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KIF1A-associated neurological disorder (KAND) is a neurodegenerative and often lethal ultrarare disease with a wide phenotypic spectrum associated with largely heterozygous de novo missense variants in KIF1A. Antisense oligonucleotide treatments represent a promising approach for personalized treatments in ultrarare diseases. Here we report the case of one patient with a severe form of KAND characterized by refractory spells of behavioral arrest and carrying a p.Pro305Leu variant in KIF1A, who was treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the mRNA from the pathogenic allele. The first intrathecal administration was complicated by an epidural cerebrospinal fluid collection, which resolved spontaneously. Otherwise, the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved. There was little change in the 6-min Walk Test distance, but qualitative changes in gait resulting in meaningful reductions in falls and increasing independence were observed. Cognitive performance was stable and did not degenerate over time. Our findings provide preliminary insights on the safety and efficacy of an allele-specific antisense oligonucleotide as a possible treatment for KAND.

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Protein phosphatase 2 regulatory subunit B56δ related neurodevelopmental disorder (PPP2R5D-related NDD) is largely caused by de novo heterozygous missense PPP2R5D variants. We report medical characteristics, longitudinal adaptive functioning, and in-person neurological, motor, cognitive, and electroencephalogram (EEG) activity for PPP2R5D-related NDD. Forty-two individuals (median age 6 years, range = 0.8-25.3) with pathogenic/likely pathogenic PPP2R5D variants were assessed, and almost all variants were missense (97.6%) and de novo (85.7%). Common clinical symptoms were developmental delay, hypotonia, macrocephaly, seizures, autism, behavioral challenges, and sleep problems. The mean Gross motor functional measure-66 was 60.2 ± 17.3% and the mean Revised upper limb module score was 25.9 ± 8.8. The Vineland-3 adaptive behavior composite score (VABS-3 ABC) at baseline was low (M = 61.7 ± 16.8). VABS-3 growth scale value scores increased from baseline in all subdomains (range = 0.6-5.9) after a mean follow-up of 1.3 ± 0.3 years. EEG beta and gamma power were negatively correlated with VABS-3 score; p < 0.05. Individuals had a mean Quality-of-life inventory-disability score of 74.7 ± 11.4. Twenty caregivers (80%) had a risk of burnout based on the Caregiver burden inventory. Overall, the most common clinical manifestations of PPP2R5D-related NDD were impaired cognitive, adaptive function, and motor skills; and EEG activity was associated with adaptive functioning. This clinical characterization describes the natural history in preparation for clinical trials.

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BACKGROUND: The Hammersmith Functional Motor Scale Expanded (HFMSE) has been widely used to assess the motor function of patients with spinal muscular atrophy (SMA) older than 2 years, with the ability to sit and/or walk. OBJECTIVE: To translate, cross-culturally adapt and validate the HFMSE to Brazilian Portuguese. METHODS: The translation process and cross-cultural adaptation followed international guidelines recommendations. The reliability and applicability of the Brazilian version consisted of the application of the HFMSE (in Brazilian Portuguese) to 20 patients with types 2 and 3 SMA. Two examiners assessed the participants for interrater reliability, through the analysis of Kappa reliability agreement (k) and intraclass correlation coefficient (ICC). RESULTS: The HFMSE was successfully translated and cross culturally adapted to Brazilian Portuguese. Twenty participants with types 2 and 3 SMA were enrolled in the study (type 2 = 6; type 3 = 14). The ICC for the total score showed very high reliability (ICC =1.00), and the reliability of each of the items individually was considered excellent (Kappa > 0.80). CONCLUSION: The Brazilian version of the HFMSE proved to be valid and reliable for the evaluation of SMA patients older than 2 years with the ability to sit and/or walk.

