[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.

Genetic, serological and clinical evaluation of childhood myasthenia syndromes- single center subgroup analysis experience in Turkey.

BACKGROUND: Congenital myasthenic syndrome is a disease that occurs due to several types such as mutations in different pre-synaptic, synaptic, post-synaptic proteins and, glycosylation defects associated with congenital myopathy. Juvenile myasthenia gravis is an autoimmune condition usually caused by antibodies targeting the acetylcholine receptor. AIMS: Our objective is to conduct an analysis on the subgroup traits exhibited by patients who have been diagnosed with congenital myasthenic syndrome and juvenile myasthenia gravis, with a focus on their long-term monitoring and management. METHODS: This study was conducted on children diagnosed with myasthenia gravis, who were under the care of Dokuz Eylul University's Department of Pediatric Neurology for a period of ten years. RESULTS: A total of 22 (12 congenital myasthenic syndrome, 10 juvenile myasthenia gravis) patients were identified. Defects in the acetylcholine receptor (6/12) were the most common type in the congenital myasthenic syndrome group. Basal-lamina-related defects (5/12) were the second most prevalent. One patient had a GFPT1 gene mutation (1/12). Patients with ocular myasthenia gravis (n = 6) exhibited milder symptoms. In the generalized myasthenia gravis group (n = 4), specifically in postpubertal girls, a more severe clinical progression was observed, leading to the implementation of more aggressive treatment strategies. CONCLUSION: This study highlights that clinical recognition of congenital myasthenic syndrome and knowledge of related genes will aid the rapid diagnosis and treatment of these rare neuromuscular disorders. Findings in the juvenile myasthenia gravis group demonstrate the impact of pubertal development and the need for timely and appropriate active therapy, including thymectomy, to improve prognosis.

Myasthenia gravis and congenital myasthenic syndromes.

Myasthenia gravis is an autoimmune disorder caused by antibodies against elements in the postsynaptic membrane at the neuromuscular junction, which leads to muscle weakness. Congenital myasthenic syndromes are rare and caused by mutations affecting pre- or postsynaptic function at the neuromuscular synapse and resulting in muscle weakness. MG has a prevalence of 150-250 and an annual incidence of 8-10 individuals per million. The majority has disease onset after age 50 years. Juvenile MG with onset in early childhood is more common in East Asia. MG is subgrouped according to type of pathogenic autoantibodies, age of onset, thymus pathology, and generalization of muscle weakness. More than 80% have antibodies against the acetylcholine receptor. The remaining have antibodies against MuSK, LRP4, or postsynaptic membrane antigens not yet identified. A thymoma is present in 10% of MG patients, and more than one-third of thymoma patients develop MG as a paraneoplastic condition. Immunosuppressive drug therapy, thymectomy, and symptomatic drug therapy with acetylcholine esterase inhibitors represent cornerstones in the treatment. The prognosis is good, with the majority of patients having mild or moderate symptoms only. Most congenital myasthenic syndromes are due to dysfunction in the postsynaptic membrane. Symptom debut is in early life. Symptomatic drug treatment has sometimes a positive effect.

Congenital myasthenic syndrome due to a genetic mutation.

ABSTRACT: Congenital myasthenic syndrome (CMS) is a group of rare genetic disorders that mimics the symptoms of myasthenia gravis, but it is due to a genetic defect. We present a case of a male CMS patient, and the course of the disease through the years. The patient initially presented with generalized muscle weakness and difficulty swallowing. During the follow-up, he developed difficulty in chewing, bilateral external ophthalmoparesis with an almost full block of eye movements and bulbar syndrome. The case illustrates both the clinical heterogeneity and the progressive worsening of the symptoms of the disease over the years. The optimal treatment for CMS is based on the molecular defect and its localization in the neuromuscular junction. In our case, treatment with pyridostigmine resulted in good long-term control of symptoms. As a result of the patient's good compliance with treatment, he was not admitted to hospital because of respiratory distress. The lack of a unified protocol for the treatment of CMS highlights the need for a more personalized approach when dealing with patients with rare diseases.

GFPT1-Associated Congenital Myasthenic Syndrome Mimicking a Glycogen Storage Disease - Diagnostic Pitfalls in Myopathology Solved by Next-Generation-Sequencing.

GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1: the previously reported missense variant c.41G > A (p.Arg14Gln) and the novel truncating variant c.1265_1268del (p.Phe422TrpfsTer26). Patients showed progressive proximal atrophic muscular weakness with respiratory involvement, and a lethal disease course in adulthood. In the diagnostic workup at that time, muscle biopsy suggested a glycogen storage disease. Initially, Pompe disease was suspected. However, enzymatic activity of acid alpha-glucosidase was normal, and gene panel analysis including 38 genes associated with limb-girdle weakness (GAA included) remained unevocative. Hence, a non-specified glycogen storage myopathy was diagnosed. A decade later, the diagnosis of GFPT1-related CMS was established by genome sequencing. Myopathological reexamination showed pronounced glycogen accumulations, that were exclusively found in denervated muscle fibers. Only single fibers showed very small tubular aggregates, identified in evaluation of serial sections. This family demonstrates how diagnostic pitfalls can be addressed by an integrative approach including broad genetic analysis and re-evaluation of clinical as well as myopathological findings.

