RARE DISEASE
Congenital myasthenic syndrome
Congenital myasthenic syndrome
Congenital myasthenic syndrome
Synonyms: CMS
Synonyms: CMS
Synonyms: CMS
Drug discovery
7
drugs
With orphan designations
Overview
Congenital myasthenic syndromes (CMS) are rare genetic disorders of neuromuscular transmission caused by mutations in genes critical for synaptic signaling (e.g., CHRNE, RAPSN, COLQ). Characterized by fatigable muscle weakness, ptosis, and respiratory/bulbar dysfunction, symptoms typically manifest by infancy or childhood. Diagnosis involves genetic testing, EMG, and exclusion of autoimmune myasthenia [1][5][6]. Treatment is tailored to the genetic subtype, emphasizing symptom management and preserving motor function [3][13][16].
Burden
Morbidity: Chronic disability (e.g., scoliosis, respiratory insufficiency), delayed motor milestones, and episodic crises requiring ICU care [6][12][14].
Mortality risk: Respiratory failure during infections or apnea events, particularly in neonatal-onset subtypes [6][14][18].
Diagnostic delays: Mean delay of 2–6 years, leading to prolonged functional impairment [12][16].
Therapies
Gene-guided pharmacotherapy: Pyridostigmine (AChE inhibitor) for AChR deficiencies; 3,4-DAP, β-adrenergic agonists (albuterol/ephedrine), or fluoxetine for specific subtypes (e.g., DOK7, slow-/fast-channel mutations) [1][3][13][16].
Avoidance of harmful agents: Acetylcholinesterase inhibitors contraindicated in COLQ or slow-channel CMS [3][5].
Supportive care: Noninvasive ventilation, feeding tubes, and orthopedic interventions for severe cases [1][8][14].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
443 drug discovery papers about Congenital myasthenic syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
443 drug discovery papers about Congenital myasthenic syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-23 | Solving Undiagnosed Neuromuscular Disorders: Uncovering Causative Genotypes Beyond Known Genes and Beyond the Exome
Neuromuscular disorders (NMDs) are a group of inherited diseases that are highly heterogeneous both clinically and genetically. The global prevalence is approximately 1 in 1,000. To date, ~700 genes have been identified to be associated with NMDs. The genetic cause of inherited NMDs in many families remains elusive even after extensive investigation, indicating the possibility of novel genes and genetic mechanisms that have yet to be explored. In addition, lack of a definitive diagnosis can interfere with disease prognosis, classification, and therapeutic options. This thesis aimed to identify the genetic cause of unsolved NMD cases by combining systematic genomic reanalysis with detailed phenotype assessment and functional studies. This would provide patients with a confirmed diagnosis, improved disease management, and access to therapy or inclusion in therapeutic trials. As part of this work, pre-existing NGS datasets from 101 previously unsolved NMD families were systematically reanalysed using updated bioinformatic approaches and phenotype-driven variant prioritization strategies. This led to a diagnostic yield of 16.83%, with causative variants identified in 17 families. In five cases, intronic variants in known NMD genes (COL6A3, SGCA, DOK7, DYSF, CHRND) were considered causative following in silico predictions and careful correlation with the phenotype. One case had an extended phenotype (PTPN11), and one case had a dual diagnosis (MYH2, KIF21A). A novel ATP2A2 missense variant was identified in two unrelated families, establishing ATP2A2 as a new NMD gene. This thesis also identified and characterized a distinct pathogenic mechanism underlying congenital myasthenic syndrome (CMS) caused by variants in the intracellular M3-M4 cytoplasmic loops of acetylcholine receptor (AChR) subunits encoded by CHRND and CHRNA1. Unlike classical AChR-related CMS, these variants showed preserved surface expression and largely normal channel kinetics in conventional functional assays. However, agrin-induced clustering assays in genetically modified C2C12 myotubes demonstrated markedly impaired AChR clustering, establishing defective postsynaptic receptor aggregation as the primary disease mechanism. In addition, this work established a novel association between a heterozygous ATP2A2 missense variant and dominantly inherited recurrent rhabdomyolysis. Functional studies showed impaired SERCA2-mediated calcium reuptake and abnormal intracellular calcium homeostasis in skeletal muscle, supporting the pathogenicity of the identified variant. Overall, this thesis showed that research-based reanalysis of pre-existing NGS data improved the diagnostic yield of previously unsolved cases consistent with previous literature, reinforcing the utility of in-depth, phenotype-driven reanalysis with expert review. The findings highlight the evolving nature of genomic reanalysis and interpretation, demonstrating that previously unsolved cases may become diagnosable as our knowledge of disease genes, variant interpretation and analytical tools continues to improve.
2026-08-25 | First Korean Case of DOK7 Congenital Myasthenic Syndrome Responsive to Ephedrine Therapy
Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic neuromuscular disorders caused by pathogenic variants in genes encoding proteins essential for neuromuscular junction development and function. Downstream of tyrosine kinase 7 (DOK7)-related CMS has been reported frequently in Europe, North America, and Japan, but not in Korea. A 7-year-old girl presented with gait disturbance, frequent falls, and difficulty climbing stairs, which had begun at 4 years of age. Examination revealed mild symmetric proximal weakness without ocular or bulbar involvement, and her serum creatine kinase level was normal. She was initially diagnosed with congenital myopathy. At 24 years of age, whole-exome sequencing identified compound heterozygous pathogenic variants in DOK7 (c.[539G>C];[1124_1127dup]), confirming DOK7 CMS. On clinical re-evaluation, she had stable proximal weakness, and repetitive nerve stimulation demonstrated a significant decremental response in the trapezius muscle. After 1 month of oral ephedrine therapy at 50 mg/day, her endurance and stair-climbing ability improved substantially. We report the first Korean case of DOK7 CMS with a favorable therapeutic response to ephedrine, emphasizing the need to consider CMS in the differential diagnosis of congenital myopathy.
2026-08-04 | Understanding the Consequences of Deficient Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1) Expression in Congenital Myasthenic Syndromes (CMS) and Elucidating New Therapeutic Strategies
Congenital myasthenic syndromes (CMS) are early onset, inheritable neuromuscular disorders caused by mutations in proteins required for neuromuscular junction (NMJ) development, maintenance, function, and motor endplate organization. Clinically, CMS are heterogeneous but typically manifest as fatigable weakness affecting facial, bulbar, ocular, respiratory, limb, and/or girdle muscles, with severity ranging from transient to permanent impairment depending on the underlying genetic defect. More than 40 genes have been implicated in CMS pathogenesis. Among these, glutamine–fructose 6 phosphate transaminase 1 (GFPT1) encodes the rate limiting enzyme of the hexosamine biosynthetic pathway (HBP). Biallelic GFPT1 mutations cause a limb girdle predominant CMS, yet the molecular basis of disease and effective treatments remain poorly understood. We hypothesized that GFPT1 deficiency generates a hypoglycosylated cellular environment that impairs neuromuscular function. Using integrated biochemical, proteomic, and functional analyses, we define the molecular consequences of GFPT1 deficiency. We demonstrate that GFPT1 CMS is a bona fide glycosylation disorder marked by impaired N linked glycosylation and altered protein O GlcNAcylation. Notably, we identify the first mis glycosylated peptide in GFPT1 CMS, located within the δ subunit of the acetylcholine receptor (AChR), providing direct evidence that reduced HBP flux disrupts glycoprotein maturation essential for NMJ transmission. Building on this mechanistic insight, we establish two metabolic strategies that restore glycosylation: galactose supplementation, which partially rescues muscle protein glycosylation, normalizes NMJ and skeletal muscle morphology, and improves behavioral outcomes; and AMDH2 knockdown, which increases O GlcNAcylation in GFPT1 deficient cellular models. Collectively, this work defines the first molecular signature of mis glycosylation in GFPT1 CMS, establishes two therapeutic strategies to restore glycan homeostasis, and identifies serglycin as a potential biomarker. These discoveries advance the mechanistic understanding of glycosylation dependent neuromuscular disease and lay the groundwork for targeted therapeutic development in GFPT1 CMS and related disorders.
2026-07-28 | Mouse Model of Fast-Channel Genetic Myasthenic Syndrome Carrying Chrne p.P141L Mutation.
Fast-channel genetic myasthenic syndromes (FCGMSs) are caused by genetic variants in muscle nicotinic acetylcholine receptor (AChR) subunits that reduce channel open times and impair neuromuscular transmission. Among these, the CHRNE p.P141L variant (εP141L) is associated with particularly severe disease. Here, we characterized a knock-in mouse model harboring the homologous p.P141L variant in Chrne (εP141L)-C57BL/6J-Chrneem1H/H made by the MRC GEMM program. Homozygous mutant mice fail to thrive, with early lethality (median survival of 16 days), closely recapitulating the severity observed in patients. Despite a preserved neuromuscular junction (NMJ) morphology and robust AChR expression, electrophysiological analyses revealed marked reductions in miniature and evoked endplate potential amplitudes and areas, accompanied by prolonged depolarization kinetics (contrary to expectations for AChR with reduced open times) and increased quantal content, indicative of impaired post-synaptic function with compensatory pre-synaptic adaptation. Notably, disease severity exceeded that of Chrne null mice, likely through competition with more functional g-subunit-containing fetal AChRs. Consistent with this, crossing εP141L mice with CHRNG-expressing mice provided little survival benefit. These findings demonstrate that dysfunctional AChR incorporation is more deleterious than receptor absence and highlight the critical role of subunit composition in sustaining neuromuscular transmission. Pharmacological enhancement of pre-synaptic release with 3,4-diaminopyridine partially improved synaptic parameters. In addition, the AChR-positive allosteric modulator DC-98 modestly improved neurotransmission. Thus, this mouse model provides a faithful platform for mechanistic studies and therapeutic development in FCGMS.
