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Objective: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies. Methods: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA). Results: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow‐up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross‐sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43). Interpretation: Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023;94:1126–1135 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this paper was to report the 2‐year follow‐up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. Methods: Sixty‐eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE‐2) at the time they started treatment and 12 and 24 months after that. Results: For both CHOP and HINE‐2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24‐month scores for the whole group. When age subgroups (<210 days, <2 years, 2–4 years, 5–11 years, 12–18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE‐2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not. Interpretation: Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children. [ABSTRACT FROM AUTHOR]

TSFM is a nuclear gene encoding the elongation factor Ts (EFTs), an essential component of mitochondrial translational machinery. Impaired mitochondrial translation is responsible for neurodegenerative disorders characterized by multiple respiratory chain complex defects, multisystemic involvement, and neuroradiological features of Leigh-like syndrome. With the use of a next-generation sequencing (NGS)–based multigene panel for mitochondrial disorders, we identified the novel TSFM homozygous variant c.547G>A (p.Gly183Ser) in a 5-year-old boy with infantile early onset encephalocardiomyopathy, sensorineural hearing loss, and peculiar partially reversible neuroimaging features. Our findings expand the phenotypic spectrum of TSFM-related encephalopathy, offering new insights into the natural history of brain involvement and suggesting that TSFM should be investigated in pediatric mitochondrial disorders with distinctive neurologic and cardiac involvement. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this international collaborative effort was to report 36-month longitudinal changes using the 6MWT in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. Materials and methods: Of the 92 patients included in the study, 24 had deletions amenable to skip exon 44, 27 exon 45, 18 exon 51, and 28 exon 53. Five patients with a single deletion of exon 52 were counted in both subgroups skipping exon 51 and 53. Results: The difference between subgroups amenable to skip different exons was not significant at 12 months but became significant at both 24 (p≤0.05) and 36 months (p≤0.01). Discussion: Mutations amenable to skip exon 53 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had better results both at baseline and at follow up. Deletions amenable to skip exon 45 were associated with a more variable pattern of progression. Single exon deletions were more often associated with less drastic changes but this was not always true in individual cases. Conclusion: Our results confirm that the progression of disease can differ between patients with different deletions, although the changes only become significant from 24 months onwards. This information is relevant because there are current clinical trials specifically targeting patients with these subgroups of mutations. [ABSTRACT FROM AUTHOR]

Background: A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases.Results: During the clinical follow-up (range: 2-44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias.Conclusion: The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases. [ABSTRACT FROM AUTHOR]

Introduction: Limb girdle muscular dystrophies (LGMDs) are characterized by high molecular heterogeneity, clinical overlap, and a paucity of specific biomarkers. Their molecular definition is fundamental for prognostic and therapeutic purposes.Methods: We created an Italian LGMD registry that included 370 molecularly defined patients. We reviewed detailed retrospective and prospective data and compared each LGMD subtype for differential diagnosis purposes.Results: LGMD types 2A and 2B are the most frequent forms in Italy. The ages at disease onset, clinical progression, and cardiac and respiratory involvement can vary greatly between each LGMD subtype. In a set of extensively studied patients, targeted next-generation sequencing (NGS) identified mutations in 36.5% of cases.Conclusion: Detailed clinical characterization combined with muscle tissue analysis is fundamental to guide differential diagnosis and to address molecular tests. NGS is useful for diagnosing forms without specific biomarkers, although, at least in our study cohort, several LGMD disease mechanisms remain to be identified. Muscle Nerve 55: 55-68, 2017. [ABSTRACT FROM AUTHOR]

POMT2-related limb girdle muscular dystrophy (LGMDR14) is a rare muscular dystrophy caused by mutations in the POMT2 gene. Thus far only 26 LGMDR14 subjects have been reported and no longitudinal natural history data are available. We describe two LGMDR14 patients followed for 20 years since infancy. Both patients presented a childhood-onset, slowly progressive pelvic girdle muscular weakness leading to loss of ambulation in the second decade in one patient, and cognitive impairment without detectable brain structural abnormalities. Glutei, paraspinal, and adductor muscles were the primarily involved muscles at MRI. This report provides natural history data on LGMDR14 subjects, with a focus on longitudinal muscle MRI. We also reviewed the LGMDR14 literature data, providing information on the LGMDR14 disease progression. Considering the high prevalence of cognitive impairment in LGMDR14 patients, a reliable application of functional outcome measures can be challenging, therefore a muscle MRI follow-up to assess disease evolution is recommended. [ABSTRACT FROM AUTHOR]

• The aim was to evaluate scoliosis onset and progression in untreated type II SMA patients. • The mean annual rate of increase of scoliosis angle was 5.63 (95%CI: 4.74–6.52). • The progression of scoliois angles was related to different variables. • Angles progressively increased with decreasing HFMSE scores or increasing age. • Our results confirm the progression of scoliosis in type II SMA. The aim of this study is to retrospectively assess onset and progression of scoliosis in type II SMA patients not treated with the approved disease modifying treatments. Scoliosis was evaluated by measuring the scoliosis angle on X-ray obtained in the anteroposterior view in sitting position (Cobb's angle method). Eighty-four patients had at least one assessment of scoliosis angle (287 assessments). There was a positive correlation between age and scoliosis angles (p <0.001) with a progressive increase of scoliosis with age. When subdividing the population by HFMSE score (<10; 11–22;> 22), there was a progressive increase in scoliosis angles with decreasing HFMSE scores. The difference between HFMSE categories was significant (p <0.001). Fifty-four patients had at least two assessments at 6-month distance and were retained for the longitudinal analysis. Using a mixed model, age, functional status and scoliosis angle at baseline were predictive on scoliosis progression. The mean annual rate of increase of scoliosis angle was 5.63 (95%CI: 4.74–6.52). Our results confirm the progression of scoliosis in untreated type II SMA providing details of the progression in relation to different variables. With different therapeutical options being available in many countries, our findings will provide reference data for establishing possible differences in the trajectories of progression with treated type II individuals. [ABSTRACT FROM AUTHOR]

Background: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment.Methods: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing.Findings: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%).Interpretation: Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

• The aim was to establish 24-month changes in type II and III SMA patients. • 107 patients (54 type II and 53 type III) were grouped by type, function and age. • 23% of patients decreased more than 2 points and 7% improving by >2 points. • Significant changes were observed after 24 but not after 12 months. • Our results suggest a progressive decline in upper limb function. The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches. [ABSTRACT FROM AUTHOR]

• Real world data on functional changes following nusinersen treatment are needed. • At 12 months from the 1st dose of nusinersen, functional increase was observed. • Age and HFMSE score are predictive of the 12-month changes on both scales. • The interpretation of nusinersen effect should consider different variables. • These data confirm and expand the ones already reported in the Cherish study. 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. [ABSTRACT FROM AUTHOR]

• Describe lost or gained activities on the HFMSE in type II SMA over 12 months. • The cohort included 614 12-month assessments from 243 patients. • Data were using with the shift analysis statistical method. • The results were analysed by age, functional level and SMN2 copy number. • The shift approach could be used as an additional tool for data analysis. 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. [ABSTRACT FROM AUTHOR]