ANTECEDENTES: A Hammersmith Functional Motor Scale Expanded (HFMSE) tem sido amplamente utilizada para avaliar a função motora de pacientes com atrofia muscular espinhal (AME) maiores de dois anos, com capacidade de sentar e/ou andar. OBJETIVO: Traduzir, adaptar transculturalmente e validar a HFMSE para o português brasileiro. MéTODOS: A tradução e a adaptação transcultural seguiram as diretrizes internacionais. A confiabilidade e a aplicabilidade da versão brasileira consistiram na aplicação da HFMSE (em português brasileiro) em 20 pacientes com AME tipos 2 e 3. Dois examinadores avaliaram os participantes quanto à confiabilidade interexaminadores, por meio da análise da concordância de confiabilidade Kappa (k) e do coeficiente de correlação intraclasse (intraclass correlation coefficient [ICC]). RESULTADOS: O processo de tradução e adaptação transcultural da HFMSE para o português brasileiro foi concluído com sucesso. Vinte participantes com AME tipos 2 e 3 foram incluídos no estudo (tipo 2 = 6; tipo 3 = 14). O ICC para o escore total apresentou confiabilidade alta (ICC = 1.00) e a confiabilidade de cada um dos itens individualmente foi considerada excelente (K > 0,80). CONCLUSãO: A HFMSE (PT-BR) mostrou-se válida e confiável para a avaliação de pacientes com AME, com mais de dois anos de idade e com capacidade de sentar-se independentemente e/ou andar.

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Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020. Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected. Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up. Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned. Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.

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PURPOSE: Pathogenic variants in kinesin family member 1A (KIF1A) are associated with KIF1A-associated neurological disorder. We report the clinical phenotypes and correlate genotypes of individuals with KIF1A-associated neurological disorder. METHODS: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic, and cognitive assessments. RESULTS: We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic KIF1A variants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland adaptive behavior composite score (VABS-ABC) was low (M = 62.9, SD = 19.1). The mean change in VABS-ABC over time was -3.1 (SD = 7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between evolutionary scale model (ESM) score for the variants and final VABS-ABC (P = .003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (P < .001). CONCLUSION: In-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.

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Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale-Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = -0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = -0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies.

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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.

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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's 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.

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BACKGROUND: Individuals with PPP2R5D-related neurodevelopmental disorder have an atypical gait pattern characterized by ataxia and incoordination. Structured, quantitative assessments are needed to further understand the impact of these impairments on function. RESEARCH QUESTION: How do gait parameters and ambulatory function of individuals with PPP2R5D-related neurodevelopmental disorder compare to age and sex matched healthy norms? METHODS: Twenty-six individuals with PPP2R5D pathogenic genetic variants participated in this observational, single visit study. Participants completed at least one of the following gait assessments: quantitative gait analysis at three different speeds (preferred pace walking (PPW), fast paced walking (FPW) and running, six-minute walk test (6MWT), 10-meter walk run (10MWR), and timed up and go (TUG). Descriptive statistics were used to summarize gait variables. Percent of predicted values were calculated using published norms. Paired t-tests and regression analyses were used to compare gait variables. RESULTS: The median age of the participants was 8 years (range 4-27) and eighteen (69.2 %) were female. Individuals with PPP2R5D-related neurodevelopmental disorder walked slower and with a wider base of support than predicted for their age and sex. Stride velocity ranged from 48.9 % to 70.1 % and stride distance from 58.5 % to 81.9 % of predicted during PPW. Percent of predicted distance walked on the 6MWT ranged from 30.6 % to 71.1 % representing varied walking impairment. Increases in stride distance, not cadence, were associated with changes in stride velocity in FPW (R2 = 0.675, p =< 0.001) and running conditions (R2 = 0.918, p =< 0.001). SIGNIFICANCE: We quantitatively assessed the abnormal gait in individuals with PPP2R5D-related neurodevelopmental disorder. These impairments may affect ability to adapt to environmental changes and participation in daily life. Rehabilitative interventions targeting gait speed and balance may improve function and safety for individuals with PPP2R5D-related neurodevelopmental disorder.

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BACKGROUND: Protein phosphatase 2 regulatory subunit B' Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder. RESULTS: Thirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1-27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1-96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = -0.733; p < 0.001), TUG (rs= -0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains. CONCLUSIONS: The GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.

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Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver-reported data (medical history, adaptive function, quality of life, and behavior issues) and in-person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure-66 score was 56.6 (SD = 14.8). Average time to complete Nine-Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty-five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory-Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder.

