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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., Competing Interests: Declaration of Competing Interest GC, RDS, JM, AMG, SDY, MP, SM, ADA, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees BIOGEN S.R.L. outside the submitted work; GC, MCP, RDS, JM, AMG, SDY, MS, BTD, EB, JD, FM, DCDV, RF, CB, EM reports personal fees ROCHE outside the submitted work; GC reports personal fees GENESIS PHARMA and Biologix outside the submitted work; GC, RDS, AMG, MP, SM, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees AVEXIS outside the submitted work; AP, SDY, reports personal fees SMA FOUNDATION outside the submitted work; SDY reports personal fees SCHOLAR ROCK outside the submitted work; ADA, JD, RF reports personal fees NOVARTIS outside the submitted work; SL, SC, LA, AF, FS, PT, MC, TD, have nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5' (upstream) and 3' (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p > 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3' adjacent nucleotide ("stop+4 model") was considered (p < 0.05) with patients with stop codon TGA and 3' adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier B.V.)

The aim of the study was to re-assess neuropsychological profile in a group of boys with Duchenne muscular dystrophy without intellectual disability and neuropsychiatric disorder three years apart from a previous evaluation, to establish possible changes over time. We were also interested in defining more in detail correlation between genotype and neuropsychological phenotype. Thirty-three of the previous 40 subjects (mean age at follow up: 10 years and 7 months) agreed to participate in the follow up study and to perform the new assessment. The results confirm a typical neuropsychological profile, with difficulty in the manipulation of stored information, poor abstract reasoning and planning capacity and impulsiveness, supporting the involvement of a cerebellar striatal cortical network for these children. The more detailed description of subgroups of subjects, according to the real expression of Dp140, let to reveal possible genotype-neuropsychological phenotype correlations, and a more general neuropsychological impairment emerged in boys without Dp140 expression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The advent of clinical trials in spinal muscular atrophy (SMA) has highlighted the need to define patterns of progression using functional scales. It has recently been suggested that the analysis of abilities gained or lost applied to functional scales better reflects meaningful changes. We defined as "gain" a positive change between scores from 0 to either 1 or 2 and as "loss" a negative change from either 2 or 1 to 0. The aim of this study was to describe, over 12 months, which abilities on the Hammersmith Functional Motor Scale Expanded (HFMSE) were more frequently lost or gained in patients with SMA II. The cohort included 614 12-month assessments from 243 patients (age range: 30 months - 63 years; mean 9.94, SD ±7.91). The peak of abilities gained occurred before the age of 5 years while the highest number of lost abilities was found in the group 5-13 years. A correlation between the HFMSE baseline score and the ordinal number of the items was found for both lost (p<0.001) or gained (p<0.001) activities. No correlation was found with SMN2 copy number. These findings will have implications for clinical trial design and for the interpretation of real-world data using new therapeutic approaches., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease ≥2 points was found in 21% at 12 months and in 35% at 24 months. An increase ≥2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing ≥2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a >2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p<0.001) and by 26% after 13 years (p = 0.003). The combination of age and HFMSE scores at baseline increased the ability to predict progression in type 2 SMA., Competing Interests: Authors and ISMAC group Declaration of Competing Interest GC, RDS, JM, ESM, AM, AMG, SDY, RS, MP, SM, ADA, EA, BTD, EB, VAS, JD, FM, DCDV, RF, EM reports personal fees as consultant, PI or member on advisory board form BIOGEN S.R.L. outside the submitted work, GC, MCP, JM, ESM, AM, AMG, SDY, MS, BTD, EB, JD, FM, FB, DCDV, RF, EM reports personal fees consultant, PI or member on advisory board from ROCHE, GC reports personal fees GENESIS PHARMA and Biologix as consultant outside the submitted work, GC, RDS, ESM, AM, AMG, RS, MP, SM, BTD, EB, VAS, JD, FM, DCDV, RF, EM reports personal fees consultant, PI or member on advisory board form AVEXIS outside the submitted work, AP, SDY, RS reports personal fees from as grant SMA FOUNDATION outside the submitted work, ESM, SDY, EM report personal fees consultant, PI or member on advisory board from SCHOLAR ROCK outside the submitted work, MS reports personal fees as CO-PI from SMA REACH UK outside the submitted work, ADA, JD, RF reports personal fee as consultant, PI or member on advisory board from NOVARTIS outside the submitted