2026-07-09 | ALG14 Variants Contribute to a Congenital Disorder of Glycosylation Characterized by Congenital Myasthenia and Epilepsy.
Asparagine-linked glycosylation 14 (ALG14) is a UDP-GlcNAc transferase that catalyzes the second sugar addition in the synthesis of the dolichol-linked oligosaccharide precursor in N-linked glycosylation, ultimately contributing to glycosylation of a wide array of proteins. Biallelic pathogenic variants in ALG14 have been suggested to lead to a congenital disorder of glycosylation (CDG) due to incomplete lipid linked oligosaccharide synthesis and ultimately hypoglycosylation of N-linked glycoproteins. In a cohort of nine previously unreported individuals with bi-allelic variants in ALG14 from eight unrelated families we demonstrate evidence of a CDG that manifests as a congenital myasthenic syndrome, epilepsy, joint contractures, and dysmorphic features. Using a Xenopus knockdown model of disease, we explored the ramifications of alg14 depletion on early neurodevelopment and used this model as a platform to test the function of previously identified ALG14 missense variants as well as missense variants from the individuals reported in this study. Investigations of the Xenopus model tissue and tissue from an affected individual elucidated a mechanism by which dysfunctional glycosylation may lead to neurological disease and establish this as a Bona fide CDG. These findings may guide evaluation of future individuals with suspected ALG14-CDG and future targeted therapeutics such as those being used in other CDG.
proteins
2026-09-11 | Congenital myasthenic syndromes in Türkiye: genetic and clinical spectrum revisited in a nationwide pediatric cohort.
Congenital myasthenic syndromes (CMS) are inherited disorders caused by defects in proteins essential for neuromuscular transmission. In this nationwide, multicenter retrospective study, we analyzed 133 genetically confirmed CMS cases from 118 unrelated families between 2017 and 2024 across 28 centers in Türkiye. Clinical, electrophysiological, and genetic data were collected from medical records. In addition, we performed a PubMed-based review of previously reported genetically confirmed Turkish CMS cases to place our findings in a broader national context. The median age at symptom onset, and the median diagnostic delay were 6 months and 24 months, respectively. Ocular involvement was the most common clinical feature, followed by respiratory and bulbar involvement. High consanguinity (82%) contributed to a predominance of homozygous variants. Variants were identified in 16 CMS-associated genes, with COLQ (34.6%), CHRNE (24.1%), and CHAT (12.8%) being the most frequent. Postsynaptic CMS was the most common anatomical subgroup. Eighteen novel variants across 11 genes expanded the mutational spectrum of CMS. Review of 23 previously published studies from Türkiye identified 139 additional genetically confirmed cases, showing a broadly similar genetic distribution, with CHRNE and COLQ predominating, followed by CHAT, whereas other CMS-associated genes were reported only sporadically. >These findings define the clinical and genetic landscape of CMS in Türkiye and, together with previously published Turkish cases, provide a broad national overview based on 272 genetically confirmed cases. The results highlight the major contribution of a limited number of genes and underscore the importance of early molecular diagnosis in a population with high consanguinity.
2026-08-31 | Muscular Rapsyn safeguards neuromuscular junction integrity during development and adult maintenance
Abstract Background Rapsyn is a pivotal scaffolding protein required for clustering nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ). Mutations in Rapsyn are a well-established cause of congenital myasthenic syndromes (CMS), leading to early-onset muscle weakness. However, although Rapsyn is expressed exclusively in skeletal muscle, the specific contribution of muscle-derived Rapsyn to NMJ development and stability has never been directly tested. Previous studies using in vivo Rapsyn silencing suggested a role for Rapsyn in adult NMJ maintenance, but the specific contribution of muscle-derived Rapsyn and the threshold level requirement to maintain adult NMJ integrity remain incompletely understood. Methods Using muscle-specific and inducible Rapsyn knockout mouse models, we examined the role of muscle-derived Rapsyn in NMJ formation, structural maintenance, and neuromuscular function across developmental and adult stages. Results Homozygous muscular Rapsyn ablation caused neonatal lethality and catastrophic NMJ disorganization. In contrast, grade reduction of Rapsyn expression in adult mice progressively induced fragmented nAChR clusters and activity-dependent neuromuscular dysfunction despite relatively preserved gross NMJ morphology. These findings indicate that reduced Rapsyn expression destabilizes postsynaptic receptor domains and produces features resembling postsynaptic dysfunction observed in myasthenic disorders. Conclusions This study demonstrates that sustained muscular Rapsyn expression is required for lifelong NMJ integrity and identifies a dose-dependent requirement for maintaining postsynaptic stability. Our findings complement previous studies demonstrating the protective effects of Rapsyn augmentation in experimental autoimmune MG by providing genetic evidence that sustained muscular Rapsyn expression is required for lifelong NMJ stability and postsynaptic resilience.
2026-07-31 | Exploring the Value of Quantitative Muscle Ultrasound in Neuromuscular Junction Disorders: A Pilot Study.
Quantitative muscle ultrasound (QMUS) is a validated technique for assessing muscle pathology, yet its role in disorders primarily affecting the neuromuscular junction (NMJ) remains unclear. This pilot study aimed to explore whether QMUS is associated with structural muscle changes in patients with acquired or genetic NMJ disorders. We conducted a retrospective study of 18 patients with confirmed NMJ disorders who underwent electrodiagnostic testing (EDx), including repetitive nerve stimulation (RNS) and/or stimulated single-fiber electromyography (SFEMG), combined with QMUS. Patients were grouped into congenital myasthenic syndromes (CMS) and acquired autoimmune myasthenia (myasthenia gravis [MG] or Lambert-Eaton myasthenic syndrome [LEMS]). QMUS scores were classified as normal, borderline, or abnormal based on muscle echogenicity z-scores derived from a validated algorithm. Abnormal EDx was present in 13 of 18 (72%) patients. Abnormal decrement (> 10%) was observed in 7/18 patients, and abnormal jitter in the orbicularis oculi muscle was found in 6/8 patients. QMUS demonstrated normal echogenicity in 14/18 (78%) patients, while 4/18 (22%) showed abnormal or borderline echogenicity, including 2/5 (40%) with generalized MG. All patients with borderline or abnormal QMUS findings had concomitant abnormal RNS and/or SFEMG. Structural muscle changes, reflected by altered echogenicity, may occur in a subset of patients with NMJ disorders, although QMUS shows limited sensitivity compared with EDx. Future studies using standardized protocols, dynamic assessments, and targeted evaluation of clinically relevant muscles, such as facial and bulbar, are needed to determine whether QMUS may serve as a complementary tool for disease characterization or monitoring.
2026-07-01 | The Differing Phenotypes of the Three Most Common Postsynaptic Congenital Myasthenic Syndromes Governed by Their Underlying Molecular Pathogenic Mechanisms.
The congenital myasthenic syndromes are rare disorders of impaired signal transmission at the neuromuscular junction. Despite next generation sequencing facilitating the identification of variants in myasthenic-associated genes, these variants are frequently of unknown significance and the clinical diagnosis can be delayed. It is mutations in the genes encoding neuromuscular junction proteins AChR, RAPSN, and DOK7 that underlie most cases. Appreciation of key phenotypic features that distinguish between AChR deficiency due to mutations in CHRNE, AChR deficiency due to mutations in RAPSN, and the "limb girdle" myasthenic syndrome due to mutations in DOK7 can facilitate early diagnosis. While severity for each of these conditions is markedly variable and thus there are exceptions to the rule, the CHRNE mutations result in stable generalized fatigable weakness with marked ophthalmoparesis, RAPSN mutations often result in respiratory crises in neonates or early childhood that tend to resolve with age, and DOK7 mutations cause a limb girdle myasthenic pattern of weakness that may present at birth or shortly after the walking motor milestone is achieved, is slowly progressive but responds well to treatment. The differences and time course for these phenotypes may be explained by the underlying molecular mechanisms. For the CHRNE mutations, patients at least partially function on the fetal form of the AChR; for RAPSN mutations, AChR clustering on the postsynaptic membrane is destabilized; and for DOK7 mutations, the stability of endplate structures is affected. Each of these disorders responds to treatments that can be life-transforming and so early recognition is key.
2026-06-09 | Congenital Myasthenic Syndromes Diagnosed in Adulthood: A Case Series Exploring Genetic and Clinical Complexities (P6-9.019)
This series describes four adult-onset or late-recognized Congenital Myasthenic Syndromes (CMS) cases, emphasizing genetic heterogeneity, diagnostic challenges, and therapeutic implications.
oligonucleotides
2022-01-04 | RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing.
Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequencing technologies has allowed identification of novel genes and mutations associated with neuromuscular pathologies, highlighting splicing defects as essential players. Deciphering the significance and relative contributions of defective RNA metabolism will be instrumental to address and counteract these malignancies. We review here recent progress on the role played by alternative splicing in ensuring functional neuromuscular junctions (NMJs), and its involvement in the pathogenesis of NMJ-related neuromuscular disorders, with particular emphasis on congenital myasthenic syndromes and muscular dystrophies. We will also discuss novel strategies based on oligonucleotides designed to bind their cognate sequences in the RNA or targeting intermediary of mRNA metabolism. These efforts resulted in several chemical classes of RNA molecules that have recently proven to be clinically effective, more potent and better tolerated than previous strategies.
2020-06-25 | [Advances in the diagnosis and treatment of congenital myasthenic syndrome].
