Gain and loss of abilities in type II SMA: A 12-month natural history study

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

Development of an academic disease registry for spinal muscular atrophy

We report the development of a new disease registry on SMA as the result of a collaboration among three national networks in United States, Italy, and United Kingdom in partnership with a biotechnology company and with the support of advocacy groups.The aim of establishing a large collaborative registry within academic centers was to establish a structured but flexible system for collection of prospective, highly curated data that will deeply phenotype all patients with SMA and follow them longitudinally over several years.This paper describes the process leading to the development of the registry including the identification of the relevant data elements, the design of an electronic CRF with a shared data dictionary, the piloting of the first version and the definition of the final version.The registry will provide a central structure for conducting academic studies based on a much larger cohort of patients than those available in the individual networks. Due to the quality control of the data collected the registry can also be used for postmarketing purposes, allowing to share, in a transparent and controlled way, real-world data with pharmaceutical partners, drug regulatory agencies, and advocacy groups for better understanding of safety and effectiveness of new treatments. (C) 2019 Published by Elsevier B.V

Age and baseline values predict 12 and 24-month functional changes in type 2 SMA

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 (\ub1 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease 652 points was found in 21% at 12 months and in 35% at 24 months. An increase 652 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing 652 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 &gt;2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p&lt;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 SM

Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen

Background and purpose Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry.Methods We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type.Results The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle &gt;50 degrees (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p &gt; 0.05).Conclusions Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes

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

none32Objective: 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&nbsp;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&nbsp;months on both HFMSE (1.18 points, p&nbsp;=&nbsp;0.004) and RULM scores (0.58 points, p&nbsp;=&nbsp;0.014) but not on the 6MWT (mean difference&nbsp;=&nbsp;6.65&nbsp;m, p&nbsp;=&nbsp;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&nbsp;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.mixedPera M.C.; Coratti G.; Bovis F.; Pane M.; Pasternak A.; Montes J.; Sansone V.A.; Dunaway Young S.; Duong T.; Messina S.; Mizzoni I.; D'Amico A.; Civitello M.; Glanzman A.M.; Bruno C.; Salmin F.; Morando S.; De Sanctis R.; Sframeli M.; Antonaci L.; Frongia A.L.; Rohwer A.; Scoto M.; De Vivo D.C.; Darras B.T.; Day J.; Martens W.; Patanella K.A.; Bertini E.; Muntoni F.; Finkel R.; Mercuri E.Pera, M. C.; Coratti, G.; Bovis, F.; Pane, M.; Pasternak, A.; Montes, J.; Sansone, V. A.; Dunaway Young, S.; Duong, T.; Messina, S.; Mizzoni, I.; D'Amico, A.; Civitello, M.; Glanzman, A. M.; Bruno, C.; Salmin, F.; Morando, S.; De Sanctis, R.; Sframeli, M.; Antonaci, L.; Frongia, A. L.; Rohwer, A.; Scoto, M.; De Vivo, D. C.; Darras, B. T.; Day, J.; Martens, W.; Patanella, K. A.; Bertini, E.; Muntoni, F.; Finkel, R.; Mercuri, E

Revised upper limb module for spinal muscular atrophy: 12 month changes

Introduction: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3. Methods: Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module. Results: The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0.45 in type 2, -0.23 in non-ambulant type 3 and -0.34 in ambulant type 3, p = 0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients. Discussion: Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non-ambulant patients of different ages in conjunction with other functional scales. Muscle Nerve 59:426\u2013430, 2019