Myasthenic Syndrome Research Articles

"A New family with Congenital Myasthenic Syndrome Caused by Compound Heterozygous CHAT Mutations"

"A New family with Congenital Myasthenic Syndrome Caused by Compound Heterozygous CHAT Mutations"

Long-Standing Lambert-Eaton Myasthenic Syndrome Caused by Undetectable Small-Cell Lung Cancer: Why We Should Follow-Up 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.

Pregnancy outcomes in patients with congenital myasthenic syndromes.

The congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders that affect neuromuscular junction transmission. Data on pregnancy outcomes in women with CMS are limited due to their infrequency. In this study we explored pregnancy with CMS in a large cohort of women attending a national specialty clinic in England. All women with CMS who had a documented pregnancy were invited to complete a questionnaire assessing clinical status during pregnancy and postpartum, pregnancy outcomes, fetal outcomes, and medication use during pregnancy. Among 16 women with CMS (acetylcholine receptor deficiency [CHRNE], slow channel syndrome [CHRNA1], DOK7, RAPSYN and glycosylation [DPAGT1 and GFPT1]), 27 pregnancies were recorded: 26 single pregnancies and 1 twin pregnancy. Symptom worsening was reported in 63% of pregnancies, but recovery to baseline function was seen in all but one patient. Miscarriage and cesarean section occurred in 31% and 33% of the women, respectively. Over half of the patients continued taking their medication during pregnancy, which included pyridostigmine (n=10), 3,4-diaminopyridine (n=9), ephedrine (n=3), salbutamol (n=3), and quinidine (n=1). No fetal malformations were recorded. Our results show that clinical worsening during pregnancy was common but rarely persistent. The majority of women with CMS can safely plan pregnancy, but close follow-up is required from their neurology and obstetric teams. Although we identified no safety concerns, continued medication use should be reviewed on a case-by-case basis.

Clinicopathological-genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre.

Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. The aim of this study was to characterize the clinical, physiological, pathohistological and genetic features of nine unrelated Chinese patients with CMS from a single neuromuscular centre. A total of nine patients aged from neonates to 34 years were enrolled who exhibited initial symptoms. Physical examinations revealed that all patients exhibited muscle weakness. Muscle biopsies demonstrated multiple myopathological changes, including increased fibre size variation, myofibrillar network disarray, necrosis, myofiber grouping, regeneration, fibre atrophy and angular fibres. Genetic testing revealed six different mutated genes, including AGRN (2/9), CHRNE (1/9), GFPT1 (1/9), GMPPB (1/9), PLEC (3/9) and SCN4A (1/9). In addition, patients exhibited differential responses to pharmacological treatment. Prompt utilization of genetic testing will identify novel variants and expand our understanding of the phenotype of this rare syndrome. Our findings contribute to the clinical, pathohistological and genetic spectrum of congenital myasthenic syndrome in China.

IVIG treatment in non-paraneoplastic Lambert- Eaton myasthenic syndrome with elevated voltage- gated calcium channels antibodies and subacute cerebellar ataxia

Non paraneoplastic Lambert Eaton myasthenic syndrome (LEMS) is rare and only very few cases have been reported to date. Besides that, LEMS is rarely associated with cerebellar ataxia. Here, we described a case of middle age gentleman who presented with subacute onset of cerebellar ataxia and subsequently found to have remarkably elevated voltage-gated calcium channels (VGCC) antibodies serum titre and LEMS. Repeated screenings for malignancies remained negative. He improved significantly with intravenous immunoglobulin (IVIG) treatment. In conclusion, even with negative malignancy screen, investigation for LEMS and measurement of VGCC level should be considered in patients with subacute cerebellar ataxia. Our case demonstrated good initial response towards IVIG treatment and hence early and timely initiation of treatment with IVIG may lead to clinical improvement. However, more clinical trials will be required in the future to further determine the long term prognosis of non-paraneoplastic cerebellar ataxia and LEMS towards IVIG treatment.

