Challenges in Diagnosing and Treating Myasthenia Gravis in Infants and Children with Presentation of Cases.

Myasthenia gravis (MG) is a rare condition that impairs function at the neuromuscular junction of skeletal muscles, seen less commonly in children. Causes include autoimmune MG, congenital myasthenic syndromes, and transient neonatal myasthenia gravis. Symptoms of weakness, hypotonia, and fatigability can be reasonably explained by more common causes, thus children with MG disorders commonly experience delays in treatment with severe consequences. This leads to the progression of disease and serious complications including myasthenic crises and exacerbations. We describe 5 cases of MG, which illustrate clinical and genetic challenges in establishing diagnosis and subsequent consequences of delayed diagnosis.

Diagnostic yield of a practical electrodiagnostic protocol discriminating between different congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) are a group of heterogeneous diseases of the neuromuscular junction. We report electrodiagnostic testing (EDX) and genetic findings in a series of 120 CMS patients tested with a simple non-invasive EDX workup with surface recording of CMAPs and 3Hz repetitive nerve stimulation of accessory, radial and deep fibular nerves. Five ENMG phenotypes were retrieved based on the presence or not of R-CMAPs and the distribution pattern of decremental CMAP responses which significantly correlated with genetic findings (p <0.00001). R-CMAPs were found in all COLQ-mutated patients (CMS1A) and Slow Channel CMS (SCCMS) (CMS1B). CMS1A exhibited greater decrements in accessory nerve RNS than CMS1B. Patients without R-CMAPs were classified into CMS2A (DOK7-, MUSK-, GFPT1-, GMPPB-, TOR1AIP-mutated) when exhibiting predominant accessory nerve RNS decrements, CMS2B (CHRNE, CHRND, RAPSN) with predominant radial nerve RNS decrements, or CMS2C (AGRN) if there were predominant fibular decrements. Our algorithm may have a major impact on diagnostic and therapeutic monitoring in CMS patients, as well as for validation of the pathogenicity of genetic variants. It should also be part of the evaluation of unexplained muscle weakness or complex neuromuscular phenotypes.

Congenital Myasthenic Syndromes in Turkey: Clinical and Molecular Characterization of 16 Cases With Three Novel Mutations.

BACKGROUND: Congenital myasthenic syndromes (CMS) are composed of numerous hereditary disorders involving genetic mutations in proteins essential to the integrity of neuromuscular transmission. The symptoms of CMS vary according to the age at onset of symptoms, and the type and severity of muscle weakness. Effective treatment and genetic counseling depend upon the underlying pathogenic molecular mechanism and subtype of CMS. METHODS: A retrospective and cross-sectional study was performed with 16 patients with a genetically confirmed diagnosis of CMS to share our experience with clinical symptoms, demographic data, genetic variants, and treatments applied. RESULTS: Sixteen patients with a specific CMS genetic diagnosis (three novel mutations) were identified, including CHRNE (n = 7), DOK7 (n = 2), AGRN (n = 2), RAPSN (n = 1), CHRNA1 (n = 1), CHRNB1 (n = 1), CHAT (n = 1), and SCN4A (n = 1). Age at onset of symptoms ranged from the neonatal period to 12 years. Genetic diagnosis was confirmed between the ages of three months and 17 years. A significant delay was determined between the onset of symptoms and genetic diagnosis of the disease. CONCLUSIONS: This study highlights the importance of genetic testing in CMS. Due to the rarity of CMS, more cases will be recognized and reported as the use of laboratory and genetic testing accelerates. We hope that our experience will grow and contribute further to the literature as clinical follow-up and treatment increase.

Diagnosis of DOK7 congenital myasthenic syndrome during pregnancy: A case report and literature review.

INTRODUCTION: Pregnancy among patients with congenital myasthenic syndrome (CMS) is a rare occurrence. Since most of the patients with CMS reach adulthood, questions regarding clinical outcome with pregnancy arise. CASE REPORT: We describe a 38-year-old Portuguese female who presented in the second trimester of pregnancy with proximal fluctuating limb-girdle weakness, hyperlordosis, waddling gait, dysphagia, dysphonia and ptosis, with no ophthalmoparesis. Initial diagnosis of seronegative myasthenia, supported by neurophysiology findings, led to unsuccessful treatment with intravenous immunoglobulin, pyridostigmine, prednisolone and plasmapheresis, and the patient slowly progressed to a severe tetraparesis with facial and bulbar involvement. Genetic testing for CMS identified a novel compound heterozygous mutation (c.1124_1127dupTGCC and c.935_936del) in the DOK7 gene. Subsequent treatment with salbutamol resulted in substantial clinical benefit. CONCLUSIONS: This case underlines the importance of considering the diagnosis of CMS in patients with fluctuating weakness during pregnancy. Patients of child-bearing potential diagnosed with CMS, particularly due to DOK7 mutations, should be counseled in advance and closely followed during pregnancy.

Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features.

BACKGROUND: Congenital myasthenic syndrome is a group of rare genetic disorders affecting transmission across the neuromuscular junction. Patients present with variable ocular, bulbar, respiratory, and extremity weakness that may respond to symptomatic therapies. METHODS: We identified 18 patients with congenital myasthenic syndrome from a pediatric neuromuscular center over a decade. Through a retrospective chart review, we characterize demographic profile, clinical features, genetic variants, treatment, and follow-up of these patients. RESULTS: Patients had the following genetic subtypes: CHRNE (6), CHAT (2), MUSK (2), DOK7 (2), COLQ (1), RAPSN (1), PREPL (1), GFPT1 (1), CHRBB1 (1), and CHRNA1 (1). The phenotype varied based on the genetic variants, though most patients have generalized fatigable weakness affecting ocular, bulbar, and extremity muscles. There was a significant delay in the diagnosis of this condition from the onset of symptoms. Although most patients improved with pyridostigmine, some subtypes showed worsening with pyridostigmine and others benefited from albuterol, ephedrine, or 3,4-diaminopyridine treatment. CONCLUSION: Increasing recognition of this rare syndrome will lead to early diagnosis and prompt treatment. Prompt utilization of genetic testing will identify novel variants and the expanding phenotype of this condition.

Congenital Myasthenic Syndromes.

Congenital myasthenic syndromes comprise a rare heterogeneous group of diseases that impair neuromuscular transmission and are characterized by muscle fatigability and transient or permanent weakness. Symptoms are often present from birth or early childhood. These syndromes have a wide range of phenotypes and severity. Caused by genetic mutations in any of the numerous genes encoding for components of the neuromuscular junction. They are classified by where in the neuromuscular junction the mutated component is located: presynaptic, synaptic, or postsynaptic. Mutations in about 30 genes have been implicated. Diagnosis can be difficult. Treatment options vary depending on the specific genetic type.

[Advances in the diagnosis and treatment of congenital myasthenic syndrome].

Congenital myasthenic syndrome (CMS) is a group of clinical and genetic heterogeneous diseases caused by impaired neuromuscular transmission due to genetic defects. At present, it has been reported that more than 30 genes can cause CMS. All CMS subtypes have the clinical features of fatigue and muscle weakness, but age of onset, symptoms, and treatment response vary with the molecular mechanisms underlying genetic defects. Pharmacotherapy and symptomatic/supportive treatment are the main methods for the treatment of CMS, and antisense oligonucleotide technology has been proven to be beneficial for CHRNA 1-related CMS in animals. Since CMS is a group of increasingly recognized clinical and genetic heterogeneous diseases, an understanding of the latest knowledge and research advances in its clinical features, genetic research, and treatment helps to give early diagnosis and treatment as well as gain a deeper understanding of the pathogenesis of CMS, so as to make new breakthroughs in the treatment of CMS.

Myasthenia Gravis and Congenital Myasthenic Syndromes.

PURPOSE OF REVIEW: Myasthenia gravis (MG) is an autoimmune neuromuscular disease that causes fluctuating weakness in ocular, bulbar, and limb muscles and can, in 15% of cases, cause myasthenic crisis, a neurologic emergency characterized by respiratory failure. Although infrequent, MG needs to be promptly recognized and treated because the potential for improvement and remission is very high. The diagnosis of MG can be challenging and delayed because of the fluctuating nature of muscle weakness and the overlap of signs and symptoms with other neuromuscular diseases.This article reviews the importance of prompt recognition of the typical signs and symptoms, best tests to confirm the diagnosis, currently available acute and chronic treatment modalities, the role of thymectomy, and the natural history of the disease. Special consideration related to the diagnosis and management in women during pregnancy and in children will also be reviewed. This article also includes an overview of congenital myasthenic syndromes. RECENT FINDINGS: Recent significant efforts in standardizing and improving the care of patients with MG have occurred, as well as new momentum in developing new drugs for patients with MG who do not adequately respond to currently available treatments. The number of clinical trials and drugs in development for MG is steadily increasing. Eculizumab has been recently approved by the US Food and Drug Administration (FDA) for adult patients with generalized MG who are acetylcholine receptor-antibody positive, based on the REGAIN (Safety and Efficacy of Eculizumab in Refractory Generalized Myasthenia Gravis) study, a phase 3, randomized, double-blind, placebo-controlled, multicenter trial. An international, multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone has demonstrated that thymectomy improves clinical outcome in patients with nonthymomatous MG. Clinical care guidelines have been published, and the recommendations for clinical research standards and the Myasthenia Gravis Foundation of America MGFA clinical classification published in 2000 have become widely accepted by the clinical and research community of MG experts. SUMMARY: MG is a highly treatable disease with many effective treatment modalities available and with a natural history that continues to improve thanks to better diagnostic tests and effective drugs. The diagnosis and management of patients affected by MG can be highly rewarding for any neurologist as most patients are able to live normal lives if treated appropriately. Nevertheless, future research is needed to address unresolved clinical issues, such as when and how to discontinue immunosuppressive medications in patients in remission, the role and timing of thymectomy in children, and better treatment options for refractory patients.

