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PubMed2026

Multi-Omics Landscape of Paraspinal Muscles in Spinal Muscular Atrophy With Scoliosis.

Most spinal muscular atrophy (SMA) patients develop severe scoliosis by late adolescence. Given that the paraspinal muscles-particularly the multifidus-are indispensable for maintaining spinal stability, their site-specific multi-omics characteristics in SMA remain insufficiently defined. Herein, integrated multi-omics sequencing was performed on bilateral multifidus samples from SMA patients and surgical controls. We identified 5219 differentially expressed genes, 1063 differentially expressed proteins and 370 differential metabolites between the control and SMA, showing significant enrichment in glucose and amino acid metabolism pathways, specifically key steps of glycolysis/gluconeogenesis. Key enzymes in the glycolytic process such as PFKM, ENO3 and PKM1 were markedly downregulated. Notably, a comparative analysis of the bilateral paraspinal muscles in SMA revealed asymmetrical metabolic signatures in carbohydrate and amino acid processing between the concave and convex sides. Key regulatory enzymes exhibited significant differential expression: PYGL, a central driver of starch and sucrose metabolism; creatine kinase, involved in arginine and proline metabolism; and PGAM2, a key mediator of glycine, serine, and threonine metabolism. These metabolic signatures indicate a complex metabolic reprogramming in the multifidus, where asymmetric disparities point to the influence of mechanical loading, while systemic dysregulation aligns with the effects of SMN depletion.

Humans↗

PubMed2026

A novel ASCC1 splice-site variant broadens the phenotypic spectrum of spinal muscular atrophy with congenital bone fractures type 2.

Spinal muscular atrophy with congenital bone fractures type 2 (SMABF2) is an ultra-rare neuromuscular disorder caused by pathogenic variants affecting the ASC-1 complex, most commonly ASCC1. The disorder is typically characterized by severe congenital hypotonia, prenatal or congenital fractures, and early respiratory failure. We report a girl with a novel homozygous intronic donor-site variant, c.95+5G>C, in ASCC1. In contrast to the classic SMABF2 phenotype, she had no congenital fractures and survived until 7 years of age. Her clinical presentation included generalized hypotonia, areflexia, minimal spontaneous movements, dysmorphic features related to fetal hypomobility, progressive respiratory insufficiency requiring tracheostomy and gastrostomy, and cardiac involvement. This case expands both the genetic and phenotypic spectrum of ASCC1-associated disease. The comparatively prolonged survival and absence of congenital fractures suggest that not all ASCC1 variants result in a fully loss-of-function phenotype. However, this interpretation remains hypothetical because functional RNA studies were not performed.

Humans↗

PubMed2024

Concomitant telomere attrition is associated with spinal muscular atrophy in highly inbred region of North India: unraveling the thread in Kashmir region.

Spinal muscular atrophy (SMA) is a rare genetic disorder that unequivocally results in the degeneration of motor neurons, leading to muscle weakness and atrophy. This condition is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which inevitably results in a deficiency of the SMN protein. In present study, we investigated the potential role of telomere attrition in SMA patients. Relative telomere length in peripheral blood lymphocytes was measured by Monochrome Multiplex Quantitative Polymerase Chain Reaction (MMQPCR) in 98 subjects and we conclusively found that SMA cases exhibit telomere attrition compared to healthy controls (P = 4 × 10- 2). Moreover, significant attrition was also observed in severe form of SMA, i.e. SMA type 0 (P = 0.04) as well.Although, the exact mechanism through which telomere shortening contributes to the pathogenesis of SMA is not fully understood and is yet to be delineated. However, one possibility is that telomere shortening leads to genomic instability and DNA damage, which can contribute to motor neuron degeneration. Another possibility is that telomere shortening leads to cellular senescence, which can impair the ability of motor neurons to regenerate and repair themselves. Recent studies have suggested that telomere shortening may be a potential therapeutic target in SMA. Thus, understanding the role of SMN1 gene in disease pathogenesis & its effect on telomere length will aid in estimating the risk & prognosis of SMA in genetically less explored & highly inbred region of Kashmir, Northern India.

Humans↗

PubMed2026

Compound muscle action potential amplitudes in newborn screen positive spinal muscular atrophy.