P.044 GMPPB mutation causes a muscular dystrophy-myasthenic spectrum

Background: Mutations in GDP-Mannose Pyrophosphorylase B (GMPPB) cause a spectrum of disease ranging from muscular dystrophy to congenital myasthenic syndrome (CMS). Recognition of neuromuscular junction dysfunction has important treatment implications. Methods: We describe a person with GMPPB mutation causing an overlapping limb girdle muscular dystrophy - myasthenic syndrome with robust response to acetylcholinesterase inhibitors. We review the literature on the muscular dystrophy - CMS and explore the phenotypic features that aid in recognizing neuromuscular junction dysfunction. Results: A 35-year-old woman presented with a 10-year history of debilitating myalgias, symmetrical limb girdle and neck weakness, and chronic CK elevation. Electromyography showed a non-irritable myopathy. Biopsies were consistent with muscular dystrophy. Whole genome sequencing revealed two heterozygous pathogenic mutations in the GMPPB gene, giving a diagnosis of genetically confirmed limb girdle muscular dystrophy. Subsequently, repetitive nerve stimulation revealed decrement in the trapezius muscle suggestive of an overlap myasthenic syndrome. She was started on pyridostigmine resulting in recovery of full motor power with significant functional improvement. Conclusions: Identification and treatment of neuromuscular junction dysfunction caused by GMPPB mutations can significantly improve motor power and function. Early onset of progressive fatigable proximal weakness, spared ocular and facial muscles, and pyridostigmine responsiveness are important features of GMPPB-related CMS.

What is in the Neuromuscular Junction Literature?

This update covers a number of treatment topics starting with Fc receptor inhibitors and the Federal Drug Administration approval of efgartigimod. Some uncertainties regarding the use of corticosteroids are addressed, namely the risk of exacerbation with initiation of treatment and how to taper. The presence and potential importance of antibody overshoot following plasmapheresis is noted and the evolving increase in usefulness of acetylcholine receptor antibodies in diagnosing ocular myasthenia. Several recent series and case reports regarding coronavirus 2019 and myasthenia gravis are reviewed. The topics of myasthenia gravis and pregnancy, and another look at thymectomy in MG are provided. Finally, a couple of case reports on Lambert-Eaton myasthenic syndrome concentrate on the ice pack test and an autoantibody association with paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome in the same patient.

Paraneoplastic syndromes in ophthalmology

Paraneoplastic syndromes consist on systemic manifestations associated with certain cancers which are not a direct consequence of tumor invasion or its metastases. It is known that autoimmunity and autoantibody synthesis play an important role in its pathophysiology due to a process of molecular mimicry. Paraneoplastic syndromes in ophthalmology are rare, but it is important to recognize them clinically because in some cases symptoms preceded the diagnosis of an underlying neoplasia. Most frequently involved cancer is small cell lung carcinoma, but there is also a relationship with other tumor etiologies such as thymoma, gynecological tumors or neuroblastoma in children. Paraneoplastic syndromes with ocular involvement can be divided into those that affect the afferent visual pathway, such as cancer-associated retinopathy, melanoma-associated retinopathy, or paraneoplastic optic neuropathy; and the ones that affect the efferent visual pathway, such as bilateral tonic pupils, Myasthenia Gravis, Lambert-Eaton syndrome or paraneoplastic cerebellar degeneration. The presence of autoantibodies is helpful in clinical practice but negativity does not exclude this diagnosis. Although evolution and prognosis is linked to primary disease, in some cases specific treatment, usually immunosuppressive therapy, can help improving patients quality of life.

Plasma lncRNA LOC338963 and mRNA AP3B2 are upregulated in paraneoplastic Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular junction disorder. Long noncoding RNA (lncRNA) can regulate the expression of mRNA and is involved in the development of autoimmune diseases, but few genetic studies are available. In this study we aimed to explore the lncRNA and mRNA changes of LEMS. Plasma lncRNA and mRNA expression profiles of three LEMS patients with small cell lung cancer (SCLC) and three matched healthy controls were analyzed by microarray. Differentially expressed lncRNAs and adjacent mRNAs were jointly analyzed, and candidates were verified by quantitative real-time polymerase chain reaction (qRT-PCR). The identified genes were subsequently evaluated in 9, 8, and 4 patients with paraneoplastic LEMS, nontumor LEMS, and SCLC, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine possible functions. A total of 320 lncRNA and 168 mRNAs were differentially expressed in the three LEMS with SCLC and compared with healthy controls. Among these, lncRNA LOC338963 and its neighboring mRNA AP3B2 were upregulated jointly, which was confirmed by qRT-PCR. qRT-PCR revealed significant upregulation of the two genes in patients with paraneoplastic LEMS compared with nontumor LEMS or SCLC. GO analysis of AP3B2 identified the enrichment terms anterograde synaptic vesicle transport and establishment of synaptic vesicle localization. KEEG analysis showed that AP3B2 was enriched in lysosomal pathways. LOC338963 and AP3B2 were upregulated in patients with paraneoplastic LEMS, suggesting their involvement in pathogenesis. These genes could be targets for exploring the pathomechanism of paraneoplastic LEMS.