Congenital myasthenic syndrome (CMS) is a group of clinical and genetic heterogeneous diseases caused by impaired neuromuscular transmission due to genetic defects. At present, it has been reported that more than 30 genes can cause CMS. All CMS subtypes have the clinical features of fatigue and muscle weakness, but age of onset, symptoms, and treatment response vary with the molecular mechanisms underlying genetic defects. Pharmacotherapy and symptomatic/supportive treatment are the main methods for the treatment of CMS, and antisense oligonucleotide technology has been proven to be beneficial for CHRNA 1-related CMS in animals. Since CMS is a group of increasingly recognized clinical and genetic heterogeneous diseases, an understanding of the latest knowledge and research advances in its clinical features, genetic research, and treatment helps to give early diagnosis and treatment as well as gain a deeper understanding of the pathogenesis of CMS, so as to make new breakthroughs in the treatment of CMS. 先天性肌无力综合征（CMS）是由于基因缺陷导致神经肌肉传导受损所引起的一组临床和遗传异质性疾病。目前，已报道可导致CMS的致病基因达30余个。所有CMS亚型都具有易疲劳和肌无力的临床特征，但发病年龄、症状和治疗反应因潜在遗传缺陷的分子机制而异。现CMS患者的治疗常采用药物治疗和对症支持治疗等方法，在动物中，反义寡核苷酸技术已被证明对CHRNA1相关的CMS是有益的。CMS作为一组日益被认可的临床和遗传异质性疾病，揭示其临床特点、基因研究和治疗等方面的最新知识和最新进展，不仅有助于对该病进行早期诊断与治疗，还将有助于对CMS发病机制的进一步深入了解，从而有望在CMS的治疗上取得新的突破。
2015-04-17 | Antisense oligonucleotide-mediated exon skipping of CHRNA1 pre-mRNA as potential therapy for Congenital Myasthenic Syndromes
CHRNA1 encodes the α subunit of nicotinic acetylcholine receptors (nAChRs) and is expressed at the neuromuscular junction. Moreover, it is one of the causative genes of Congenital Myasthenic Syndromes (CMS). CHRNA1 undergoes alternative splicing to produce two splice variants: P3A(-), without exon P3A, and P3A(+), with the exon P3A. Only P3A(-) forms functional nAChR. Aberrant alternative splicing caused by intronic or exonic point mutations in patients leads to an extraordinary increase in P3A(+) and a concomitant decrease in P3A(-). Consequently this resulted in a shortage of functional receptors. Aiming to restore the imbalance between the two splice products, antisense oligonucleotides (AONs) were employed to induce exon P3A skipping. Three AON sequences were designed to sterically block the putative binding sequences for splicing factors necessary for exon recognition. Herein, we show that AON complementary to the 5' splice site of the exon was the most effective at exon skipping of the minigene with causative mutations, as well as endogenous wild-type CHRNA1. We conclude that single administration of the AON against the 5' splice site is a promising therapeutic approach for patients based on the dose-dependent effect of the AON and the additive effect of combined AONs. This conclusion is favorable to patients with inherited diseases of uncertain etiology that arise from aberrant splicing leading to a subsequent loss of functional translation products because our findings encourage the option of AON treatment as a therapeutic for these prospectively identified diseases.
2008-09-04 | hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome
In humans and great apes, CHRNA1 encoding the muscle nicotinic acetylcholine receptor α subunit carries an inframe exon P3A, the inclusion of which yields a nonfunctional α subunit. In muscle, the P3A(−) and P3A(+) transcripts are generated in a 1:1 ratio but the functional significance and regulation of the alternative splicing remain elusive. An intronic mutation (IVS3-8G>A), identified in a patient with congenital myasthenic syndrome, disrupts an intronic splicing silencer (ISS) and results in exclusive inclusion of the downstream P3A exon. We found that the ISS-binding splicing trans-factor was heterogeneous nuclear ribonucleoprotein (hnRNP) H and the mutation attenuated the affinity of hnRNP for the ISS ∼100-fold. We next showed that direct placement of hnRNP H to the 3′ end of intron 3 silences, and siRNA-mediated downregulation of hnRNP H enhances recognition of exon P3A. Analysis of the human genome suggested that the hnRNPH-binding UGGG motif is overrepresented close to the 3′ ends of introns. Pursuing this clue, we showed that alternative exons of GRIP1, FAS, VPS13C and NRCAM are downregulated by hnRNP H. Our findings imply that the presence of the hnRNP H-binding motif close to the 3′ end of an intron is an essential but underestimated splicing regulator of the downstream exon.
2007-08-13 | Restoring balance at the neuromuscular junction
Argov and colleagues present the results of a Phase 1b trial of an oral antisense oligonucleotide, EN101 (Monarsen, Ester Neurosciences Ltd.), for treatment of myasthenia gravis (MG) in this issue of Neurology ®.1 The brief report and the authors' humble description of their study belie the remarkable story and potential for broad impact of their work. Why do I make this statement? 1) The science behind EN101 is fascinating and was rapidly translated to the clinic. 2) Of great surprise is that the agent is efficacious when given orally. 3) Human trials of antisense oligonucleotide technology have been disappointing, but this trial suggests a therapeutic benefit, which should bolster hope for this approach for drug development. 4) The work has broad implications beyond MG. It has long been appreciated that the AChE-synaptic (AChE-S) isoform is critical in terminating the action of ACh to prevent repeated activation of the acetylcholine receptor (AChR) (see figure). Supporting the importance of this critical function is the observation that mutations of the AChE-S gene lead to cholinesterase deficiency and a congenital myasthenic syndrome. The AChE-S is distributed through the primary and secondary synaptic clefts of …
gene therapies
2024-02-26 | Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia.
Congenital myasthenic syndromes (CMS) are a group of inherited disorders characterised by defective neuromuscular transmission and fatigable muscle weakness. Mutations in DOK7 , a gene encoding a post-synaptic protein crucial in the formation and stabilisation of the neuromuscular junction (NMJ), rank among the leading three prevalent causes of CMS in diverse populations globally. The majority of DOK7 CMS patients experience varying degrees of disability despite receiving optimised treatment, necessitating the development of improved therapeutic approaches. Here we executed a dose escalation pre-clinical trial using a DOK7-CMS mouse model to assess the efficacy of Amp-101, an innovative AAV gene replacement therapy. Amp-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. We show that at doses 6x10 13 vg/kg and 1x10 14 vg/kg, Amp-101 generated enlarged NMJs and rescued the very severe phenotype of the model. Treated mice became at least as strong as WT littermates and the diaphragm and tibialis anterior muscles displayed robust expression of DOK7. This data suggests that Amp-101 is a promising candidate to move forward to clinic trials.
2023-08-28 | Long-term muscle-specific overexpression of DOK7 in mice using AAV9-tMCK-DOK7.
Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation and maintenance of post-synaptic elements of the NMJ, and downstream of tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular pathology in pre-clinical disease models of CMS and MND. However, long-term consequences of DOK7 expression have been sparsely investigated and targeted overexpression of DOK7 in skeletal muscle yet to be established. Here, we developed and characterized a novel AAV9-DOK7 facilitating forced expression of DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically delivered to newborn mice that were monitored over 6 months. DOK7 overexpression was restricted to skeletal muscles. Body weight, blood biochemistry, and histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In contrast, forced expression of DOK7 resulted in enlargement of both the pre- and post-synaptic components of the NMJ, without causing denervation. We conclude that muscle-specific DOK7 overexpression can be achieved in a safe manner, with the capacity to target NMJs in vivo.
2022-12-09 | Congenital myasthenic syndromes (CMS) a rare cause of uncommon fatigue
Introduction and purpose:
Muscle weakness in newborns, infants and young children can be caused by disorders of the neuromuscular junction (NMJ). Congenital myasthenic syndromes (CMS) are a group of rare genetic diseases whose symptoms resemble the clinical picture of autoimmune myasthenia gravis. There are many mutations that can disrupt the neuromuscular transmission leading to pathology. The diagnosis of CMS is based on genetic testing. The aim of this study is to draw clinicians' attention to the symptoms and present current forms of CMS diagnosis and management.
State of knowledge:
An increasing number of genetic changes are associated with CMS pathology. They are divided, depending on the location in the NMJ of the encoded protein, into presynaptic, synaptic and postsynaptic. The most common disorder is the mutation of CHRNE, which is responsible for the expression of one of the subunits in the structure of the acetylcholine receptor. Regardless of the type of disease, the characteristic symptom is uncommon fatigue of skeletal muscles. It may present as ptosis of one or both eyelids or gait disturbance. The interview, laboratory tests and EMG are helpful in the diagnosis, but genetic tests play a key role. They can target specific mutations or cover the entire genome comprehensively. Currently used drugs alleviate the course of CMS by increasing the release of acetylcholine or increasing the concentration of acetylcholine in the synaptic cleft.
Conclusion:
Because of its rarity and variability, many CMS patients may be misdiagnosed. It is important to implement extensive genetic diagnostics and early implementation of treatment. There is a need for long-term studies of CMS cases and implementation of therapies targeted at specific mutations.