Congenital myasthenic syndromes.

OBJECTIVES: Congenital myasthenic syndromes (CMSs) are a genotypically and phenotypically heterogeneous group of neuromuscular disorders, which have in common an impaired neuromuscular transmission. Since the field of CMSs is steadily expanding, the present review aimed at summarizing and discussing current knowledge and recent advances concerning the etiology, clinical presentation, diagnosis, and treatment of CMSs. METHODS: Systematic literature review. RESULTS: Currently, mutations in 32 genes are made responsible for autosomal dominant or autosomal recessive CMSs. These mutations concern 8 presynaptic, 4 synaptic, 15 post-synaptic, and 5 glycosilation proteins. These proteins function as ion-channels, enzymes, or structural, signalling, sensor, or transporter proteins. The most common causative genes are CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1. Phenotypically, these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay. Cognitive disability, dysmorphism, neuropathy, or epilepsy are rare. Low- or high-frequency repetitive nerve stimulation may show an abnormal increment or decrement, and SF-EMG an increased jitter or blockings. Most CMSs respond favourably to acetylcholine-esterase inhibitors, 3,4-diamino-pyridine, salbutamol, albuterol, ephedrine, fluoxetine, or atracurium. CONCLUSIONS: CMSs are an increasingly recognised group of genetically transmitted defects, which usually respond favorably to drugs enhancing the neuromuscular transmission. CMSs need to be differentiated from neuromuscular disorders due to muscle or nerve dysfunction.

[Congenital myasthenic syndromes in adulthood : Challenging, rare but treatable]. / Kongenitale myasthene Syndrome im Erwachsenenalter : Diagnostisch herausfordernd, selten, aber behandelbar.

The congenital myasthenic syndromes (CMS) represent a heterogeneous group of diseases with a broad spectrum of phenotypes. The common characteristic is an inherited genetic defect of the neuromuscular junction. Although in some patients the specific gene defect remains to be detected, the increasing identification of causative genes in recent years has already provided unique insights into the functionality of structural proteins at the neuromuscular junction. Neonatal and early childhood onset is observed in most CMS subtypes; however, late onset in adolescence or adulthood also occurs and establishing the diagnosis at these stages imposes particular challenges. To enable appropriate therapeutic interventions for an at least in principle treatable condition, determining the genetic cause is warranted. In this overview, the critical clinical and diagnostic features of the different CMS subtypes are presented and illustrated using typical cases. Furthermore, specific diagnostic clues are outlined. Finally, the overlap between CMS and muscular dystrophies is discussed. Illustrating characteristic patient examples, the essential clinical and additional diagnostic findings of various CMS subtypes and special diagnostic indications are presented.

Italian recommendations for diagnosis and management of congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) are genetic disorders due to mutations in genes encoding proteins involved in the neuromuscular junction structure and function. CMS usually present in young children, but perinatal and adult onset has been reported. Clinical presentation is highly heterogeneous, ranging from mild symptoms to severe manifestations, sometimes with life-threatening respiratory episodes, especially in the first decade of life. Although considered rare, CMS are probably underestimated due to diagnostic difficulties. Because of the several therapeutic opportunities, CMS should be always considered in the differential diagnosis of neuromuscular disorders. The Italian Network on CMS proposes here recommendations for proper CMS diagnosis and management, aiming to guide clinicians in their practical approach to CMS patients.

Congenital myasthenic syndromes in adult neurology clinic: A long road to diagnosis and therapy.

