Materiały źródłowe

• #1 Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4520251/

  The specific diagnosis of some syndromes is facilitated by clinical clues pointing to a disease gene. In absence of such clues, exome sequencing is a useful tool for finding the disease gene. […] A generic diagnosis of a CMS can be made on the basis of onset at birth to early childhood, fatigable weakness affecting especially the ocular and other cranial muscles, a positive family history, and a decremental EMG response or an abnormal single-fiber EMG. However, some CMS present later in life, the weakness can affect proximal and torso rather than cranial muscles, and the decremental EMG response may be detected only after prolonged subtetanic stimulation. […] The genetic diagnosis of a specific CMS is greatly facilitated when clinical, and EMG studies point to a candidate gene. If a sufficient number of affected and unaffected relatives is available, linkage analysis can point to a candidate chromosomal locus.

• #1 Congenital myasthenic syndromes – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/congenital-myasthenic-syndrome/diagnosis-treatment/drc-20557730

  Your doctor will do a physical examination including a neurological exam and review symptoms and medical history to check for signs of a congenital myasthenic syndrome. Your doctor may also order tests to exclude other conditions with similar symptoms. […] The following tests can help diagnose a congenital myasthenic syndrome and determine how severe the disorder is. […] Blood tests. A blood test might reveal the presence of abnormal antibodies that disrupt signals between your nerves and your muscles. Other blood tests may be helpful to rule out other conditions that may have similar symptoms. […] Electromyography (EMG). EMG is a diagnostic procedure to assess the health of muscles and the nerve cells that control them, called motor neurons. EMG results can reveal nerve dysfunction, muscle dysfunction or problems with signal transmission between the nerves and muscles.

• #1 Congenital myasthenic syndromes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1025-5

  Diagnosing CMS relies on a thorough work-up by means of the history, clinical exam, blood tests, electrophysiological investigations, lung function tests, polysomnography, the tensilon test, eventually muscle biopsy, and the confirmation of a heterocygote or biallelic pathogenic variant in one of the 32 CMS genes. […] A CMS should be generally suspected if 1. there is easy fatigability or permanent weakness, most frequently in the ocular, facial, bulbar, axial, respiratory, or limb muscles with onset from birth to childhood; 2. the family history is positive for clinical manifestations of CMS; 3. history and clinical exam suggest myasthenia gravis but where AchR-, MUSK-, and LRP4-antibody tests are negative; 4. LF-RNS evokes a decrement of 10% or if SF-EMG shows increased jitter or blockings; 5. clinical manifestations respond to AchEI; 6. there is a lack of improvement upon immunosuppressive therapy; 7. the family history suggests an AD/AR transmitted disease; 8. there is absence of a major pathology on muscle biopsy; and if 9. a specific syndrome (e.g. Escobar syndrome, Pierson syndrome (eye disease and nephropathy)) is present.

• #1 Congenital Myasthenic Syndrome (CMS): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/congenital-myasthenic-syndrome

  Congenital myasthenic syndrome is a group of conditions where physical activity leads to muscle weakness. Treatment is available, but there’s no cure for this genetic condition. […] A healthcare provider will diagnose congenital myasthenic syndrome after a physical and neurological exam. They’ll review your symptoms and take a complete medical history. If they suspect CMS, they may ask you to perform a physical activity under their supervision to observe how your body reacts, like walking up stairs, for example. […] Genetic testing helps your healthcare provider detect the gene change that’s causing your symptoms. Your provider may draw a small sample of your blood to examine your DNA. The gene change can help your provider detect what type of CMS you have and where in your neuromuscular junction there’s an issue.

• #1 Congenital Myasthenic Syndromes – EyeWiki

  https://eyewiki.org/Congenital_Myasthenic_Syndromes

  Congenital myasthenic syndromes (CMS) are diagnosed via a combination of clinical findings and genetic testing. […] The diagnosis of CMS is established with characteristic findings on clinical exam, neurophysiological studies, serum studies, poor or good response to acetylcholinesterase inhibitors and immunosuppressive therapeutics, muscle biopsy, and family history in combination with identification of one or more mutations known to be associated with the condition. […] CMS should be suspected if a patient has easily fatigable or persistent weakness in ocular, facial, bulbar, limb, axial, or respiratory muscles, especially when onset is at birth or in childhood. […] Low- and high-frequency repetitive nerve stimulation (RNS) electrophysiological tests can be used to support a diagnosis of CMS. […] Serum anti-acetylcholine receptor and anti-MuSK antibodies are negative in CMS because it is not an antibody-mediated disease. […] Single gene testing, multigene panel testing, or genomic sequencing can be used to identify genetic mutations of CMS.

• #1 Congenital Myasthenic Syndromes | CheckRare

  https://checkrare.com/congenital-myasthenic-syndromes/

  The diagnosis of CMS is based on clinical findings, a decremental EMG response of the compound muscle action potential (CMAP) on low-frequency (2-3 Hz) stimulation, a positive response to acetylcholinesterase (AchE) inhibitors, absence of anti-acetylcholine receptor (AChR) and anti-MuSK antibodies in the serum, and lack of improvement of clinical symptoms with immunosuppressive therapy. Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS.

