Communicative development inventory in type 1 and presymptomatic infants with spinal muscular atrophy: a cohort study.

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.

Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy.

The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.

Different trajectories in upper limb and gross motor function in spinal muscular atrophy.

INTRODUCTION: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 mo. METHODS: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-mo changes also included the analysis of concordance between scales with changes grouped as stable (±2 points), improved (>+2) or declined (>-2). RESULTS: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2, the point of slope change was 4.1 y for the HFMSE and 5.8 for the RULM, while for type 3, it was 6 y for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least two assessments at 12 mo. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups. DISCUSSION: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

Nusinersen in pediatric and adult patients with type III spinal muscular atrophy.

OBJECTIVE: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. METHODS: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment. RESULTS: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. INTERPRETATION: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen.

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.

A critical review of patient and parent caregiver oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in spinal muscular atrophy.

The positive outcome of different therapeutic approaches for spinal muscular atrophy (SMA) in clinical trials and in clinical practice have highlighted the need to establish if functional changes are associated with possible changes of patient health-related quality of life or have an effect on activities of daily living and caregiver burden. The aim of this paper is to provide a critical review of the tools previously or currently used to measure quality of life, activity of daily living, and caregiver burden in SMA. We identified 36 measures. Only 6 tools were specifically developed for SMA while the others had been used and at least partially validated in wider groups of neuromuscular disorders including SMA. Twelve of the 36 focused on health-related quality of life, 5 on activities of daily living and 9 on caregiver burden. Ten included a combination of items. The review provides a roadmap of the different tools indicating their suitability for different SMA types or age groups. Scales assessing activities of daily living and care burden can provide patients and carers perspective on functional changes over time that should be added to the observer rated scales used in clinic.

Long-term progression in type II spinal muscular atrophy: A retrospective observational study.

OBJECTIVE: To report the long-term progression in a cohort of patients with type II spinal muscular atrophy (SMA) assessed with the Hammersmith Functional Motor Scale-Expanded. METHODS: Seventy-three patients (age 2.6-25 years) were included in the study. Twenty-eight of the 73 were first assessed before the age of 5 years and had been followed up for ≈5 years or longer. We observed an overall progression that was not linear. A piecewise regression analysis showed an improvement of scores in the younger patients with a point of slope change at ≈5 years of age, a decline between 5 and 13 years of age, and stability/slower decline after that. RESULTS: Patients with the lowest scores at baseline had the earliest onset of scoliosis and a higher need for noninvasive ventilation compared to those with higher scores. Our results confirm that on the long-term follow-up all patients with type II SMA show a clear and progressive decline. CONCLUSION: The severity of functional impairment at baseline can help to predict the magnitude of changes over time and the overall progression, including onset of scoliosis and need for noninvasive ventilation.

Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain.

Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.