The rRNA epitranscriptome and myonuclear SNORD landscape in skeletal muscle fibers contributes to ribosome heterogeneity and is altered by hypertrophic stimulus.

In cell biology, ribosomal RNA (rRNA) 2'O-methyl (2'-O-Me) is the most prevalent post-transcriptional chemical modification contributing to ribosome heterogeneity. The modification involves a family of small nucleolar RNAs (snoRNAs) and is specified by box C/D snoRNAs (SNORDs). Given the importance of ribosome biogenesis for skeletal muscle growth, we asked if rRNA 2'-O-Me in nascent ribosomes synthesized in response to a growth stimulus is an unrecognized mode of ribosome heterogeneity in muscle. To determine the pattern and dynamics of 2'-O-Me rRNA, we used a sequencing-based profiling method called RiboMeth-seq. We applied this method to tissue-derived rRNA of skeletal muscle and rRNA specifically from the muscle fiber using an inducible myofiber-specific RiboTag mouse in sedentary and mechanically overloaded conditions. These analyses were complemented by myonuclear-specific small RNA sequencing to profile SNORDs and link the rRNA epitranscriptome to known regulatory elements generated within the muscle fiber. We demonstrate for the first time that mechanical overload of skeletal muscle 1) induces decreased 2'-O-Me at a subset of skeletal muscle rRNAand 2) alters the SNORD profile in isolated myonuclei. These findings point to a transient diversification of the ribosome pool via 2'-O-Me during growth and adaptation in skeletal muscle. These findings suggest changes in ribosome heterogeneity at the 2'-O-Me level during muscle hypertrophy and lay the foundation for studies investigating the functional implications of these newly identified "growth-induced" ribosomes.

The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation duchenne muscular dystrophy - a consensus derived using a modified Delphi methodology in Eastern Europe, Greece, Israel and Sweden.

BACKGROUND: This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. METHODS: The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. RESULTS: A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. CONCLUSIONS: The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).

Improvements in health status and utility associated with ataluren for the treatment of nonsense mutation Duchenne muscular dystrophy.

INTRODUCTION: Little is known of the impact of ataluren on health status and utility in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). In this work we sought to investigate the clinical expert consensus of these topics in a Delphi panel study. METHODS: Six Swedish neuromuscular experts participated in this study. Consensus was investigated for responses to the Health Utilities Index (HUI) and a visual analog scale (VAS) for ambulatory and nonambulatory patients treated with ataluren plus best supportive care vs best supportive care alone. RESULTS: Consensus was obtained after three panel rounds across treatments and disease stages, except for HUI question 10 (ability to use hands and fingers) for nonambulatory patients. Utility differences between treatments were 0.31 for ambulatory patients, and 0.15 to 0.18 for nonambulatory patients, respectively. The corresponding VAS differences were 12 and 13. DISCUSSION: The outcomes of this study support the association of ataluren for the treatment of nmDMD with improved health status and utility.

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients.

INTRODUCTION: Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. Patient Group and Methods: Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. RESULTS: The median age at presentation was 8.0 (0.1-17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (ACTN2, MYPN, and TTN) or in metabolic and signal transduction genes (BRAF and TAZ). Likely pathogenic TAZ variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (MYH6, MYH7, and MYLK2). In 4 patients, variants of unknown significance in ion-channel genes were detected. CONCLUSION: We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.

Life expectancy at birth in Duchenne muscular dystrophy: a systematic review and meta-analysis.

Several studies indicate that prognosis for survival in Duchenne muscular dystrophy (DMD) has improved in recent decades. However, published evidence is inconclusive and some estimates may be obsolete due to improvements in standards of care, in particular the routine use of mechanical ventilatory support in advanced stages of the disease. In this systematic review and meta-analysis (PROSPERO identifier: CRD42019121800), we searched MEDLINE (through PubMed), CINAHL, Embase, PsycINFO, and Web of Science for studies published from inception up until December 31, 2018, reporting results of life expectancy in DMD. We pooled median survival estimates from individual studies using the median of medians, and weighted median of medians, methods. Risk of bias was established with the Newcastle-Ottawa Scale. Results were stratified by ventilatory support and risk of bias. We identified 15 publications involving 2662 patients from 12 countries from all inhabited continents except Africa. Median life expectancy without ventilatory support ranged between 14.4 and 27.0 years (pooled median: 19.0 years, 95% CI 18.0-20.9; weighted pooled median: 19.4 years, 18.2-20.1). Median life expectancy with ventilatory support, introduced in most settings in the 1990s, ranged between 21.0 and 39.6 years (pooled median: 29.9 years, 26.5-30.8; weighted pooled median: 31.8 years, 29.3-36.2). Risk of bias had little impact on pooled results. In conclusion, median life expectancy at birth in DMD seems to have improved considerably during the last decades. With current standards of care, many patients with DMD can now expect to live into their fourth decade of life.