• #1 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/articles/2019-aug-july/congenital-myasthenic-syndrome-treatment

  Clinical phenotypes of CMS overlap with other neuromuscular diseases, most notably myasthenia gravis (MG), an autoimmune disease also characterized by weakness, fatigability, and ptosis (1 or both eyelids). […] Diagnosis of CMS is established with clinical and electrodiagnostic features and identification of a causative mutation. […] In some instances, a clinical diagnosis can be made without finding a causative gene (eg, individuals who exhibit fatigable weakness, especially of ocular and other cranial muscles, at birth or early childhood). […] Clinical diagnosis may rely on history, clinical exams, blood tests, incremental or decremental responses or abnormal single-fiber EMG (SF-EMG) study results, lung function tests, polysomnography, the Tensilon test, and muscle biopsy. […] The most common causes of CMS are mutations in genes encoding subunits of the AChR (ie, CHRNA1, CHRNB1, CHRND, or CHRNE), which account for approximately 50% of cases.

• #1 Congenital myasthenic syndromes | MedLink Neurology

  https://www.medlink.com/articles/congenital-myasthenic-syndromes

  The EMG examination should include repetitive stimulation of nerves at 2 to 3 Hz in search of a greater than 10% decrement of the fifth compared to the first evoked CMAP in multiple muscles, and especially in muscles that are significantly weak. […] Next generation sequencing for known congenital myasthenic syndromes is commercially available and facilitates diagnosis and management by neuromuscular specialists. […] The congenital myasthenic syndromes either decrease or increase the synaptic response to ACh. When a congenital myasthenic syndrome reduces the synaptic response, cholinesterase inhibitors, which increase the number of AChRs activated by each quantum, and 3,4-DAP, which increases the number of quanta released by nerve impulse, are used. […] A better approach to mutation discovery is whole-exome or whole genome sequencing.

• #1 Congenital myasthenic syndromes – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/congenital-myasthenic-syndrome/diagnosis-treatment/drc-20557730

  Repetitive nerve stimulation. In this nerve conduction study, electrodes are attached to your skin over the muscles to be tested. Small pulses of electricity are sent through the electrodes to measure the nerve’s ability to send a signal to your muscle. The nerve is tested repeatedly to see if its ability to send signals worsens with fatigue. […] Genetic testing. This can identify the specific affected gene that’s responsible for the congenital myasthenic syndrome and which treatments may be beneficial. […] Cholinesterase challenge test. Cholinesterase inhibitor medication, such as pyridostigmine, is given to determine if improvement in muscle fatigue occurs with repetitive movement. […] Other tests. These may include lung function tests to assess breathing and oxygenation, a sleep study to assess breathing and apnea during sleep, or a muscle biopsy to look at muscle fibers.

• #1 Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2020.17.2.73

  We report detailed clinical and genetic features of eleven cases with CMS. All patients shared the clinical features of muscle weakness, but the age of onset, distribution and severity of weakness, and response to treatment were very diverse according to the genes harboring the mutations. Typical clinical features were generalized muscle weakness presenting in the neonatal period or early infancy. Diurnal variation of weakness was not so much distinct during infantile and early childhood period and often appeared after childhood as an important clinical clue. […] The response to treatment depends on the subtype of CMS. Traditionally, pyridostigmine, a competitive acetylcholinesterase inhibitor, was the mainstay of treatment for the neuromuscular junction disorders. Oral pyridostigmine can be given at an initial dose of 0.5 to 1 mg/kg every 4 to 6 hours and the maximum recommended total daily dose is 7 mg/kg. Consistent with previous reports, our patients with defects of acetylcholine receptor, presynaptic choline transporter, and protein glycosylation had much benefited from pyridostigmine. But some subtypes such as endplate acetylcholinesterase deficiency due to COLQ mutations and DOK7-related CMS are known to refractory or deteriorate with pyridostigmine.

• #1 CMSP – Overview: Inherited Congenital Myasthenic Syndrome Gene Panel, Varies

  https://www.mayocliniclabs.com/test-catalog/overview/617519

  Establishing a molecular diagnosis for patients with congenital myasthenic syndrome. […] Identifying variants within genes known to be associated with congenital myasthenic syndrome, allowing for predictive testing of at-risk family members. […] Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for congenital myasthenic syndromes. […] The combination of the wide variability in symptoms and age of presentation can make congenital myasthenic syndromes hard to diagnosis. […] Given that congenital myasthenic syndromes are a heterogeneous group of disorders, multigene panels can be an efficient and cost-effective way to establish a molecular diagnosis for individuals.

• #1 Congenital myasthenic syndrome | PPT

  https://www.slideshare.net/slideshow/congenital-myasthenic-syndrome-184070693/184070693

  Congenital myasthenic syndrome (CMS) is a rare heterogeneous group of genetic disorders that affect neuromuscular transmission. Diagnosis involves neurophysiology testing showing a decremental response on repetitive nerve stimulation and increased jitter on single fiber EMG. Genetic testing and muscle biopsy can help identify the underlying cause, which may include defects in presynaptic, synaptic, or postsynaptic proteins. […] Diagnosis Neurophysiology:- Decremental (10%) response on RNST In slow channel syndrome and COLQ congenital myasthenia, the decremental response is rate-dependent. Single fiber EMG is more sensitive but less specific Increased jitter on single fiber EMG. […] Diagnosis Muscle biopsy:- Shows mild non specific changes in form of increased fiber size variability, type 2 fiber atrophy, central nuclei with necrosis and regeneration of fibers. Tubular aggregates of sarcoplasmic reticulum seen in GFPT1, DPAGT1 and ALG2. Cytochemical and immunohistochemical localization at the EP of AChE, AChR, chat, agrin, rapsyn,musk,dok-7. Quantitative electron microscopy and cytochemistry. […] Diagnosis Genetic study:- Mutation analysis Linkage analysis Whole genome sequencing Microarray based comparative genomic hybridization to detect large scale deletions or duplications.

