Myasthenic Syndrome Research Articles

Rectal cancer with solitary hepatic metastasis and Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune neuromuscular disease mediated by antibodies to voltage-gated calcium channels (VGCCs) at the neuromuscular junction. LEMS often presents as a paraneoplastic disease. Between 40% to 62% of patients diagnosed with LEMS are confirmed to have small cell lung cancer (SCLC). There are few concerned reports on Gastrointestinal carcinomas. This article reports the treatment process of a young woman with rectal cancer and liver metastasis who associated with LEMS to summarize relevant clinical experience and reduce the rate of clinical misdiagnosis.

Congenital Myasthenic Syndromes

Congenital myasthenic syndromes (CMS) are characterized by congenital defects in the neuromuscular signal transmission and are caused by pathogenic variants in 36 genes. Recently identified forms of CMS include TOR1AIP1-CMS, CHD8-CMS, PURA-CMS, and TEFM-CMS. Most forms of CMS are caused by autosomal recessive variants, whereas four forms of CMS are caused by autosomal dominant variants, in which adult-onset cases are not rare. As myasthenic features are not always observed and muscle hypotrophy is sometimes observed, CMS should be considered in differential diagnosis of congenital myopathies and other neuromuscular diseases. Low- and high-frequency repetitive nerve stimulation is essential to diagnose CMS for patients who develop muscle weakness at less than 2 years of age. Tubular aggregates are observed in muscle biopsy in four forms of CMS, and serum CK levels are elevated in some forms of CMS. As rational therapies are available for most forms of CMS, identification of causative gene variants by genetic analysis is required.

Immune mediated myasthenia gravis in children, current concepts and new treatments: A narrative review article.

Myasthenia gravis (MG) is the most frequent transmission disease in the neuromuscular junction. Juvenile myasthenia gravis (JMG) is an autoimmune antibody-mediated disease of postsynaptic endplate defined as MG presentation in patients before the age of 18 years old. While many clinical features of JMG are identical to the adults, there are some significant differences between them regarding presentation, clinical course, antibody level, and thymus histopathology. In JMG, ocular symptoms are more frequent, the clinical course is comparably benign, and the outcome is better than adult MG. Antibodies attack the muscle endplate proteins in the postsynaptic membrane and interfere with transmission. These antibodies in most patients are against the acetylcholine receptors, but they may also be directed toward muscle-specific kinase, lipoprotein-related protein 4, and agrin. Findings show racial influences and genetic effects on the occurrence of JMG. The essential clinical symptom is fatigable weakness of muscles that can be in the form of isolated ocular type or more disseminated weakness. The diagnosis of JMG is essentially clinical, with fluctuating patterns of weakness and easy fatigability, but a series of diagnostic evaluations can confirm the diagnosis. Precise diagnostic evaluation and distinction from congenital myasthenic syndromes is critical. The treatment plan is conducted according to the clinical course (ocular or generalized), antibody type, and disease severity. The mainstay of treatment includes symptomatic therapy, long-lasting immunosuppressive treatment and treatment of myasthenic crisis. Novel medications are introduced and conducted to the specific pathophysiologic mechanisms of the disease, and they are used primarily in the refractory MG.

Chapter 5 - Congenital myasthenic syndromes

The neuromuscular junction is a prototypic synapse that has been extensively studied and provides a model for smaller and less accessible central synapses. Central to transmission at the neuromuscular synapse is the muscle acetylcholine receptor cation channel. Studies of the genetic disorders affecting the neuromuscular junction, termed congenital myasthenic syndromes, have illustrated how impaired signal transmission may be caused by a variety of mutations both within the ion channel itself and by the context of the ion channel within the synapse. Thus, multiple pathogenic mutations are also identified in proteins affecting the clustering, location, and density of the receptor within the overall synaptic structure. Disease severity ranges from death in childhood to mild disability throughout life. In addition, in utero, fetal akinesia due to impaired neuromuscular transmission may cause developmental abnormalities. Early studies identified mutations in the genes encoding the acetylcholine receptor subunits that impair ion channel gating or reduce the number of endplate receptors or a combination of the two, giving rise to "slow channel," "fast channel," or deficiency syndromes. Subsequently, it became clear that myasthenic syndromes also stem from mutations in proteins involved in neurotransmitter release, the formation and maintenance of the neuromuscular synapse, or glycosylation. This chapter describes the patient phenotypes, the diverse range of molecular mechanisms for synaptic dysfunction, and the corresponding therapeutic strategies, including drug combinations, that can be tailored to the many subtypes.