Neuromuscular Active Zone Structure and Function in Healthy and Lambert-Eaton Myasthenic Syndrome States.

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.

Physiological Roles of the Autoantibodies to the 78-Kilodalton Glucose-Regulated Protein (GRP78) in Cancer and Autoimmune Diseases.

The 78 kDa glucose-regulated protein (GRP78), a member of the 70 kDa heat-shock family of molecular chaperones (HSP70), is essential for the regulation of the unfolded protein response (UPR) resulting from cellular endoplasmic reticulum (ER) stress. During ER stress, GRP78 evades retention mechanisms and is translocated to the cell surface (csGRP78) where it functions as an autoantigen. Autoantibodies to GRP78 appear in prostate, ovarian, gastric, malignant melanoma, and colorectal cancers. They are also found in autoimmune pathologies such as rheumatoid arthritis (RA), neuromyelitis optica (NMO), anti-myelin oligodendrocyte glycoprotein antibody-associated disorder (AMOGAD), Lambert-Eaton myasthenic syndrome (LEMS), multiple sclerosis (MS), neuropsychiatric systemic lupus erythematosus (NPSLE) and type 1 diabetes (T1D). In NMO, MS, and NPSLE these autoantibodies disrupt and move across the blood-brain barrier (BBB), facilitating their entry and that of other pathogenic antibodies to the brain. Although csGRP78 is common in both cancer and autoimmune diseases, there are major differences in the specificity of its autoantibodies. Here, we discuss how ER mechanisms modulate csGRP78 antigenicity and the production of autoantibodies, permitting this chaperone to function as a dual compartmentalized receptor with independent signaling pathways that promote either pro-proliferative or apoptotic signaling, depending on whether the autoantibodies bind csGRP78 N- or C-terminal regions.

The European Lambert-Eaton Myasthenic Syndrome Registry: Long-Term Outcomes Following Symptomatic Treatment.

IntroductionLambert–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.MethodsThirty 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.ResultsAmong 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.ConclusionNo new safety signals were observed following long-term management of LEMS with 3,4-DAPP.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-022-00354-8.

Lambert-Eaton Myasthenic Syndrome and Paraneoplastic Cerebellar Degeneration as Harbingers of Merkel Cell Carcinoma with Unknown Primary: A Rare Case Presentation. (P1-1.Virtual)

Lambert-Eaton Myasthenic Syndrome and Paraneoplastic Cerebellar Degeneration as Harbingers of Merkel Cell Carcinoma with Unknown Primary: A Rare Case Presentation. (P1-1.Virtual)

A Case of Lambert Eaton Myasthenic Syndrome with Cerebellar Ataxia Complicated by Encephalopathy and Confounded by Generalized Pain (P6-13.009)

A Case of Lambert Eaton Myasthenic Syndrome with Cerebellar Ataxia Complicated by Encephalopathy and Confounded by Generalized Pain (P6-13.009)

Novel congenital myasthenic syndrome caused by homozygous mutation in 3′-UTR of low-density lipoprotein receptor-related protein 6 (LRP6) gene (P7-13.010)

Novel congenital myasthenic syndrome caused by homozygous mutation in 3′-UTR of low-density lipoprotein receptor-related protein 6 (LRP6) gene (P7-13.010)

A Diagnostic Dilemma: Normal Repetitive Nerve Stimulation in Lambert-Eaton Myasthenic Syndrome

It is important for the diagnosis of Lambert-Eaton myasthenic syndrome (LEMS) to confirm the incremental response at high-rate stimulation or after brief exercise in the repetitive nerve stimulation (RNS) test. Therefore, it may be difficult to diagnose LEMS if the RNS test is normal initially. We report a patient with LEMS whose diagnosis was delayed due to normal RNS findings. We believe that anti-P/Q-type voltage-gated calcium channel antibody testing is crucial in the diagnosis of LEMS.

P 7 SARS-CoV2 infection causes a worsening of the modified ranking scale (mRS) in patients with neuromuscular diseases – first results of the German covid19-nme registry

