Congenital Myasthenia Syndrome Research Articles

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

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

Congenital myasthenic syndromes: increasingly complex.

Congenital myasthenia syndromes (CMS) are treatable, inherited disorders affecting neuromuscular transmission. We highlight that the involvement of an increasing number of proteins is making the understanding of the disease mechanisms and potential treatments progressively more complex. Although early studies identified mutations of proteins directly involved in synaptic transmission at the neuromuscular junction, recently, next-generation sequencing has facilitated the identification of many novel mutations in genes that encode proteins that have a far wider expression profile, some even ubiquitously expressed, but whose defective function leads to impaired neuromuscular transmission. Unsurprisingly, mutations in these genes often causes a wider phenotypic disease spectrum where defective neuromuscular transmission forms only one component. This has implications for the management of CMS patients. Given the widening nonneuromuscular junction phenotypes in the newly identified forms of CMS, new therapies need to include disease-modifying approaches that address not only neuromuscular weakness but also the multisystem involvement. Whilst the current treatments for CMS are highly effective for many subtypes there remains, in a proportion of CMS patients, an unmet need for more efficacious therapies.

Effective treatment with oral Salbutamol on late onset respiratory impairment in a DOK7 Congenital Myasthenia Syndrome: a case report.

DOK7 gene deficiency is a neuromuscular disease with an alteration in post-synaptic neuromuscular junction, leading to progressive respiratory impairment. Although, the therapy is not standardized, adrenergic agonists are suggested as first-line treatment. Case presentation: Our patient had an ambiguous late childhood-onset and had a generalized muscle weakness free of respiratory symptoms during the early phase of the disease. Subsequently, when the respiratory muscle and the diaphragm involvement was impaired, a substantial loss of respiratory function with hypopneas and severe desaturation was detected. It was noteworthy the striking respiratory beneficial impact of oral salbutamol in the resolution of symptoms and functional impairments, leading to a remarkable respiratory improvement and a better quality of life. Conclusion: Oral salbutamol treatment combined to a timely clinical recognition led to an outstanding respiratory improvement.

Congenital Myasthenia Syndrome Due to a Novel DPAGT1 Gene Mutation - An Error of Glycosylation Masquerading as a Congenital Myopathy.

Congenital Myasthenia Syndrome Due to a Novel DPAGT1 Gene Mutation - An Error of Glycosylation Masquerading as a Congenital Myopathy.

Mechanism of hydrophobic gating in the acetylcholine receptor channel pore.

Neuromuscular acetylcholine receptors (AChRs) are hetero-pentameric, ligand-gated ion channels. The binding of the neurotransmitter acetylcholine (ACh) to two target sites promotes a global conformational change of the receptor that opens the channel and allows ion conduction through the channel pore. Here, by measuring free-energy changes from single-channel current recordings and using molecular dynamics simulations, we elucidate how a constricted hydrophobic region acts as a "gate" to regulate the channel opening in the pore of AChRs. Mutations of gate residues, including those implicated in congenital myasthenia syndrome, lower the permeation barrier of the channel substantially and increase the unliganded gating equilibrium constant (constitutive channel openings). Correlations between hydrophobicity and the observed free-energy changes, supported by calculations of water densities in the wild-type versus mutant channel pores, provide evidence for hydrophobic wetting-dewetting transition at the gate. The analysis of a coupled interaction network provides insight into the molecular mechanism of closed- versus open-state conformational changes at the gate. Studies of the transition state by "phi"(φ)-value analysis indicate that agonist binding serves to stabilize both the transition and the open state. Intersubunit interaction energy measurements and molecular dynamics simulations suggest that channel opening involves tilting of the pore-lining M2 helices, asymmetric outward rotation of amino acid side chains, and wetting transition of the gate region that lowers the barrier to ion permeation and stabilizes the channel open conformation. Our work provides new insight into the hydrophobic gate opening and shows why the gate mutations result in constitutive AChR channel activity.

Agenesis of Pectoralis Major Muscle in Late-Onset GFPT1-Related Congenital Myasthenic Syndrome: A Case Report.

The objective of this study was to expand the phenotypic spectrum of glutamine-fructose-6-phosphate transaminase 1 (GFPT1)-related congenital myasthenia syndrome (CMS). A 61-year-old man with agenesis of the left pectoralis major muscle presented with progressive muscle weakness for a decade that transiently improved after exertion. His examination revealed proximal and distal muscle weakness in upper extremities and proximal muscle weakness in lower extremities. Muscle enzymes were elevated. An electromyogram revealed a myopathic pattern; however, a muscle biopsy of deltoid muscle and genetic testing for limb-girdle muscular dystrophies were nondiagnostic. A 3-Hz repetitive nerve stimulation of the spinal accessory nerve recording from trapezius muscle demonstrated a >20% drop in amplitude of the 5th compound motor action potential relative to 1st at both baseline and after 45-second exercise. Acetylcholine receptor binding, lipoprotein-related protein 4, muscle-specific kinase, and voltage-gated calcium channel P/Q antibodies were negative. Genetic testing targeting CMS revealed 2 likely pathogenic variants within GFPT1: novel c.7+2T>G (intron 1) that was predicted to result in a null allele and known c*22 C>A (exon 19) associated with reduced GFPT1 expression. His muscle strength dramatically improved after pyridostigmine initiation. In addition to other reported neurodevelopmental abnormalities, pectoralis major muscle agenesis (or Poland syndrome) may be a clinical manifestation of GFPT1-related CMS.

