Congenital Myasthenic Syndrome Research Articles

Slow-Channel Congenital Myasthenic Syndrome Due to the Novel Variant c.1396G_A in CHRNA1 That Responds Favorably to 3,4-Diaminopyridine: A Case Report

Slow-Channel Congenital Myasthenic Syndrome Due to the Novel Variant c.1396G_A in CHRNA1 That Responds Favorably to 3,4-Diaminopyridine: A Case Report

Assessing the Utility of ColabFold and AlphaMissense in Determining Missense Variant Pathogenicity for Congenital Myasthenic Syndromes

Background/Objectives: Congenital myasthenic syndromes (CMSs) are caused by variants in >30 genes with increasing numbers of variants of unknown significance (VUS) discovered by next-generation sequencing. Establishing VUS pathogenicity requires in vitro studies that slow diagnosis and treatment initiation. The recently developed protein structure prediction software AlphaFold2/ColabFold has revolutionized structural biology; such predictions have also been leveraged in AlphaMissense, which predicts ClinVar variant pathogenicity with 90% accuracy. Few reports, however, have tested these tools on rigorously characterized clinical data. We therefore assessed ColabFold and AlphaMissense as diagnostic aids for CMSs, using variants of the CHRN genes that encode the nicotinic acetylcholine receptor (nAChR). Methods: Utilizing a dataset of 61 clinically validated CHRN variants, (1) we evaluated the possibility of a ColabFold metric (either predicted structural disruption, prediction confidence, or prediction quality) that distinguishes variant pathogenicity; (2) we assessed AlphaMissense’s ability to differentiate variant pathogenicity; and (3) we compared AlphaMissense to the existing pathogenicity prediction programs AlamutVP and EVE. Results: Analyzing the variant effects on ColabFold CHRN structure prediction, prediction confidence, and prediction quality did not yield any reliable pathogenicity indicative metric. However, AlphaMissense predicted variant pathogenicity with 63.93% accuracy in our dataset—a much greater proportion than AlamutVP (27.87%) and EVE (28.33%). Conclusions: Emerging in silico tools can revolutionize genetic disease diagnosis—however, improvement, refinement, and clinical validation are imperative prior to practical acquisition.

Limb-Girdle Type Congenital Myasthenic Syndrome Anticipated With Scoliosis: A Case Report

Limb-Girdle Type Congenital Myasthenic Syndrome Anticipated With Scoliosis: A Case Report

A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).

The neuromuscular junction (NMJ) is the site where the motor neuron innervates skeletal muscle, enabling muscular contraction. Congenital myasthenic syndromes (CMS) arise when mutations in any of the approximately 35 known causative genes cause impaired neuromuscular transmission at the NMJ, resulting in fatigable muscle weakness. A subset of five of these CMS-causative genes are associated with protein glycosylation. Glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) is the rate-limiting enzyme within the hexosamine biosynthetic pathway (HBP), a metabolic pathway that produces the precursors for glycosylation. We hypothesized that deficiency in Gfpt1 expression results in aberrant or reduced glycosylation, impairing the proper assembly and stability of key NMJ-associated proteins. Using both in vitro and in vivo Gfpt1-deficient models, we determined that the acetylcholine receptor delta subunit (AChRδ) has reduced expression and is hypo-glycosylated. Using laser capture microdissection, NMJs were harvested from Gfpt1 knockout mouse muscle. A lower-molecular-weight species of AChRδ was identified at the NMJ that was not detected in controls. Furthermore, Gfpt1-deficient muscle lysates showed impairment in protein O-GlcNAcylation and sialylation, suggesting that multiple glycan chains are impacted. Other key NMJ-associated proteins, in addition to AChRδ, may also be differentially glycosylated in Gfpt1-deficient muscle.