OBJECTIVE: To evaluate the utility of compound muscle action potential (CMAP) amplitudes as biomarkers of disease severity in newborn screening (NBS)-positive infants with spinal muscular atrophy (SMA). METHODS: We conducted a retrospective review of 21 infants identified through SMA NBS (11 with 2 SMN2 copies and 10 with 3 SMN2 copies). Baseline and serial right median, ulnar, and fibular motor nerve CMAP amplitudes (millivolts, mV) were obtained during the study. Functional outcomes were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). RESULTS: At baseline, infants with 2 SMN2 copies demonstrated significantly lower median, ulnar, and fibular CMAP amplitudes compared with infants with 3 SMN2 copies (p < 0.05). In contrast, baseline CHOP-INTEND scores did not differ significantly between the two groups. Prior to genetic confirmation, a right median CMAP amplitude ≥3.2 mV predicted ≥3 SMN2 copies. Following treatment, right median and fibular CMAP amplitudes demonstrated significant improvement over time, including in analyses accounting for SMN2 copies number. CONCLUSION: CMAP amplitudes obtained from multiple upper- and lower-extremity motor nerves provided objective electrophysiological measures that distinguished infants with two versus three SMN2 copies, despite similar baseline CHOP-INTEND scores. Furthermore, CMAP abnormalities were detectable in some cases before confirmatory genetic testing results became available. Serial CMAP measurements demonstrated significant longitudinal changes following treatment, whereas functional assessments approached ceiling values, supporting the potential value of electrophysiological monitoring in the era of disease-modifying therapies. SIGNIFICANCE: CMAP assessment is a useful adjunct in the evaluation of infants identified through SMA NBS.

Humans↗

PubMed2026

Molecular diagnosis of spinal muscular atrophy: Experience in a pediatric hospital in Argentina.

Introduction. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by the loss of the SMN1 gene, with a variable clinical spectrum determined primarily by the number of copies of the SMN2 gene. The development of new therapies underscores the importance of early molecular diagnosis and genotype-phenotype characterization. Objective. To describe 27 years of experience in the molecular diagnosis of SMA at a pediatric referral hospital in Argentina and to evaluate the correlation between SMN2 copy number and the SMA types.Population and methods. A retrospective descriptive study was conducted on 1060 pediatric patients with clinically suspected SMA who were evaluated between 1997 and 2024. Molecular diagnosis was performed using PCR-RFLP and, since 2012, MLPA to determine SMN1 and SMN2 copy number. Genotype-phenotype correlation was evaluated in 260 patients with complete clinical characterization. Results. The diagnosis was confirmed in 513 patients. A homozygous deletion of the SMN1 gene was detected in 99.6% of unrelated cases. The positivity rate increased over time. A significant correlation was observed between the number of SMN2 copies and the type of SMA, with milder phenotypes associated with a higher number of copies. Conclusion. Molecular diagnosis of SMA enabled accurate and timely characterization of patients, avoiding invasive procedures and optimizing therapeutic decision-making. Genotype-phenotype correlation is a fundamental tool for prognosis and clinical management, highlighting the importance of an interdisciplinary approach.

Argentina↗

PubMed2024

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets.

PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.

Humans↗

PubMed2026

Characteristics of early-onset, rapidly progressive scoliosis in spinal muscular atrophy type I treated with disease-modifying therapy -a multicenter retrospective study conducted in Japan.

In the era of disease-modifying therapy (DMT), almost all patients with spinal muscular atrophy (SMA) type I treated after onset, but before 6 months of age, develop early-onset, rapidly progressive scoliosis by 2 years of age, despite improvements in their motor function. Seven symptomatic patients with SMA type I who were treated before the age of 6 months were included in this retrospective observational study. Scoliosis had developed in all patients by 27 months of age. Among them, the patients who could stand with support or independently (standing patients; n = 3) tended to present with more progressive scoliosis than the sitters (n = 4). All standing patients demonstrated thoracic hyperkyphosis before or at the time of their scoliosis diagnosis. Despite receiving DMT, these patients continued to show residual key manifestations of SMA type I. Chronic difficulty maintaining posture due to trunk muscle weakness in the lying, sitting, or standing position was considered to be the main contributor to the development and progression of the scoliosis. The development and progression of such scoliosis, which begins in infancy, may be related to inappropriate postural management, which is not currently recognized as such by clinicians, caregivers, or guardians. In this population, it is important to closely monitor patients for such scoliosis from soon after the diagnosis of SMA. As this type of scoliosis progresses rapidly during the early developmental stage, when surgery is not possible, it is necessary to establish a proactive non-surgical management strategy for it.

