment, we also did not observe the progressive reduction previously reported in untreated patients.

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease attributable to mutations in DMD, leading to a deficient and less functional dystrophin, mainly in skeletal and cardiac muscle. Understanding the natural history of BMD is crucial for optimizing patient care and developing targeted treatments. Retrospective data were collected from 943 patients diagnosed with BMD based on a combination of clinical, biochemical and genetic criteria followed by 17 Italian neuromuscular centres. Patients' demographics, main signs and symptoms at BMD onset, neuropsychiatric comorbidities, age at loss of ambulation, cardiac left ventricular ejection fraction, pulmonary forced vital capacity and DMD mutations were collected. Disease milestones were analysed in specific DMD mutational groups. The median age at the last assessment was 26.0 (16.6-41.9) years, with a median age at diagnosis of 7.5 (4.0-14.0) years. In 55% of patients, the diagnosis was prompted by the incidental finding of hyperCKaemia. At the last assessment, 13.5% of patients had lost the ability to walk at a median age estimated by Kaplan-Meier analysis of 69 years. Thirty per cent of patients exhibited left ventricular impairment and 2.7% respiratory involvement. Ten per cent of patients carried out-of-frame mutations, 4% nonsense mutations and 86% in-frame deletions/duplications. The subset of in-frame deletions was classified further based on the specific mutations. Patients carrying del45-49 compared with del45-47 were associated with an earlier loss of ambulation (P = 1 × 10-4), whereas patients with del45-55 (P = 0.005), del48 (P = 0.02) and del48-49 (P = 0.02) were correlated with a later loss of ambulation compared with del45-47. Both del45-55 (P = 0.002) and del48 (P = 0.003) were significantly associated with decreased odds of developing a pathological left ventricular ejection fraction compared with del45-47. Our results contribute to a better understanding of the natural history of BMD and capture precious data in the era of emerging therapies. The knowledge of the specific DMD mutation might help to define a prognosis in a subset of BMD patients and will serve as a model for the design of future therapies.

Duchenne muscular dystrophy (DMD) is an X–linked recessive neuromuscular disorder associated with early and progressive degeneration of skeletal, smooth, and cardiac muscles, with progressive loss of ambulation, respiratory failure, and dilated cardiomyopathy. To date, there is limited data in the literature regarding the impact of different classes of cardioactive drugs on left ventricular dysfunction associated with DMD. Specifically, the only drugs shown to have a prognostic impact are corticosteroids and ACE inhibitors, whose use is recommended from the age of 10. However, most DMD patients experience a progressive decline in left ventricular function starting in the second decade of life. The scarcity of data in the literature, combined with the complexity of therapeutic management, often prevents the implementation of optimal heart failure therapy. To evaluate whether treatment with SGLT inhibitors (dapagliflozin) is well–tolerated and effective in patients with DMD and asymptomatic left ventricular systolic dysfunction. From 2022 to 2024, we enrolled 23 non–ambulatory patients with DMD (mean age 25±4.28) and a left ventricular ejection fraction ranging from 22% to 40% on echocardiography, without symptoms of heart failure. All patients were already on optimal medical therapy with Sacubitril/Valsartan or ACEi/ARB, beta–blockers, and anti–aldosterone agents at the maximum tolerated dose, according to the 2021 ESC heart failure guidelines. Therapy with dapagliflozin was introduced at the standard dose of 10 mg/day, with baseline renal function assessed using cystatin C. Clinical and echocardiographic follow–up was performed at 6 and 12 months. At baseline assessment, the mean left ventricular ejection fraction (LVEF) was 31%. A significant improvement in LVEF was observed after 6 months (35%; p‹0.005) and at 12 months (38%; p‹0.005). A significant reduction in heart failure biomarker levels (NT–proBNP) was observed at 6 months (mean baseline value 703 pg/mL vs 374 pg/mL at 6 months, p=0.004); however, this reduction was not maintained at 12 months. Renal function, assessed using cystatin C, remained stable during follow–up. In one patient, the drug was discontinued due to poor tolerance. Our data suggest that, in patients with DMD and reduced ejection fraction, therapy with dapagliflozin may improve left ventricular function, with a satisfactory safety profile.

Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination (n = 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA (n = 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients (n = 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months. Conclusion: Our findings suggest that early clinical signs may contribute to predict motor milestones development.

The advent of disease modifying therapies in Spinal Muscular Atrophy (SMA) has changed the natural history of the disease, increasing life expectancy and quality of life but, at the same time, raising new clinical challenges. The aim of this study is to explore the neurobehavioral profile in treated individuals with SMA type I and subjects identified by newborn screening (NBS). Twenty-eight individuals aged 2-10 years underwent a comprehensive behavioral assessment using three screening questionnaires (Strengths and Difficulties Questionnaire (SDQ), Social Communication Questionnaire (SCQ), and Sensory Profile (SP)), which provide information regarding the risk of behavioral disorders and autism. A cognitive evaluation, and a clinical observation were performed by two independent observers. Twenty-two individuals with SMA type I and 6 patients identified with NBS were included. None had abnormal clinical scores in the SCQ questionnaire, 4 had borderline scores, but in two of the 4 the scores were normal when the motor items were removed. SDQ showed some abnormal results in 10/28 subjects. The clinical observation confirmed the result of the screening questionnaires in 17/28 subjects and highlighted behavioral issues in 4/28 not detected by the questionnaires. Our findings confirm that neurobehavioral disorders may occur in subjects with SMA and highlight the challenges in choosing the appropriate assessment tools. Questionnaires such as SCQ do not appear to be adequate as they often failed to identify signs detected by other tools. SDQ appeared to be the most appropriate tool in our cohort. In our experience, a structured clinical observation was also helpful to identify behavioral problems, suggesting that, in the absence of disease specific tools, the use of different instruments may help to better identify the type and the frequency of behavioral problems.

There is emerging evidence that SMA1 children treated with disease modifying therapies (DMTs) develop expressive language abilities although these do not follow typical trajectories. Very little is known about other aspects of communication, including social communication abilities. We conducted a cross-sectional study aiming to investigate parents-reported expressive language and social communication skills in SMA1 patients treated with DMTs at two Neuromuscular Centres, the Dubowitz Neuromuscular Centre, London (UK) and the Centro Clinico Nemo Pediatrico, Rome (Italy). Parents of SMA1 children were asked to complete the MacArthur-Bates Communicative Development Inventory (MB-CDI) for children aged 8months+, to investigate the developing abilities in early language, and the Social Communication Questionnaire (SCQ) for children aged 4years+, to identify potential social communication difficulties. For the SCQ, a cut-off ≥ 11 was selected to improve sensitivity and reduce the likelihood of false negatives. Fifteen parents agreed to complete the MB-CDI (age range: 2 years 2 months – 6 years 9 months). Results demonstrated the acquisition of some verbal skills in 13/15, although with scores below normal ranges. Thirty-seven parents agreed to complete the SCQ (age range: 4 years 0 months – 9 years 0 months). Twenty-one/37 parents were unable to answer one or more questions (range 1–22) due to their child being nonverbal and/or not strong enough to perform the action(s) so, those items were excluded from the total score. Four/37 (11%) showed a total SCQ score ≥11, suggesting the need of further investigations for autism spectrum disorder. Three/4 had completed the MB-CDI and were among the children able to say the lowest number of words. Other areas of concern emerging from the SCQ included routines/ritualized patterns of behaviour (14/37, 38%), and hyperreactivity to sensory input (5/37, 13%). Treated SMA1 children can acquire expressive language skills, although this can be delayed. A noteworthy percentage of them also present with social communication difficulties later on in life, especially when expressive language is more severely affected. Large prospective studies are warranted to better characterize the spectrum of language and social communication abilities in this population.