Discovery and pharmacological characterization of novel positive allosteric modulators acting on skeletal muscle-type nicotinic acetylcholine receptors

Skeletal muscle-type nicotinic acetylcholine receptors (m-nAChRs) are ligand-gated ion channels that open after activation by ACh and whose signals cause muscle contraction. Defects in neurotransmission are reported in disorders such as myasthenia gravis (MG) and congenital myasthenia syndromes (CMS). Although treatments for these disorders exist, therapies which significantly increase muscle strength have yet to be reported. Positive allosteric modulators (PAMs), which promote ACh signaling through AChRs, are expected to be promising therapeutic agents. In this study, we identified an m-nAChR PAM called AS3513678 by high-throughput screening using human myotube cells and modified it to obtain novel compounds (AS3566987 and AS3580239) that showed even stronger PAM activity. AS3580239 caused a leftward shift in the ACh concentration-response curve and was 14.0-fold potent at 10 μM compared with vehicle. Next, we examined the effect of AS3580239 on electrically-induced isometric contraction of the extensor digitorum longus (EDL) muscle in wild-type (WT) and MG model rats. AS3580239 enhanced EDL muscle contraction in both WT and MG model rats at 30 μM. These data suggest that AS3580239 improved neurotransmission and enhanced muscle strength. Thus, m-nAChR PAMs may be a useful treatment for neuromuscular diseases.

VP.42 Clinical characteristics, molecular genetics and long-term clinical outcomes in 43 patients with congenital myasthenia syndrome due to RAPSYN mutation

Congenital myasthenic syndromes (CMS) are a group of rare inherited disorders of neuromuscular transmission. Rapsyn (receptor-associated protein of the synapse) is a post-synaptic protein that binds to the acetylcholine receptor (AChR) subunits and has a crucial role in AChR clustering at the post synaptic membrane. We describe the clinical characteristics, molecular genetic findings, and long-term clinical outcomes in 43 patients with CMS due to <i>RAPSYN</i> mutations seen at three UK specialist neuromuscular centres. 43 patients (20 females) with confirmed <i>RAPSYN</i> mutations and at least one follow-up visit were included. Median age at last follow up was 18 years (range 4-73 years). Symptoms at onset, included arthrogryposis 41%, ptosis 44%, respiratory involvement 48%, limb weakness/motor delay 67% and feeding difficulties 62%. Recurrent apnoea was the commonest respiratory symptom, 46% required short term and 7% required long-term respiratory support for apnoea management. 32% patients required nasogastric or gastrostomy feeding. Typical pattern of weakness was ptosis, facial weakness, axial, generalised or proximal weakness in limbs. 95% patients had ptosis, 62% patients had a divergent/ convergent squint and ophthalmoplegia was absent in all but one. All patients achieved independent ambulation, median age in 27 patients was 16 months (range 12- 48 months). At last follow up, all but one patient was independently ambulant. At last follow up 25% patients had no CMS features, 37% only ptosis and remainder had mild limb weakness. All patients were on normal oral diet except one who remained on mixture of oral and gastrostomy feeds since childhood. Patients who required long-term respiratory support in childhood were weaned off it successfully and no patient had respiratory crisis after 7 years of age. Except for 2, all patients had N88K mutation (homozygous in 14 patients). All but one patient was on treatment. Pyridostigmine was first line with good response in all treated patients, 28% required additional 3,4 diaminopyridine and 2% salbutamol. Two patients were able to reduce treatment in 2nd/3rd decade. In summary, this is the largest cohort of RAPSYN patients with clinical and genetic characteristics and also long-term outcome which was of consistent clinical improvements after 1st decade and stability in adult life in majority of patients, a crucial information for treating clinicians, patients and families.

General anesthesia for treating scoliosis with congenital myasthenia syndrome: a case report

BackgroundCongenital myasthenia syndrome is a heterogeneous disease with impaired neuromuscular transmission.Case presentationThis report describes a 13-year-old child with congenital myasthenia syndrome who underwent surgery for scoliosis under general anesthesia. We used a small dose of rocuronium, neuromuscular transmission monitoring, and non-invasive positive pressure ventilation for postoperative respiratory management. There were no respiratory complications during the perioperative period.ConclusionAs there are only a few reports on the anesthetic management of patients with congenital myasthenia syndrome, we applied the principles of managing autoimmune myasthenia gravis. The postoperative management described herein can prevent respiratory complications in patients with congenital myasthenia syndrome.