Congenital Myasthenic Syndrome: case study from a tertiary care institute of Western India

Objective. To describe clinical characteristics, genetic details and management of patients of congenital myasthenic syndrome. Methods. A retrospective study was carried out from 2020 to 2023. Patient who presented with ptosis, ophthalmoplegia, proximal limb weakness with genetically confirmed mutations for CMS were included in the study. Patients who were positive for Acetylcholine receptor antibody (AChRAb) or Muscle specific kinase (MuSK) antibody or any other antibodies suggestive of acquired myasthenia were excluded from the study. Outcome. 6 genetically proven patients were identified out of which 4 patients had CHRNE mutation, 1 patient had CHRNA1 mutation and 1 patient had Dok7 mutation. Mean delay in diagnosis was 15 years. Patient with Dok 7 mutation responded to salbutamol, 1 patient of CHRNE mutation required combination of pyridostigmine, fluoxetine and salbutamol, rest all patient responded to pyridostigmine. It took 4 weeks for improvement after starting salbutamol in patient with Dok7 mutation. Conclusion. Although rare, CMS is potentially treatable group of disease. Patient presenting with early onset muscular weakness should be evaluated thoroughly and CMS should be considered in presence of eyelid ptosis, ophthalmoplegia and proximal weakness with diurnal fluctuations. RNS and genetic testing are paramount in achieving an early diagnosis.

Миастенический синдром Ламберта – Итона: собственное клиническое наблюдение, обзор литературы

Миастенический синдром Ламберта – Итона относится к редким аутоиммунным заболеваниям нервно-мышечной передачи, при котором происходит образование антител против потенциалзависимых кальциевых каналов пресинаптических нервных окончаний. Выделяют паранеопластическую и аутоиммунную формы данного заболевания. Чаще всего встречается паранеопластическая форма миастенического синдрома Ламберта – Итона. Диагностика данного заболевания осуществляется на основании жалоб и клиники: мышечной слабости, снижения глубоких рефлексов, вегетативной дисфункции, выявления антител к потенциалзависимым кальциевым каналам типа P/Q и данных электронейромиографии. Диагностика и лечение миастенического синдрома Ламберта – Итона вызывают значительные сложности, что обусловлено редкостью патологии, неспецифичностью клинической картины, малой доступностью лабораторного подтверждения, высокой вероятностью выявления онкопатологии. В статье изложен современный обзор литературы и представлен клинический случай с результатами собственного диагностического поиска. Lambert-Eaton myasthenic syndrome is a rare autoimmune disease of neuromuscular transmission in which antibodies are formed against voltage-gated calcium channels at presynaptic nerve endings. There are paraneoplastic and autoimmune forms of this disease. The most common paraneoplastic form of Lambert-Eaton myasthenic syndrome occurs. Diagnosis of this disease is carried out on the basis of complaints and clinical picture: muscle weakness, decreased deep reflexes, autonomic dysfunction, detection of antibodies to voltage-gated calcium channels of the P/Q type and electroneuromyography data. Diagnosis and treatment of Lambert-Eaton myasthenic syndrome causes significant difficulties, which is due to the rarity of the pathology, the non-specificity of the clinical picture, the low availability of laboratory confirmation, and the high probability of detecting oncopathology. The article presents a modern review of the literature and presents a clinical case with the results of our own diagnostic search.