A mini-review and implementation model for using ataluren to treat nonsense mutation Duchenne muscular dystrophy.

AIM: Ataluren has been approved for treating nonsense mutation Duchenne muscular dystrophy (nmDMD), and there are currently discussions concerning drug access and applications beyond the development programme. This study provides an overview of nmDMD and ataluren, stipulates clinical rules for treatment initiation and discontinuation and proposes a model for the implementation of orphan drugs in clinical practice in Sweden. METHODS: This was a targeted mini-review of the literature from 1995 to 2018, which included cohort studies, guidelines, randomised clinical trials, clinical commentaries and reviews. The review covered the pathophysiology, epidemiology and burden of nmDMD and the clinical programme for ataluren. RESULTS: Based on the current evidence, and our experiences, we recommend that patients with nmDMD should be given ataluren as soon as possible after diagnosis and this treatment should continue until they reach a forced vital capacity of <30%, and, or, a score of at least six on the Brooke upper extremity scale. We propose an implementation model that comprises a coordinating specialist physician and a national expert committee responsible for providing clinical intelligence to ensure appropriate use. CONCLUSION: Our clinical recommendations and proposed implementation model will inform the optimum medical management of nmDMD in Sweden and help ensure timely, equal access to ataluren and similar orphan drugs.

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy.

Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here, we report a new clinical phenotype of filaminopathy in four unrelated patients with early-onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.3557C>T, p.A1186V, rs1114167361 in three probands and c.[3547G>C; 3548C>T], p.A1183L, rs1131692185 in one proband). In all cases, concurrent myopathy was confirmed by neurological examination, electromyography, and morphological studies. Three of the patients also presented with arthrogryposis. The pathogenicity of the described missense variants was verified by cellular and morphological studies and by in vivo modeling in zebrafish. Combination of in silico and experimental approaches revealed that FLNC missense variants localized in Ig-loop segments often lead to development of RCM. The described FLNC mutations associated with early-onset RCMP extend cardiac spectrum of filaminopathies and facilitate the differential diagnosis of restrictive cardiac phenotype associated with neuromuscular involvement in children.

Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. METHODS: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487. FINDINGS: Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment. INTERPRETATION: Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint. FUNDING: PTC Therapeutics.

Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.

The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.

Parents' Experiences and Wishes at End of Life in Children with Spinal Muscular Atrophy Types I and II.

OBJECTIVE: To explore experiences and wishes of bereaved parents concerning end-of-life care for their child with severe spinal muscular atrophy. STUDY DESIGN: A follow-up survey was conducted in 2013 on parents of deceased Swedish children who were born between 2000 and 2010 and later diagnosed with spinal muscular atrophy type I or II (n = 48). The questions used in this study covered location of death (LoD), support from health care staff, and parents' wishes and concerns about their child's end-of-life care. RESULTS: One-half of those who had wishes about LoD (16/32) wanted their child to die at home, rather than at the hospital. All of those who wanted the child to die at the hospital had their wishes fulfilled. Among those who wanted the child to die at home, 10 of 16 got their wish. Among parents who talked with a physician about how they wanted their child to pass away (n = 26), all but 2 had their wishes fulfilled. Thirty-six parents (75%) reported that their child had siblings: 12 reported that the sibling was too young for professional psychological support, and only 4 of the remaining 24 siblings received such support after the death of their brother or sister. CONCLUSIONS: Parents' communication with the physician about their wishes and concerns regarding their child's end-of-life care and preferred LoD contributed to their wishes being fulfilled. The wish of hospital death was fulfilled more often than the wish of home deaths. A vast majority of siblings did not receive psychological support after death of their brother or sister.