Background: Patients with neuromuscular diseases (NMD) are classified as risk groups for a potentially severe course of a SARS-CoV-2 infection. An online registry (www.covid19-nme.com) was developed to gather information about the severity of COVID19, a potential progression of NMD through the SARS-CoV-2 infection and the possible influence of medication on the course of the infection.Methods: Since February 2021, patients of all ages (children, adolescents and adults) with NMD and an infection with SARS-CoV-2 have been included in this register. In addition to demographic data, pre-existing diseases and therapies, information about the NMD, the course of the SARS-CoV-2 infection as well as the clinical findings before and after the infection are recorded.Results: So far 94 patients (37% female, age: median 60 years (1-94 years)) from Germany and Austria have been recorded. The diagnoses represent the entire spectrum of NMD: different forms of polyneuropathies (PN) including CIDP and hereditary PN, ICUAW, myasthenic syndromes, motor neuron diseases (SMA and ALS) as well as various muscle diseases such as dystrophinopathies and myotonic syndromes. The collected mRS (measure for description of neurological impairment) depicts a significant worsening after the SARS-CoV2 infection (p = 0.02; Wilcoxon), whereby the patients with ICUAW were excluded from the analysis. The duration of symptoms showed a positive correlation with age (r = 0.343; p = 0.005) and weight (r = 0.291; p = 0.030), but not with the type of NMD. In total, 13 patients deceased due to the SARS-CoV2 infection. The probability of a fatal outcome of COVID19 correlates with increasing age (r = 0.313; p = 0.004) but not the type of NMD. The ventilation situation did not change in NMD patients due to the infection with SARS-CoV2.Summary: The first results of the evaluation of the covid-19.nme registry indicate that the clinical symptoms of NMD progress due to an infection with SARS-CoV2. The underlying cause for this remains unclear. Autoimmunological processes and a possible neurotropy can be considered as pathophysiological mechanisms.

The CMS19 disease model specifies a pivotal role for collagen XIII in bone homeostasis

Mutations in the COL13A1 gene result in congenital myasthenic syndrome type 19 (CMS19), a disease of neuromuscular synapses and including various skeletal manifestations, particularly facial dysmorphisms. The phenotypic consequences in Col13a1 null mice (Col13a1−/−) recapitulate the muscle findings of the CMS19 patients. Collagen XIII (ColXIII) is exists as two forms, a transmembrane protein and a soluble molecule. While the Col13a1−/− mice have poorly formed neuromuscular junctions, the prevention of shedding of the ColXIII ectodomain in the Col13a1tm/tm mice results in acetylcholine receptor clusters of increased size and complexity. In view of the bone abnormalities in CMS19, we here studied the tubular and calvarial bone morphology of the Col13a1−/− mice. We discovered several craniofacial malformations, albeit less pronounced ones than in the human disease, and a reduction of cortical bone mass in aged mice. In the Col13a1tm/tm mice, where ColXIII is synthesized but the ectodomain shedding is prevented due to a mutation in a protease recognition sequence, the cortical bone mass decreased as well with age and the cephalometric analyses revealed significant craniofacial abnormalities but no clear phenotypical pattern. To conclude, our data indicates an intrinsic role for ColXIII, particularly the soluble form, in the upkeep of bone with aging and suggests the possibility of previously undiscovered bone pathologies in patients with CMS19.

Adaptive Remodeling of the Neuromuscular Junction with Aging.

Aging is associated with gradual degeneration, in mass and function, of the neuromuscular system. This process, referred to as “sarcopenia”, is considered a disease by itself, and it has been linked to a number of other serious maladies such as type II diabetes, osteoporosis, arthritis, cardiovascular disease, and even dementia. While the molecular causes of sarcopenia remain to be fully elucidated, recent findings have implicated the neuromuscular junction (NMJ) as being an important locus in the development and progression of that malady. This synapse, which connects motor neurons to the muscle fibers that they innervate, has been found to degenerate with age, contributing both to senescent-related declines in muscle mass and function. The NMJ also shows plasticity in response to a number of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and Lambert-Eaton myasthenic syndrome (LEMS). Here, the structural and functional degradation of the NMJ associated with aging and disease is described, along with the measures that might be taken to effectively mitigate, if not fully prevent, that degeneration.

Moderate phenotype of a congenital myasthenic syndrome type 19 caused by mutation of the COL13A1 gene: a case report

BackgroundCongenital myasthenic syndromes caused by mutations in the COL13A1 gene are very rare and have a phenotype described as severe. We present the first case of congenital myasthenic syndrome described in Algeria and the Maghreb with a new mutation of this gene.Case presentationWe present an 8-year-old Algerian female patient, who presented with a moderate phenotype with bilateral ptosis that fluctuates during the day and has occurred since birth. During the investigation, and despite the very probable congenital origin, we ruled out other diagnoses that could induce pathology of the neuromuscular junction. The genetic study confirmed our diagnosis suspicion by highlighting a new mutation in the COL13A1 gene.ConclusionWe report a case with a mutation of the Col13A1 gene, reported in the Maghreb (North Africa), and whose phenotype is moderate compared with the majority of cases found in the literature.