2018-09-05 | CONGENITAL MYASTHENIC SYNDROMES AND MYASTHENIA
Neuromuscular disorders (NMDs) contain a broad group of disorders with overlapping symptoms and is therefore difficult to differentiate clinically. A subgroup is a plethora of rare and different congenital myasthenic syndromes (CMS) with different inheritance patterns, severity and possible treatments. Since May 2017, we have offered an expanded gene panel based on Next-generation Sequencing (NGS) to patients with NMDs, including CMS. We performed a NGS-analysis with a gene list of 328 genes on almost 150 patients where standard ``gene by gene testing'' had not yielded a diagnosis. NGS was performed using Illumina TruSight One Sequencing panel (4813 genes) and run on an Illumina NextSeq 500 Desktop Sequencer. Analyses were done using Illumina BaseSpace BWA Enrichment Workflow and annotation, filtration and variant curation were done using Cartagenia Bench and Alamut Vision. Of the aprx. 150 patients tested by the extended panel, we found three patients with definite CMS based on genetic results of probable and possible pathogenic variants, as well as response to treatments directed by these results. A newborn girl with severe neonatal onset suspected of severe anterior horn disease, was compound heterozygous for variants in CHRNA1. A 15-year-old boy thought to have congenital myopathy from a few months of age, had two alterations in DOK7. The third, a newborn boy with severe onset, was compound heterozygous for two alterations in CHRND. A fourth patient carried two alterations in CHRNE, and it remains to be seen whether they are of clinical significance. An extended gene panel designed for NMDs including CMS, resulted in some surprising findings with therapeutic potential.
2015-09-16 | COLQ variant associated with D evon R ex and S phynx feline hereditary myopathy
Summary Some Devon Rex and Sphynx cats have a variably progressive myopathy characterized by appendicular and axial muscle weakness, megaesophagus, pharyngeal weakness and fatigability with exercise. Muscle biopsies from affected cats demonstrated variable pathological changes ranging from dystrophic features to minimal abnormalities. Affected cats have exacerbation of weakness following anticholinesterase dosing, a clue that there is an underlying congenital myasthenic syndrome (CMS). A genome‐wide association study and whole‐genome sequencing suggested a causal variant for this entity was a c.1190G>A variant causing a cysteine to tyrosine substitution (p.Cys397Tyr) within the C‐terminal domain of collagen‐like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase ( COLQ ). Alpha‐dystroglycan expression, which is associated with COLQ anchorage at the motor end‐plate, has been shown to be deficient in affected cats. Eighteen affected cats were identified by genotyping, including cats from the original clinical descriptions in 1993 and subsequent publications. Eight Devon Rex and one Sphynx not associated with the study were identified as carriers, suggesting an allele frequency of ~2.0% in Devon Rex. Over 350 tested cats from other breeds did not have the variant. Characteristic clinical features and variant presence in all affected cats suggest a model for COLQ CMS. The association between the COLQ variant and this CMS affords clinicians the opportunity to confirm diagnosis via genetic testing and permits owners and breeders to identify carriers in the population. Moreover, accurate diagnosis increases available therapeutic options for affected cats based on an understanding of the pathophysiology and experience from human CMS associated with COLQ variants.
other
2026-07-18 | Longitudinal behavioral profiling reveals early-onset and persistent motor dysfunction in a VAChT-KD model for congenital myasthenic syndrome.
The vesicular acetylcholine transporter knockdown (VAChT-KD) mouse is a genetic model of congenital myasthenic syndrome (CMS) characterized by impaired cholinergic transmission at the neuromuscular junction, resulting in presynaptic neuromuscular dysfunction. Here, we performed a longitudinal behavioral analysis to determine the onset and progression of motor deficits across development and adulthood, including potential sex-dependent effects. VAChT-KD mice exhibited early and persistent motor impairments. Neonatal animals showed reduced strength, impaired coordination, and delayed motor development compared to controls, and these deficits persisted into adulthood. Motor performance was consistently impaired in tests of global strength, while other behavioral measures revealed age- and sex-dependent differences. Notably, repeated exposure to motor tasks improved performance in mutant mice, indicating a learning component that partially compensates for underlying deficits. Across behavioral paradigms, genotype and age emerged as the primary determinants of motor performance. Importantly, the identification of early disease onset and measurable functional deficits across development highlights a critical window for therapeutic intervention. These findings support the use of VAChT-KD mice as a translational platform for testing early-stage therapies and underscore the importance of considering behavioral adaptation when designing preclinical studies for neuromuscular disorders.
2026-06-09 | Phase 1b Study of the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Efficacy of ARGX-119 in Participants with DOK7 Congenital Myasthenic Syndromes (S32.007)
This phase 1b, multicenter, double-blinded, placebo-controlled study (NCT06436742) evaluated safety, tolerability, pharmacokinetics, immunogenicity, and efficacy of ARGX-119 in adults with DOK7 congenital myasthenic syndromes (DOK7-CMS).
2026-05-18 | Gene-specific response to muscle specific kinase agonist antibody in the treatment of congenital myasthenic syndromes.
Congenital myasthenic syndromes (CMS) are a group of rare disorders characterized by fatigable muscle weakness and caused by impaired neuromuscular junction (NMJ) function. CMS symptoms are highly variable, but it can be detrimental and lead to death. There are over 40 different genetic subtypes, including AGRN-CMS and COLQ-CMS. AGRN encodes for neuralagrin, which is released from the nerve terminal and triggers muscle-specific kinase phosphorylation (pMuSK). pMuSK is essential for NMJ development and maintenance, thus agrin deficiency causes NMJ impairment. COLQ encodes for collagenous subunit Q (ColQ), which anchors acetylcholinesterase and stabilizes MuSK. As a result, COLQ deficiency results in NMJ degeneration from prolonged transmission signals and decreased pMuSK. Current treatments for AGRN-CMS and COLQ-CMS are limited, highlighting the importance of finding more efficient therapies. Recently, a MuSK agonist antibody (ARGX-119) with high affinity for the Frizzled-like domain showed remarkable rescue of a Dok7-CMS mouse model. We hypothesized a derivative antibody of ARGX-119 (3B2) could benefit Agrn- and ColQ-CMS mouse models. Agrn-CMS mice were treated at postnatal day 5 (P5), P15 and P35, and ColQ-CMS mice were treated weekly from P22 to P57. In Agrn-CMS mice, 3B2 treatment rescued survival, bodyweight, fibre type switching and pMuSK levels, and improved forelimb grip strength and NMJ morphology. In ColQ-CMS mice, 3B2 treatment was unable to rescue deficits observed. Our findings suggest that MuSK agonists may benefit patients with AGRN-CMS, which should be tested in clinical trials. Our study emphasizes that effective CMS treatment is gene-dependent and relies on an accurate genetic diagnosis.
2026-01-05 | [Functional analysis of the mutant channels associated with skeletal muscle channelopathies].
Skeletal muscle channelopathies are rare genetic disorders caused by mutations in voltage-gated ion channel genes that regulate sarcomere excitability, including the CLCN1 gene encoding ClC-1, the KCNJ2 gene encoding Kir2.1, the SCN4A gene encoding Nav1.4, and the CACNA1S gene encoding Cav1.1. More than one hundred heterozygous missense mutations have been identified in SCN4A, representing a broad spectrum of clinical phenotypes, including sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). In addition, recent case reports have shown that compound heterozygous mutations or homozygous mutations in SCN4A are associated with congenital myopathy or congenital myasthenic syndrome. Regarding the pathological mechanisms of SCM/PMC and HyperPP, a large number of electrophysiological analyses have shown an association between the functional alteration of the mutant Nav1.4 and the clinical phenotype. On the other hand, HypoPP has long been a mysterious disorder. In 2007, the recent discovery of aberrant leak currents, called "gating pore currents", brought a breakthrough in the field of HypoPP research and contributed to the elucidation of the structure-function relationship of the voltage sensing domain of voltage-gated ion channels. However, there has been little progress in the discovery of the therapeutics. Recently, we have generated HEK293T-based HypoPP model cell lines aiming to establish the in vitro platform for the high-throughput drug screening. Our HypoPP model cells would provide new insight into the development of novel therapeutics for channelopathies.
2025-09-26 | Screening for Congenital Myasthenic Syndromes in Adults With Seronegative Myasthenia Gravis Using Next-Generation Sequencing.
Myasthenia gravis (MG) is a disorder of the neuromuscular junction, typically associated with autoantibodies (Abs) that impair neuromuscular transmission. However, approximately 10% of cases are seronegative. Emerging evidence suggests that seronegative MG (SNMG) may be mimicked by hereditary conditions, particularly congenital myasthenic syndromes (CMSs), which require different treatments. In this study, we aimed to determine the proportion of CMS among patients diagnosed with SNMG. We used whole-exome sequencing (WES) in adult patients (aged ≥18 years) diagnosed with SNMG who were enrolled at 3 Austrian tertiary neuromuscular centers between August 2022 and January 2024. Genetic testing was conducted in individuals who remained seronegative after comprehensive serologic testing to exclude Abs against (clustered) acetylcholine receptors, muscle-specific kinase, lipoprotein receptor-related protein 4, and voltage-gated calcium channels. Moreover, we aimed to analyze clinical and demographic factors associated with the likelihood of receiving a molecular diagnosis. A total of 50 patients with SNMG (35 [70%] female) were referred for exome-based genetic screening. The median age at disease onset was 35 years (interquartile range 24.0-46.0 years). Seven patients (14%) were genetically diagnosed with CMS through WES (4 with CHRNE and 3 with RAPSN variants). In addition, findings of uncertain clinical significance were reported in 4 cases, implicating CACNA1S, DOK7, DPAGT1, and RAPSN. Although patients with CMS tended to have a younger age at disease onset in univariate analysis (p = 0.04, r = 0.29), no clinical or demographic factors remained significantly associated with a molecular diagnosis after correction for multiple testing. Only 1 patient with a confirmed CMS diagnosis reported a positive family history. Six individuals with CMS (86%) had either received immunomodulatory treatments (n = 4) or undergone thymectomy (n = 4). Of the 4 patients with CMS receiving immunotherapies, 3 were reported to have experienced at least a partial response. Our findings provide evidence that a considerable proportion of patients diagnosed with SNMG have an underlying hereditary etiology. Notably, a (subjective) response to immunotherapies does not exclude a molecular CMS diagnosis. In conclusion, offering genetic testing to seronegative patients with myasthenic syndromes may have profound therapeutic implications.