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Abstract Background The Hammersmith Functional Motor Scale Expanded (HFMSE) has been widely used to assess the motor function of patients with spinal muscular atrophy (SMA) older than 2 years, with the ability to sit and/or walk. Objective To translate, cross-culturally adapt and validate the HFMSE to Brazilian Portuguese. Methods The translation process and cross-cultural adaptation followed international guidelines recommendations. The reliability and applicability of the Brazilian version consisted of the application of the HFMSE (in Brazilian Portuguese) to 20 patients with types 2 and 3 SMA. Two examiners assessed the participants for interrater reliability, through the analysis of Kappa reliability agreement (k) and intraclass correlation coefficient (ICC). Results The HFMSE was successfully translated and cross culturally adapted to Brazilian Portuguese. Twenty participants with types 2 and 3 SMA were enrolled in the study (type 2 = 6; type 3 = 14). The ICC for the total score showed very high reliability (ICC =1.00), and the reliability of each of the items individually was considered excellent (Kappa > 0.80). Conclusion The Brazilian version of the HFMSE proved to be valid and reliable for the evaluation of SMA patients older than 2 years with the ability to sit and/or walk.

Resumo Antecedentes A Hammersmith Functional Motor Scale Expanded (HFMSE) tem sido amplamente utilizada para avaliar a função motora de pacientes com atrofia muscular espinhal (AME) maiores de dois anos, com capacidade de sentar e/ou andar. Objetivo Traduzir, adaptar transculturalmente e validar a HFMSE para o português brasileiro. Métodos A tradução e a adaptação transcultural seguiram as diretrizes internacionais. A confiabilidade e a aplicabilidade da versão brasileira consistiram na aplicação da HFMSE (em português brasileiro) em 20 pacientes com AME tipos 2 e 3. Dois examinadores avaliaram os participantes quanto à confiabilidade interexaminadores, por meio da análise da concordância de confiabilidade Kappa (k) e do coeficiente de correlação intraclasse (intraclass correlation coefficient [ICC]). Resultados O processo de tradução e adaptação transcultural da HFMSE para o português brasileiro foi concluído com sucesso. Vinte participantes com AME tipos 2 e 3 foram incluídos no estudo (tipo 2 = 6; tipo 3 = 14). O ICC para o escore total apresentou confiabilidade alta (ICC = 1.00) e a confiabilidade de cada um dos itens individualmente foi considerada excelente (K > 0,80). Conclusão A HFMSE (PT-BR) mostrou-se válida e confiável para a avaliação de pacientes com AME, com mais de dois anos de idade e com capacidade de sentar-se independentemente e/ou andar.

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Measuring center-of-pressure (COP) trajectories in out-of-the-lab environments may provide valuable information about changes in gait and balance function related to natural disease progression or treatment in neurological disorders. Traditional equipment to acquire COP trajectories includes stationary force plates, instrumented treadmills, electronic walkways, and insoles featuring high-density force sensing arrays, all of which are expensive and not widely accessible. This study introduces novel deep recurrent neural networks that can accurately estimate dynamic COP trajectories by fusing data from affordable and heterogeneous insole-embedded sensors (namely, an eight-cell array of force sensitive resistors (FSRs) and an inertial measurement unit (IMU)). The method was validated against gold-standard equipment during out-of-the-lab ambulatory tasks that simulated real-world walking. Root-mean-square errors (RMSE) in the mediolateral (ML) and anteroposterior (AP) directions obtained from healthy individuals (ML: 0.51 cm, AP: 1.44 cm) and individuals with neuromuscular conditions (ML: 0.59 cm, AP: 1.53 cm) indicated technical validity. In individuals with neuromuscular conditions, COP-derived metrics showed significant correlations with validated clinical measures of ambulatory function and lower-extremity muscle strength, providing proof-of-concept evidence of the convergent validity of the proposed method for clinical applications.

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Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a -1.4 (95% CI -2.6, -0.2) point decrease in HFMSE (p = 0.02) and a -1.2 (95% CI -2.1, -0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline.

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BACKGROUND: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose. OBJECTIVE: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A. METHODS: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses. RESULTS: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1-12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing. CONCLUSIONS: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

