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Introduction: Myasthenia gravis disease (MGD) and inflammatory myopathy (IM) are commonly reported in the literature and usually appear with thymic pathology. Lambert-Eton myasthenic syndrome (LEMS) associated with IM is extremely rare. Case Presentation: We report a 42-year-old female patient who presented with proximal muscle weakness of the upper and lower limbs, normal creatinine kinase (CK) level, and positive acetylcholine and voltage-gated calcium channel receptor antibodies. There were no oculobulbar symptoms and no history of thymoma, and the electrophysiological tests were unremarkable. Muscle biopsy revealed focal perimysial and perivascular inflammation, predominantly B-cell lymphocytes, in a non-necrotizing muscle. Conclusions: LEMS associated with IM, particularly B-cell inflammation, has never been reported in the absence of cancer history. Clinical investigations and myopathological features can help establish the diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Lambert-Eaton myasthenia syndrome (LEMS) is a rare autoimmune disorder characterized by autoantibodies targeting presynaptic neuromuscular junctions. It results in muscle weakness and autonomic dysfunction. LEMS can be idiopathic or associated with neoplastic diseases, often small-cell lung cancer. This case report describes a rare instance of paraneoplastic LEMS in a man with non-Hodgkin lymphoma. Case Presentation: A 57-year-old male with non-Hodgkin lymphoma presented with progressive muscle weakness, diminished reflexes, and autonomic symptoms. Diagnosis revealed LEMS with autoantibodies against voltage-gated calcium channels. Immunosuppressive therapy and lymphoma treatment led to significant improvement in his condition. Conclusion: This case highlights the rare occurrence of paraneoplastic LEMS in a patient with non-Hodgkin lymphoma. Recognition and timely management of LEMS alongside lymphoma treatment can lead to significant clinical improvement, emphasizing the need for increased awareness of such complex associations. [ABSTRACT FROM AUTHOR]

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BackgroundWhile immune checkpoint inhibitors (ICIs) have been revolutionary in the treatment of cancer, their administration has been associated with a variety of immune-related adverse events (irAEs), including myasthenia gravis (MG), and Lambert-Eaton myasthenic syndrome (LEMS).ObjectiveTo provide a comprehensive synthesis of the evidence supporting an etiological role for ICIs in MG and LEMS in patients with no prior history of autoimmune disease.HypothesisICIs may trigger MG and LEMS in patients with no prior susceptibility to autoimmune disease.MethodsRelevant primary research on Medline was interrogated using a series of search algorithms. Search terms were constructed based on the PICOS tool endorsed by the Cochrane Collaboration, which describes population, intervention, comparison, outcomes, and study design. Papers were screened according to inclusion and exclusion criteria. Additional papers were retrieved from the reference lists of screened papers. Each paper included in the qualitative synthesis was assigned an integrated metric of evidence (IME) value, ranging from 0 to 7, based on study design, quality of data, likelihood of a causal link between the immune checkpoint inhibitor(s) and MG/LEMS, confidence of MG/LEMS diagnosis, and the number of patients treated with an ICI prior to MG/LEMS diagnosis.ResultsNinety-four papers describing at least one patient treated with ICI(s) prior to the onset of MG and/or LEMS were documented. Overall evidence for a causal link between ICI administration and MG/LEMS was low, with a median IME value of 2.88 (range 2.05–6.61).ConclusionsThere is a paucity of evidence in support of an etiological relationship between ICIs and MG/LEMS, due largely to the lack of mechanistic studies and/or prospective clinical trials with relevant study endpoints. The current literature is dominated by case reports and retrospective cohort studies, which inherently yield only low-level evidence, supporting the need for further work in this area. A role of ICIs in the etiology of MG/LEMS remains plausible, arguing for continued vigilance for irAEs in patients treated with these drugs. We argue that there is a need for future mechanistic, high quality, large-scale studies specifically investigating the possible etiological role of ICIs in MG/LEMS.