• #1 Congenital Myasthenia Service — Nuffield Department of Clinical Neurosciences

  https://www.ndcn.ox.ac.uk/research/congenital-myasthenia-service

  We provide a nationally commissioned specialised service for the diagnosis and management of children and adults in whom a congenital myasthenic syndrome is suspected. […] The service is funded by the National Commissioning Group (NCG, formerly the National Specialist Commissioning Advisory Group), as part of the Diagnostic and Advisory Service for Rare Neuromuscular Disorders. […] Gene screening is performed at the clinical genetics laboratories, Oxford. Where novel mutations are identified Professor Beesons research laboratory has developed an increasing repertoire of functional analyses to confirm pathogenicity. The clinical service has close links with the research laboratory which has been responsible for the identification of novel CMS-associated genes. […] Information about genetic screening and sample requirements, and how to refer patients, can be found on the Oxford University Hospitals NHS Foundation Trust website. […] Muscle MRI in CMS study a prospective study to investigate whether muscle MRI can help to differentiate between CMS subtypes. […] The Neuromuscular Disorders Group focuses on understanding congenital myasthenic syndromes at the molecular level as the basis for the development of new treatments.

• #1 SciELO Brazil – Congenital myasthenic syndrome in a cohort of patients with ‘double’ seronegative myasthenia gravis Congenital myasthenic syndrome in a cohort of patients with ‘double’ seronegative myasthenia gravis

  https://www.scielo.br/j/anp/a/fNy8Rc4G4vbDYPLjtk4VDwx/

  However, in sporadic patients with no reported affected family, other signs can help the diagnosis: age at onset, delayed motor development, hypotonia, ptosis, ophthalmoplegia, weakness that may worsen on exertion, skeletal deformities, standard response to the use of acetylcholinesterase inhibitors, and no response to treatment with immunosuppressants. […] An abnormal decrement on low-frequency repetitive nerve stimulation (RNS) or an increased jitter on single-fibre electromyography (SFEMG) confirms an underlying neuromuscular transmission defect in CMS, but these electrodiagnostic findings are similar to those in MG. […] This fact makes it difficult to electrophysiologically differentiate CMS from MG. […] In this situation, the presence of serum antibodies, e.g. anti-acetylcholinesterase receptor (AChR), is helpful to distinguish between the diseases.

• #1 Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2020.17.2.73

  Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center Journal of Genetic Medicine 2020;17:73-78 Published online December 31, 2020; https://doi.org/10.5734/JGM.2020.17.2.73 2020 Korean Society of Medical Genetics and Genomics. […] Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of disorders characterized by impaired neuromuscular transmission. This study aims to provide the clue for early diagnosis and improved therapeutic strategies in CMS. […] Through the targeted panel sequencing including twenty CMS causative genes, eleven patients were genetically confirmed and enrolled in this study. A retrospective medical record review was carried out for the clinical and laboratory data analysis. […] The age of patients ranged from 5 to 23 years, with the median age of 16 years. The peak age at onset of symptoms was the neonatal period. Seven out of the eleven patients were symptomatic at birth. The most commonly reported initial finding was generalized hypotonia with poor sucking and crying. Mean time to accurate diagnosis was 9.35.0 years. Total fifteen different variants in seven genes associated with CMS (DOK7, AGRN, RAPSN, CHRNE, COLQ, SLC5A7, and GFPT1) were identified.

• #1 Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2020.17.2.73

  Our study suggested the importance of molecular diagnosis of CMS to warrant appropriate treatment. Due to the wide heterogeneity of clinical and genetic features, the diagnosis of CMS remains challenging even for experienced clinicians. The number of causative genes continues to grow and the clinical differentiation of subtypes is usually very difficult. The advent of NGS technologies opened a new era of molecular genetic diagnosis in various neuromuscular disorders. Since molecular diagnosis is crucial for the therapeutic decision making in CMS, it is important for clinicians to recognize clinical clues and confirm the genetic analysis earlier.

• #1

  https://link.springer.com/article/10.1007/s00415-017-8689-3

  Genetic diagnosis for these conditions is all the more imperative given that effective treatments may prevent these life-threatening crises, but treatment response varies depending on the genetic subtype. […] The underlying mechanism of EA in disorders of neuromuscular transmission is unknown. […] In our cohort, average diagnostic delay was substantial at 8 months. […] In practice, however, many patients may be admitted directly to intensive care units and may not be examined by a paediatric neurologist or neuromuscular specialist during these crises. […] In early infancy, abnormal neurophysiology tests may be the only indication of a NMJ disorder. […] Failure to perform this additional test could result in the diagnosis of CMS-EA being discounted. […] Given the risk of fatal apnoeas if the diagnosis is missed, and the potential for clinical improvement with AChEIs, these prolonged studies should be performed if deficiency of ACh re-synthesis is suspected.