small molecules
2026-09-23 | Solving Undiagnosed Neuromuscular Disorders: Uncovering Causative Genotypes Beyond Known Genes and Beyond the Exome
Neuromuscular disorders (NMDs) are a group of inherited diseases that are highly heterogeneous both clinically and genetically. The global prevalence is approximately 1 in 1,000. To date, ~700 genes have been identified to be associated with NMDs. The genetic cause of inherited NMDs in many families remains elusive even after extensive investigation, indicating the possibility of novel genes and genetic mechanisms that have yet to be explored. In addition, lack of a definitive diagnosis can interfere with disease prognosis, classification, and therapeutic options. This thesis aimed to identify the genetic cause of unsolved NMD cases by combining systematic genomic reanalysis with detailed phenotype assessment and functional studies. This would provide patients with a confirmed diagnosis, improved disease management, and access to therapy or inclusion in therapeutic trials. As part of this work, pre-existing NGS datasets from 101 previously unsolved NMD families were systematically reanalysed using updated bioinformatic approaches and phenotype-driven variant prioritization strategies. This led to a diagnostic yield of 16.83%, with causative variants identified in 17 families. In five cases, intronic variants in known NMD genes (COL6A3, SGCA, DOK7, DYSF, CHRND) were considered causative following in silico predictions and careful correlation with the phenotype. One case had an extended phenotype (PTPN11), and one case had a dual diagnosis (MYH2, KIF21A). A novel ATP2A2 missense variant was identified in two unrelated families, establishing ATP2A2 as a new NMD gene. This thesis also identified and characterized a distinct pathogenic mechanism underlying congenital myasthenic syndrome (CMS) caused by variants in the intracellular M3-M4 cytoplasmic loops of acetylcholine receptor (AChR) subunits encoded by CHRND and CHRNA1. Unlike classical AChR-related CMS, these variants showed preserved surface expression and largely normal channel kinetics in conventional functional assays. However, agrin-induced clustering assays in genetically modified C2C12 myotubes demonstrated markedly impaired AChR clustering, establishing defective postsynaptic receptor aggregation as the primary disease mechanism. In addition, this work established a novel association between a heterozygous ATP2A2 missense variant and dominantly inherited recurrent rhabdomyolysis. Functional studies showed impaired SERCA2-mediated calcium reuptake and abnormal intracellular calcium homeostasis in skeletal muscle, supporting the pathogenicity of the identified variant. Overall, this thesis showed that research-based reanalysis of pre-existing NGS data improved the diagnostic yield of previously unsolved cases consistent with previous literature, reinforcing the utility of in-depth, phenotype-driven reanalysis with expert review. The findings highlight the evolving nature of genomic reanalysis and interpretation, demonstrating that previously unsolved cases may become diagnosable as our knowledge of disease genes, variant interpretation and analytical tools continues to improve.
2026-08-25 | First Korean Case of DOK7 Congenital Myasthenic Syndrome Responsive to Ephedrine Therapy
Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic neuromuscular disorders caused by pathogenic variants in genes encoding proteins essential for neuromuscular junction development and function. Downstream of tyrosine kinase 7 (DOK7)-related CMS has been reported frequently in Europe, North America, and Japan, but not in Korea. A 7-year-old girl presented with gait disturbance, frequent falls, and difficulty climbing stairs, which had begun at 4 years of age. Examination revealed mild symmetric proximal weakness without ocular or bulbar involvement, and her serum creatine kinase level was normal. She was initially diagnosed with congenital myopathy. At 24 years of age, whole-exome sequencing identified compound heterozygous pathogenic variants in DOK7 (c.[539G>C];[1124_1127dup]), confirming DOK7 CMS. On clinical re-evaluation, she had stable proximal weakness, and repetitive nerve stimulation demonstrated a significant decremental response in the trapezius muscle. After 1 month of oral ephedrine therapy at 50 mg/day, her endurance and stair-climbing ability improved substantially. We report the first Korean case of DOK7 CMS with a favorable therapeutic response to ephedrine, emphasizing the need to consider CMS in the differential diagnosis of congenital myopathy.
2026-08-04 | Understanding the Consequences of Deficient Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1) Expression in Congenital Myasthenic Syndromes (CMS) and Elucidating New Therapeutic Strategies
Congenital myasthenic syndromes (CMS) are early onset, inheritable neuromuscular disorders caused by mutations in proteins required for neuromuscular junction (NMJ) development, maintenance, function, and motor endplate organization. Clinically, CMS are heterogeneous but typically manifest as fatigable weakness affecting facial, bulbar, ocular, respiratory, limb, and/or girdle muscles, with severity ranging from transient to permanent impairment depending on the underlying genetic defect. More than 40 genes have been implicated in CMS pathogenesis. Among these, glutamine–fructose 6 phosphate transaminase 1 (GFPT1) encodes the rate limiting enzyme of the hexosamine biosynthetic pathway (HBP). Biallelic GFPT1 mutations cause a limb girdle predominant CMS, yet the molecular basis of disease and effective treatments remain poorly understood. We hypothesized that GFPT1 deficiency generates a hypoglycosylated cellular environment that impairs neuromuscular function. Using integrated biochemical, proteomic, and functional analyses, we define the molecular consequences of GFPT1 deficiency. We demonstrate that GFPT1 CMS is a bona fide glycosylation disorder marked by impaired N linked glycosylation and altered protein O GlcNAcylation. Notably, we identify the first mis glycosylated peptide in GFPT1 CMS, located within the δ subunit of the acetylcholine receptor (AChR), providing direct evidence that reduced HBP flux disrupts glycoprotein maturation essential for NMJ transmission. Building on this mechanistic insight, we establish two metabolic strategies that restore glycosylation: galactose supplementation, which partially rescues muscle protein glycosylation, normalizes NMJ and skeletal muscle morphology, and improves behavioral outcomes; and AMDH2 knockdown, which increases O GlcNAcylation in GFPT1 deficient cellular models. Collectively, this work defines the first molecular signature of mis glycosylation in GFPT1 CMS, establishes two therapeutic strategies to restore glycan homeostasis, and identifies serglycin as a potential biomarker. These discoveries advance the mechanistic understanding of glycosylation dependent neuromuscular disease and lay the groundwork for targeted therapeutic development in GFPT1 CMS and related disorders.
2026-07-28 | Mouse Model of Fast-Channel Genetic Myasthenic Syndrome Carrying Chrne p.P141L Mutation.
Fast-channel genetic myasthenic syndromes (FCGMSs) are caused by genetic variants in muscle nicotinic acetylcholine receptor (AChR) subunits that reduce channel open times and impair neuromuscular transmission. Among these, the CHRNE p.P141L variant (εP141L) is associated with particularly severe disease. Here, we characterized a knock-in mouse model harboring the homologous p.P141L variant in Chrne (εP141L)-C57BL/6J-Chrneem1H/H made by the MRC GEMM program. Homozygous mutant mice fail to thrive, with early lethality (median survival of 16 days), closely recapitulating the severity observed in patients. Despite a preserved neuromuscular junction (NMJ) morphology and robust AChR expression, electrophysiological analyses revealed marked reductions in miniature and evoked endplate potential amplitudes and areas, accompanied by prolonged depolarization kinetics (contrary to expectations for AChR with reduced open times) and increased quantal content, indicative of impaired post-synaptic function with compensatory pre-synaptic adaptation. Notably, disease severity exceeded that of Chrne null mice, likely through competition with more functional g-subunit-containing fetal AChRs. Consistent with this, crossing εP141L mice with CHRNG-expressing mice provided little survival benefit. These findings demonstrate that dysfunctional AChR incorporation is more deleterious than receptor absence and highlight the critical role of subunit composition in sustaining neuromuscular transmission. Pharmacological enhancement of pre-synaptic release with 3,4-diaminopyridine partially improved synaptic parameters. In addition, the AChR-positive allosteric modulator DC-98 modestly improved neurotransmission. Thus, this mouse model provides a faithful platform for mechanistic studies and therapeutic development in FCGMS.
2026-07-09 | ALG14 Variants Contribute to a Congenital Disorder of Glycosylation Characterized by Congenital Myasthenia and Epilepsy.
Asparagine-linked glycosylation 14 (ALG14) is a UDP-GlcNAc transferase that catalyzes the second sugar addition in the synthesis of the dolichol-linked oligosaccharide precursor in N-linked glycosylation, ultimately contributing to glycosylation of a wide array of proteins. Biallelic pathogenic variants in ALG14 have been suggested to lead to a congenital disorder of glycosylation (CDG) due to incomplete lipid linked oligosaccharide synthesis and ultimately hypoglycosylation of N-linked glycoproteins. In a cohort of nine previously unreported individuals with bi-allelic variants in ALG14 from eight unrelated families we demonstrate evidence of a CDG that manifests as a congenital myasthenic syndrome, epilepsy, joint contractures, and dysmorphic features. Using a Xenopus knockdown model of disease, we explored the ramifications of alg14 depletion on early neurodevelopment and used this model as a platform to test the function of previously identified ALG14 missense variants as well as missense variants from the individuals reported in this study. Investigations of the Xenopus model tissue and tissue from an affected individual elucidated a mechanism by which dysfunctional glycosylation may lead to neurological disease and establish this as a Bona fide CDG. These findings may guide evaluation of future individuals with suspected ALG14-CDG and future targeted therapeutics such as those being used in other CDG.
proteins
2026-09-11 | Congenital myasthenic syndromes in Türkiye: genetic and clinical spectrum revisited in a nationwide pediatric cohort.