The advent of disease-modifying therapies has reduced the risk to develop bulbar difficulties that were invariably found in untreated infants with type I SMA. The aim of this study was to assess possible longitudinal patterns of swallowing abilities in a cohort of treated infants with type I SMA and to identify factors that may predict bulbar outcome. The cohort includes 75 type I infants, one with 1, 63 with 2 and 11 with 3 SMN2 copies treated at an age ranging between 0.06 and 4.98 years (mean 1.34). Follow-up after treatment ranged between 1 and 7.66 years. Sixty-nine patients were treated with Nusinersen, with 18/69 subsequently switching to onasemnogene abeparvovec and another 6 patients only received onasemnogene abeparvovec. All patients were classified at baseline, when treatment started, and at follow-up according to their functional bulbar level and the need for tube feeding. At the last follow-up, 36/75 (48%) had no need for tube feeding and 39 had gastrostomy. Seven of the 39 who had tube feeding were also able to be fed by mouth. Twenty-nine of the 39 infants with tube feeding at follow-up already had bulbar difficulties when treatment was started. The level of bulbar involvement measured by the OrSAT levels was significantly associated with bulbar outcome (p=<.001). Other factors, such as a reduced SMN2 copy number (1 or 2 copies), SMA type 1.1 subtype or treatment started at a later age were also related to an increased risk of tube feeding but the association was not significant.

The aim of this study was to assess the need for tube feeding in a cohort of treated infants with type I SMA and to identify predictive factors. All patients were classified at baseline, when treatment started, and at follow-up according to their functional level and the need for tube feeding. Fisher’s exact test was used to examine the associations between the outcome at the last follow-up and SMA type, SMN2 copy number, and baseline nutritional status. ANOVA was performed to compare CHOP INTEND scores and age at treatment initiation with outcomes. The cohort includes 75 type I SMA infants treated between 0.1 and 5 years of age. At the last follow-up, 34 had no need for tube feeding, 9 had tube feeding but were also able to be fed by mouth, and 32 had tube feeding and were unable to be fed by mouth. Thirty of the 41 infants with tube feeding at follow-up already had feeding difficulties when treatment was started. The need for tube feeding at follow-up was associated with the level of feeding involvement at baseline and with CHOP INTEND scores [p < 0.001] but not with SMN2 copy number, SMA type 1 subtypes or age at treatment. The results of this study suggest that the need for tube feeding is not frequent in treated infants with type I SMA and, when occurring, can be predicted by the level of feeding involvement and low CHOP INTEND scores at baseline.

Objective The aim of this study was to assess early language acquisitions in treated individuals with spinal muscular atrophy (SMA) type 1 and in infants identified by newborn screening (NBS). Methods Parents of SMA individuals aged between 8 and 36 months were asked to fill in the MacArthur-Bates Communicative Development Inventory (MB-CDI) that assesses comprehension, gesture and expressive skills. A follow-up assessment was performed in 21 of the 36. Results The MB-CDI was completed by parents of 24 type 1 and 12 infants identified by NBS. Comprehension skills were preserved in 81% of the type 1 SMA and in 87% infants identified by NBS. Gesture abilities were <5th centile in 55% of the type 1 SMA and in none of those identified by NBS. Lexical expressions were <5th centile in more than 80% type 1 SMA and in 50% of infants identified by NBS. At follow-up, despite an increase in lexical expression skills, the scores remained below the fifth centile in 43% type 1 SMA and in 86% of infants identified by NBS. Conclusions These results suggest that language and communication development may follow a similar pattern to that observed in motor function with the possibility to develop skills (eg, ability to say clear words) that are not usually present in untreated infants but with a level of performance that does not reach that of their typically developing peers.

Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic–dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.

The increasing pressure to include non ambulant Duchenne muscular dystrophy (DMD) boys in clinical trials has highlighted the need for outcome measures that could address the impact of upper limb function on activities of daily living. The aim of the present study was to establish the correlation between the recently developed Patient Reported Outcome Measure for the upper limb (PROM UL) and the observer rated functional scale Performance of Upper Limb (PUL 2.0) in a large cohort of DMD boys and young adults. As part of a larger natural history study, non ambulant DMD patients were assessed using PUL2.0 and PROM UL. One hundred and twenty-five concurrent PUL 2.0 and PROM UL evaluations from 60 non ambulant DMD boys were taken into consideration. The total PROM UL scores showed a strong correlation with both PUL 2.0 total scores and with PUL 2.0 entry item score. The strong correlation between the two tools confirms the clinical meaningfulness of the PUL2.0 and that the PROM UL can help to detect the gradient of progression of upper limb involvement.

BACKGROUND:We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number.METHODS:The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II).RESULTS:Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not.CONCLUSIONS:Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.

Background:Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs. Methods:46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings:CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation:Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding:None.