• #1 Congenital myasthenic syndromes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1025-5

  The most important electrophysiological investigation to support the CMS diagnosis are LF-RNS and HF-RNS. LF-RNS usually shows a decrement and only rarely an increment. […] If RNS is normal, muscle contractions or exercise should be performed prior to the test. […] In patients carrying SYT1 mutations, CMAP amplitudes may be initially low but may markedly increase after forced exercise, like in Lambert-Eaton myasthenic syndrome. […] The first mutation in the CHRNE gene causing a CMS has been reported already in 2000. […] Since then various different types of mutations have been reported and it is estimated that up to half of the patients with a CMS carry a CHRNE mutation, thus representing the gene most frequently mutated in CMS. […] Most patients respond favourably to AchEI. However, in some patients pyridostigmine and 3,4-DAP may be ineffective or may worsen the phenotype. […] Whenever patients with myasthenic symptoms do not present with AchR- or MUSK-antibodies, do not respond to immunosuppressive treatment, have a positive family history for their phenotype, and show impaired neuromuscular transmission upon RNS or SF-EMG, a CMS should be considered.

• #1 Diagnosing congenital myasthenic syndrome — Oxford Neuroscience

  https://www.neuroscience.ox.ac.uk/how-we-are-making-a-difference/diagnosing-congenital-myasthenic-syndrome

  Research at the at the Nuffield Department of Clinical Neurosciences has had a profound effect on the diagnosis and treatment of patients with Congenital Myasthenic Syndrome. […] By the late early 2000s the genetic mutations giving rise to many cases had been discovered. […] Work by Professor David Beeson and his team at the Nuffield Department of Clinical Neurosciences has had a profound effect on the diagnosis and treatment of patients with this form of the disease. […] For the first time scientists understood the cause of the disease in this group and the mechanism by which these mutations lead to muscle weakness. […] The team also defined the clinical spectrum of patients with this form of the disease and together with the ability to identify DOK7 mutations this provides the basis of reliable diagnosis.

• #1 Congenital myasthenic syndromes – about our research – Lochmüller Lab

  https://lochmullerlab.org/research-area/cms/

  Congenital myasthenic syndromes (CMS) are rare inherited neuromuscular disorders characterized by fatigable weakness of skeletal muscle owing to compromised function of the neuromuscular junction (NMJ). […] However, between 20 and 40% of patients with CMS remain without a molecular diagnosis after exome sequencing, and part of our research focuses on gene discovery to solve these remaining unsolved cases through the latest genome sequencing and multi-omics approaches. […] The mechanism of the therapeutic effect of 2 adrenergic receptor agonists in CMS is not understood, and our lab is investigating the mode of action of these drugs in specific CMS subtypes with the aim of exploring potential modifications to improve efficacy and better target treatment. […] In collaboration with colleagues from the European Solve-RD project, we are working to develop a treatabolome for CMS a database of treatable variants that can be incorporated into genetic databases and analysis systems in order to flag up to the treating clinician or geneticist that a potential treatment is available. The hope is that this will increase the speed with which individuals with CMS receive the correct treatment.

• #1

  https://link.springer.com/article/10.1007/s00415-017-8689-3

  Administration of one or more drugs is indicated once the diagnosis of CMS-EA is established. […] Given the likelihood of recurring episodes, the potential for psychomotor impairment due to secondary hypoxic brain damage, and the positive effect of available treatments, CMS-EA is an important diagnosis not to miss.

• #2 Congenital myasthenic syndromes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1025-5

  Diagnosing CMS relies on a thorough work-up by means of the history, clinical exam, blood tests, electrophysiological investigations, lung function tests, polysomnography, the tensilon test, eventually muscle biopsy, and the confirmation of a heterocygote or biallelic pathogenic variant in one of the 32 CMS genes. […] A CMS should be generally suspected if 1. there is easy fatigability or permanent weakness, most frequently in the ocular, facial, bulbar, axial, respiratory, or limb muscles with onset from birth to childhood; 2. the family history is positive for clinical manifestations of CMS; 3. history and clinical exam suggest myasthenia gravis but where AchR-, MUSK-, and LRP4-antibody tests are negative; 4. LF-RNS evokes a decrement of 10% or if SF-EMG shows increased jitter or blockings; 5. clinical manifestations respond to AchEI; 6. there is a lack of improvement upon immunosuppressive therapy; 7. the family history suggests an AD/AR transmitted disease; 8. there is absence of a major pathology on muscle biopsy; and if 9. a specific syndrome (e.g. Escobar syndrome, Pierson syndrome (eye disease and nephropathy)) is present.

• #2 Diagnosis – Congenital Myasthenic Syndromes (CMS) – Diseases | Muscular Dystrophy Association

  https://www.mda.org/disease/congenital-myasthenic-syndromes/diagnosis

  Weakness and fatigue are common in the general population, but the degree and pattern of these symptoms particularly ptosis (droopy eyelids) and other signs of weakness in the eye muscles should alert a neurologist to the possibility of CMS. […] The neurologist is likely to ask many questions and to conduct a physical exam to determine the extent of weakness. […] If the physical exam is consistent with myasthenia gravis (MG), the neurologist usually orders a blood test designed to detect antibodies to the ACh receptor. A negative test for ACh receptor antibodies in the serum (blood) can help distinguish CMS from MG but doesnt rule out seronegative MG. […] If the blood tests are negative, the next step is usually electrodiagnostic testing, in which electrodes are used to measure the electrical signals in muscle.