Congenital myasthenic syndromes (CMS) are inherited disorders caused by defects in proteins essential for neuromuscular transmission. In this nationwide, multicenter retrospective study, we analyzed 133 genetically confirmed CMS cases from 118 unrelated families between 2017 and 2024 across 28 centers in Türkiye. Clinical, electrophysiological, and genetic data were collected from medical records. In addition, we performed a PubMed-based review of previously reported genetically confirmed Turkish CMS cases to place our findings in a broader national context. The median age at symptom onset, and the median diagnostic delay were 6 months and 24 months, respectively. Ocular involvement was the most common clinical feature, followed by respiratory and bulbar involvement. High consanguinity (82%) contributed to a predominance of homozygous variants. Variants were identified in 16 CMS-associated genes, with COLQ (34.6%), CHRNE (24.1%), and CHAT (12.8%) being the most frequent. Postsynaptic CMS was the most common anatomical subgroup. Eighteen novel variants across 11 genes expanded the mutational spectrum of CMS. Review of 23 previously published studies from Türkiye identified 139 additional genetically confirmed cases, showing a broadly similar genetic distribution, with CHRNE and COLQ predominating, followed by CHAT, whereas other CMS-associated genes were reported only sporadically. >These findings define the clinical and genetic landscape of CMS in Türkiye and, together with previously published Turkish cases, provide a broad national overview based on 272 genetically confirmed cases. The results highlight the major contribution of a limited number of genes and underscore the importance of early molecular diagnosis in a population with high consanguinity.
2026-08-31 | Muscular Rapsyn safeguards neuromuscular junction integrity during development and adult maintenance
Abstract Background Rapsyn is a pivotal scaffolding protein required for clustering nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ). Mutations in Rapsyn are a well-established cause of congenital myasthenic syndromes (CMS), leading to early-onset muscle weakness. However, although Rapsyn is expressed exclusively in skeletal muscle, the specific contribution of muscle-derived Rapsyn to NMJ development and stability has never been directly tested. Previous studies using in vivo Rapsyn silencing suggested a role for Rapsyn in adult NMJ maintenance, but the specific contribution of muscle-derived Rapsyn and the threshold level requirement to maintain adult NMJ integrity remain incompletely understood. Methods Using muscle-specific and inducible Rapsyn knockout mouse models, we examined the role of muscle-derived Rapsyn in NMJ formation, structural maintenance, and neuromuscular function across developmental and adult stages. Results Homozygous muscular Rapsyn ablation caused neonatal lethality and catastrophic NMJ disorganization. In contrast, grade reduction of Rapsyn expression in adult mice progressively induced fragmented nAChR clusters and activity-dependent neuromuscular dysfunction despite relatively preserved gross NMJ morphology. These findings indicate that reduced Rapsyn expression destabilizes postsynaptic receptor domains and produces features resembling postsynaptic dysfunction observed in myasthenic disorders. Conclusions This study demonstrates that sustained muscular Rapsyn expression is required for lifelong NMJ integrity and identifies a dose-dependent requirement for maintaining postsynaptic stability. Our findings complement previous studies demonstrating the protective effects of Rapsyn augmentation in experimental autoimmune MG by providing genetic evidence that sustained muscular Rapsyn expression is required for lifelong NMJ stability and postsynaptic resilience.
2026-07-31 | Exploring the Value of Quantitative Muscle Ultrasound in Neuromuscular Junction Disorders: A Pilot Study.
Quantitative muscle ultrasound (QMUS) is a validated technique for assessing muscle pathology, yet its role in disorders primarily affecting the neuromuscular junction (NMJ) remains unclear. This pilot study aimed to explore whether QMUS is associated with structural muscle changes in patients with acquired or genetic NMJ disorders. We conducted a retrospective study of 18 patients with confirmed NMJ disorders who underwent electrodiagnostic testing (EDx), including repetitive nerve stimulation (RNS) and/or stimulated single-fiber electromyography (SFEMG), combined with QMUS. Patients were grouped into congenital myasthenic syndromes (CMS) and acquired autoimmune myasthenia (myasthenia gravis [MG] or Lambert-Eaton myasthenic syndrome [LEMS]). QMUS scores were classified as normal, borderline, or abnormal based on muscle echogenicity z-scores derived from a validated algorithm. Abnormal EDx was present in 13 of 18 (72%) patients. Abnormal decrement (> 10%) was observed in 7/18 patients, and abnormal jitter in the orbicularis oculi muscle was found in 6/8 patients. QMUS demonstrated normal echogenicity in 14/18 (78%) patients, while 4/18 (22%) showed abnormal or borderline echogenicity, including 2/5 (40%) with generalized MG. All patients with borderline or abnormal QMUS findings had concomitant abnormal RNS and/or SFEMG. Structural muscle changes, reflected by altered echogenicity, may occur in a subset of patients with NMJ disorders, although QMUS shows limited sensitivity compared with EDx. Future studies using standardized protocols, dynamic assessments, and targeted evaluation of clinically relevant muscles, such as facial and bulbar, are needed to determine whether QMUS may serve as a complementary tool for disease characterization or monitoring.
2026-07-01 | The Differing Phenotypes of the Three Most Common Postsynaptic Congenital Myasthenic Syndromes Governed by Their Underlying Molecular Pathogenic Mechanisms.
The congenital myasthenic syndromes are rare disorders of impaired signal transmission at the neuromuscular junction. Despite next generation sequencing facilitating the identification of variants in myasthenic-associated genes, these variants are frequently of unknown significance and the clinical diagnosis can be delayed. It is mutations in the genes encoding neuromuscular junction proteins AChR, RAPSN, and DOK7 that underlie most cases. Appreciation of key phenotypic features that distinguish between AChR deficiency due to mutations in CHRNE, AChR deficiency due to mutations in RAPSN, and the "limb girdle" myasthenic syndrome due to mutations in DOK7 can facilitate early diagnosis. While severity for each of these conditions is markedly variable and thus there are exceptions to the rule, the CHRNE mutations result in stable generalized fatigable weakness with marked ophthalmoparesis, RAPSN mutations often result in respiratory crises in neonates or early childhood that tend to resolve with age, and DOK7 mutations cause a limb girdle myasthenic pattern of weakness that may present at birth or shortly after the walking motor milestone is achieved, is slowly progressive but responds well to treatment. The differences and time course for these phenotypes may be explained by the underlying molecular mechanisms. For the CHRNE mutations, patients at least partially function on the fetal form of the AChR; for RAPSN mutations, AChR clustering on the postsynaptic membrane is destabilized; and for DOK7 mutations, the stability of endplate structures is affected. Each of these disorders responds to treatments that can be life-transforming and so early recognition is key.
2026-06-09 | Congenital Myasthenic Syndromes Diagnosed in Adulthood: A Case Series Exploring Genetic and Clinical Complexities (P6-9.019)
This series describes four adult-onset or late-recognized Congenital Myasthenic Syndromes (CMS) cases, emphasizing genetic heterogeneity, diagnostic challenges, and therapeutic implications.
oligonucleotides
2022-01-04 | RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing.
Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequencing technologies has allowed identification of novel genes and mutations associated with neuromuscular pathologies, highlighting splicing defects as essential players. Deciphering the significance and relative contributions of defective RNA metabolism will be instrumental to address and counteract these malignancies. We review here recent progress on the role played by alternative splicing in ensuring functional neuromuscular junctions (NMJs), and its involvement in the pathogenesis of NMJ-related neuromuscular disorders, with particular emphasis on congenital myasthenic syndromes and muscular dystrophies. We will also discuss novel strategies based on oligonucleotides designed to bind their cognate sequences in the RNA or targeting intermediary of mRNA metabolism. These efforts resulted in several chemical classes of RNA molecules that have recently proven to be clinically effective, more potent and better tolerated than previous strategies.
2020-06-25 | [Advances in the diagnosis and treatment of congenital myasthenic syndrome].