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Paraneoplastic syndrome is a group of clinical symptoms that occur in the state of systemic malignant tumors. Paraneoplastic syndrome of the nervous system can affect any part of the central and peripheral nervous system and may also affect the eyes. In neuroophthalmology, paraneoplastic syndrome has a variety of manifestations that can affect both the afferent and efferent visual systems. The afferent system may involve the optic nerve, retina and uvea; the efferent system may involve eye movement, neuromuscular joints or involuntary eye movements and pupil abnormalities and may also have other neurological symptoms outside the visual system. This article discusses the clinical manifestations, pathological mechanisms, detection methods and treatment methods of paraneoplastic syndrome in neuroophthalmology. The performance of paraneoplastic syndrome is diverse, the diagnosis is difficult, and the treatment should be considered systematically. Differential diagnosis, optimal evaluation and management of these manifestations is not only the key to treatment but also a challenge. [ABSTRACT FROM AUTHOR]

However, the Orphan Drug Act is intended to increase I approvals i for treatments for orphan diseases, and it appears that Catalyst just may have served the intent of the ODA by being the first company to take and complete the path that the ODA created for that very purpose. FDA took the unique approach (FDA's admission) of "administratively dividing" Jacobus's NDA into pediatric and adult populations. It is not clear why Jacobus required 27 years (1990-2017) from the grant of orphan drug status to file its initial NDA, but Jacobus apparently had been selling its product under FDA's compassionate use exemption for 25 years (1993-2018) before Catalyst finally got official FDA approval (thereby cutting Jacobus out of its market). [Extracted from the article]

Introduction: Lambert–Eaton myasthenic syndrome (LEMS) is characterized by autoantibodies against voltage-gated calcium channels (VGCC) at the neuromuscular junction causing proximal muscle weakness, decreased tendon reflexes, and autonomic changes. The European LEMS registry aimed to collate observational safety data for 3,4-diaminopyridine phosphate (3,4-DAPP) and examine long-term outcomes for patients with LEMS. Methods: Thirty centers across four countries participated in the non-interventional European LEMS registry. Any patients diagnosed with LEMS by means of clinical assessment and abnormal neurophysiological testing, or clinical assessment and positive for VGCC antibodies were eligible to participate. Patients were monitored using standard assessments for LEMS-related clinical manifestations. Results: Among 96 evaluable participants, 50 (52.1%) were being treated with 3,4-DAPP, 21 (21.9%) with 3,4-diaminopyridine (3,4-DAP), and 25 (26.0%) with other treatments (e.g., pyridostigmine, corticosteroids, immunoglobulins, and azathioprine); 74 participants (77.1%) were exposed to 3,4-DAPP at any time. Quantitative myasthenia gravis scores were similar across treatment groups. Muscle strength was generally good and maintained during follow-up. Cerebellar ataxia, defined as a negative Romberg's test and at least one other positive ataxia test, was observed in 30 (56.6%) patients. Most participants had reduced reflex tone and limited functioning. Sustained or improved functioning was observed in participants administered 3,4-DAPP. Inconsistent and sporadic functional improvement and regression was observed with 3,4-DAP and other treatments. Fifty-five treatment-related adverse events (AEs) were reported by 32 (33.3%) participants. Eight (8.3%) participants reported nine treatment-related serious AEs. No new safety signals were identified. Conclusion: No new safety signals were observed following long-term management of LEMS with 3,4-DAPP. [ABSTRACT FROM AUTHOR]

We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C > T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50% decrement of compound muscle action potential amplitudes but 250% facilitation immediately after exercise, similar to that seen in Lambert-Eaton myasthenic syndrome. Endplate studies demonstrated a profound reduction of the endplate potential quantal content but normal amplitudes of miniature endplate potentials. Electron microscopy showed endplates with increased postsynaptic folding that were denuded or only partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin α5 to SV2A and impaired laminin-521 cell adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding α-laminins.

Abstract Background Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission. The objective was to examine the efficacy and safety of 3,4-diaminopyridine (3,4-DAP) in patients with LEMS. Methods We searched several databases to identify relevant studies, including PubMed, EMBASE, Web of Science, MEDLINE, Cochrane Neuromuscular Disease Group Specialized Register and the Cochrane Central Register of Controlled Trials(CENTRAL). The primary outcome, quantitative myasthenia gravis (QMG) score and the secondary outcome, compound muscle action potentials (CMAP) amplitude were pooled by meta-analysis. Results Six randomised controlled trials (RCTs) involving 115 patients with LEMS were included. QMG score showed a significant decrease (improvement) of 2.76 points (95 % CI, -4.08 to -1.45, p

Lambert-Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine (3,4-DAP) free base is an investigational orphan drug used to treat LEM-related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4-DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two-compartment and one-compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (Emax ) model characterized the exposure-response relationship well. The PK/PD model was applied to identify a suggested dosing approach for 3,4-DAP free base.