OBJECTIVE: To investigate the diagnostic challenges of congenital myasthenic syndromes (CMS) in adult neuromuscular practice. METHODS: We searched the Mayo Clinic database for patients with CMS diagnosed in adulthood in the neuromuscular clinic between 2000 and 2016. Clinical, laboratory, and electrodiagnostic data were reviewed. RESULTS: We identified 34 patients with CMS, 30 of whom had a molecular diagnosis (14 DOK7, 6 RAPSN, 2 LRP4, 2 COLQ, 2 slow-channel syndrome, 1 primary acetylcholine receptor deficiency, 1 AGRN, 1 GFPT1, and 1 SCN4A). Ophthalmoparesis was often mild and present in 13 patients. Predominant limb-girdle weakness occurred in 19 patients. Two patients had only ptosis. Age at onset ranged from birth to 39 years (median 5 years). The median time from onset to diagnosis was 26 years (range 4-56 years). Thirteen patients had affected family members. Fatigable weakness was present when examined. Creatine kinase was elevated in 4 of 23 patients (range 1.2-4.2 times the upper limit of normal). Repetitive nerve stimulation revealed a decrement in 30 patients. Thirty-two patients were previously misdiagnosed with seronegative myasthenia gravis (n = 16), muscle diseases (n = 15), weakness of undetermined cause (n = 8), and others (n = 4). Fifteen patients received immunotherapy or thymectomy without benefits. Fourteen of the 25 patients receiving pyridostigmine did not improve or worsen. CONCLUSION: Misdiagnosis occurred in 94% of the adult patients with CMS and causes a median diagnostic delay of nearly 3 decades from symptom onset. Seronegative myasthenia gravis and muscle diseases were the 2 most common misdiagnoses, which led to treatment delay and unnecessary exposure to immunotherapy, thymectomy, or muscle biopsy.

A new severe mutation in the SLC5A7 gene related to congenital myasthenic syndrome type 20.

Congenital myasthenic syndromes are a group of genetically determined rare diseases resulting from ultrastructural alterations in synaptic proteins. Up to 32 genes are known to be involved in those syndromes and many mutations have been reported, of which less than 8% affect the presynaptic complex. One of these syndromes is caused by the impairment of the presynaptic sodium-dependent high-affinity choline transporter 1, as a result of a mutation of the SCL5A7 gene associated with congenital myasthenic syndrome type 20 (MIM # 617143). We present a new case of this syndrome, caused by a mutation not previously described. A full term infant presented with acute respiratory failure and generalized weakness. The genetic analysis revealed the patient to be compound heterozygous for a new mutation of the SCL5A7 gene. The genetic analysis of congenital myasthenic syndromes provide information on the ultrastructural underlying mechanisms, which is valuable for differential diagnosis and specific treatments.

Protein-anchoring therapy to target extracellular matrix proteins to their physiological destinations.

Endplate acetylcholinesterase (AChE) deficiency is a form of congenital myasthenic syndrome (CMS) caused by mutations in COLQ, which encodes collagen Q (ColQ). ColQ is an extracellular matrix (ECM) protein that anchors AChE to the synaptic basal lamina. Biglycan, encoded by BGN, is another ECM protein that binds to the dystrophin-associated protein complex (DAPC) on skeletal muscle, which links the actin cytoskeleton and ECM proteins to stabilize the sarcolemma during repeated muscle contractions. Upregulation of biglycan stabilizes the DPAC. Gene therapy can potentially ameliorate any disease that can be recapitulated in cultured cells. However, the difficulty of tissue-specific and developmental stage-specific regulated expression of transgenes, as well as the difficulty of introducing a transgene into all cells in a specific tissue, prevents us from successfully applying gene therapy to many human diseases. In contrast to intracellular proteins, an ECM protein is anchored to the target tissue via its specific binding affinity for protein(s) expressed on the cell surface within the target tissue. Exploiting this unique feature of ECM proteins, we developed protein-anchoring therapy in which a transgene product expressed even in remote tissues can be delivered and anchored to a target tissue using specific binding signals. We demonstrate the application of protein-anchoring therapy to two disease models. First, intravenous administration of adeno-associated virus (AAV) serotype 8-COLQ to Colq-deficient mice, resulting in specific anchoring of ectopically expressed ColQ-AChE at the NMJ, markedly improved motor functions, synaptic transmission, and the ultrastructure of the neuromuscular junction (NMJ). In the second example, Mdx mice, a model for Duchenne muscular dystrophy, were intravenously injected with AAV8-BGN. The treatment ameliorated motor deficits, mitigated muscle histopathologies, decreased plasma creatine kinase activities, and upregulated expression of utrophin and DAPC component proteins. We propose that protein-anchoring therapy could be applied to hereditary/acquired defects in ECM and secreted proteins, as well as therapeutic overexpression of such factors.