A protocol to develop clinical guidelines for inclusion-body myositis.

INTRODUCTION: Inclusion-body myositis (IBM) is a late-onset idiopathic inflammatory myopathy associated with selective and progressive muscle weakness and atrophy. Current clinical management of IBM is largely supportive due to its uncertain etiology and lack of effective treatment. Establishing a consensus of opinion on questions relating to diagnosis and management of IBM is expected to help reduce inconsistencies in the care and resources allocated to those living with this condition. METHODS: A protocol has been developed to produce best practice clinical guidelines for IBM based on a combination of published research and expert consensus. CONCLUSIONS: In this study we describe the proposed protocol for developing methods for producing robust and transparent clinical guidance on aspects of diagnosis, drug treatment, physical and practical management, respiration, nutrition and cardiac management, psychosocial management, and multidisciplinary care.

Various lamin A/C mutations alter expression profile of mesenchymal stem cells in mutation specific manner.

Various mutations in LMNA gene, encoding for nuclear lamin A/C protein, lead to laminopathies and contribute to over ten human disorders, mostly affecting tissues of mesenchymal origin such as fat tissue, muscle tissue, and bones. Recently it was demonstrated that lamins not only play a structural role providing communication between extra-nuclear structures and components of cell nucleus but also control cell fate and differentiation. In our study we assessed the effect of various LMNA mutations on the expression profile of mesenchymal multipotent stem cells (MMSC) during adipogenic and osteogenic differentiation. We used lentiviral approach to modify human MMSC with LMNA-constructs bearing mutations associated with different laminopathies--G465D, R482L, G232E, R527C, and R471C. The impact of various mutations on MMSC differentiation properties and expression profile was assessed by colony-forming unit analysis, histological staining, expression of the key differentiation markers promoting adipogenesis and osteogenesis followed by the analysis of the whole set of genes involved in lineage-specific differentiation using PCR expression arrays. We demonstrate that various LMNA mutations influence the differentiation efficacy of MMSC in mutation-specific manner. Each LMNA mutation promotes a unique expression pattern of genes involved in a lineage-specific differentiation and this pattern is shared by the phenotype-specific mutations.

Muscle dysfunction and structural defects of dystrophin-null sapje mutant zebrafish larvae are rescued by ataluren treatment.

Sapje zebrafish carry a mutation in the dystrophin gene, which results in a premature stop codon, and a severe muscle phenotype. They display several of the structural characteristics of Duchenne muscular dystrophy (DMD). Ataluren (PTC124) is proposed to cause readthrough of premature stop codons and has been introduced as a potential treatment of genetic disorders. Clinical trials in DMD have shown promise, although with complex dose dependency. We have established physiology techniques, enabling high resolution of contractile function in skeletal muscle of zebrafish larvae. We aimed to provide a mechanical analysis of sapje larval muscle and examine effects of ataluren. Homozygous 5 d postfertilization (dpf) sapje larvae exhibited structural defects with 50% decrease in active tension. Ataluren (0.1-1 µM, 3-5 dpf) improved contractile function (~60% improvement of force at 0.5 µM) and dystrophin expression. Controls were not affected. Higher doses (5 µM, 35 µM) impaired contractile function, an effect also observed in controls, suggesting unspecific negative effects at high concentrations. In summary, Sapje larvae exhibit impaired contractile performance and provide a relevant DMD model for functional studies. Ataluren significantly improves skeletal muscle function in the sapje larvae, most likely reflecting an observed increase in dystrophin expression. The bell-shaped dose dependence in sapje resembles that previously reported in clinical DMD studies.