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.

Bedside and laboratory diagnostic testing in myasthenia.

Myasthenia gravis (MG) and congenital myasthenic syndromes (CMS) are a group of disorders with a well characterised autoimmune or genetic and neurophysiological basis. We reviewed the literature from the last 20 years assessing the utility of various neurophysiological, immunological, provocative and genetic tests in MG and CMS. Diagnostic sensitivity of repetitive nerve stimulation test ranges between 14 and 94% and specificity between 73 and 100%; sensitivity of single-fibre EMG (SFEMG) test ranges between 64 and 100% and specificity between 22 and 100%; anti-acetylcholine receptor (AChR) antibody sensitivity ranges from 13 to 97% and specificity ranges from 95 to 100%. Overall, SFEMG has the highest sensitivity while positive anti-AChR antibodies have the highest specificity. Newer testing strategies that have been investigated over the last couple of decades include ocular vestibular-evoked myogenic potentials, otoacoustic emissions and disease-specific circulating miRNAs in serum for autoimmune myasthenia, as well as next-generation sequencing for genetic testing of CMS. While there has been significant progress in developing newer testing strategies for diagnosing MG and CMS over the last couple of decades, more research is needed to assess the utility of these newer tools regarding their sensitivity and specificity.

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

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

Congenital myasthenic syndrome in a cohort of patients with 'double' seronegative myasthenia gravis / Síndrome miastênica congênita em uma série de pacientes com miastenia gravis duplo soronegativa

ABSTRACT Background: Congenital myasthenic syndromes (CMS) have some phenotypic overlap with seronegative myasthenia gravis (SNMG). Objective: The aim of this single center study was to assess the minimum occurrence of CMS misdiagnosed as double SNMG in a Brazilian cohort. Methods: The genetic analysis of the most common mutations in CHRNE, RAPSN, and DOK7 genes was used as the main screening tool. Results: We performed genetic analysis in 22 patients with a previous diagnosis of 'double' SNMG. In this study, one CMS patient was confirmed due to the presence of compound heterozygous variants in the CHRNE gene (c.130insG/p.Cys210Phe). Conclusions: This study confirmed that CMS due to CHNRE mutations can be mistaken for SNMG. In addition, our study estimated the prevalence of misdiagnosed CMS to be 4.5% in 'double' SNMG patients of our center. Based on our findings, genetic screening could be helpful in the diagnostic workup of patients with 'double' SNMG in whom differential diagnosis is recommended.

RESUMO Antecedentes: As síndromes miastênicas congênitas (SMC) podem ter sobreposição fenotípica com a miastenia gravis soronegativa (MG-SN). Objetivo: Estabelecer a prevalência mínima de SMC diagnosticada inicialmente como MG duplo soronegativa em uma série de casos brasileiros. Métodos: A análise genética das mutações mais comuns nos genes CHRNE, RAPSN e DOK7 foi usada como o principal exame de triagem. Resultados: Vinte e dois pacientes com diagnóstico prévio de MG-SN foram geneticamente analisados, sendo que uma paciente foi confirmada com SMC devido a presença de variante em heterozigose composta no gene CHRNE (c.130insG/p.Cys210Phe). Conclusões: O presente estudo confirma que SMC devido mutação no gene CHNRE pode ser inicialmente diagnosticada como MG-SN. O estudo estimou como 4,5% a prevalência de diagnóstico de SMC entre nossos pacientes préviamente diagnosticados como MG-SN. Com base nesse estudo, a análise genética pode ser recomendada para investigação do diagnóstico diferencial em pacientes com MG-SN.

Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis.

OBJECTIVES: To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. METHODS: Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non-CMS molecular diagnosis. RESULTS: Seventy-nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty-one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non-CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS. CONCLUSIONS: Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.

Congenital myasthenic syndrome in a cohort of patients with 'double' seronegative myasthenia gravis.

BACKGROUND: Congenital myasthenic syndromes (CMS) have some phenotypic overlap with seronegative myasthenia gravis (SNMG). OBJECTIVE: The aim of this single center study was to assess the minimum occurrence of CMS misdiagnosed as double SNMG in a Brazilian cohort. METHODS: The genetic analysis of the most common mutations in CHRNE, RAPSN, and DOK7 genes was used as the main screening tool. RESULTS: We performed genetic analysis in 22 patients with a previous diagnosis of 'double' SNMG. In this study, one CMS patient was confirmed due to the presence of compound heterozygous variants in the CHRNE gene (c.130insG/p.Cys210Phe). CONCLUSIONS: This study confirmed that CMS due to CHNRE mutations can be mistaken for SNMG. In addition, our study estimated the prevalence of misdiagnosed CMS to be 4.5% in 'double' SNMG patients of our center. Based on our findings, genetic screening could be helpful in the diagnostic workup of patients with 'double' SNMG in whom differential diagnosis is recommended.