A Rare Case of Congenital Myasthenia Syndrome 11 Caused by a Novel Mutation in RAPSN Diagnosed with Rapid Whole Genome Sequencing (rWGS). (P18-5.004)

A Rare Case of Congenital Myasthenia Syndrome 11 Caused by a Novel Mutation in RAPSN Diagnosed with Rapid Whole Genome Sequencing (rWGS). (P18-5.004)

Diverse myopathological features in the congenital myasthenia syndrome with GFPT1 mutation.

IntroductionMutations in the GFPT1 gene are associated with a particular subtype of congenital myasthenia syndrome (CMS) called limb‐girdle myasthenia with tubular aggregates. However, not all patients show tubular aggregates in muscle biopsy, suggesting the diversity of myopathology should be further investigated.MethodsIn this study, we reported two unrelated patients clinically characterized by easy fatigability, limb‐girdle muscle weakness, positive decrements of repetitive stimulation, and response to pyridostigmine. The routine examinations of myopathology were conducted. The causative gene was explored by whole‐exome screening. In addition, we summarized all GFPT1‐related CMS patients with muscle biopsy in the literature.ResultsPathogenic biallelic GFPT1 mutations were identified in the two patients. In patient one, muscle biopsy indicated vacuolar myopathic changes and atypical pathological changes of myofibrillar myopathy characterized by desmin deposits, Z‐disc disorganization, and electronic dense granulofilamentous aggregation. In patient two, muscle biopsy showed typical myopathy with tubular aggregates. Among the 51 reported GFPT1‐related CMS patients with muscle biopsy, most of them showed tubular aggregates myopathy, while rimmed vacuolar myopathy, autophagic vacuolar myopathy, mitochondria‐like myopathy, neurogenic myopathy, and unspecific myopathic changes were also observed in some patients. These extra‐synaptic pathological changes might be associated with GFPT1‐deficiency hypoglycosylation and altered function of muscle‐specific glycoproteins, as well as partly responsible for the permanent muscle weakness and resistance to acetylcholinesterase inhibitor therapy.ConclusionsMost patients with GFPT1‐related CMS had tubular aggregates in the muscle biopsy, but some patients could show great diversities of the pathological change. The myopathological findings might be a biomarker to predict the prognosis of the disease.

Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene.

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases

BackgroundWe used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres.MethodsWES was performed...

A case study on various disorders and defects present in congenital myasthenia syndrome

The Congenital Myasthenia Syndromes (CMS) are a different gathering of problems that have a hidden deformity in the transmission of signs from nerve cells to muscles. These problems are described by muscle shortcoming, which is declined upon effort. The time of beginning, seriousness of introducing indications and dissemination of muscle shortcoming can shift starting with one patient then onto the next. The synapse, acetylcholine, or ACh for short that goes about as a compound 'courier' with guidelines for the muscles to contract. A three years old child female patient was brought to our department with the complaints of drooping of the left eyelid after one week she developed drooping of right eye. With scientific and laboratory discoveries, she is identified by congenital myasthenia and treatment was started. Evidence from case notes, history, review and accept. Muscle fatigue habits included limb, trunk, bulbar, respiratory, nasal, extraocular muscles and patients reacted with anticholinesterase and 3,4-diaminopyridine. Quick channel syndrome compared with AChR in serious respiratory emergencies in infancy or early childhood. Two children's fatalities, also in care and family history of sibling deaths, highlight the need for effective genetic diagnosis.

Congenital myasthenia syndrome in a Chinese family with mutations in MUSK: A hotspot mutation and literature review

Congenital myasthenic syndrome (CMS) caused by mutations in MUSK is very rare and the genotype-phenotype relationship in MUSK related CMS is still unclear. Here we identified two patients carrying a homozygous hotspot mutation, c.308A > G in MUSK from a Chinese family. Both of them presented predominant bulbar weakness and atrophy of bilateral temporalis and masticatory muscles. To address the phenotype-genotype relationship, a total of 27 MUSK related CMS patients were reviewed. Patients with nonsense, frameshift or splicing mutations showed earlier onset (10/13 vs 2/14 neonatal onset, p = 0.0018) and more occurrence of vocal cord paralysis or stridor (8/13 vs 0/14, p = 0.0006), indicating a more severe phenotype. Comparing with patients carrying other missense mutations, the four patients carrying a homozygous c.308A > G mutation showed the female predominance (4/10 vs 4/4) and dramatic exacerbation after emotional or physiological stresses (2/10 vs 4/4) like pregnancy, menstrual periods and infection. All these indicated a genotype-phenotype relationship in MUSK-related CMS.