Bisphosphonates in Glucocorticoid-Treated Patients With Duchenne Muscular Dystrophy: A Systematic Review and Grading of the Evidence

BACKGROUND AND OBJECTIVES: Bisphosphonates are routinely used to treat osteoporosis in patients with Duchenne muscular dystrophy (DMD), a rare, severely debilitating neuromuscular disease. We sought to synthesize and grade benefits and harms evidence of bisphosphonates in glucocorticoid-treated patients with DMD. METHODS: In this systematic review (PROSPERO identifier: CRD42020157606), we searched MEDLINE, CINAHL, Embase, PsycINFO, Web of Science, and CENTRAL for articles published from inception up to and including March 31, 2023, reporting results in any language from any study type. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: We identified 19 publications involving 1,010 children and adults from 12 countries across all inhabited continents except South America. We found high-quality evidence that bisphosphonates significantly increase the areal lumbar spine bone mineral density (BMD) Z score in glucocorticoid-treated patients with DMD. The greatest improvements were recorded in controlled settings among patients treated with intravenous zoledronate. Evidence of benefits to fracture risks was inconclusive and/or of low quality, primarily due to lack of controlled data and small samples. Bisphosphonates were generally well-tolerated, although adverse events related to the first infusion (i.e., "acute phase reaction") were frequently reported. DISCUSSION: There is high-quality evidence supporting the use of bisphosphonates to increase the areal lumbar spine BMD Z score in patients with DMD and glucocorticoid-induced osteoporosis. Our synthesis and grading affirm current recommendations put forward in the 2018 DMD Clinical Care Considerations and should be helpful in raising awareness about anticipated benefits of bisphosphonates, prevailing unmet needs, and potential safety issues in their use.

Healthcare resource utilisation and direct medical cost for individuals with 5q spinal muscular atrophy in Sweden.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, progressive, neuromuscular disorder. Recent advances in treatment require an updated assessment of burden to inform reimbursement decisions. OBJECTIVES: To quantify healthcare resource utilisation (HCRU) and cost of care for patients with SMA. METHODS: Cohort study of patients with SMA identified in the Swedish National Patient Registry (2007-2018), matched to a reference cohort grouped into four SMA types (1, 2, 3, unspecified adult onset [UAO]). HCRU included inpatient admissions, outpatient visits, procedures, and dispensed medications. Direct medical costs were estimated by multiplying HCRU by respective unit costs. Average annual HCRU and medical costs were modelled for SMA versus reference cohorts to estimate differences attributable to the disease (i.e., average treatment effect estimand). The trajectory of direct costs over time were assessed using synthetic cohorts. RESULTS: We identified 290 SMA patients. Annualised HCRU was higher in SMA patients compared with reference cohorts. Highest risk ratios were observed for inpatient overnight stays for type 1 (risk ratio [RR]: 29.2; 95% confidence interval [CI]: 16.0, 53.5) and type 2 (RR: 23.3; 95% CI: 16.4,33.1). Mean annual direct medical costs per patient for each year since first diagnosis were greatest for type 1 (€114,185 and SMA-attributable: €113,380), type 2 (€61,876 and SMA-attributable: €61,237), type 3 (€45,518 and SMA-attributable: €44,556), and UAO (€4046 and SMA-attributable: €2098). Costs were greatest in the 2-3 years after the first diagnosis for all types. DISCUSSION AND CONCLUSION: The economic burden attributable to SMA is significant. Further research is needed to understand the burden in other European countries and the impact of new treatments.

Spinal Muscular Atrophy Update in Best Practices: Recommendations for Diagnosis Considerations.

Background and Objectives: Spinal muscular atrophy (SMA) is an autosomal recessive progressive neurodegenerative primary motor neuron disorder caused by biallelic variants of the survival motor neuron 1 (SMN1) gene. The most recent SMA best practice recommendations were published in 2018 shortly after the approval of the first SMN-enhancing treatment. The availability of disease-modifying therapies for 5q SMA and implementation of SMA newborn screening (NBS) has led to urgency to update the SMA best practice recommendations for diagnosis and to reevaluate the current classification of SMA. In addition, the availability of disease-modifying therapies has opened the door to explore improved diagnosis of adult-onset SMA. Methods: A systematic literature review was conducted on SMA NBS. An SMA working group of American and European health care providers developed recommendations through a modified Delphi technique with serial surveys and virtual meeting feedback on SMA diagnosis to fill information gaps for topics with limited evidence. A community working group of an individual with SMA and caregivers provided insight and perspective on SMA diagnosis and support through a virtual meeting to guide recommendations. Results: The health care provider working group achieved consensus that SMA NBS is essential to include in the updated best practice for SMA diagnosis (100%). Recommendations for the following are described: characterizing NBS-identified infants before treatment; minimum recommendations for starting or offering SMA NBS in a state or country; recommendations for activities and services to be provided by an SMA specialty care center accepting SMA NBS referrals; and recommendations for partnership with individuals with SMA and caregivers to support NBS-identified infants and their caregivers. Limited data are available to advance efficient diagnosis of adult-onset SMA. Discussion: Updating best practice recommendations for SMA diagnosis to include SMA NBS implementation is essential to advancing care for individuals with SMA. In addition to testing, processes for the efficient management of positive newborn screen with access to knowledgeable and skilled health care providers and access to treatment options is critical to successful early diagnosis. Additional evidence is required to improve adult-onset SMA diagnosis.