• #2 Congenital Myasthenic Syndrome (CMS): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/congenital-myasthenic-syndrome

  Congenital myasthenic syndrome is a group of conditions where physical activity leads to muscle weakness. Treatment is available, but there’s no cure for this genetic condition. […] A healthcare provider will diagnose congenital myasthenic syndrome after a physical and neurological exam. They’ll review your symptoms and take a complete medical history. If they suspect CMS, they may ask you to perform a physical activity under their supervision to observe how your body reacts, like walking up stairs, for example. […] Genetic testing helps your healthcare provider detect the gene change that’s causing your symptoms. Your provider may draw a small sample of your blood to examine your DNA. The gene change can help your provider detect what type of CMS you have and where in your neuromuscular junction there’s an issue.

• #2 Congenital myasthenic syndromes – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/congenital-myasthenic-syndrome/diagnosis-treatment/drc-20557730

  Repetitive nerve stimulation. In this nerve conduction study, electrodes are attached to your skin over the muscles to be tested. Small pulses of electricity are sent through the electrodes to measure the nerve’s ability to send a signal to your muscle. The nerve is tested repeatedly to see if its ability to send signals worsens with fatigue. […] Genetic testing. This can identify the specific affected gene that’s responsible for the congenital myasthenic syndrome and which treatments may be beneficial. […] Cholinesterase challenge test. Cholinesterase inhibitor medication, such as pyridostigmine, is given to determine if improvement in muscle fatigue occurs with repetitive movement. […] Other tests. These may include lung function tests to assess breathing and oxygenation, a sleep study to assess breathing and apnea during sleep, or a muscle biopsy to look at muscle fibers.

• #2 Congenital myasthenic syndromes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1025-5

  The most important electrophysiological investigation to support the CMS diagnosis are LF-RNS and HF-RNS. LF-RNS usually shows a decrement and only rarely an increment. […] If RNS is normal, muscle contractions or exercise should be performed prior to the test. […] In patients carrying SYT1 mutations, CMAP amplitudes may be initially low but may markedly increase after forced exercise, like in Lambert-Eaton myasthenic syndrome. […] The first mutation in the CHRNE gene causing a CMS has been reported already in 2000. […] Since then various different types of mutations have been reported and it is estimated that up to half of the patients with a CMS carry a CHRNE mutation, thus representing the gene most frequently mutated in CMS. […] Most patients respond favourably to AchEI. However, in some patients pyridostigmine and 3,4-DAP may be ineffective or may worsen the phenotype. […] Whenever patients with myasthenic symptoms do not present with AchR- or MUSK-antibodies, do not respond to immunosuppressive treatment, have a positive family history for their phenotype, and show impaired neuromuscular transmission upon RNS or SF-EMG, a CMS should be considered.

• #2 Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

  https://www.mdpi.com/1422-0067/24/4/3730

  Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles. […] RNS or single-fiber electromyography (SFEMG) is required to diagnose CMS. However, next-generation sequencing technologies have enabled extensive genetic analysis, and a plethora of CMS patients have been diagnosed and reported in the absence of RNS or SFEMG.

• #2 Diagnosis – Congenital Myasthenic Syndromes (CMS) – Diseases | Muscular Dystrophy Association

  https://www.mda.org/disease/congenital-myasthenic-syndromes/diagnosis

  In addition to or in place of electrodiagnosis, the neurologist might try giving an intravenous injection of edrophonium (Tensilon), a fast-acting cholinesterase inhibitor. A temporary increase in strength after this „Tensilon test” is consistent with CMS. […] A family history of myasthenic symptoms supports the CMS diagnosis but isn’t necessary for CMS to occur. Genetic testing and physiological tests on biopsied muscle tissue may be needed to define some types of CMS.

• #2 Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4520251/

  Testing for CMS mutations in previously identified CMS genes is now commercially available but is best used in a targeted manner based on specific clinical clues. In recent years, whole exome sequencing has been used to identify CMS mutations. […] Although available at only few medical centers, they are important for identifying direct effects of the mutations on neuromuscular transmission, characterizing novel CMS, and providing clues for therapy.

• #2 Congenital Myasthenic Syndromes – Clinical Tree

  https://clinicalpub.com/congenital-myasthenic-syndromes/

  The use of microarray chips designed to detect variants in currently identified CMS disease genes will likely increase in the near future. […] Exome sequencing has now become a powerful tool for obtaining a genetic diagnosis when other approaches fail. […] DNA from both parents, and whenever possible from other affected family members, should be analyzed. […] The bioinformatics analysis of the enormous amount of generated data remains challenging, and the putative pathogenic mutations must be confirmed by Sanger sequencing. […] Ideally, pathogenicity of novel variants should be evaluated by expression studies.

• #2 Inherited Congenital Myasthenic Syndrome Gene Panel, Varies – St. Joseph Hospital

  https://sjhnhlab.testcatalog.org/show/CMSP

  Test Code CMSP Inherited Congenital Myasthenic Syndrome Gene Panel, Varies […] Establishing a molecular diagnosis for patients with congenital myasthenic syndrome […] Identifying variants within genes known to be associated with congenital myasthenic syndrome, allowing for predictive testing of at-risk family members […] This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 28 genes associated with congenital myasthenic syndromes: AGRN, ALG14, ALG2, CHAT, CHRNA1, CHRNB1, CHRND, CHRNE, COL13A1, COLQ, DNM2, DOK7, DPAGT1, GAA, GFPT1, GMPPB, LAMB2, LRP4, MUSK, PLEC, PREPL, RAPSN, SCN4A, SLC18A3, SLC25A1, SLC5A7, SYT2, and VAMP1. For more information see Targeted Genes and Methodology Details for Inherited Congenital Myasthenic Syndrome Gene Panel and Method Description.