Humans↗

PubMed2025

Arginine methylation-dependent METTL14-SMN interaction regulates RNA m6A homeostasis.

N6-methyladenosine (m6A) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating m6A remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the m6A methyltransferase complex. SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner. Mutations in the SMN Tudor domain identified in spinal muscular atrophy (SMA) disrupt its interaction with METTL14 and reduce m6A levels in patient-derived fibroblasts, linking m6A dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair m6A deposition on the mRNAs of DNA repair genes, mirroring the effects of METTL14 hypomethylation. Consequently, SMA patient fibroblasts are hypersensitive to DNA-damaging agents due to reduced levels of DNA repair gene expression. To explore the function of METTL14 arginine methylation in vivo, we generated a Mettl14 methylation-deficient mouse model (Mettl14RK). Although this model does not show SMA-like phenotypes, the mutants are partially embryonic lethal and show abnormal hematopoiesis, underscoring a role for methylated METTL14 in early development.

Methyltransferases↗

PubMed2026

The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity.

The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.

Humans↗

PubMed2008

Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes.

Delivery of genes to the brain and spinal cord across the blood-brain barrier (BBB) has not yet been achieved. Here we show that adeno-associated virus (AAV) 9 injected intravenously bypasses the BBB and efficiently targets cells of the central nervous system (CNS). Injection of AAV9-GFP into neonatal mice through the facial vein results in extensive transduction of dorsal root ganglia and motor neurons throughout the spinal cord and widespread transduction of neurons throughout the brain, including the neocortex, hippocampus and cerebellum. In adult mice, tail vein injection of AAV9-GFP leads to robust transduction of astrocytes throughout the entire CNS, with limited neuronal transduction. This approach may enable the development of gene therapies for a range of neurodegenerative diseases, such as spinal muscular atrophy, through targeting of motor neurons, and amyotrophic lateral sclerosis, through targeting of astrocytes. It may also be useful for rapid postnatal genetic manipulations in basic neuroscience studies.

Animals↗

PubMed2026

The SMN locus in the T2T era: Structure, gene conversion, and clinical implications.

Long-read sequencing, paralog-aware variant calling, and telomere-to-telomere (T2T) human genome assemblies now enable the resolution of copy-, haplotype-, and nucleotide-level complexities in segmentally duplicated loci, which were previously inaccessible with short-read sequencing. In this review, we highlight how current technologies and analysis methods reveal extensive diversity in copy number (CN), structure, and gene conversion within the spinal muscular atrophy-associated survival motor neuron (SMN) locus. We summarize how understanding population-level structural variation could be translated into clinical practice, where a nucleotide-level view of the SMN locus may refine prognostic accuracy beyond SMN2 CN and explain variable treatment responses. Finally, we discuss how the approaches and methodologies required to study the SMN locus may be applied elsewhere, providing a scaffold to characterize other complex human genetic regions.

Humans↗

PubMed2024

Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.

Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13+/- hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13+/- transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.

Humans↗

PubMed2026

289th ENMC international workshop: assessing and managing emerging AAV related toxicities after gene therapy for neuromuscular disorders, 26 - 28 September 2025, Hoofddorp, The Netherlands.

Adeno-associated virus (AAV) mediated gene therapies has emerged as a potentially transformative treatment approaches for neuromuscular disorders, with two FDA-approved products now in widespread clinical use: onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy and delandistrogene moxeparvovec-rokl (Elevidys) for Duchenne Muscular Dystrophy. However, severe and occasionally fatal adverse events affecting vital organs, including the blood, liver, muscle, and heart, have emerged in both clinical trials and real-world post marketing settings. The 289th European NeuroMuscular Centre (ENMC) workshop convened 38 participants from patient advocacy groups, industry, and preclinical and clinical research groups to collaboratively review these toxicities, their underlying mechanisms, and potential mitigation and monitoring strategies. Discussions addressed the clinical spectrum and biological drivers of these events, the respective roles of innate and adaptive immunity, the contribution of specific vector characteristics as well as of the specific disease and recipient. The application of risk stratification and immunosuppressive regimens for prevention, monitoring, and management were considered. Emerging toxicities, including capillary leak syndrome, endothelial and dorsal root ganglia injuries, were reviewed alongside corresponding preclinical data from non-human primates. Participants agreed on the need to harmonize standard operating procedures, clinical guidelines, and data-sharing practices, and endorsed collaborative initiatives to proactively address critical gaps and unresolved key questions through a patient-centered framework.