Clinical and research strategies for limb-girdle congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) are a group of rare disorders that cause fatigable muscle weakness due to defective signal transmission at the neuromuscular junction, a specialized synapse between peripheral motor neurons and their target muscle fibers. There are now over 30 causative genes that have been reported for CMS. Of these, there are 10 that are associated with a limb-girdle pattern of muscle weakness and are thus classed as LG-CMS. Next-generation sequencing and advanced methods of data sharing are likely to uncover further genes that are associated with similar clinical phenotypes, contributing to better diagnosis and effective treatment of LG-CMS patients. This review highlights clinical and pathological hallmarks of LG-CMS in relation to the underlying genetic defects and pathways. Tailored animal and cell models are essential to elucidate the exact function and pathomechanisms at the neuromuscular synapse that underlie LG-CMS. The integration of genomics and proteomics data derived from these models and patients reveals new and often unexpected insights that are relevant beyond the rare genetic disorder of LG-CMS and may extend to the functioning of mammalian synapses in health and disease more generally.

Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions.

Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromuscular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS.

[Current status of congenital myasthenic syndromes]. / Estado actual de los sindromes miastenicos congenitos.

Since Engel reported the first case of congenital myasthenia in 1977 and the first pathogenic gene was found in 1995, knowledge about congenital myasthenic syndromes has continued to grow. Over the years, the pathogenic basis, its clinical features, the phenotype-genotype correlations that have been established and its therapeutic management have all been described. In this group of diseases the safety margin of neuromuscular transmission is altered by different mechanisms: in the synthesis or storage of acetylcholine quanta in the synaptic vesicles, in the calcium-mediated release of acetylcholine in the nerve terminal or in the efficiency of the quantum released to generate a post-synaptic depolarisation. Increased knowledge about them has enabled a number of different therapeutic strategies to be established. In this review the main updates on these syndromes are reported, including: the genes described as classifying 50% of cases, their current classification based on the localisation of the proteins that alter neuromuscular transmission, including a new group of congenital myasthenias, glycosylation disorders, the main key diagnoses and the therapeutic management of this group of under-diagnosed patients.

TITLE: Estado actual de los sindromes miastenicos congenitos.Desde la descripcion de Engel del primer caso de miastenia congenita en 1977 y el hallazgo en 1995 del primer gen patogeno, el conocimiento de los sindromes miastenicos congenitos se ha ido desarrollando, y se han descrito la base patogena, sus caracteristicas clinicas, las correlaciones fenotipo-genotipo establecidas y su abordaje terapeutico. En este grupo de enfermedades se altera el margen de seguridad de la transmision neuromuscular por distintos mecanismos: en la sintesis o almacenamiento de los quantum de acetilcolina en las vesiculas sinapticas, en la liberacion de acetilcolina en el nervio terminal mediada por calcio o en la eficiencia de la cuanta liberada para generar una despolarizacion postsinaptica. Su conocimiento ha permitido establecer distintas estrategias terapeuticas. En esta revision se describen las principales actualizaciones de estos sindromes: los genes descritos que clasifican un 50% de los casos, su clasificacion actual basandose en la localizacion de las proteinas que alteran la transmision neuromuscular, incluyendo un nuevo grupo de miastenias congenitas, los trastornos de la glicosilacion, las principales claves diagnosticas y el abordaje terapeutico de este grupo de pacientes infradiagnosticados.

[Juvenile-onset muscular diseases]. / Muskelsykdommer med debut i barnealder.

Children with muscular diseases constitute an important group in paediatric neurology. Some of the conditions are very serious and require extensive interdisciplinary treatment and facilitation. There is some degree of optimism regarding the possibility of causal treatment in some of the conditions.

Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE 1267delG mutation. A long-term follow-up.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders. Mutations in CHRNE are one of the most common cause of them and the ɛ1267delG frameshifting mutation is described to be present on at least one allele of 60% of patients with CHRNE mutations. We present a comprehensive description of the heterogeneous clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit in nine members of two large Gipsy kindreds. Our observations indicate that founder Roma mutation 1267delG leads to a phenotype further characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP; but also by facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness that sometimes entails the loss of ambulation. Interestingly, we found in our series a remarkable proportion of patients with a progressive or fluctuating course of the disease. This finding is in some contrast with previous idea that considered this form of CMS as benign, non progressive, and with a low impact on the capacity of ambulation.