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BACKGROUND: Physical activity (PA) provides many substantial benefits to help reduce risk for cardiometabolic disease, improve cognitive function, and improve quality of life. Individuals with neuromuscular disorders (NMDs), such as spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are characterized by muscular weakness and fatigue, which limits the capacity to reach the recommended guidelines of PA. Measuring PA in these populations can provide insight to participation in daily activities, track disease progression, and monitor efficacy of drug treatments. OBJECTIVE: The objective of this study was to identify how PA is measured in SMA and DMD using instrumented and self-report methods, and how these methods are employed in ambulatory and non-ambulatory groups. METHODS: A scoping review was performed to identify studies that reported PA in these neuromuscular disorders. Inclusion was determined after a multi-stage review process by several reviewers, followed by an in-depth analysis of metrics reported by each tool that was used. RESULTS: A total of nineteen studies were identified and included in this review. Sixteen studies included instrumented measures and four studies utilized self-reported measures, with eleven studies also reporting PA information from a non-ambulatory group. A variety of metrics have been reported using both classes of measurement tools. CONCLUSION: Although a wide variety of research exists that details both instrumented and self-reported measurement tools, feasibility, cost, and study aims are important factors to consider in addition to testing methodology when selecting which type of tool to use. We recommend using a combination of instrumented and self-report measures to provide context to the PA measured in these populations. Improvements in both instrumented and self-report methodologies will add valuable knowledge about the disease burden and efficacy of treatment and disease management methods in SMA and DMD.

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Fatigue, a common symptom, together with the characteristic of performance fatigability, are well-documented features of SMA that impact quality of life and function. Importantly, establishing associations between multidimensional self-reported fatigue scales and patient performance has proven difficult. This review was conducted to evaluate the various patient-reported fatigue scales applied in SMA, with the objective of considering the limitations and advantages of each measure. Variable use of fatigue-related nomenclature, including conflicting terminology interpretation, has affected assessment of physical fatigue attributes, specifically perceived fatigability. This review encourages the development of original patient-reported scales to enable perceived fatigability assessment, providing a potential complementary method of evaluating treatment response.

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The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

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INTRODUCTION/AIMS: The Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) was first developed as a secondary functional outcome measure to detect changes over time in patients with spinal muscular atrophy (SMA) in clinical trials. Its modified version evaluates 10 activities of daily living. The aim of the study was to analyze modified SMAFRS data using item response theory psychometric models. METHODS: A total of 253 responses from 41 adult patients with ambulatory and non-ambulatory SMA types 2, 3, and 4 were analyzed. Rasch analysis was used to explore item-person targeting, fit statistics, category response functioning, dimensionality, and differential item functioning. RESULTS: Most items had good fitting with the exception of "toileting" and "respiratory." There were no major floor or ceiling effects, and most items covered a good range of disability with only a negligible breech of uni-dimensionality from eating, dressing, and respiratory items. Differential item function highlighted differences in toileting, turning, transferring, walking, and respiratory items between ambulatory and non-ambulatory populations. DISCUSSION: Despite subtle misfitting of certain items, mainly related to respiratory and bulbar function, overall modified SMAFRS remained a psychometrically stable and unidimensional outcome measure. There were some differences in measuring properties of certain functional items between ambulatory and non-ambulatory items that need to be taken into consideration in clinical trial design. Overall, the modified SMAFRS is a psychometrically reliable tool in assessment of adult patients with SMA.

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INTRODUCTION/AIMS: Fatiguability and perceived fatigue are common unrelated symptoms in ambulatory individuals with spinal muscular atrophy (SMA). Ratings of perceived exertion (RPE) measures the sense of effort during an activity and has been used as a proxy for fatigue. Relationships between perceived fatigue, fatiguability, and RPE have been described in healthy populations, but the relationship in SMA has not been examined. METHODS: Eighteen ambulatory individuals with SMA and 16 age-matched controls (age, 13 to 57 years; 26 [76.5%] males) performed the 6-minute walk test (6MWT) and cardiopulmonary exercise tolerance test (CPET) and completed the International Physical Activity Questionnaire---short form (IPAQ). RPE was collected during the CPET and 6MWT. Fatiguability was measured during the 6MWT. Physical activity (PA) volume was calculated using the IPAQ. Wilcoxon rank-sum tests were used to compare groups. Spearman correlation coefficients evaluated associations between variables. SMA subgroups were predetermined using 6MWT distances of over or under 300 meters. RESULTS: There were no significant associations between fatiguability and RPE or PA in SMA (P > .05). PA was strongly associated with 6MWT RPE (r = 0.71) in SMA individuals who walked fewer than 300 meters (n = 7). There were no significant associations between any variables in controls (P > .05). DISCUSSION: RPE is not associated with fatiguability in SMA. The possible association of PA and RPE may reflect the increased intensity of the 6MWT in weaker patients. RPE represents a sense of effort during exercise and should not be used as a substitute for fatiguability but may be a measure of patient experience during exercise.

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