LRP4 site-specific variants in the third β-propeller domain causes congenital myasthenic syndrome type 17

LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction and is central to its development, maintenance, and function. Pathogenic variants of LRP4 that specifically affect the canonical WNT signaling pathway are known to be associated with Cenani-Lenz syndactyly syndrome or the overlapping condition sclerosteosis. However, site-specific pathogenic variants of LRP4 have been associated with the congenital myasthenic syndrome (CMS) type 17 with no abnormal bone phenotype. Only two studies reported biallelic variants of LRP4 associated with CMS17 that presented during childhood. All three reported variants (NM_002334.4: p.Glu1233Ala, p.Glu1233Lys, or p.Arg1277His) are located within the 3′-edge of the third β-propeller domain of LRP4. We report on a patient with a biallelic variant of the LRP4 gene presenting with a severe and neonatal lethal phenotype; we also provide a literature review of the previously reported patients. A female neonate, born to healthy consanguineous parents, presented with severe hypotonia, congenital diaphragmatic hernia, pulmonary hypertension, and progressive hypoxemia. Two of her siblings presented with a similar condition in the past, and all three died shortly after birth. Clinical exome sequencing revealed homozygosity for the pathogenic variant NM_002334.4:c.3698A > C (p.[Glu1233Ala]).

Pathophysiology of Childhood-Onset Myasthenia: Abnormalities of Neuromuscular Junction and Autoimmunity and Its Background.

The pathophysiology of myasthenia gravis (MG) has been largely elucidated over the past half century, and treatment methods have advanced. However, the number of cases of childhood-onset MG is smaller than that of adult MG, and the treatment of childhood-onset MG has continued to be based on research in the adult field. Research on pathophysiology and treatment methods that account for the unique growth and development of children is now desired. According to an epidemiological survey conducted by the Ministry of Health, Labour and Welfare of Japan, the number of patients with MG by age of onset in Japan is high in early childhood. In recent years, MG has been reported from many countries around the world, but the pattern of the number of patients by age of onset differs between East Asia and Western Europe, confirming that the Japanese pattern is common in East Asia. Furthermore, there are racial differences in autoimmune MG and congenital myasthenic syndromes according to immunogenetic background, and their pathophysiology and relationships are gradually becoming clear. In addition, treatment options are also recognized in different regions of the world. In this review article, I will present recent findings focusing on the differences in pathophysiology.

What Is in the Neuromuscular Junction Literature?

Abstract This update covers several articles on diagnosis and misdiagnosis of myasthenia gravis (MG), the role of complement in MG, and then an impressive number of recent treatment trials. There is a negative study on any corticosteroid-sparing effect of intravenous immunoglobulin. A number of positive studies are reviewed. Open-label extension studies of phase 3 trials showed benefit regarding quality of life with efgartigimod and in functional measures with ravulizumab. The phase 3 RAISE trial of zilucoplan, a self-administered complement C5 inhibitor, is covered as well as the MyCarinG trial of rozanolixizumab. The notion of using fast-acting therapies early in the course of MG is addressed. The last sections center on MG and Lambert–Eaton myasthenic syndrome as a consequence of immune checkpoint inhibitor therapy.

Unique genotypic pattern in Indian DPAGT1 congenital myasthenic syndrome patients with two likely founder mutations

Unique genotypic pattern in Indian DPAGT1 congenital myasthenic syndrome patients with two likely founder mutations

Characterisation of a novel mouse model for congenital myasthenic syndrome due to a mutation in CHRND

Characterisation of a novel mouse model for congenital myasthenic syndrome due to a mutation in CHRND

Contribution of collagen XIII to lung function and development of pulmonary fibrosis

BackgroundCollagen XIII is a transmembrane collagen associated with neuromuscular junction development, and in humans its deficiency results in congenital myasthenic syndrome type 19 (CMS19), which leads to breathing difficulties. CMS19...

Paraneoplastic cerebellar degeneration after improvement of Lambert–Eaton myasthenic syndrome

AbstractA 57‐year‐old man presented with progressive muscle weakness in the lower limbs, with elevated anti‐P/Q‐type voltage‐gated calcium channel antibody levels. A repetitive stimulation test showed waxing with high‐frequency stimulation. He was diagnosed with Lambert–Eaton myasthenic syndrome (LEMS) and small‐cell lung cancer. After four courses of cisplatin and etoposide, computed tomography showed a decrease in tumor size and muscle weakness improved. After 3 months, the patient presented with progressive ataxic gait and dysarthria and was admitted to our hospital. Magnetic resonance imaging revealed slight cerebellar atrophy. We diagnosed the patient with paraneoplastic cerebellar degeneration (PCD)‐LEMS. The patient received intravenous immunoglobulin therapy, steroid pulse therapy, and plasmapheresis. The patient's cerebellar ataxia then improved. This represents a rare case of PCD‐LEMS after improvement of LEMS.