Adaptive immune response↗

PubMed2017

Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond.

The use of recombinant adeno-associated viruses (rAAVs) ushered in a new millennium of gene transfer for therapeutic treatment of a number of conditions, including congenital blindness, hemophilia, and spinal muscular atrophy. rAAV vectors have remarkable staying power from a therapeutic standpoint, withstanding several ebbs and flows. As new technologies such as clustered regularly interspaced short palindromic repeat genome editing emerge, it is now the delivery tool-the AAV vector-that is the stalwart. The long-standing safety of this vector in a multitude of clinical settings makes rAAV a selling point in the advancement of approaches for gene replacement, gene knockdown, gene editing, and genome modification/engineering. The research community is building on these advances to develop more tailored delivery approaches and to tweak the genome in new and unique ways. Intertwining these approaches with newly engineered rAAV vectors is greatly expanding the available tools to manipulate gene expression with a therapeutic intent.

Dependovirus↗

PubMed2026

Are components of the histone gene expression machinery functionally repurposed in terminally differentiated cells?

The expression of metazoan replication-dependent histone genes is controlled by the nuclear protein at the ataxia-telangiectasia locus (NPAT) and U7 small nuclear ribonucleoprotein particle (snRNP). NPAT activates transcription of histone genes during S-phase, whereas U7 snRNP is a multi-subunit endonuclease that cleaves the resultant transcripts at the 3' end, yielding mature histone mRNAs. In cycling cells, NPAT and U7 snRNP with its four unique components, U7 snRNA, Lsm10, Lsm11 and FLASH, are highly enriched in histone locus bodies (HLBs), the nuclear condensates formed near histone gene loci. Here, we show that in muscle and neural cells that have ceased to replicate their chromatin and permanently exited the cell cycle, HLBs are dismantled and NPAT, FLASH and Lsm11 are detected in the cytoplasm. This observation suggests that in postmitotic cells, NPAT and U7 snRNP become repurposed for functions unrelated to generating histone mRNAs. We identified a highly conserved region in Lsm11 that engages in various protein-protein interactions and likely acts as a universal platform that controls the assembly, localization and function of Lsm11 complexes, including U7 snRNP, during cell growth and differentiation. Since the assembly of U7 snRNP requires survival motor neuron, the protein mutated in spinal muscular atrophy, our results may provide a new perspective on the pathophysiology of this neuromuscular disorder.

Histones↗

PubMed2026

Advances in the Application of Adenine Base Editor (ABE) in Biology and Medicine: Prospects and Challenges.

Adenine base editors (ABEs), which achieve A·T to G·C conversions in the genome precisely, symbolize a groundbreaking development in genetic engineering across animal, plant, and microbial systems. This review systematically summed up the research progress and current challenges of ABE in medical and biological applications: it outlined the historical context and pivotal milestones of its technological development; it emphasized major therapeutic advances for genetic diseases including spinal muscular atrophy, mitochondrial genetic disorders, and hyperlipidemia; it provided a comprehensive overview of its prospective uses for enhancing genetic traits in agricultural crops, including grains and fruits; this review conducted a multidimensional assessment of ABE performance through systematic comparison with other base editing technologies, comprehensively evaluating both editing efficiency and inherent limitations. It specifically addresses biosecurity risks such as off-target effects and genomic instability. Finally, safety concerns were proposed as the central challenge hindering its clinical translation, although ABE holds immense promise for precision medicine and agricultural breeding. Unlike previous reviews that mainly summarized early ABE development and general applications, this review particularly emphasizes recently engineered ABE systems, translational bottlenecks, delivery strategies, comparative clinical feasibility, and unresolved biosafety challenges that currently limit broader therapeutic and agricultural applications.

Adenine base editors↗