Combination disease-modifying treatment in spinal muscular atrophy: A proposed classification

We sought to devise a rational, systematic approach for defining/grouping survival motor neuron-targeted disease-modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two-part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add-on, transient add-on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA

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 (± 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

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

Neurofilament as a potential biomarker for spinal muscular atrophy

Objective: To evaluate plasma phosphorylated neurofilament heavy chain (pNF-H) as a biomarker in spinal muscular atrophy (SMA). Methods: Levels of pNF-H were measured using the ProteinSimple® platform in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease. Results: Median pNF-H plasma level was 167.0 pg/mL (7.46-7,030; n = 34) in children without SMA (aged 7 weeks-18 years) and was higher in those aged < 1 versus 1-18 years (P = 0.0002). In ENDEAR participants with infantile-onset SMA, median baseline pNF-H level (15,400 pg/mL; 2390-50,100; n = 117) was ~10-fold higher than that of age-matched infants without SMA (P < 0.0001) and ~90-fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF-H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF-H levels: nusinersen-treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control-treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months. Interpretation: Plasma pNF-H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF-H levels followed by relative stabilization. Together these data suggest plasma pNF-H is a promising marker of disease activity/treatment response in infants with SMA

Determining minimal clinically important differences in the Hammersmith Functional Motor Scale Expanded for untreated spinal muscular atrophy patients: An international study

\ua9 2024 The Authors. European Journal of Neurology published by John Wiley &amp; Sons Ltd on behalf of European Academy of Neurology.Background and purpose: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. Methods: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire. Results: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of −2 for type II and −4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and −3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type. Conclusions: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies

Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a\u27s than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes

Clinical variability in spinal muscular atrophy type III

Objective: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. Methods: HFMSE longitudinal changes were assessed using piecewise linear mixed‐effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12‐month assessments. Results: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (β = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (β = −1.15, p < 0.0001) and IIIB (β = −0.69, p = 0.002). Interpretation: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real‐world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109–111

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field