2024 update: European consensus statement on gene therapy for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is one of the most common genetic diseases and was, until recently, a leading genetic cause of infant mortality. Three disease-modifying treatments have dramatically changed the disease trajectories and outcome for severely affected infants (SMA type 1), especially when initiated in the presymptomatic phase. One of these treatments is the adeno-associated viral vector 9 (AAV9) based gene therapy onasemnogene abeparvovec (Zolgensma®), which is delivered systemically and has been approved by the European Medicine Agency for SMA patients with up to three copies of the SMN2 gene or with the clinical presentation of SMA type 1. While this broad indication provides flexibility in patient selection, it also raises concerns about the risk-benefit ratio for patients with limited or no evidence supporting treatment. In 2020, we convened a European neuromuscular expert working group to support the rational use of onasemnogene abeparvovec, employing a modified Delphi methodology. After three years, we have assembled a similar yet larger group of European experts who assessed the emerging evidence of onasemnogene abeparvovec's role in treating older and heavier SMA patients, integrating insights from recent clinical trials and real-world evidence. This effort resulted in 12 consensus statements, with strong consensus achieved on 9 and consensus on the remaining 3, reflecting the evolving role of onasemnogene abeparvovec in treating SMA.

Diagnostic challenge in desmin cardiomyopathy with transformation of clinical phenotypes.

Desmin cardiomyopathy is a rare cause of congestive heart failure. Its clinical manifestation in adulthood often is associated with conduction disorders and a neuromuscular phenotype. Only a few cases have been reported, with early manifestation in childhood mostly due to severe cardiomyopathy dilation and conduction abnormalities. However, the disease can result in the variety of clinical phenotypes, including hypertrophic, restrictive, and arrhythmogenic cardiomyopathy. This report describes the first case of desmin cardiomyopathy with early manifestation in adolescence and transformation of several clinical phenotypes over time, representing sufficient difficulties for the correct clinical diagnosis and treatment of the disease at an early stage.

Health-related quality of life of children with spinal muscular atrophy in Sweden: A prospective cohort study in the era of disease-modifying therapy.

The objective of this study was to estimate change over time in health-related quality of life (HRQoL) of children with spinal muscular atrophy (SMA) in Sweden. Children with SMA were identified via the National Patient Register by the National Board of Health and Welfare in Sweden. Patient HRQoL was caregiver proxy-assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales at baseline, as well as at 6, 12, and 18 months of follow-up. Results were stratified by SMA type. Mothers and fathers to 27 children with SMA (mean patient age: 9.17 years; 59% female) participated in the study. All patients received disease-modifying therapy. At baseline, across SMA types, the mean total score was estimated at between 52.68 and 59.19, Physical Functioning score at between 26.39 and 40.34, Emotional Functioning score at between 66.82 and 68.57, Social Functioning score at between 55.00 and 70.45, and School Functioning score at between 70.45 and 78.33. The mean annual total score change was estimated at -2.03 for SMA type I, 4.11 for SMA type II, and 1.12 for SMA type III. In conclusion, we show that SMA has a detrimental impact on HRQoL that extends above and beyond somatic disability. Children with SMA type II experienced a dramatic increase in HRQoL over time, predominantly related to improvement in physical and social functioning. Our data helps quantify the patient burden of disease and adds to the rapidly expanding body of evidence of the effectiveness of recently approved disease-modifying therapies for SMA.