The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within AZs, the relationships between the voltage-gated calcium channels and docked synaptic vesicles govern the probability of acetylcholine release during single action potentials, and the short-term plasticity characteristics during short, high frequency trains of action potentials. Understanding these relationships is important not only for healthy synapses, but also to better understand the pathophysiology of neuromuscular diseases. In particular, we are interested in Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder in which neurotransmitter release from the NMJ decreases, leading to severe muscle weakness. In LEMS, the reduced neurotransmission is traditionally thought to be caused by the antibody-mediated removal of presynaptic voltage-gated calcium channels. However, recent experimental data and AZ computer simulations have predicted that a disruption in the normally highly organized active zone structure, and perhaps autoantibodies to other presynaptic proteins, contribute significantly to pathological effects in the active zone and the characteristics of chemical transmitters. [ABSTRACT FROM AUTHOR]

Background: The Lambert-Eaton myasthenic syndrome (LEMS) is a rare disorder characterized by proximal muscle weakness and autonomic dysfunction due to involvement of the neuromuscular junction A case of delayed unilateral recovery from spinal anesthesia in a patient with LEMS undergoing open cholecystectomy is described. Case presentation: A 42-year-old lady, on treatment for LEMS with pyridostigmine, prednisolone, and azathioprine presented with cholelithiasis and was scheduled for open cholecystectomy. Neuraxial anesthesia combined with a light plane of general anesthesia provided adequate muscle relaxation without the use of neuromuscular blocking drugs. In spite of perioperative continuation of anticholinesterases, the patient required 12 h post-surgery for complete bilateral motor recovery from spinal anesthesia. Conclusions: A combination of spinal anesthesia with a light plane of general anesthesia appears to be a safe anesthetic technique for managing patients with Lambert-Eaton myasthenic syndrome undergoing open cholecystectomy. However, neurologically asymptomatic patients with good treatment compliance may also show an unusual delay in recovery from neuraxial anesthesia. [ABSTRACT FROM AUTHOR]

Lambert-Eaton myasthenic syndrome (LEMS) is an autoantibody-mediated disease of the neuromuscular junction characterized by muscular weakness. Autoantibodies to presynaptic P/Q-type voltage-gated calcium channels (VGCCs) induce defective neuromuscular function. In severe cases, current immunosuppressive and immunomodulatory treatment strategies are often insufficient. First reports show beneficial effects of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy in patients with autoantibody-mediated myasthenia gravis. We report a patient with isolated idiopathic LEMS treated with autologous anti-CD19-CAR-T cells. In this patient, CAR-T infusion leads to expansion of predominantly CD4 + CAR-T cells with a terminally differentiated effector memory cells re-expressing CD45RA (TEMRA)-like phenotype indicating cytotoxic capabilities and subsequent B cell depletion. VGCC antibody titers decrease, resulting in a clinical improvement of LEMS symptoms, e.g., 8-fold increase in walking distance. The patient does not show relevant side effects except for cytokine release syndrome grade 2 and intermittent neutropenia suggesting that anti-CD19 CAR-T cell therapy may be a treatment option in patients with LEMS., Competing Interests: Declaration of interests D.B. is an employee and shareholder of Kyverna Therapeutics with pending patent applications., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Myasthenia gravis and Lambert-Eaton myasthenic syndrome are antibody-mediated autoimmune diseases of the neuromuscular junction that usually present with weakness in ocular muscles and in proximal muscles of the limb and trunk. Prognosis regarding muscle strength, functional abilities, quality of life, and survival is generally good. However, some patients do not respond to treatment. Symptomatic drugs, corticosteroids, and steroid-sparing immunosuppressive drugs remain the cornerstone of treatment. In the past few years, new biological agents against complement, the FcRn receptor, or B-cell antigens have been tested in clinical trials. These new therapies extend the possibilities for targeted immunotherapies and promise exciting new options with a relatively rapid mode of action. Challenges in their use might occur, with barriers due to an increase in cost of care and additional considerations in the choice of drugs, and potential consequences of infection and vaccination due to the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Autoimmune neuromuscular junction disorders are rare. However, myasthenia gravis is being increasingly recognised in people older than 50 years. In the past 5-10 years, epidemiological studies worldwide suggest an incidence of acetylcholine receptor antibody-positive myasthenia gravis of up to 29 cases per 1 million people per year. Muscle-specific tyrosine kinase antibody-positive myasthenia gravis and Lambert-Eaton myasthenic syndrome are about 20 times less common. Several diagnostic methods are available for autoimmune neuromuscular junction disorders, including serological antibody, electrophysiological, imaging, and pharmacological tests. The course of disease can be followed up with internationally accepted clinical scores or patient-reported outcome measures. For prognostic purposes, determining whether the disease is paraneoplastic is of great importance, as myasthenia gravis can be associated with thymoma and Lambert-Eaton myasthenic syndrome with small-cell lung cancer. However, despite well defined diagnostic parameters to classify patients into subgroups, objective biomarkers for use in the clinic or in clinical trials to predict the course of myasthenia gravis and Lambert-Eaton myasthenic syndrome are needed. [ABSTRACT FROM AUTHOR]

