A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders.

The emergence of adeno-associated virus (AAV)-based gene therapy has brought hope to patients with severe monogenic disorders. However, immune responses to AAV vectors and transgene products present challenges that require effective immunosuppressive strategies. This systematic review focuses on the immunosuppressive protocols used in 38 clinical trials and 35 real-world studies, considering a range of monogenic diseases, AAV serotypes, and administration routes. The review underscores the need for a deeper understanding of immunosuppressive regimens to enhance the safety and effectiveness of AAV-based gene therapy. Characterizing the immunological responses associated with various gene therapy treatments is crucial for optimizing treatment protocols and ensuring the safety and efficacy of forthcoming gene therapy interventions. Further research and understanding of the impact of immunosuppression on disease, therapy, and route of administration will contribute to the development of more effective and safer gene therapy approaches in the future.

Titin copy number variations associated with dominant inherited phenotypes.

BACKGROUND: Titinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs in TTN have been reported without clear genotype-phenotype associations. METHODS: Our study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in the TTN gene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients' muscles and performed genotype-phenotype inheritance association study by combining the clinical and biological data of these eight families. RESULTS: Seven deletion-type CNVs in the TTN gene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype-phenotype associations of titinopathies. CONCLUSION: Identifying TTN CNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in the TTN gene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype-phenotype associations of titinopathies, mainly distal myopathy in most of the patients.

Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.

BACKGROUND: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure. CONCLUSIONS: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).

Risdiplam in Type 1 Spinal Muscular Atrophy.

BACKGROUND: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. METHODS: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. RESULTS: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. CONCLUSIONS: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Pathogenic DPAGT1 variants in limb-girdle congenital myasthenic syndrome (LG-CMS) associated with tubular aggregates and ORAI1 hypoglycosylation.

AIMS: Limb-girdle congenital myasthenic syndrome (LG-CMS) is a genetically heterogeneous disorder characterized by muscle weakness and fatigability. The LG-CMS gene DPAGT1 codes for an essential enzyme of the glycosylation pathway, a posttranslational modification mechanism shaping the structure and function of proteins. In DPAGT1-related LG-CMS, reduced glycosylation of the acetylcholine receptor (AChR) reduces its localization at the neuromuscular junction (NMJ), and results in diminished neuromuscular transmission. LG-CMS patients also show tubular aggregates on muscle biopsy, but the origin and potential contribution of the aggregates to disease development are not understood. Here, we describe two LG-CMS patients with the aim of providing a molecular diagnosis and to shed light on the pathways implicated in tubular aggregate formation. METHODS: Following clinical examination of the patients, we performed next-generation sequencing (NGS) to identify the genetic causes, analysed the biopsies at the histological and ultrastructural levels, investigated the composition of the tubular aggregates, and performed experiments on protein glycosylation. RESULTS: We identified novel pathogenic DPAGT1 variants in both patients, and pyridostigmine treatment quantitatively improved muscle force and function. The tubular aggregates contained proteins of the sarcoplasmic reticulum (SR) and structurally conformed to the aggregates observed in tubular aggregate myopathy (TAM). TAM arises from overactivation of the plasma membrane calcium channel ORAI1, and functional studies on muscle extracts from our LG-CMS patients evidenced abnormal ORAI1 glycosylation. CONCLUSIONS: We expand the genetic variant spectrum of LG-CMS and provide a genotype/phenotype correlation for pathogenic DPAGT1 variants. The discovery of ORAI1 hypoglycosylation in our patients highlights a physiopathological link between LG-CMS and TAM.

Quantitative measures of motor development in Angelman syndrome.

Angelman Syndrome is a rare neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, characteristic behavior, and movement disorders. Clinical gait analysis provides the opportunity for movement quantification to investigate an observed maladaptive change in gait pattern and offers an objective outcome of change. Pressure-sensor-based technology, inertial and activity monitoring, and instrumented gait analysis (IGA) were employed to define motor abnormalities in Angelman syndrome. Temporal-spatial gait parameters of persons with Angelman Syndrome (pwAS) show deficiencies in gait performance through walking speed, step length, step width, and walk ratio. pwAS walk with reduced step lengths, increased step width, and greater variability. Three-dimensional motion kinematics showed increased anterior pelvic tilt, hip flexion, and knee flexion. PwAS have a walk ratio more than two standard deviations below controls. Dynamic electromyography showed prolonged activation of knee extensors, which was associated with a decreased range of motion and the presence of hip flexion contractures. Use of multiple gait tracking modalities revealed that pwAS exhibit a change in gait pattern to a flexed knee gait pattern.  Cross-sectional studies of individuals with AS show a regression toward this maladaptive gait pattern over development in pwAS ages 4-11. PwAS unexpectedly did not have spasticity associated with change in gait pattern. Multiple quantitative measures of motor patterning may offer early biomarkers of gait decline consistent with critical periods of intervention, insight into appropriate management strategies, objective primary outcomes, and early indicators of adverse events.

Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein. METHODS: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured. RESULTS: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg. CONCLUSIONS: SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long-term efficacy and safety of risdiplam are being assessed with ongoing treatment.

The ethics of crowdfunding in paediatric neurology.

In the last decade, there has been a dramatic increase in the number of families resorting to internet-based public appeals to fund access to novel, highly expensive, or experimental therapies for rare disorders. Medical crowdfunding may provide a means to fund treatments or interventions, but it raises individual and societal ethical questions. In this review, we consider the ethical challenges crowdfunding poses in paediatric neurology, drawing on the example of gene therapy for spinal muscular atrophy. We discuss physician responsibilities, and how neurologists should respond to crowdfunding that they encounter in clinical practice. We also briefly consider actions that can be taken by clinicians, charities, and crowdfunding websites to reduce harms. The best way to mitigate these harms may be to target the high costs and restrictive criteria that limit access to many novel treatments, and to optimize treatment utility, for instance by newborn screening. WHAT THIS PAPER ADDS: Crowdfunding is a social phenomenon arising from families' inability to access desired treatment. Treatments sought by crowdfunding range from those that are clearly beneficial (but unaffordable) to those that would be ineffective and potentially harmful. Crowdfunding carries a range of harms and risks to families and children and has wider social impact.

Financial cost and quality of life of patients with spinal muscular atrophy identified by symptoms or newborn screening.

AIM: To compare the societal financial costs and quality of life (QoL) of untreated patients with spinal muscular atrophy (SMA) and treated patients identified because they presented symptoms or were identified by early testing (sibling or newborn screening). METHOD: Data from two different sources were used: data collected prospectively in untreated patients from 2016 to 2018 and data collected during a prospective follow-up study from 2018 to 2021. Patients or their caregiver completed a questionnaire that included questions on direct medical and non-medical costs, indirect non-medical costs, and health-related QoL. RESULTS: Data (median; range) were available for 149 patients (93 untreated - 10 years; 2 years-59 years), 42 patients (6 years 3 months; 9 months-58 years) treated after presenting with symptoms, and 14 patients (1 year 7 months; 5 months-2 years) treated after early diagnosis. Total costs were lower in untreated patients due to the high cost of drugs used in treated patients. Costs were lower for treated patients who were identified by early testing than for treated patients identified because they presented with symptoms. In all groups, patients with two SMN2 copies had higher costs than those with more copies. INTERPRETATION: Early patient identification and treatment offer the opportunity to reduce the total societal costs of SMA where treatments are available for presymptomatic and postsymptomatic patients. WHAT THIS PAPER ADDS: Untreated patients with spinal muscular atrophy had lower total financial costs than treated patients. Total financial costs were lower for treated patients identified by early screening than for treated patients identified after symptom onset. Direct financial costs excluding treatment were much lower in treated patients identified by early screening. Hospitalization costs were much lower in patients identified by early screening.

COSTO ECONÓMICO Y CALIDAD DE VIDA DE PACIENTES CON ATROFIA MUSCULAR ESPINAL IDENTIFICADOS POR SÍNTOMAS O CRIBADO NEONATAL: OBJETIVO: Comparar los costos financieros sociales y la calidad de vida (QoL) de pacientes no tratados con atrofia muscular espinal (AME) y pacientes tratados, identificados porque presentaron síntomas o fueron identificados mediante pruebas tempranas (cribado de hermanos o recién nacidos). MÉTODO: Se utilizaron datos de dos fuentes diferentes: datos recopilados prospectivamente en pacientes no tratados de 2016 a 2018 y datos recopilados durante un estudio de seguimiento prospectivo de 2018 a 2021. Los pacientes o sus cuidadores completaron un cuestionario que incluía preguntas sobre cuestiones médicas y no médicas directas. -costos médicos, costos indirectos no médicos y calidad de vida relacionada con la salud. RESULTADOS: Los datos (mediana; rango) estaban disponibles para 149 pacientes (93 sin tratamiento - 10 años; 2 años - 59 años), 42 pacientes (6 años 3 meses; 9 meses - 58 años) tratados después de presentar síntomas y 14 pacientes (1 año 7 meses; 5 meses-2 años) tratados tras un diagnóstico precoz. Los costos totales fueron menores en los pacientes no tratados debido al alto costo de los medicamentos utilizados en los pacientes tratados. Los costos fueron más bajos para los pacientes tratados que fueron identificados mediante pruebas tempranas que para los pacientes tratados identificados porque presentaban síntomas. En todos los grupos, los pacientes con dos copias de SMN2 tuvieron costos más altos que aquellos con más copias. INTERPRETACIÓN: La identificación y el tratamiento tempranos de los pacientes ofrecen la oportunidad de reducir los costos sociales totales de la AME, en lugares donde los tratamientos están disponibles para pacientes presintomáticos y postsintomáticos.