209P Custom orthosis improves mobility and caregiver experience in an adolescent with congenital myasthenic syndrome and myofibrillar myopathy

209P Custom orthosis improves mobility and caregiver experience in an adolescent with congenital myasthenic syndrome and myofibrillar myopathy

CHRNE-related Congenital Myasthenic Syndrome in Iran: Clinical and Molecular Insights

Variants in the CHRNE gene can lead to a condition called congenital myasthenic syndrome (CMS), which affects the neuromuscular junction (NMJ). CHRNE mutations are the most common cause of CMS. Seventy-seven patients with a possible diagnosis of CMS were referred to the neuromuscular clinic of Shariati Hospital affiliated with the Tehran University of Medical Sciences. We performed whole-exome sequencing (WES) to determine the underlying defect in a group of individuals with a possible diagnosis of CMS. Clinical features and morphological and molecular data on 33 patients with mutations in CHRNE were described. Age of onset, age at diagnosis, consanguinity, family history, motor milestone delay, ophthalmoparesis, generalized fatigue, dysphagia, neurophysiologic findings, and response to treatment of the patients were assessed. Nineteen CHRNE variants including 10 novel ones were identified. The most common mutations were c.1327del; (p.Glu443LysfsTer64) in four different families and c.1252-1267dup; (p.Cys423SerfsTer38) in three families. Clinical onset was mostly at birth or under one year with bilateral fatigable ptosis, ophthalmoplegia, bulbar weakness, and proximal muscle weakness. All patients were treated with pyridostigmine ± salbutamol, which resulted in improvement of motor function, dysphagia, and breathing.

245P Exploring the relationship between an instrumented walking test and community physical activity in individuals with congenital myasthenic syndrome

245P Exploring the relationship between an instrumented walking test and community physical activity in individuals with congenital myasthenic syndrome

500P The 6-minute walk test in a small group of patients with congenital myasthenic syndromes

500P The 6-minute walk test in a small group of patients with congenital myasthenic syndromes

498P Neuromuscular centre effect on prevalence of congenital myasthenic syndrome (CMS) in the UK

498P Neuromuscular centre effect on prevalence of congenital myasthenic syndrome (CMS) in the UK

511P Blood biomarkers in a cohort of patients with CHRNE-associated congenital myasthenic syndrome

511P Blood biomarkers in a cohort of patients with CHRNE-associated congenital myasthenic syndrome

241P Long term follow-up of CHRNE congenital myasthenic syndrome (CMS) – a retrospective multi-centre cohort study

241P Long term follow-up of CHRNE congenital myasthenic syndrome (CMS) – a retrospective multi-centre cohort study

234P Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis

234P Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis

244P A natural history study of congenital myasthenic syndromes, to establish reliable outcome measures suitable for clinical and research assessment

244P A natural history study of congenital myasthenic syndromes, to establish reliable outcome measures suitable for clinical and research assessment

237P Advancing the understanding of VAMP1-related congenital myasthenic syndrome: phenotypic insights, favorable response to 3,4-diaminopyridine, and clinical characterization of five new cases

237P Advancing the understanding of VAMP1-related congenital myasthenic syndrome: phenotypic insights, favorable response to 3,4-diaminopyridine, and clinical characterization of five new cases

240P Late presentation DOK7 congenital myasthenia syndrome (CMS), misdiagnosed as myasthenia gravis (MG)– a case series

240P Late presentation DOK7 congenital myasthenia syndrome (CMS), misdiagnosed as myasthenia gravis (MG)– a case series

Клинические популяционно-генетические исследования наследственных болезней среди детского населения Северной Осетии – Алании

Currently, there is limited understanding about the cumulative prevalence, diversity, and frequency of distinct orphan hereditary diseases (OHDs) in the pediatric population, both within the Russian Federation and in the global literature. This gap exists despite a significant demand for such knowledge in healthcare and society. Variability and heterogeneity of the above indicators are common across different populations, reflecting significant genetic heterogeneity of OHDs. The study aimed to assess OHDs in the pediatric population of the Republic of North Ossetia – Alania (RNO-A). A total of 543,817 people were evaluated, including 145,560 children aged 0–18 years. The cumulative prevalence of autosomal recessive (AR), autosomal dominant (AD), and X-linked (XL) OHDs was determined. The findings indicate an overall prevalence of OHDs among children of the RNO-A of 1 : 119, meaning that approximately 1% of children are diagnosed with these conditions. Notably, the total burden in children of all types of OHDs in rural areas exceeds that in urban areas and district centers by more than twofold. We identified 1,241 patients from 1,037 families with 241 distinct OHDs (109 with AD inheritance, 102 with AR inheritance, and 30 with XL inheritance). Three diseases were particularly prevalent in this population and have not been documented in similar studies: congenital myasthenia type 12, a rare form of congenital adrenal cortex dysfunction (3-beta-hydroxysteroid dehydrogenase deficiency), and brachydactyly E — amelogenesis — mental retardation — nanism syndrome. Thus, the population of the RNO-A exhibits a unique spectrum of OHDs caused by rare mutations, some of which are infrequent in other populations of the world and the Russian Federation. The significantly higher prevalence of these disorders in rural populations is noteworthy, underscoring the need for tailored, region-specific programs aimed at preventing childhood disability and/or mortality.