Lambert-Eaton syndrome is a rare paraneoplastic disorder of the neuromuscular junction, characterized by impaired release of acetylcholine, which causes proximal muscle weakness, depressed tendon reflexes, and autonomic changes. Most cases of Lambert-Eaton syndrome present in small-cell lung carcinoma, and only a few cases have been reported in other lung subtypes. Herein, we report a case of 69 years old male patient with Lambert-Eaton syndrome as a rare association with a pulmonary large-cell neuroendocrine carcinoma, which presented 5 months before neoplasm diagnosis. A lobectomy was auspiciously performed. A review of the literature is also presented. [ABSTRACT FROM AUTHOR]

Purpose of review: This article reviews the current treatment strategies for patients with Lambert-Eaton myasthenic syndrome (LEMS) including potassium channel blockers, immunosuppressant therapies, and management of dysautonomia. Recent findings: Since the first report in 1983, 3,4-diaminopyridine (amifampridine) has been used as a symptomatic treatment for LEMS. The biggest recent development in LEMS treatment is the approval of two amifampridine drugs in 2018 by the Food and Drug Administration (FDA). Amifampridine phosphate (Firdapse®) is a salt form that was approved for adult patients with LEMS. Amifampridine (Ruzurgi®) was approved for children aged 6 to 17 years old. Summary: The primary treatment option for LEMS remains amifampridine, and the efficacy of both FDA-approved formulations has been demonstrated in high-quality clinical trials. Other immunosuppressant treatments, such as corticosteroids, azathioprine, mycophenolate mofetil, and rituximab, can be used when amifampridine is unavailable, are contraindicated, or do not fully control patient symptoms. For the management of acute exacerbations or severe disease, IVIg or plasma exchange can be considered. High-quality evidence supporting the use of immunosuppressive and immunomodulatory treatments in LEMS patients is generally lacking. Treatment response can be monitored by bedside exams and the Triple Timed Up-and-Go test. [ABSTRACT FROM AUTHOR]

Background: Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission. The objective was to examine the efficacy and safety of 3,4-diaminopyridine (3,4-DAP) in patients with LEMS.Methods: We searched several databases to identify relevant studies, including PubMed, EMBASE, Web of Science, MEDLINE, Cochrane Neuromuscular Disease Group Specialized Register and the Cochrane Central Register of Controlled Trials(CENTRAL). The primary outcome, quantitative myasthenia gravis (QMG) score and the secondary outcome, compound muscle action potentials (CMAP) amplitude were pooled by meta-analysis.Results: Six randomised controlled trials (RCTs) involving 115 patients with LEMS were included. QMG score showed a significant decrease (improvement) of 2.76 points (95 % CI, -4.08 to -1.45, p < 0.001) after treatment with 3, 4-DAP. Moreover, the overall mean CMAP amplitude improved significantly in LEMS patients with 3, 4-DAP treatment, compared with placebo treatment (mean difference 1.34 mV, 95 % CI, 0.98 to 1.70, p < 0.001). The overall assessment of all included trials showed a low risk of bias and low heterogeneity.Conclusions: The pooled results of RCTs demonsrated with moderate to high evidence that 3,4-DAP has a significant effect on LEMS treatment, with improvements in muscle strength score and CMAP amplitude. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune disorders affecting neuromuscular transmission. Their combined occurrence is rare, and treatment remains challenging. Two women diagnosed with concomitant MG/LEMS experienced severe, increasing disease activity despite multiple immunotherapies. Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise for treating autoimmune diseases. This report details the safe application of anti-CD19 CAR T cells for treating concomitant MG/LEMS. After CAR T cell therapy, both patients experienced rapid clinical recovery and regained full mobility. Deep B cell depletion and normalization of acetylcholine receptor and voltage-gated calcium channel N-type autoantibody levels paralleled major neurological responses. Within 2 months, both patients returned to everyday life, from wheelchair dependency to bicycling and mountain hiking, and remain stable at 6 and 4 months post-CAR T cell infusion, respectively. This report highlights the potential for anti-CD19 CAR T cells to achieve profound clinical effects in the treatment of neuroimmunological diseases. • Anti-CD19 CAR T cell therapy led to clinical recovery in two cases of MG and LEMS • Patients regained full mobility, with ongoing recovery 4- and 6-months post infusion • Deep B cell depletion and normalization of pathogenic autoantibodies was observed • Application of anti-CD19 CAR T cells was safe, with manageable side effects Myasthenia gravis and Lambert-Eaton myasthenic syndrome are autoimmune disorders affecting neuromuscular transmission, for which effective therapies are limited. Motte et al. demonstrate safe application of anti-CD19 chimeric antigen receptor T cell therapy for two patients with these concomitant conditions, resulting in profound recovery of clinical parameters and mobility. [ABSTRACT FROM AUTHOR]