Successful treatment of congenital myasthenic syndrome caused by a novel compound heterozygous variant in RAPSN.

BACKGROUND: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course. CASE REPORT: A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine. CONCLUSION: The patient's diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS.

Dominant and recessive congenital myasthenic syndromes caused by SYT2 mutations.

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.

Developing outcome measures of disease activity in pediatric myasthenia.

INTRODUCTION: Pediatric myasthenia encompasses juvenile myasthenia gravis (JMG) and congenital myasthenic syndrome (CMS), which are chronic disorders with fluctuating symptoms amenable to medical therapy. Disease activity and treatment response may be difficult to assess, but, unlike adults, outcome measures have not been developed in children. METHODS: The study was performed in children (0-18 years of age) at the neuromuscular center of a pediatric hospital over a 3-year period. Patients were recruited prospectively as part of their routine clinical care. Demographic data, diagnosis (JMG/CMS), and the following scales were recorded at each visit: Myasthenia Gravis Foundation of America (MGFA) class, Myasthenia Gravis Composite (MGC), and Pediatric Myasthenia-Quality of Life 15 (PM-QOL15). RESULTS: Thirty-three patients (24 JMG, 9 CMS) were included in the study, 22 had two or more visits. We established known-groups validity of the MGC and PM-QOL15 scores as compared with the MGFA class. To establish concurrent validity, we constructed a receiver-operating characteristic curve and calculated threshold values of MGC and PM-QOL15 with optimal sensitivity and specificity for identifying a patient with more severe (MGFA III or higher) disease. Finally, we demonstrated the concordance between the MGC and PM-QOL15 by their statistically significant positive Pearson and Spearman correlations. DISCUSSION: Our study suggests that MGC and PM-QOL15 are important disease outcome measures in pediatric myasthenia that are easy to administer and provide reliable assessment of disease activity in the clinic setting. Further studies are needed to validate their use for pediatric clinical research trials.

Development of neovascular glaucoma after intraocular surgery in Pierson syndrome.

Purpose: To report a patient with Pierson syndrome who presented with neovascular glaucoma (NVG) after cataract surgery.Methods: Retrospective case report.Results: A 17-year old monocular female presented with sudden onset of pain and decreased vision in the right eye. On examination, she had intraocular pressure (IOP) of 50 mmHg, aggressive iris neovascularization (NVI) and 3-piece IOL. Fundus examination revealed pale disc with tessellated fundus and parapapillary atrophy. Vascular arcades were vertically stretched with avascular ischemic retina starting from the near periphery. Macula appeared thin and atrophic. An intravitreal injection of 0.05 mg/0.1 ml bevacizumab was given to the right eye followed by Ahmed glaucoma valve (AGV) implantation. Assessment of her brother revealed similar posterior segment changes. A subsequent urine analysis showed proteinuria and high albumin to creatinine ratio. Next-generation sequencing for LAMB2 gene revealed a homozygous c.4573 + 1 G > A variant confirming the diagnosis of Pierson syndrome.Conclusion: This case expands our knowledge on retinal ischemia in the setting of Pierson syndrome. Close monitoring after intraocular surgery is recommended to look for the development of NVG.

Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype.

Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.

Determinants of the repetitive-CMAP occurrence and therapy efficacy in slow-channel myasthenia.

OBJECTIVE: To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel congenital myasthenic syndrome (SCCMS). METHODS: Neurologic examination, EMG study, laboratory test, muscle biopsy, and next-generation and Sanger sequencing; literature review of reported patients with SCCMS, including EMG, kinetics of mutant acetylcholine receptors (AChRs), and response to therapy; and simulation of the decay phase of endplate potential (EPP) were performed. RESULTS: Three newly characterized and 57 reported patients with SCCMS with mutations of AChR subunits were included. In patients with R-CMAP, the length of channel opening bursts of mutant AChR was increased 8.68 ± 2.82 (mean ± SD)-fold compared to wild-type; in patients without R-CMAP, the length was increased 3.84 ± 0.65-fold (95% confidence interval 3.18-6.50, p = 0.000014). The EPP amplitude after refractory period of action potential in muscle fiber is above the threshold in patients with R-CMAP but below the threshold in patients without R-CMAP. In patients with good results from channel blocker therapy, treatment was initiated 11.60 ± 5.17 years after onset of symptoms; in patients with no to moderate benefit from channel blocker therapy, treatment was initiated 30.70 ± 12.72 years after onset (95% confidence interval -28.57 to -9.63, p = 0.00089). CONCLUSIONS: In SCCMS, the R-CMAP occurrence is related to the extent of prolongation of the opening episodes of mutant AChR channel. Channel blocker treatment is more effective the sooner it is started after the onset of symptoms. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that channel blocker therapy in patients with SCCMS improves symptoms.