235P Cross sectional study of 187 patients with congenital myasthenia syndrome, describing the clinical phenotypes, genetic mutations, and single point standardised assessment scores

235P Cross sectional study of 187 patients with congenital myasthenia syndrome, describing the clinical phenotypes, genetic mutations, and single point standardised assessment scores

ARGX-119 is an agonist antibody for human MuSK that reverses disease relapse in a mouse model of congenital myasthenic syndrome.

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.

Type and Frequency of Misdiagnosis and Time Lag to Diagnosis in Patients with Chronic Progressive External Ophthalmoplegia.

Since ptosis is an early feature of chronic progressive external ophthalmoplegia (CPEO), patients are commonly misdiagnosed with other causes of ptosis. This study aims to report the type and frequency of misdiagnosis and time lag to diagnosis and the palpebral fissure transfer (PFT) procedure in patients with CPEO. This is a retrospective analysis of consecutive patients with CPEO who underwent PFT between 2006 and 2017. The data on previous diagnoses and treatments, age at definitive diagnosis of CPEO, and clinical manifestations were recorded. While the diagnosis of CPEO was based on clinical examination, 75% (24/32) of patients had undergone a confirmatory muscle biopsy and genetic tests. There were 32 patients (19 females) with a mean age of 24.8 years (range, 13-36) at the final diagnosis and 34.1 years (range, 15-56) at the time of PFT. Also, 78% (25/32) of patients had been initially misdiagnosed with congenital ptosis (60%; 15/25) and ocular myasthenia gravis (OMG) (40%; 10/25). The majority of patients (20/32) had one to three previous eyelid surgical procedures, of which 90% (18/20) were performed before the definitive diagnosis of CPEO. The mean time lag from the first surgical procedure to CPEO diagnosis and PFT was 6.2 and 14.7 years, respectively. In a referral center, 78% of the patients with CPEO were initially misdiagnosed with congenital ptosis and OMG, and 56% of them underwent ptosis repair before the diagnosis. While the onset of the disease was in the first or second decades of life, diagnosis was delayed up to a mean age of 25 years. Reviewing early family photos and paying attention to other signs of CPEO could prevent misdiagnosis.

Characterization of Clinical Phenotypes in Congenital Myasthenic Syndrome Associated with the c.1327delG Frameshift Mutation in CHRNE Encoding the Acetylcholine Receptor Epsilon Subunit.

Congenital myasthenic syndromes (CMS) are a group of rare but often treatable inherited disorders of neuromuscular transmission characterized by fatigable skeletal muscle weakness. In this paper we present the largest phenotypic analysis to date of a cohort of patients carrying the pathogenic variant c.1327delG in the CHRNE gene, leading to CHRNE-CMS. This study aims to identify the phenotypic variability in CMS associated with c.1327delG mutation in the CHRNE gene. Disease specific symptoms were assessed using specific standardized tests for autoimmune myasthenia (Quantitative Myasthenia Gravis score) as well as patient-reported scales for symptom severity. Evaluated clinical manifestations included ocular symptoms (ophthalmoparesis and ptosis), bulbar weakness, axial muscle weakness, proximal and distal muscle weakness, and respiratory function. Patients were allocated into three groups according to clinical impression of disease severity: mild, moderate, and severe. We studied 91 Bulgarian Roma patients, carrying the same causative homozygous CHRNE c.1327delG mutation. Bulbar weakness was present in patients throughout all levels of severity of CHRNE-CMS in this study. However, difficulties in eating and swallowing are more prominent characteristics in the moderate and severe clinical phenotypes. Diplopia and ptosis resulting from fatigue of the extraocular muscles were permanent features regardless of disease severity or age. Levels of axial, proximal and distal muscle weakness were variable between disease groups. The statistical analysis showed significant differences between the patients in the three groups, emphasizing a possible variation in symptom manifestation in the evaluated patient population despite the disease originating from the same genetic mutation. Impairment of respiratory function was more prominent in severely affected patients, which might result from loss of compensatory muscle function in those individuals. Results from our study indicate significant phenotypic heterogeneity leading to mild, moderate, or severe clinical manifestation in CHRNE-CMS, despite the genotypic homogeneity.