3,4-Aminopyridine or Amifampridine belongs to the aminopyridine class of drugs which is used to treat multiple sclerosis and Lambert-Eaton Myasthenic Syndrome (LEMS). Aminopyridine pharmaceuticals inhibit presynaptic potassium channels. This increases available acetylcholine in the nerve cleft which leads to improved strength in this patient population. While overdoses have been reported of 4-Aminopyridine, no case reports of acute 3.4-Aminopyridine overdose are currently available. A 67 year old man presented to the emergency department 30 min after ingesting 100 mg of amifampridine in a suicide attempt. Within an hour of ingestion he experienced tachycardia, tachypnea, hypertension and tremor. The patient then started to experience seizures and had a cardiac arrest 3 h after the ingestion. The patient achieved return of spontaneous circulation but proceeded to have refractory seizures. Despite significant and escalating doses of anti-epileptic medications, the patient continued to have seizures until 18 h after ingestion. His anti-epileptic medications were weaned over the following days and he had no more seizures. This is a report of a novel overdose of 3,4-Aminopyridine, a medication that belongs to the aminopyridine class of pharmaceuticals that have been well used for many years. Aminopyridine overdoses are commonly thought to carry low morbidity and mortality; however, our patient had both a cardiac arrest and refractory status epilepticus. Ultimately, this case suggests that patients who overdose on 3,4-Aminopyridine could become critically ill and their presentation may be far more severe than that of other medications of the same class. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti‐SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61‐year‐old male patient who presented with an unusual anti‐SOX1 positive PNS. The right tibialis anterior showed noticeable low‐amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert‐Eaton myasthenic syndrome (LEMS). Typical MRI and PET‐CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5–6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC.

Background: Lambert-Eaton myasthenic syndrome (LEMS) is a rare disorder of the neuromuscular junction. Clinical features include proximal muscle weakness, markedly in the lower limbs, reduced deep tendon reflexes that can increase after exercise, and autonomic disturbances. The clinical picture as well as knowledge of the laboratory test that accompany LEMS will permit early recognition of the disease, that is crucial because it is often associated with malignancy, especially small cell lung cancer (SCLC). In this article we present a patient with proximal muscle weakness and typical changes on repetitive nerve stimulation, as well as a short literature review on the topic. Conclusions: The diagnosis of LEMS is usually made on clinical grounds. The diagnosis is confirmed by electrophysiological testing, main features including decrement response on slow repetitive nerves stimulation (3Hz), and an increment of more than 100% in CMAP amplitude after brief exercise, or high frequency repetitive stimulation (30-50 Hz). Immunological panel assay with positive P/Q-type VGCC antibody is strongly suggestive of LEMS. While symptomatic treatment with 3,4 – diaminopyridine is available, one of the main priorities is evaluation for underlying malignancies in these patients, the most common being SCLC. Evaluation of patients with LEMS and no known cancer should start with CT of the chest, abdomen and pelvis. Brain imaging is recommended if focal neurological signs are present. If the initial evaluation of the patient is negative, repeated screening for malignancy after 6 months and up to two years is recommended.