Congenital myasthenic syndrome (CMS) is a group of clinical and genetic heterogeneous diseases caused by impaired neuromuscular transmission due to genetic defects. At present, it has been reported that more than 30 genes can cause CMS. All CMS subtypes have the clinical features of fatigue and muscle weakness, but age of onset, symptoms, and treatment response vary with the molecular mechanisms underlying genetic defects. Pharmacotherapy and symptomatic/supportive treatment are the main methods for the treatment of CMS, and antisense oligonucleotide technology has been proven to be beneficial for CHRNA 1-related CMS in animals. Since CMS is a group of increasingly recognized clinical and genetic heterogeneous diseases, an understanding of the latest knowledge and research advances in its clinical features, genetic research, and treatment helps to give early diagnosis and treatment as well as gain a deeper understanding of the pathogenesis of CMS, so as to make new breakthroughs in the treatment of CMS. 先天性肌无力综合征（CMS）是由于基因缺陷导致神经肌肉传导受损所引起的一组临床和遗传异质性疾病。目前，已报道可导致CMS的致病基因达30余个。所有CMS亚型都具有易疲劳和肌无力的临床特征，但发病年龄、症状和治疗反应因潜在遗传缺陷的分子机制而异。现CMS患者的治疗常采用药物治疗和对症支持治疗等方法，在动物中，反义寡核苷酸技术已被证明对CHRNA1相关的CMS是有益的。CMS作为一组日益被认可的临床和遗传异质性疾病，揭示其临床特点、基因研究和治疗等方面的最新知识和最新进展，不仅有助于对该病进行早期诊断与治疗，还将有助于对CMS发病机制的进一步深入了解，从而有望在CMS的治疗上取得新的突破。
2015-04-17 | Antisense oligonucleotide-mediated exon skipping of CHRNA1 pre-mRNA as potential therapy for Congenital Myasthenic Syndromes
CHRNA1 encodes the α subunit of nicotinic acetylcholine receptors (nAChRs) and is expressed at the neuromuscular junction. Moreover, it is one of the causative genes of Congenital Myasthenic Syndromes (CMS). CHRNA1 undergoes alternative splicing to produce two splice variants: P3A(-), without exon P3A, and P3A(+), with the exon P3A. Only P3A(-) forms functional nAChR. Aberrant alternative splicing caused by intronic or exonic point mutations in patients leads to an extraordinary increase in P3A(+) and a concomitant decrease in P3A(-). Consequently this resulted in a shortage of functional receptors. Aiming to restore the imbalance between the two splice products, antisense oligonucleotides (AONs) were employed to induce exon P3A skipping. Three AON sequences were designed to sterically block the putative binding sequences for splicing factors necessary for exon recognition. Herein, we show that AON complementary to the 5' splice site of the exon was the most effective at exon skipping of the minigene with causative mutations, as well as endogenous wild-type CHRNA1. We conclude that single administration of the AON against the 5' splice site is a promising therapeutic approach for patients based on the dose-dependent effect of the AON and the additive effect of combined AONs. This conclusion is favorable to patients with inherited diseases of uncertain etiology that arise from aberrant splicing leading to a subsequent loss of functional translation products because our findings encourage the option of AON treatment as a therapeutic for these prospectively identified diseases.
2008-09-04 | hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome
In humans and great apes, CHRNA1 encoding the muscle nicotinic acetylcholine receptor α subunit carries an inframe exon P3A, the inclusion of which yields a nonfunctional α subunit. In muscle, the P3A(−) and P3A(+) transcripts are generated in a 1:1 ratio but the functional significance and regulation of the alternative splicing remain elusive. An intronic mutation (IVS3-8G>A), identified in a patient with congenital myasthenic syndrome, disrupts an intronic splicing silencer (ISS) and results in exclusive inclusion of the downstream P3A exon. We found that the ISS-binding splicing trans-factor was heterogeneous nuclear ribonucleoprotein (hnRNP) H and the mutation attenuated the affinity of hnRNP for the ISS ∼100-fold. We next showed that direct placement of hnRNP H to the 3′ end of intron 3 silences, and siRNA-mediated downregulation of hnRNP H enhances recognition of exon P3A. Analysis of the human genome suggested that the hnRNPH-binding UGGG motif is overrepresented close to the 3′ ends of introns. Pursuing this clue, we showed that alternative exons of GRIP1, FAS, VPS13C and NRCAM are downregulated by hnRNP H. Our findings imply that the presence of the hnRNP H-binding motif close to the 3′ end of an intron is an essential but underestimated splicing regulator of the downstream exon.
2007-08-13 | Restoring balance at the neuromuscular junction
Argov and colleagues present the results of a Phase 1b trial of an oral antisense oligonucleotide, EN101 (Monarsen, Ester Neurosciences Ltd.), for treatment of myasthenia gravis (MG) in this issue of Neurology ®.1 The brief report and the authors' humble description of their study belie the remarkable story and potential for broad impact of their work. Why do I make this statement? 1) The science behind EN101 is fascinating and was rapidly translated to the clinic. 2) Of great surprise is that the agent is efficacious when given orally. 3) Human trials of antisense oligonucleotide technology have been disappointing, but this trial suggests a therapeutic benefit, which should bolster hope for this approach for drug development. 4) The work has broad implications beyond MG. It has long been appreciated that the AChE-synaptic (AChE-S) isoform is critical in terminating the action of ACh to prevent repeated activation of the acetylcholine receptor (AChR) (see figure). Supporting the importance of this critical function is the observation that mutations of the AChE-S gene lead to cholinesterase deficiency and a congenital myasthenic syndrome. The AChE-S is distributed through the primary and secondary synaptic clefts of …
gene therapies
2024-02-26 | Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia.
Congenital myasthenic syndromes (CMS) are a group of inherited disorders characterised by defective neuromuscular transmission and fatigable muscle weakness. Mutations in DOK7 , a gene encoding a post-synaptic protein crucial in the formation and stabilisation of the neuromuscular junction (NMJ), rank among the leading three prevalent causes of CMS in diverse populations globally. The majority of DOK7 CMS patients experience varying degrees of disability despite receiving optimised treatment, necessitating the development of improved therapeutic approaches. Here we executed a dose escalation pre-clinical trial using a DOK7-CMS mouse model to assess the efficacy of Amp-101, an innovative AAV gene replacement therapy. Amp-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. We show that at doses 6x10 13 vg/kg and 1x10 14 vg/kg, Amp-101 generated enlarged NMJs and rescued the very severe phenotype of the model. Treated mice became at least as strong as WT littermates and the diaphragm and tibialis anterior muscles displayed robust expression of DOK7. This data suggests that Amp-101 is a promising candidate to move forward to clinic trials.
2023-08-28 | Long-term muscle-specific overexpression of DOK7 in mice using AAV9-tMCK-DOK7.
Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation and maintenance of post-synaptic elements of the NMJ, and downstream of tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular pathology in pre-clinical disease models of CMS and MND. However, long-term consequences of DOK7 expression have been sparsely investigated and targeted overexpression of DOK7 in skeletal muscle yet to be established. Here, we developed and characterized a novel AAV9-DOK7 facilitating forced expression of DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically delivered to newborn mice that were monitored over 6 months. DOK7 overexpression was restricted to skeletal muscles. Body weight, blood biochemistry, and histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In contrast, forced expression of DOK7 resulted in enlargement of both the pre- and post-synaptic components of the NMJ, without causing denervation. We conclude that muscle-specific DOK7 overexpression can be achieved in a safe manner, with the capacity to target NMJs in vivo.
2022-12-09 | Congenital myasthenic syndromes (CMS) a rare cause of uncommon fatigue
Introduction and purpose:
Muscle weakness in newborns, infants and young children can be caused by disorders of the neuromuscular junction (NMJ). Congenital myasthenic syndromes (CMS) are a group of rare genetic diseases whose symptoms resemble the clinical picture of autoimmune myasthenia gravis. There are many mutations that can disrupt the neuromuscular transmission leading to pathology. The diagnosis of CMS is based on genetic testing. The aim of this study is to draw clinicians' attention to the symptoms and present current forms of CMS diagnosis and management.
State of knowledge:
An increasing number of genetic changes are associated with CMS pathology. They are divided, depending on the location in the NMJ of the encoded protein, into presynaptic, synaptic and postsynaptic. The most common disorder is the mutation of CHRNE, which is responsible for the expression of one of the subunits in the structure of the acetylcholine receptor. Regardless of the type of disease, the characteristic symptom is uncommon fatigue of skeletal muscles. It may present as ptosis of one or both eyelids or gait disturbance. The interview, laboratory tests and EMG are helpful in the diagnosis, but genetic tests play a key role. They can target specific mutations or cover the entire genome comprehensively. Currently used drugs alleviate the course of CMS by increasing the release of acetylcholine or increasing the concentration of acetylcholine in the synaptic cleft.
Conclusion:
Because of its rarity and variability, many CMS patients may be misdiagnosed. It is important to implement extensive genetic diagnostics and early implementation of treatment. There is a need for long-term studies of CMS cases and implementation of therapies targeted at specific mutations.
2018-09-05 | CONGENITAL MYASTHENIC SYNDROMES AND MYASTHENIA
Neuromuscular disorders (NMDs) contain a broad group of disorders with overlapping symptoms and is therefore difficult to differentiate clinically. A subgroup is a plethora of rare and different congenital myasthenic syndromes (CMS) with different inheritance patterns, severity and possible treatments. Since May 2017, we have offered an expanded gene panel based on Next-generation Sequencing (NGS) to patients with NMDs, including CMS. We performed a NGS-analysis with a gene list of 328 genes on almost 150 patients where standard ``gene by gene testing'' had not yielded a diagnosis. NGS was performed using Illumina TruSight One Sequencing panel (4813 genes) and run on an Illumina NextSeq 500 Desktop Sequencer. Analyses were done using Illumina BaseSpace BWA Enrichment Workflow and annotation, filtration and variant curation were done using Cartagenia Bench and Alamut Vision. Of the aprx. 150 patients tested by the extended panel, we found three patients with definite CMS based on genetic results of probable and possible pathogenic variants, as well as response to treatments directed by these results. A newborn girl with severe neonatal onset suspected of severe anterior horn disease, was compound heterozygous for variants in CHRNA1. A 15-year-old boy thought to have congenital myopathy from a few months of age, had two alterations in DOK7. The third, a newborn boy with severe onset, was compound heterozygous for two alterations in CHRND. A fourth patient carried two alterations in CHRNE, and it remains to be seen whether they are of clinical significance. An extended gene panel designed for NMDs including CMS, resulted in some surprising findings with therapeutic potential.