Use of MFM-20 to monitor SMA types 1 and 2 patients treated with nusinersen.

OBJECTIVE: To evaluate sensitivity to change and discriminant validity of the 20-item Motor Function Measure (MFM-20) in 2-7-year-old patients with spinal muscular atrophy types 1 (SMA1) or 2 (SMA2) treated with nusinersen. METHODS: Children aged 2 to 7 years old with SMA1 or SMA2 treated with nusinersen were assessed at least three times using the MFM-20 over an average follow-up time of 17 months. Evolution of 4-month-standardized MFM-20 scores was calculated for each MFM-20 domain (D1 standing and transfers, D2 axial and proximal, D3 distal) and for the total score (TS). RESULTS: Included in the study were 22 SMA1 subjects and 19 SMA2 subjects. Baseline MFM scores were significantly lower in patients with SMA1 than SMA2 (TS 29.5% vs. 48.3%, D1 4.5% vs. 10.6%, D2 43.6% vs. 72.6%, D3 51.2% vs. 75.0%). When considering the mean change during nusinersen treatment, standardized over a 4-month period, TS was improved for both SMA1 (+ 4.1%, SRM 1.5) and SMA2 (+ 2.8%, SRM 0.89) patients. For SMA1 patients, considerable changes were observed in D2 (+ 6.2%, SRM 0.89) and D3 (+ 6.0%, SRM 0.72), whereas the change in D1 was small (+ 0.5%, SRM 0.44). In SMA2 2 subjects, D3 was improved to a larger extent (+ 4.2%, SRM 0.53) than D1 (+ 1.8% SRM 0.63) or D2 (+ 3.2%, SRM 0.69). CONCLUSION: Our results validate use of MFM-20 to monitor function of young SMA1 and SMA2 subjects treated with nusinersen. Significant motor function improvements following treatment were observed in both SMA1 and SMA2 patients.

TOR1AIP1-Associated Nuclear Envelopathies.

Human TOR1AIP1 encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various biological processes and human diseases. The clinical spectrum of diseases related to mutations in TOR1AIP1 is broad, including muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease with or without progeroid features. Although rare, these recessively inherited disorders often lead to early death or considerable functional impairment. Developing a better understanding of the roles of LAP1 and mutant TOR1AIP1-associated phenotypes is paramount to allow therapeutic development. To facilitate further studies, this review provides an overview of the known interactions of LAP1 and summarizes the evidence for the function of this protein in human health. We then review the mutations in the TOR1AIP1 gene and the clinical and pathological characteristics of subjects with these mutations. Lastly, we discuss challenges to be addressed in the future.

Scoring People With Spinal Muscular Atrophy on the Motor Function Measure Using the Microsoft Kinect.

PURPOSE: Assess the ability of the Kinect to capture movement and posture of people with spinal muscular atrophy (SMA) during completion of 14 items of the Motor Function Measure, a validated functional rating scale for people with neuromuscular diseases. METHODS: Multicenter feasibility study in which Motor Function Measure items were scored as usual by the participant's therapist during the completion (Score-T) while another therapist scored items based only on the visualization of digital data collected using the Kinect (Score-D). Agreement and disagreement were investigated. RESULTS: Twenty people with SMA type 2 or 3 were participants; 142 items were recorded and analyzed. There was 31.7% agreement between Score-T and Score-D for participants with SMA type 2, and 76.2% for those with SMA type 3. CONCLUSIONS: The results prevent us from considering the use of Kinect capture to deduce an automated scoring, but this device may be of interest to highlight potential compensations.

Very Low Residual Dystrophin Quantity Is Associated with Milder Dystrophinopathy.