Introduction/Aims: We studied a patient with a congenital myasthenic syndrome (CMS) caused by a dominant mutation in the synaptotagmin 2 gene (SYT2) and compared the clinical features of this patient with those of a previously described patient with a recessive mutation in the same gene. Methods: We performed electrodiagnostic (EDX) studies, genetic studies, muscle biopsy, microelectrode recordings and electron microscopy (EM). Results: Both patients presented with muscle weakness and bulbar deficits, which were worse in the recessive form. EDX studies showed presynaptic failure, which was more prominent in the recessive form. Microelectrode studies in the dominant form showed a marked reduction of the quantal content, which increased linearly with higher frequencies of nerve stimulation. The MEPP frequencies were normal at rest but increased markedly with higher frequencies of nerve stimulation. The EM demonstrated overdeveloped postsynaptic folding, and abundant endosomes, multivesicular bodies and degenerative lamellar bodies inside small nerve terminals. Discussion: The recessive form of CMS caused by a SYT2 mutation showed far more severe clinical manifestations than the dominant form. The pathogenesis of the dominant form likely involves a dominant‐negative effect due to disruption of the dual function of synaptotagmin as a Ca2+‐sensor and modulator of synaptic vesicle exocytosis. [ABSTRACT FROM AUTHOR]

• Registries are a valuable collection of information, especially in rare diseases. • Patient- and physician-reported data provide complementary information. • Annual data collection will continuously provide valuable longitudinal insights. Disorders of the neuromuscular junction (NMJ) comprise a spectrum of rare diseases causing muscle fatigability and weakness, leading to life-long effects on quality of life. We established the Dutch-Belgian registry for NMJ disorders, based on a unique combination of patient- and physician-reported information. Information on natural course, disease burden, prevalence of complications and comorbidity is collected through patient-reported standardized questionnaires and verified using medical documentation. Currently, the registry contains information of 565 Myasthenia Gravis (MG) patients and 38 Lambert-Eaton myasthenic syndrome (LEMS) patients, constituting approximately 25% (MG) and 80% (LEMS) of patients in the Netherlands. This is a very large registry, with the highest participation rate per capita. In addition to confirming many disease characteristics previously described in the literature, this registry provides several novel insights. The reported rate of potentially corticosteroid-related comorbidity, including hypertension, heart disease, osteoporosis and type 2 diabetes was high, emphasizing the need to commence corticosteroid-sparing immune suppressive treatment as soon as possible. The reported rate of other auto-immune diseases is far higher than previously expected: 27% of MG and 38% of LEMS patients, and a surprisingly high number of MG patients (47%) is unaware of their antibody status. In conclusion, this registry provides a valuable collection of information regarding MG and LEMS disease course. Continuous collection of annual follow-up data will provide further longitudinal insights in disease burden, course and treatment effect. [ABSTRACT FROM AUTHOR]

Physicians often encounter patients with unexplained muscle weakness and dysphagia. Lambert–Eaton myasthenic syndrome (LEMS) can cause unexplained weakness or dysphagia and is often accompanied by neoplastic conditions. A 64-year-old man who had several risk factors—14 kg weight loss over the last 4 years, 20 years of experience working as a coal miner, and being a 50 pack-year ex-smoker—complained of dysphagia, intermittent diplopia, mild weakness, and hypotonia. The initial computed tomography (CT) and follow-up positron emission tomography (PET) CT did not reveal any malignancy. After continuous follow-up for this LEMS, small-cell lung cancer (SCLC, cTxN1M0) was found on a serial follow-up chest CT 21 months after the LEMS diagnosis. The patient was treated with chemotherapy. LEMS is rare and is often accompanied by malignancy. This case highlights the importance of being concerned about LEMS diagnoses and of long-term follow-up for unexplained LEMS.

Physicians often encounter patients with unexplained muscle weakness and dysphagia. Lambert–Eaton myasthenic syndrome (LEMS) can cause unexplained weakness or dysphagia and is often accompanied by neoplastic conditions. A 64-year-old man who had several risk factors—14 kg weight loss over the last 4 years, 20 years of experience working as a coal miner, and being a 50 pack-year ex-smoker—complained of dysphagia, intermittent diplopia, mild weakness, and hypotonia. The initial computed tomography (CT) and follow-up positron emission tomography (PET) CT did not reveal any malignancy. After continuous follow-up for this LEMS, small-cell lung cancer (SCLC, cTxN1M0) was found on a serial follow-up chest CT 21 months after the LEMS diagnosis. The patient was treated with chemotherapy. LEMS is rare and is often accompanied by malignancy. This case highlights the importance of being concerned about LEMS diagnoses and of long-term follow-up for unexplained LEMS. [ABSTRACT FROM AUTHOR]