• #2 CMSP – Overview: Inherited Congenital Myasthenic Syndrome Gene Panel, Varies

  https://www.mayocliniclabs.com/test-catalog/Overview/617519

  Establishing a molecular diagnosis for patients with congenital myasthenic syndrome. […] Identifying variants within genes known to be associated with congenital myasthenic syndrome, allowing for predictive testing of at-risk family members. […] Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for congenital myasthenic syndromes. […] The combination of the wide variability in symptoms and age of presentation can make congenital myasthenic syndromes hard to diagnosis. […] Given that congenital myasthenic syndromes are a heterogeneous group of disorders, multigene panels can be an efficient and cost-effective way to establish a molecular diagnosis for individuals.

• #2 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/articles/2019-aug-july/congenital-myasthenic-syndrome-treatment

  Clinical phenotypes of CMS overlap with other neuromuscular diseases, most notably myasthenia gravis (MG), an autoimmune disease also characterized by weakness, fatigability, and ptosis (1 or both eyelids). […] Diagnosis of CMS is established with clinical and electrodiagnostic features and identification of a causative mutation. […] In some instances, a clinical diagnosis can be made without finding a causative gene (eg, individuals who exhibit fatigable weakness, especially of ocular and other cranial muscles, at birth or early childhood). […] Clinical diagnosis may rely on history, clinical exams, blood tests, incremental or decremental responses or abnormal single-fiber EMG (SF-EMG) study results, lung function tests, polysomnography, the Tensilon test, and muscle biopsy. […] The most common causes of CMS are mutations in genes encoding subunits of the AChR (ie, CHRNA1, CHRNB1, CHRND, or CHRNE), which account for approximately 50% of cases.

• #2 Delayed Diagnosis of Congenital Myasthenic Syndromes Erroneously Interpreted as Mitochondrial Myopathies

  https://www.mdpi.com/2077-0383/12/9/3308

  Background: Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness. […] Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy. […] The diverse phenotypes and presentations of CMS lead to a broad differential diagnosis, which differs between the childhood-onset CMS and the adult-onset CMS. […] The importance of identifying CMS relies on the potential benefit of symptomatic treatment. […] Conducting a directed neurological examination to look for signs of fatigability, along with a neurophysiological study with RNS directed at weak muscles, is crucial to guide genetic studies toward CMS. […] Diagnosing CMS is essential because symptomatic and stabilizing treatments are available which can significantly improve the quality of life of affected patients.

• #2 Congenital Myasthenic Syndromes (CMS) – Rare Awareness Rare Education

  https://rareportal.org.au/rare-disease/congenital-myasthenic-syndromes-cms/

  Diagnosis of congenital myasthenic syndromes (CMS) may involve a combination of medical and family history, physical examination, electromyography (EMG) testing to determine a defect in neuromuscular transmission as well as molecular genetic testing to identify the causal gene. […] Differential diagnosis information can be found at GeneReviews: Congenital Myasthenic Syndromes (Differential Diagnosis of Congenital Myasthenic Syndromes).

• #2 How Not to Miss Congenital Myasthenic Syndromes in Adultslogo-32logo-40logo-60NEJM Journal WatchnejmJW_1L_RGB-b

  https://www.jwatch.org/na47716/2018/10/24/how-not-miss-congenital-myasthenic-syndromes-adults

  Congenital myasthenic syndromes that were eventually diagnosed in adulthood had been missed for decades in 94% of patients; clues to diagnosis are presented here. […] The authors studied 34 patients diagnosed with CMS as adults, 15 of whom had classic myasthenic features, including extraocular muscle involvement or ptosis; 19 showed predominantly limb-girdle involvement. […] Previous misdiagnosis was associated with inappropriate diagnostic measures (e.g., muscle biopsy) and treatment (e.g., immunotherapy, thymectomy). […] Diagnostic clues suggesting CMS included (1) positive family history, (2) onset in childhood or delayed motor milestones, (3) lack of response to immunotherapy or pyridostigmine, and (4) repetitive responses to nerve stimulation. Genetic testing, now available commercially, revealed the definitive diagnoses. […] Maintaining an awareness of diagnostic clues and utilizing now readily available genetic testing is key to diagnosis in myasthenic patients without evident autoantibodies.

• #2 Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2020.17.2.73

  High clinical suspicion and timely molecular diagnosis is particularly important for the tailored therapy to maximize clinical improvement in CMS. […] The causative genes for congenital myasthenia syndrome are very diverse. More than 30 causative genes of CMS have been reported to date and new genes are constantly being discovered. Commonly identified causative genes of CMS include CHRNE, RAPSN, COLQ, DOK7, GFPT1, and CHAT with variations of ethnicity. Since next generation sequencing has been increasingly used for the diagnosis of hereditary myopathies, a number of patients with CMS have been genetically diagnosed and receiving drug treatment with remarkable clinical improvement. The importance of genetic diagnosis is particularly emphasized because the response to medical treatment varies depending on the molecular subtypes in CMS.

