Antireflux surgery may be required in patients with spinal muscular atrophy type 2 (SMA2), but disease-specific experience is limited. To our knowledge, we report the first robot-assisted Nissen fundoplication in SMA2. A 23-year-old woman with severe gastroesophageal reflux disease, bulbar dysfunction, impaired secretion management, severe restrictive respiratory impairment, a previous failed intubation, and fixed musculoskeletal deformities was referred for surgery. Multidisciplinary planning led to fibreoptic nasotracheal intubation under deep sevoflurane sedation and topical anaesthesia, preserving spontaneous ventilation. Intubation was achieved on the first attempt without desaturation or haemodynamic instability. Robot-assisted Nissen fundoplication with Mikulicz pyloroplasty was completed using adapted positioning and port placement. Robotic liver retraction and suction through a 10-Fr nasogastric tube introduced via a robotic port avoided additional access. Positioning required 30 min, operative time was 110 min, including 65 min of console time, and total procedural time from the start of positioning to skin closure was 140 min. After complete neuromuscular recovery, the patient was extubated 2 h 43 min after surgery directly onto non-invasive ventilation. No complications occurred, and she was discharged on postoperative day 5. At 1 month, contrast imaging confirmed the absence of reflux and satisfactory gastric emptying. At a 4-month multidisciplinary clinical assessment, she reported no reflux-related symptoms and improved management of salivary secretions during ongoing follow-up with our logopedists. Robot-assisted Nissen fundoplication in SMA2 is feasible in expert hands when supported by tailored anaesthetic and surgical planning.

Spinal muscular atrophy (SMA) is an autosomal recessively inherited disease leading to severe and progressive muscle weakness due to loss of motor neurons in the spinal cord and the brainstem. Motor neuron degeneration is caused by the absence of a functional SMN1 gene copy, a gene located on 5q13.2, encoding the SMN ("survival of motor neuron") protein. Initially classified into five groups with varying severity (SMA type 0-4), SMA is now regarded as a progressive neurodegenerative disease with a continuum of clinical severity, which genetic and epigenetic modifiers can modulate. The highly homologous gene SMN2, which differs only at a single nucleotide position within the coding sequence (c.840C > T), can modify SMA disease severity due to its ability to drive low SMN protein expression levels. SMN2 copy number and at least two SMN2 variants are known as protective factors and are currently recommended for reporting in genetic testing. As therapies either replacing functional SMN1 or targeting RNA expression to increase SMN2 splicing became available since 2016, rapid genetic confirmation of SMA together with SMN2 copy number status became even more important. Here, we report on a pediatric case of SMA type 3 that could be solved only by functional transcript-level investigation using RNA sequencing following muscle biopsy after several iterations of inconclusive genetic testing. Due to an unusual genotype and multiple SMN2 copies concealing a subtle nonsense variant, DNA-based (next-generation) sequencing failed to provide a clear result. This case report is a cautionary tale hoping to trigger careful re-evaluation in similar unsolved cases.

This article reviews the history, epidemiology, genetics, clinical presentation, multidisciplinary management, and established and emerging therapies for patients with spinal muscular atrophy.

Although technological advances in molecular genetics over the last few decades have greatly expedited the identification of mutations in many genetic diseases, the translation of the genetic mechanisms into a clinical setting has been quite challenging, with a minimum number of effective treatments available. The advancements in antisense therapy have revolutionized the field of neuromuscular disorders as well as lipid-mediated diseases. With the approval of splice-switching antisense oligonucleotide (AO)-based therapies for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD), several modified AOs are now being evaluated in clinical trials for the treatment of several disorders. To activate RNase H-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed that have a PS backbone flanked with the modified AOs on both sides. Mipomersen (trade name Kynamro), a 2'-O-methoxyethyl (MOE) gapmer, was approved by the Food and Drug Administration (FDA) for the treatment of homozygous familial hypercholesterolemia (HoFH) in 2013. Volanesorsen, another 20-mer MOE gapmer, has shown to be successful in lowering the levels of triglycerides (TGs) in several lipid disorders and has received conditional approval in the European Union for the treatment of familial chylomicronemia syndrome (FCS) in May 2019 following successful results from phase II/III clinical trials. This chapter focuses on the clinical applications of gapmer AOs for general dyslipidemia and lipodystrophy.