Homozygous Duplication in the CHRNE in a Family with Congenital Myasthenic Syndrome 4C: 18-Year Follow Up.

Congenital myasthenic syndromes (CMSs) are rare inherited diseases characterized by muscle weakness and fatigability on exertion resulting from defects in the neuromuscular junctions. Mutations in 32 genes have been reported as the underlying causes of CMS, with mutations in the cholinergic receptor nicotinic epsilon subunit (CHRNE) being the most common cause of the disease. Methodology and Materials: This study investigated a large consanguineous family with multiple individuals suffering from abnormal fatigue and muscle weakness in the ocular and limb regions. Moreover, the affected individuals were followed up for 18 years to observe the clinical course of the disease. High-quality exome sequencing followed by bidirectional Sanger sequencing revealed a homozygous duplication variant (NM_000080.4: c.1220-8_1227dup) in the splice acceptor site of exon 11 of the CHRNE gene. This variant is predicted to cause frameshift and premature termination (p.Cys410ProfsTer51). Both parents had heterozygous duplication variants with no clinical symptoms. The personalized treatment of the affected individuals resulted in a marked improvement in the clinical symptoms. More than 80% of the disease symptoms in the affected individuals subsided after the use of pyridostigmine and salbutamol (4 mg). This is the first report of long-term follow up of cases with homozygous insertion (c.1220-8_1227dup) in the CHRNE gene. Furthermore, this report expands the phenotypic symptoms associated with the CHRNE mutation.

Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series.

The RASopathies are a group of genetic rare diseases caused by mutations affecting genes involved in the RAS/MAPK (RAS-mitogen activated protein kinase) pathway. Among them, PTPN11 pathogenic variants are responsible for approximately 50% of Noonan syndrome (NS) cases and, albeit to a lesser extent, of Leopard syndrome (LPRD1), which present a few overlapping clinical features, such as facial dysmorphism, developmental delay, cardiac defects, and skeletal deformities. Motor impairment and decreased muscle strength have been recently reported. The etiology of the muscle involvement in these disorders is still not clear but probably multifactorial, considering the role of the RAS/MAPK pathway in skeletal muscle development and Acetylcholine Receptors (AChR) clustering at the neuromuscular junction (NMJ). We report, herein, four unrelated children carrying three different heterozygous mutations in the PTPN11 gene. Intriguingly, their phenotypic features first led to a clinical suspicion of congenital myasthenic syndrome (CMS), due to exercise-induced fatigability with a variable degree of muscle weakness, and serum proteomic profiling compatible with a NMJ defect. Moreover, muscle fatigue improved after treatment with CMS-specific medication. Although the link between PTPN11 gene and neuromuscular transmission is unconfirmed, an increasing number of patients with RASopathies are affected by muscle weakness and fatigability. Hence, NS or LPDR1 should be considered in children with suspected CMS but negative genetic workup for known CMS genes or additional symptoms indicative of NS, such as facial dysmorphism or intellectual disability.

Tata Laksana Lambert Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder resulting from a paraneoplastic or autoimmune reaction. More than half LEMS cases are associated with small cell lung carcinoma (SCLC). The main clinical manifestation is muscle weakness. The pathophysiology is due to the generation of the autoantibodies against voltage-gated calcium channels (VGCCs) on presynaptic nerve terminals leading to a decrease in neurotransmitter acethylcholine (ACh). Various treatments such as tumor treatments, immunomodulatory, and symptomatic treatment have been studied, but further research is needed.

Congenital myasthenic syndromes: a retrospective natural history study of respiratory outcomes in a single centre.

