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Background There is an increasing number of papers reporting the real world use of Nusinersen in different cohorts of SMA patients. Main body The aim of this paper was to critically review the literature reporting real world data on motor function in type 2 and 3 patients treated with Nusinersen, subdividing the results according to SMA type, age and type of assessment and performing a meta-analysis of the available results. We also report the available data collected in untreated patients using the same measures. Of the 400 papers identified searching for Nusinersen and spinal muscular atrophy, 19 reported motor function in types 2 and 3: 13 in adults, 4 in children and 2 included both. Twelve papers reported untreated patients’ data. All studies reported positive changes on at least one of the functional measures and at every time point while all-untreated cohorts showed negative changes. Conclusion Our review suggests that Nusinersen provides a favorable benefit in motor function across a wide range of SMA type 2 and 3 patients over a 10–14 month observation period. Although a direct comparison with studies reporting data from untreated patients cannot be made, the longitudinal changes in the treated cohorts (consistently positive) are divergent from those observed in the untreated cohorts (consistently negative). The difference could be observed both in the global cohorts and in smaller groups subdivided according to age, type or functional status.

The advent of new therapies has increased the need to achieve early diagnosis in Spinal Muscular Atrophy (SMA). The aim of the present study was to define the age of diagnosis in the three main types of SMA with pediatric-onset and the timing between the recognition of clinical signs and confirmed genetic diagnosis. All patients with a confirmed diagnosis of type I, II, III SMA followed in 5 Italian centers were included in this study, assessing age at symptoms onset, presenting sign or symptom, age at diagnosis, interval between clinical onset and diagnosis and type of medical investigations conducted in order to obtain the diagnosis. The cohort included 480 patients, 191 affected by SMA type I, 210 by type II and 79 by type III. The mean age at diagnosis was 4.70 months (SD ±2.82) in type I, 15.6 months (SD±5.88) in type II, and 4.34 years (SD±4.01) in type III. The mean time between symptom onset and diagnosis was 1.94 months (SD±1.84) in type I, 5.28 months (SD±4.68) in type II and 16.8 months (SD±18.72) in type III. Our results suggest that despite improved care recommendations there is still a marked diagnostic delay, especially in type III. At the time new therapies are becoming available more attention should be devoted to reducing such delay as there is consistent evidence of the benefit of early treatment.

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 --2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6-10: -7.9 m/year; 11-19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.

Background The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Main text Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores. Conclusion A detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials.

Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

It is known from previous literature that type II Spinal Muscular Atrophy (SMA) patients generally, after the age of 5 years, presents a steep deterioration until puberty followed by a relative stability, as most abilities have been lost. Although it is possible to identify points of slope indicating early improvement, steep decline and relative stabilizations, there is still a lot of variability within each age group and it’s not always possible to predict individual trajectories of progression from age only. The aim of the study was to develop a predictive model based on machine learning using an XGBoost algorithm for regression and report, explore and quantify, in a single centre longitudinal natural history study, the influence of clinical variables on the 6/12-months Hammersmith Motor Functional Scale Expanded score prediction (HFMSE). This study represents the first approach to artificial intelligence and trained models for the prediction of individualized trajectories of HFMSE disease progression using individual characteristics of the patient. The application of this method to larger cohorts may allow to identify different classes of progression, a crucial information at the time of the new commercially available therapies.

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.

The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers.

Background The worldwide landscape of patient registries in the neuromuscular disease (NMD) field has significantly changed in the last 10 years, with the international TREAT-NMD network acting as strong driver. At the same time, the European Medicines Agency and the large federations of rare disease patient organizations (POs), such as EURORDIS, contributed to a great cultural change, by promoting a paradigm shift from product-registries to patient-centred registries. In Italy, several NMD POs and Fondazione Telethon undertook the development of a TREAT-NMD linked patient registry in 2009, with the referring clinical network providing input and support to this initiative through the years. This article describes the outcome of this joint effort and shares the experience gained. Methods The Italian NMD registry is based on an informatics technology platform, structured according to the most rigorous legal national and European requirements for management of patient sensitive data. A user-friendly web interface allows both direct patients and clinicians’ participation. The platform’s design permits expansion to incorporate new modules and new registries, and is suitable of interoperability with other international efforts. Results When the Italian NMD Registry was initiated, an ad hoc legal entity (NMD Registry Association) was devised to manage registries’ data. Currently, several disease-specific databases are hosted on the platform. They collect molecular and clinical details of individuals affected by Duchenne or Becker muscular dystrophy, Charcot-Marie-Tooth disease, transthyretin type-familial amyloidotic polyneuropathy, muscle glycogen storage disorders, spinal and bulbar muscular atrophy, and spinal muscular atrophy. These disease-specific registries are at different stage of development, and the NMD Registry itself has gone through several implementation steps to fulfil different technical and governance needs. The new governance model is based on the agreement between the NMD Registry Association and the professional societies representing the Italian NMD clinical network. Overall, up to now the NMD registry has collected data on more than 2000 individuals living with a NMD condition. Conclusions The Italian NMD Registry is a flexible platform that manages several condition-specific databases and is suitable to upgrade. All stakeholders participate in its management, with clear roles and responsibilities. This governance model has been key to its success. In fact, it favored patient empowerment and their direct participation in research, while also engaging the expert clinicians of the Italian network in the collection of accurate clinical data according to the best clinical practices.

Objective The aim of this paper was to report the 2‐year follow‐up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. Methods Sixty‐eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE‐2) at the time they started treatment and 12 and 24 months after that. Results For both CHOP and HINE‐2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24‐month scores for the whole group. When age subgroups (<210 days, <2 years, 2–4 years, 5–11 years, 12–18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE‐2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not. Interpretation Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children.