• #2 The Importance of Clinical Trials for Congenital Myasthenic Syndromes (CMS) — Know Rare

  https://www.knowrare.com/blog-v2/why-clinical-trials-are-crucial-for-congenital-myasthenic-syndromes-cms

  Blood tests with genetic typing establish the diagnosis of CMS, but its important to know which of the gene mutations are the cause of it. […] CMS can be difficult to diagnose because its symptoms resemble so many other diseases. Surveys have shown that up to 80% of young children with CMS are misdiagnosed, while 94% of adults are misdiagnosed. […] As of now, there are not many large studies about the experiences of those who have been diagnosed with CMS.

• #2

  https://link.springer.com/article/10.1007/s00415-017-8689-3

  Administration of one or more drugs is indicated once the diagnosis of CMS-EA is established. […] Given the likelihood of recurring episodes, the potential for psychomotor impairment due to secondary hypoxic brain damage, and the positive effect of available treatments, CMS-EA is an important diagnosis not to miss.

• #2 Congenital myasthenic syndrome secondary to pathogenic variants in the SLC5A7 gene: report of two cases | BMC Medical Genomics | Full Text

  https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01977-6

  In the CHT1-CMS acetylcholinesterase inhibitors, such as pyridostigmine, by virtue of increasing the amount of ACh available to interact with the receptor, improve neuromuscular transmission. […] However, in some CMS variants such those resulting from mutations in Agrin and ColQ, pyridostigmine can result in an untoward effect. […] Moreover, since in CHT1-CM the therapeutic response to pyridostigmine is incomplete, sympathomimetic medications, such as Salbutamol and Ephedrine are often needed to support neuromuscular transmission. […] For this reason, early genetic diagnosis is essential since therapeutic intervention could improve the morbidity and mortality of the disease.

• #2

  https://journals.lww.com/co-neurology/fulltext/2024/10000/congenital_myasthenic_syndromes__increasingly.9.aspx

  Congenital myasthenia syndromes (CMS) are treatable, inherited disorders affecting neuromuscular transmission. A suspected diagnosis is based on typical clinical features, decremental responses of 10% or more on repetitive nerve stimulation (RNS) and/or abnormal jitter and block on single-fibre EMG. The inheritance pattern in CMS is autosomal recessive except for dominant pattern seen in slow channel syndromes, SNAP25, PURA and some SYT2 patients. Given the widening nonneuromuscular junction phenotypes in the newly identified forms of CMS, new therapies need to include disease-modifying approaches that address not only neuromuscular weakness but also the multisystem involvement. The clinical use of next-generation sequencing greatly facilitates detection of mutations in larger genes, such as AGRN, LRP4, MUSK, COLQ, and thus increases in reported prevalence is likely to continue. The common drugs used are acetylcholinesterase inhibitors (Pyridostigmine), 3,4 diaminopyridine (3,4-DAP), Salbutamol and Ephedrine. Acetylcholinesterase inhibitors slow the breakdown of acetylcholine in the synaptic cleft and hence prolong its activity. Pyridostigmine (Mestinon) is most commonly prescribed and is the first-line treatment in presynaptic CMS, AChR deficiency CMS, fast channel CMS and CMS due to glycosylation defects. Currently there are no licensed drugs specifically for CMS treatment and all the drugs used are off-label, the doses and formulations used in CMS can be different to the licensed uses.

• #2 Diagnosing congenital myasthenic syndrome — Oxford Neuroscience

  https://www.neuroscience.ox.ac.uk/how-we-are-making-a-difference/diagnosing-congenital-myasthenic-syndrome

  Diagnostic testing for DOK7 mutations is now routine for patients with suspected CMS. […] A diagnostic service handling samples from the UK and Europe is provided by the Churchill Hospital and the Weatherall Institute of Molecular Medicine. […] As a result of the research by David Beeson and others in Oxford, the Department of Health set up a National Diagnostic and Advisory Service for CMS based at the John Radcliffe and Churchill Hospitals. […] A national outpatient service is provided at which patients are advised about the genetic basis of the condition and offered the most appropriate treatment.

• #2 Congenital Myasthenic Syndromes Overview – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1168/

  The purpose of this overview is to: […] Review the differential diagnosis of CMS; […] Provide an evaluation strategy to identify the genetic cause of CMS in a proband; […] Laboratory testing is directed at identifying lab findings associated with a CMS, especially findings on EMG and response to acetylcholinesterase inhibitors. […] Establishing a specific genetic cause of a congenital myasthenic syndrome (CMS): […] Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. […] A multigene panel that includes some or all of the genes listed in Table 2 is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. […] Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered.

• #2

  https://link.springer.com/article/10.1007/s10072-018-3682-x

  Congenital myasthenic syndromes (CMS) are genetic disorders due to mutations in genes encoding proteins involved in the neuromuscular junction structure and function. […] 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.