Respiratory problems are a major cause of morbidity and mortality in patients with congenital myasthenic syndromes, a rare heterogeneous group of neuromuscular disorders caused by genetic defects impacting the structure and function of the neuromuscular junction. Recurrent, life-threatening episodic apnoea in early infancy and childhood and progressive respiratory failure requiring ventilation are features of certain genotypes of congenital myasthenic syndromes. Robb et al. published empirical guidance on respiratory management of the congenital myasthenic syndromes, but other than this workshop report, there are little published longitudinal natural history data on respiratory outcomes of these disorders. We report a retrospective, single-centre study on respiratory outcomes in a cohort of 40 well characterized genetically confirmed cases of congenital myasthenic syndromes, including 10 distinct subtypes (DOK7, COLQ, RAPSN, CHAT, CHRNA1, CHRNG, COL13A1, CHRNE, CHRNE fast channel syndrome and CHRNA1 slow channel syndrome), with many followed up over 20 years in our centre. A quantitative and longitudinal analysis of key spirometry and sleep study parameters, as well as a description of historical hospital admissions for respiratory decompensation, provides a snapshot of the respiratory trajectory of congenital myasthenic syndrome patients based on genotype.

Recombinant cellular model system for human muscle-type nicotinic acetylcholine receptor α12β1δε

The human muscle-type nicotinic acetylcholine receptor α12β1δε (nAChR) is a complex transmembrane receptor needed for drug screening for disorders like congenital myasthenic syndromes and multiple pterygium syndrome. Until today, most models are still using the nAChR from Torpedo californica electric ray. A simple reproducible cellular system expressing functional human muscle-type nAChR is still missing. This study addressed this issue and further tested the hypothesis that different chaperones, both biological and chemical, and posttranslational modification supporting substances as well as hypothermic incubation are able to increase the nAChR yield. Therefore, Gibson cloning was used to generate transfer plasmids carrying the sequence of nAChR or chosen biological chaperones to support the nAChR folding in the cellular host. Viral transduction was used for stable integration of these transgenes in Chinese hamster ovary cells (CHO). Proteins were detected with Western blot, in-cell and on-cell Western, and the function of the receptor with voltage clamp analysis. We show that the internalization of nAChR into plasma membranes was sufficient for detection and function. Additional transgenic overexpression of biological chaperones did result in a reduced nAChR expression. Chemical chaperones, posttranslational modification supporting substances, and hypothermic conditions are well-suited supporting applications to increase the protein levels of different subunits. This study presents a stable and functional cell line that expresses human muscle-type nAChR and yields can be further increased using the chemical chaperone nicotine without affecting cell viability. The simplified access to this model system should enable numerous applications beyond drug development.Graphical abstractGraphical abstract created with http://biorender.com

P2.31-03 Lambert-Eaton Myasthenic Syndrome is Underrecognized in Small Cell Lung Cancer: An Analysis of Real-World Data

P2.31-03 Lambert-Eaton Myasthenic Syndrome is Underrecognized in Small Cell Lung Cancer: An Analysis of Real-World Data

Congenital myasthenic syndrome type 2C in a neonate: Redefining the phenotype of CHRNB1‐related myasthenic syndromes

AbstractObjectiveWe present a neonate with generalized weakness due to autosomal recessive congenital myasthenic syndrome type 2C (CMS2C) resulting from a compound heterozygous mutation in the CHRNB1 gene.Patient descriptionOur patient was determined by multiple methodologies to have a diagnosis of CMS2C (OMIM #616314). Whole‐genome sequencing revealed two distinct variants in the CHRNB1 gene (OMIM *100710): a maternally inherited 2 kb pathogenic microdeletion on chromosome 17p13.1 and a paternally inherited intronic deletion (c.1218‐9_1218‐7) that was reported by the laboratory as a variant of unknown significance.ConclusionsCMS2C is a rare autosomal recessive genetic condition associated with early‐onset muscle weakness. Our patient had a paternally inherited deletion in CHRNB1 (c.1218‐9_1218‐7) that was initially described as a variant of unknown significance. We suggest this finding is “likely pathogenic,” as this aberration has not been commonly described. He also had a partial deletion of CHRNB1 in the maternally inherited allele, which provides further evidence that partial gene deletions may be a more common molecular mechanism than previously known for this condition. The combination of the clinical presentation and electrophysiologic data allowed us to understand the molecular findings and ultimately diagnose CMS2C in our patient.