OBJECTIVE: This study was undertaken to determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations. METHODS: We performed a retrospective multicentric cohort study by using molecular and clinical data from patients with DMD mutations registered in the Universal Mutation Database-DMD France database. Patients with intronic, splice site, or nonsense DMD mutations, with available muscle biopsy Western blot data, were included irrespective of whether they presented with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD). Patients were separated into 3 groups based on dystrophin protein levels. Clinical outcomes were ages at appearance of first symptoms; loss of ambulation; fall in vital capacity and left ventricular ejection fraction; interventions such as spinal fusion, tracheostomy, and noninvasive ventilation; and death. RESULTS: Of 3,880 patients with DMD mutations, 90 with mutations of interest were included. Forty-two patients expressed no dystrophin (group A), and 31 of 42 (74%) developed DMD. Thirty-four patients had dystrophin quantities < 5% (group B), and 21 of 34 (61%) developed BMD. Fourteen patients had dystrophin quantities ≥ 5% (group C), and all but 4 who lost ambulation beyond 24 years of age were ambulant. Dystrophin quantities of <5%, as low as <0.5%, were associated with milder phenotype for most of the evaluated clinical outcomes, including age at loss of ambulation (p < 0.001). INTERPRETATION: Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD. ANN NEUROL 2021;89:280-292.

A systematic review of adeno-associated virus gene therapies in neurology: the need for consistent safety monitoring of a promising treatment.

Adeno-associated virus (AAV) gene therapies are generating much excitement in the rare disease field, particularly for previously untreatable neurological conditions. Efficacy has been claimed for several gene therapy products and the number of trials is rapidly increasing. However, reports of severe treatment-related adverse reactions are emerging, including death. There is still insufficient knowledge about their aetiology, prevention and treatment. We therefore undertook to systematically review publicly available data on AAV gene therapies in order to collate existing information on both safety and efficacy. Here, we review emerging efficacy reports of these novel therapies, many of which show promise. We also collate an increasing number of adverse reactions. Overwhelmingly, these results make a case for unified reporting of adverse events. This is likely to be critical for improving the safety of these promising treatments.

Home-based gait analysis as an exploratory endpoint during a multicenter phase 1 trial in limb girdle muscular dystrophy type R2 and facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Limb girdle muscular dystrophy type 2B (LGMDR2) and facioscapulohumeral muscular dystrophy (FSHD) are genetic muscular dystrophies with an increasing number of potential therapeutic approaches. The aim of this study is to report the data of exploratory digital outcomes extracted from wearable magneto-inertial sensors used in a non-controlled environment for ambulant patients with FSHD and LGMDR2 in a short-term, multicenter clinical study. METHODS: Digital outcomes (stride length, stride speed, and walk parameters in a non-controlled environment) were used as exploratory outcomes in the open-label study ATYR1940-C-004 in ambulant patients during the 3 mo of ATYR1940 treatment and 1 mo of follow-up. Activity and gait variables were calculated from the data recorded in 30-day sub-periods using the sensors. For each sub-period, activity and gait parameters were compared between FSHD and LGMDR2 patients. Change from baseline over the 4-mo study period was assessed. RESULTS: Ten patients (5 FSHD, 5 LGMDR2) were ambulant and compliant for analysis. Gait parameters, but not activity variables, were significantly lower in LGMDR2 compared to FSHD patients at baseline. Longitudinal analyses showed a slight but significant decrease in stride speed at month 4 for all subjects. Activity variables such as total number of strides per day were highly variable from month to month in individual patients, and no visit effects were found for this variable. DISCUSSION: The present study suggests that home-recorded stride speed constitutes a precise and sensitive outcome in ambulant patients with FSHD and LGMDR2.

Genotype-related respiratory progression in Duchenne muscular dystrophy-A multicenter international study.

INTRODUCTION/AIMS: Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long-term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon-skipping therapeutic strategies. METHODS: This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid-naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53). RESULTS: We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow-up was 3 (range, 0.3-8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age. DISCUSSION: The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon-skipping therapies.

ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy.

OBJECTIVE: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. METHODS: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. RESULTS: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. INTERPRETATION: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.

Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases.

OBJECTIVES: Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression. METHODS: In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment. RESULTS: Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM. CONCLUSIONS: Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement. KEY POINTS: • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODS: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTS: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).

Spinal muscular atrophy care in the COVID-19 pandemic era.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID-19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID-19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic- or institution-specific policies and precautions for COVID-19.