Electrodiagnostic elucidation of a novel variant in the acetylcholine receptor gene identified by rapid trio exome sequencing, leading to the diagnosis and treatment of congenital myasthenia syndrome in an infant presenting with fetal akinesia deformation sequence. (P3.7-006)

Electrodiagnostic elucidation of a novel variant in the acetylcholine receptor gene identified by rapid trio exome sequencing, leading to the diagnosis and treatment of congenital myasthenia syndrome in an infant presenting with fetal akinesia deformation sequence. (P3.7-006)

Case report: congenital myasthenia syndrome in a newborn with antibodies against acetylcholyne receptor

Case report: congenital myasthenia syndrome in a newborn with antibodies against acetylcholyne receptor

Congenital Myasthenic Syndromes: a Clinical and Treatment Approach.

Congenital myasthenia syndromes are clinically and genetically heterogeneous but treatable conditions. Careful selection of drug therapy is paramount as the same drug can be effective, ineffective, and even harmful in different congenital myasthenia syndromes. The purpose of this article is to review current treatment options for these conditions. Next-generation sequencing has accelerated the discovery of new genes and facilitated the description of novel congenital myasthenic syndromes. Retrospective therapy data from these newly identified syndromes has provided additional insight on the management of these conditions. Cholinergic agents, β-adrenergic agonists, and open-channel blockers remain the principal treatment modalities, and their optimal use depends on an accurate genetic diagnosis and the timely clinical recognition of the disease. In particular, pyridostigmine, usually a first-line agent, should be avoided in DOK7, acetylcholinesterase deficiency, and slow-channel congenital myasthenic syndromes. Beta-adrenergic agonists have been recognized as a first-line agent for a number of congenital myasthenic syndromes, particularly DOK7 and acetylcholinesterase deficiency, whereas long-lived open-channel blockers of the acetylcholine receptor (AChR) ion channel are indicated for the slow-channel congenital myasthenic syndrome. Beta-adrenergic agonists additionally have an important adjunct treatment for congenital myasthenia syndrome due to glycosylation defects, fast channel syndrome, AChR deficiency, and choline acetyltransferase deficiency (ChaT) and therefore may be particularly important in the treatment of syndromes due to defects in motor endplate development and repair. Unlike in autoimmune myasthenia gravis, there is no role for immunotherapy in congenital myasthenic syndromes. If available, a genetic diagnosis should drive the choice for a first-line treatment agent between cholinergic agents, β-adrenergic agents, and open-channel blockers. Evaluation and supportive care at centers with experience in these rare syndromes likely are paramount in achieving optimal outcomes. Furthermore, gene discovery for congenital myasthenic syndromes has provided novel insights on the role of protein glycosylation, endplate maintenance and repair, and synaptic vesicle exocytosis in neuromuscular transmission. These insights may lead to new therapeutic strategies in both congenital and autoimmune myasthenic diseases in the future.

P.415 - Congenital myasthenia syndromes: clinical description of a pediatric cohort

Congenital myasthenic syndromes (CMS) are a group of heterogeneous diseases caused by mutations in genes encoding for proteins involved in the neuromuscular junction that lead to an impaired signal transmission. We describe the clinical and paraclinical history of 12 patients with genetically confirmed CMS (1 CHRND, 2 AGRN, 1 DOK7, 1 MUSK, 4 RAPSN, 1 DPAGT1, 2 COLQ). Fatigable weakness was mentioned in all patients. The first symptom appeared at the latest in the first month of life (extremes: antenatal to less than 1 month of life). 4 patients had neonatal stridor. 11 patients had at least one severe respiratory decompensation with intubation. 8 had been tracheotomized. One patient died (COLQ mutation). 5 patients had arthrogryposis, 1 postural syndrome. Ptosis was reported in 11 patients. 9 of 10 patients who had reached the age of gait walked, (average age: 40 months; median age: 24 months). All patients with RAPSN mutation had clinodactyly. Electromyographic analysis showed neuromuscular junction abnormalities in 9 of 11 patients. Stimulated single fiber was always abnormal (done in 5 patients). Muscle biopsy exhibited mainly type 1 fibers predominance. Histology study of motor endplate performed in 2 patients was abnormal. Diagnostic delay was 35 months on average with a median at 9 months. From a therapeutic point of view, patients with mutations in the RAPSN gene were all significantly improved by anticholinesterasic monotherapy. A bi or triple therapy was required in the others (anticholinesterase, salbutamol / ephedrine, 3–4 DAP). Anticholinesterase drugs aggravated myasthenic syndrome in 3 patients (AGRN, DOK7 and COLQ mutations). The diagnosis of SMC is challenging due to life threatening complications, especially since a specific treatment exists.