2015-09-16 | COLQ variant associated with D evon R ex and S phynx feline hereditary myopathy
Summary Some Devon Rex and Sphynx cats have a variably progressive myopathy characterized by appendicular and axial muscle weakness, megaesophagus, pharyngeal weakness and fatigability with exercise. Muscle biopsies from affected cats demonstrated variable pathological changes ranging from dystrophic features to minimal abnormalities. Affected cats have exacerbation of weakness following anticholinesterase dosing, a clue that there is an underlying congenital myasthenic syndrome (CMS). A genome‐wide association study and whole‐genome sequencing suggested a causal variant for this entity was a c.1190G>A variant causing a cysteine to tyrosine substitution (p.Cys397Tyr) within the C‐terminal domain of collagen‐like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase ( COLQ ). Alpha‐dystroglycan expression, which is associated with COLQ anchorage at the motor end‐plate, has been shown to be deficient in affected cats. Eighteen affected cats were identified by genotyping, including cats from the original clinical descriptions in 1993 and subsequent publications. Eight Devon Rex and one Sphynx not associated with the study were identified as carriers, suggesting an allele frequency of ~2.0% in Devon Rex. Over 350 tested cats from other breeds did not have the variant. Characteristic clinical features and variant presence in all affected cats suggest a model for COLQ CMS. The association between the COLQ variant and this CMS affords clinicians the opportunity to confirm diagnosis via genetic testing and permits owners and breeders to identify carriers in the population. Moreover, accurate diagnosis increases available therapeutic options for affected cats based on an understanding of the pathophysiology and experience from human CMS associated with COLQ variants.
other
2026-07-18 | Longitudinal behavioral profiling reveals early-onset and persistent motor dysfunction in a VAChT-KD model for congenital myasthenic syndrome.
The vesicular acetylcholine transporter knockdown (VAChT-KD) mouse is a genetic model of congenital myasthenic syndrome (CMS) characterized by impaired cholinergic transmission at the neuromuscular junction, resulting in presynaptic neuromuscular dysfunction. Here, we performed a longitudinal behavioral analysis to determine the onset and progression of motor deficits across development and adulthood, including potential sex-dependent effects. VAChT-KD mice exhibited early and persistent motor impairments. Neonatal animals showed reduced strength, impaired coordination, and delayed motor development compared to controls, and these deficits persisted into adulthood. Motor performance was consistently impaired in tests of global strength, while other behavioral measures revealed age- and sex-dependent differences. Notably, repeated exposure to motor tasks improved performance in mutant mice, indicating a learning component that partially compensates for underlying deficits. Across behavioral paradigms, genotype and age emerged as the primary determinants of motor performance. Importantly, the identification of early disease onset and measurable functional deficits across development highlights a critical window for therapeutic intervention. These findings support the use of VAChT-KD mice as a translational platform for testing early-stage therapies and underscore the importance of considering behavioral adaptation when designing preclinical studies for neuromuscular disorders.
2026-06-09 | Phase 1b Study of the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Efficacy of ARGX-119 in Participants with DOK7 Congenital Myasthenic Syndromes (S32.007)
This phase 1b, multicenter, double-blinded, placebo-controlled study (NCT06436742) evaluated safety, tolerability, pharmacokinetics, immunogenicity, and efficacy of ARGX-119 in adults with DOK7 congenital myasthenic syndromes (DOK7-CMS).
2026-05-18 | Gene-specific response to muscle specific kinase agonist antibody in the treatment of congenital myasthenic syndromes.
Congenital myasthenic syndromes (CMS) are a group of rare disorders characterized by fatigable muscle weakness and caused by impaired neuromuscular junction (NMJ) function. CMS symptoms are highly variable, but it can be detrimental and lead to death. There are over 40 different genetic subtypes, including AGRN-CMS and COLQ-CMS. AGRN encodes for neuralagrin, which is released from the nerve terminal and triggers muscle-specific kinase phosphorylation (pMuSK). pMuSK is essential for NMJ development and maintenance, thus agrin deficiency causes NMJ impairment. COLQ encodes for collagenous subunit Q (ColQ), which anchors acetylcholinesterase and stabilizes MuSK. As a result, COLQ deficiency results in NMJ degeneration from prolonged transmission signals and decreased pMuSK. Current treatments for AGRN-CMS and COLQ-CMS are limited, highlighting the importance of finding more efficient therapies. Recently, a MuSK agonist antibody (ARGX-119) with high affinity for the Frizzled-like domain showed remarkable rescue of a Dok7-CMS mouse model. We hypothesized a derivative antibody of ARGX-119 (3B2) could benefit Agrn- and ColQ-CMS mouse models. Agrn-CMS mice were treated at postnatal day 5 (P5), P15 and P35, and ColQ-CMS mice were treated weekly from P22 to P57. In Agrn-CMS mice, 3B2 treatment rescued survival, bodyweight, fibre type switching and pMuSK levels, and improved forelimb grip strength and NMJ morphology. In ColQ-CMS mice, 3B2 treatment was unable to rescue deficits observed. Our findings suggest that MuSK agonists may benefit patients with AGRN-CMS, which should be tested in clinical trials. Our study emphasizes that effective CMS treatment is gene-dependent and relies on an accurate genetic diagnosis.
2026-01-05 | [Functional analysis of the mutant channels associated with skeletal muscle channelopathies].
Skeletal muscle channelopathies are rare genetic disorders caused by mutations in voltage-gated ion channel genes that regulate sarcomere excitability, including the CLCN1 gene encoding ClC-1, the KCNJ2 gene encoding Kir2.1, the SCN4A gene encoding Nav1.4, and the CACNA1S gene encoding Cav1.1. More than one hundred heterozygous missense mutations have been identified in SCN4A, representing a broad spectrum of clinical phenotypes, including sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). In addition, recent case reports have shown that compound heterozygous mutations or homozygous mutations in SCN4A are associated with congenital myopathy or congenital myasthenic syndrome. Regarding the pathological mechanisms of SCM/PMC and HyperPP, a large number of electrophysiological analyses have shown an association between the functional alteration of the mutant Nav1.4 and the clinical phenotype. On the other hand, HypoPP has long been a mysterious disorder. In 2007, the recent discovery of aberrant leak currents, called "gating pore currents", brought a breakthrough in the field of HypoPP research and contributed to the elucidation of the structure-function relationship of the voltage sensing domain of voltage-gated ion channels. However, there has been little progress in the discovery of the therapeutics. Recently, we have generated HEK293T-based HypoPP model cell lines aiming to establish the in vitro platform for the high-throughput drug screening. Our HypoPP model cells would provide new insight into the development of novel therapeutics for channelopathies.
2025-09-26 | Screening for Congenital Myasthenic Syndromes in Adults With Seronegative Myasthenia Gravis Using Next-Generation Sequencing.
Myasthenia gravis (MG) is a disorder of the neuromuscular junction, typically associated with autoantibodies (Abs) that impair neuromuscular transmission. However, approximately 10% of cases are seronegative. Emerging evidence suggests that seronegative MG (SNMG) may be mimicked by hereditary conditions, particularly congenital myasthenic syndromes (CMSs), which require different treatments. In this study, we aimed to determine the proportion of CMS among patients diagnosed with SNMG. We used whole-exome sequencing (WES) in adult patients (aged ≥18 years) diagnosed with SNMG who were enrolled at 3 Austrian tertiary neuromuscular centers between August 2022 and January 2024. Genetic testing was conducted in individuals who remained seronegative after comprehensive serologic testing to exclude Abs against (clustered) acetylcholine receptors, muscle-specific kinase, lipoprotein receptor-related protein 4, and voltage-gated calcium channels. Moreover, we aimed to analyze clinical and demographic factors associated with the likelihood of receiving a molecular diagnosis. A total of 50 patients with SNMG (35 [70%] female) were referred for exome-based genetic screening. The median age at disease onset was 35 years (interquartile range 24.0-46.0 years). Seven patients (14%) were genetically diagnosed with CMS through WES (4 with CHRNE and 3 with RAPSN variants). In addition, findings of uncertain clinical significance were reported in 4 cases, implicating CACNA1S, DOK7, DPAGT1, and RAPSN. Although patients with CMS tended to have a younger age at disease onset in univariate analysis (p = 0.04, r = 0.29), no clinical or demographic factors remained significantly associated with a molecular diagnosis after correction for multiple testing. Only 1 patient with a confirmed CMS diagnosis reported a positive family history. Six individuals with CMS (86%) had either received immunomodulatory treatments (n = 4) or undergone thymectomy (n = 4). Of the 4 patients with CMS receiving immunotherapies, 3 were reported to have experienced at least a partial response. Our findings provide evidence that a considerable proportion of patients diagnosed with SNMG have an underlying hereditary etiology. Notably, a (subjective) response to immunotherapies does not exclude a molecular CMS diagnosis. In conclusion, offering genetic testing to seronegative patients with myasthenic syndromes may have profound therapeutic implications.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
7 orphan drug designations for Congenital myasthenic syndrome.
7 orphan drug designations for Congenital myasthenic syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
adeno-associated virus serotype 9 human choline acetyltransferase (AVCHAT-01X) | gene therapies | FDA | — | Muscular Dystrophy Association, Inc. |
Humanised IgG1 monoclonal antibody against muscle specific kinase | antibodies | EMA | Argenx | |
a fully humanized immunoglobulin gamma 1 (IgG1) agonistic monoclonal antibody (mAb) that specifically targets and activates MuSK | antibodies | FDA | argenx BV | |
AAV9 gene therapy encoding the Dok7 protein | gene therapies | FDA | — | Amplo Biotechnology Inc. |
Adeno Associated Virus Serotype 8 Encoding the Collagen Q Gene | gene therapies | FDA | — | Amplo Biotechnology Inc. |
3,4-diaminopyridine | small molecules | FDA | Catalyst Pharmaceuticals, Inc. | |
amifampridine phosphate | small molecules | FDA | Catalyst Pharmaceuticals |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.