• #3 Congenital Myasthenic Syndromes – EyeWiki

  https://eyewiki.org/Congenital_Myasthenic_Syndromes

  Congenital myasthenic syndromes (CMS) are diagnosed via a combination of clinical findings and genetic testing. […] The diagnosis of CMS is established with characteristic findings on clinical exam, neurophysiological studies, serum studies, poor or good response to acetylcholinesterase inhibitors and immunosuppressive therapeutics, muscle biopsy, and family history in combination with identification of one or more mutations known to be associated with the condition. […] CMS should be suspected if a patient has easily fatigable or persistent weakness in ocular, facial, bulbar, limb, axial, or respiratory muscles, especially when onset is at birth or in childhood. […] Low- and high-frequency repetitive nerve stimulation (RNS) electrophysiological tests can be used to support a diagnosis of CMS. […] Serum anti-acetylcholine receptor and anti-MuSK antibodies are negative in CMS because it is not an antibody-mediated disease. […] Single gene testing, multigene panel testing, or genomic sequencing can be used to identify genetic mutations of CMS.

• #3 Congenital Myasthenic Syndromes Overview – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1168/

  The purpose of this overview is to: […] Review the differential diagnosis of CMS; […] Provide an evaluation strategy to identify the genetic cause of CMS in a proband; […] Laboratory testing is directed at identifying lab findings associated with a CMS, especially findings on EMG and response to acetylcholinesterase inhibitors. […] Establishing a specific genetic cause of a congenital myasthenic syndrome (CMS): […] Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. […] A multigene panel that includes some or all of the genes listed in Table 2 is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. […] Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered.

• #3 Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2020.17.2.73

  We describe the clinical and genetic characteristics of CMS patients diagnosed and treated in a single tertiary center. Through this, we aim to provide the clue for early diagnosis and improved therapeutic strategies in CMS. […] We found eleven CMS patients from ten unrelated families. The age of patients ranged from 5 to 23 years, with the median age of 16 years. The peak age at onset of symptoms was the neonatal period. Seven out of the eleven patients were symptomatic at birth. The most commonly reported initial finding was generalized hypotonia with poor suck and cry. Diurnal variation in seven cases and mild ptosis in six cases were observed. Respiratory distress at birth was noticed in seven patients, four of them suffered transiently and recovered after the neonatal period. Eight patients showed variable degrees of scoliosis. Mean time to accurate diagnosis was 9.35.0 years. Total fifteen different variants in seven genes associated with CMS (DOK7, AGRN, RAPSN, CHRNE, COLQ, SLC5A7, and GFPT1) were identified.

• #3 How Not to Miss Congenital Myasthenic Syndromes in Adultslogo-32logo-40logo-60NEJM Journal WatchnejmJW_1L_RGB-b

  https://www.jwatch.org/na47716/2018/10/24/how-not-miss-congenital-myasthenic-syndromes-adults

  Congenital myasthenic syndromes that were eventually diagnosed in adulthood had been missed for decades in 94% of patients; clues to diagnosis are presented here. […] The authors studied 34 patients diagnosed with CMS as adults, 15 of whom had classic myasthenic features, including extraocular muscle involvement or ptosis; 19 showed predominantly limb-girdle involvement. […] Previous misdiagnosis was associated with inappropriate diagnostic measures (e.g., muscle biopsy) and treatment (e.g., immunotherapy, thymectomy). […] Diagnostic clues suggesting CMS included (1) positive family history, (2) onset in childhood or delayed motor milestones, (3) lack of response to immunotherapy or pyridostigmine, and (4) repetitive responses to nerve stimulation. Genetic testing, now available commercially, revealed the definitive diagnoses. […] Maintaining an awareness of diagnostic clues and utilizing now readily available genetic testing is key to diagnosis in myasthenic patients without evident autoantibodies.

• #3 Delayed Diagnosis of Congenital Myasthenic Syndromes Erroneously Interpreted as Mitochondrial Myopathies

  https://www.mdpi.com/2077-0383/12/9/3308

  Background: Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness. […] Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy. […] The diverse phenotypes and presentations of CMS lead to a broad differential diagnosis, which differs between the childhood-onset CMS and the adult-onset CMS. […] The importance of identifying CMS relies on the potential benefit of symptomatic treatment. […] Conducting a directed neurological examination to look for signs of fatigability, along with a neurophysiological study with RNS directed at weak muscles, is crucial to guide genetic studies toward CMS. […] Diagnosing CMS is essential because symptomatic and stabilizing treatments are available which can significantly improve the quality of life of affected patients.

• #3 Oxford Congenital Myasthenia Service referrals – Oxford University Hospitals

  https://www.ouh.nhs.uk/services/referrals/neurosciences/myasthenia.aspx

  The Oxford Congenital Myasthenia Service is a national referral centre for children and adults in whom a Congenital Myasthenic Syndrome (CMS) is suspected. […] These depend on a combined approach incorporating: clinical assessment, specialised electromyography, analysis of DNA, analysis of serum antibodies (anti-acetylcholine receptor and anti-MUSK), outpatient or inpatient evaluation of specific therapy. […] Currently we are able to screen for mutations in the following genes: CHRNA, CHRNB, CHRND and CHRNE – the genes encoding the muscle acetylcholine receptor (AChR), RAPSN – responsible for clustering AChR at the neuromuscular junction (NMJ), COLQ – which anchors acetlycholinesterase at the NMJ, CHAT – choline acetlytransferase involved in the synthesis of acetylcholine, DOK7 – involved in maintaining NMJ structure, CHRNG – the fetal AChR gamma subunit in which mutations can cause Escobar’s syndrome (screening is on a research basis at present – but will shortly be transferred to the CPA accredited laboratory), MUSK – the gene for muscle specific tyrosine kinase can also be screened on a research basis.

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