work, SL, JEE, SC, EM, LA, AF, MVDH, FS, CMB, MC, RML, MM, MS, GV, TD, NG, ANO, have nothing to disclose. All authors from Italy, UK and US are part of institutions that receive funding from Biogen for a SMA disease registry (ISMAR), (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this prospective multicentric study was to document disease progression in young boys affected by Duchenne muscular dystrophy (DMD) between age 3 and 6 years (±3 months) using the North Star Ambulatory Assessment scale. One hundred fifty-three DMD boys (573 assessments) younger than 6 years (mean: 4.68, SD: 0.84) with a genetically proven DMD diagnoses were included. Our results showed North Star Ambulatory Assessment scores progressively increased with age. The largest increase was observed between age 3 and 4 years but further increase was steadily observed until age of 6 years. Using a multiple linear regression analysis, we found that both the use of corticosteroids and the site of mutation significantly contributed to the North Star Ambulatory Assessment changes (p < 0.001). At each age point, boys on corticosteroid treatment had higher scores than corticosteroid naïve ones (p < 0.001). Similarly, patients with mutations downstream exon 44, had lower baseline scores and lower magnitude of changes compared to those with mutations located at the 5' end of the gene (p < 0,001). Very few boys achieved the age appropriate maximum score. These results provide useful information for the assessment and counselling of young DMD boys and for the design of clinical trials in this age group., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We report preliminary data on the six month use of Nusinersen in 104 type 1 patients of age ranging from three months to 19 years, 9 months. Ten of the 104 were classified as 1.1, 58 as 1.5 and 36 as 1.9. Three patients had one SMN2 copy, 65 had two and 24 had three copies. In 12 the SMN2 copy number was not available. After six months an improvement of more than two points was found in 58 of the 104 (55.7%) on the CHOP INTEND and in 21 of the 104 (20.19%) on the Hammersmith Infant Neurological Examination (HINE). Changes more than two points were found in 26/71 patients older than two years, and in seven of the 20 older than 10 years. Changes ≥ four points were found in 20/71 older than two years, and in six of the 20 patients older than 10 years. The difference between baseline and six months on both CHOP INTEND and HINE was significant for the whole group (p < 0.001) as well as for the subgroups with two (p < 0.001), and three SMN2 copies (p < 0.001). Our preliminary results suggest that functional improvement can be observed in type 1 patients outside the range of the inclusion criteria used in the Endear study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of our prospective observational study was to assess profiles of cognitive function and a possible impairment of executive functions in a cohort of boys with Duchenne muscular dystrophy without intellectual and behavior disability. Forty Duchenne boys (range of age: 6 years to 11 years and 6 months) were assessed by Wechsler Intelligence scale and battery of tests including tasks assessing working memory and executive functions (inhibition and switching, problem solving and planning). In our cohort some aspects of cognitive function were often impaired. These included multitasking, problem solving, inhibition and working memory necessary to plan and direct goal oriented behavior. Our results support the suggestion that aspects of cognitive function could be impaired even in boys without intellectual disability and support the hypothesis that executive functions may play an important role in specific aspects of cognitive impairment in Duchenne muscular dystrophy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The advent of clinical trials has highlighted the need for natural history studies reporting disease progression in type 1 spinal muscular atrophy. The aim of this study was to assess functional changes using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale in a cohort of type 1 infants. Nutritional and respiratory longitudinal data were also recorded. Patients were classified according to the severity of the phenotype and age of onset. SMN2 copies were also assessed. Twenty patients were included, eight with early onset most severe phenotype, eight with the more typical type 1 phenotype and 4, who achieved some head control, with a milder phenotype. Both baseline values and trajectories of progression were different in the three subgroups (p = 0.0001). Infants with the most severe phenotype had the lowest scores (below 20) on their first assessment and had the most rapid decline. Those with the typical phenotype had scores generally between 20 and 40 and also had a fast decline. The infants with the milder phenotype had the highest scores, generally above 35, and a much slower deterioration. Infants with three SMN2 copies had an overall milder phenotype and milder progression while two SMN2 copies were found in all three subgroups., (Copyright © 2017. Published by Elsevier B.V.)