Biogenesis of UsnRNPs occurs in distinct steps in the nucleus and the cytoplasm. Sequential cytoplasmic actions of CLNS1A in the PRMT5 complex and of the SMN complex assemble the Sm core structure consisting of RNA and proteins. Nuclear SMN, condensed in Cajal Bodies, promotes late maturation steps. Whether cytoplasmic SMN undergoes condensation, and how this contributes to UsnRNP biogenesis or homeostasis, is poorly defined. Here, we show that molecular crowding stress induces rapid, reversible condensation of cytoplasmic SMN into droplets and filamentous assemblies, S-bodies, that sequester mislocalized cytoplasmic UsnRNPs along microtubules. During stress recovery, S-bodies undergo microtubule-dependent reorganization into split SMN-CLNS1A condensates, Janus bodies, that promote clearance of mislocalized UsnRNPs. Strikingly, cellular models of the SMN-associated disease spinal muscular atrophy fail to assemble S-bodies and to clear cytoplasmic UsnRNPs. Our findings identify stress-induced SMN condensation as a mechanism to buffer and resolve cytoplasmic UsnRNP mislocalization and reveal impaired tolerance to molecular crowding as a hallmark of spinal muscular atrophy.

Polyglutamine diseases comprise a family of nine age-dependent disorders caused by CAG triplet-repeat expansions that produce misfolded proteins with elongated glutamine tracts. Although these diseases share proteotoxic stress and engagement of protein quality control pathways as responses to their presence and disruptive activities, they differ in protein context, normal function, localization, interactomes and selective vulnerability. Here, we review how expanded polyglutamine proteins engage ubiquitin-dependent protein quality control across Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17. Rather than treating protein quality control as a uniform response, we emphasize pathway selectivity. A central theme arises across these diseases: mutant polyglutamine proteins are recognized by ubiquitin-related machinery, but recognition does not necessarily produce productive degradation. Instead, disease-specific outcomes are shaped by tissue context, subcellular localization, aggregate state, disease protein fragmentation, normal protein function, compensatory pathway activation and local proteostasis capacity over time. The information synthesized in this review may help the field develop a more comparative and granular understanding of processes and pathways that are shared or divergent among polyglutamine diseases and may also inform more targeted therapeutic strategies for this family of incurable disorders.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by insufficient levels of survival motor neuron (SMN) protein due to mutations in the SMN1 gene, leading to progressive degeneration of lower motor neurons in the spinal cord. In this comprehensive narrative review, we extensively summarise the clinical efficacy and real-world effectiveness of approved disease-modifying therapies, including nusinersen, onasemnogene abeparvovec, and risdiplam, underscoring significant improvements in survival, motor milestones, and quality of life, particularly with early treatment initiation. Safety profiles and post-marketing surveillance data are examined, revealing manageable adverse events aligned with clinical trial findings. Economic evaluations are also discussed, illustrating the high costs associated with SMA therapies and the challenges in cost-effectiveness under conventional thresholds, while noting the potential advantages of some treatments in specific contexts. In the review, we explore the promising pipeline of investigational therapies targeting both SMN-dependent and independent mechanisms such as muscle enhancers and neuromuscular junction modifiers, reflecting evolving multidimensional treatment strategies. Future directions emphasise early diagnosis through newborn screening, optimised treatment regimens, combination therapies, biomarker-guided personalised approaches, and comprehensive multidisciplinary care. Lessons from SMA provide a valuable framework for rare-disease management, highlighting the importance of mechanistic insights, early intervention, collaborative research, patient advocacy, and innovative health technology assessment to improve access and outcomes. Our aim is for the review to guide clinical practice, research priorities, and health policy by synthesising contemporary advances and challenges in SMA treatment and care.

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder associated with motor neuron degeneration, yet the role of the well-conserved Survival of Motor Neuron (SMN) protein in muscle remains insufficiently understood. Using the Drosophila neuromuscular junction (NMJ) as a model, we combined tissue-specific Smn depletion with transcriptomic profiling and prior genetic modifier screens to identify SMN-dependent genes that contribute to synaptic architecture. Functional screening of candidate genes significantly and selectively effected in muscle identified genes whose knockdown phenocopied NMJ morphometry defects characteristic of Smn loss-of-function (LOF), including FER, CAP, HDAC4, Nhe2, and Raskol. Unlike other genes in this group, analysis of postsynaptic architecture using a subsynaptic reticulum (SSR) biomarker disrupted by Smn LOF singled out the conserved tyrosine kinase FER as an SMN-dependent gene in muscle that influences this prominent feature of the NMJ. Analysis of different FER transcripts suggests that elevation of the FERp100 protein isoform in Smn LOF muscle tissue leads to a dominant-negative effect likely to disrupt signaling via the MAPK-family kinase Basket (Bsk) to regulate the downstream phosphatase Puckered (Puc).