Materiały źródłowe

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

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

  The congenital myasthenic syndromes are diverse disorders linked by abnormal signal transmission at the motor endplate that stem from defects in single or multiple proteins. […] Multiple endplate proteins are affected by mutations of single enzymes required for protein glycosylation, and deletion of PREPL exerts its effect by activating adaptor protein 1. […] The specific diagnosis of some syndromes is facilitated by clinical clues pointing to a disease gene. […] Deeper understanding of disease mechanisms come from structural and in vitro electrophysiologic studies of the patient endplate, and from engineering the mutant and wild-type gene into a suitable expression system that can be interrogated by appropriate electrophysiologic and biochemical studies. […] The congenital myasthenic syndromes (CMS) are inherited disorders in which the safety margin of neuromuscular transmission is impaired by one or more specific mechanisms.

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

  https://pubmed.ncbi.nlm.nih.gov/25792100/

  The congenital myasthenic syndromes (CMS) are a diverse group of genetic disorders caused by abnormal signal transmission at the motor endplate, a special synaptic contact between motor axons and each skeletal muscle fibre. Most CMS stem from molecular defects in the muscle nicotinic acetylcholine receptor, but they can also be caused by mutations in presynaptic proteins, mutations in proteins associated with the synaptic basal lamina, defects in endplate development and maintenance, or defects in protein glycosylation. […] Greater understanding of the mechanisms of CMS have been obtained from structural and electrophysiological studies of the endplate, and from biochemical studies.

• #3 Congenital myasthenic syndromes – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/congenital-myasthenic-syndrome/symptoms-causes/syc-20354754

  Congenital myasthenic syndromes are a group of rare hereditary conditions caused by a gene change that results in muscle weakness, which worsens with physical activity. […] The changed gene also determines many of the signs and symptoms and severity of the condition. […] Congenital myasthenic syndromes are classified by which location is affected in the neuromuscular junction the area that provides signals (impulses) between the nerve cells and the muscle cells to trigger movement (synapses). Disrupted signals that cause loss of muscle function can occur in different locations: […] Some types of congenital myasthenic syndromes are the result of congenital disorders of glycosylation. Glycosylation is a complex chemical process that plays a role in regulating communication between cells. Glycosylation defects can adversely affect the transmission of signals from nerve cells to muscles.

• #4 Myasthenia gravis – Wikipedia

  https://en.wikipedia.org/wiki/Myasthenia_gravis

  Myasthenia gravis is an autoimmune synaptopathy. The disorder occurs when the immune system malfunctions and generates antibodies that attack the body’s tissues. The antibodies in MG attack a normal human protein, the nicotinic acetylcholine receptor, or a related protein called MuSK, a muscle-specific kinase. Other, less frequent antibodies are found against LRP4, agrin, and titin proteins. […] Human leukocyte antigen haplotypes are associated with increased susceptibility to myasthenia gravis and other autoimmune disorders. Relatives of people with myasthenia gravis have a higher percentage of other immune disorders. […] The thymus gland cells form part of the body’s immune system. In those with myasthenia gravis, the thymus gland is large and abnormal. It sometimes contains clusters of immune cells that indicate lymphoid hyperplasia, and the thymus gland may give wrong instructions to immune cells. […] Signs and symptoms of myasthenia presenting from infancy or childhood may be one of the congenital myasthenic syndromes, which can be inherited in either an autosomal dominant or recessive manner. There are currently over two dozen types of congenital myasthenic syndromes.

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

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

  Like myasthenia gravis (MG), CMS is characterized by weakness and fatigue resulting from problems at the neuromuscular junction the place where nerve and muscle cells meet. But while MG is autoimmune, CMS is an inherited disease caused by defective genes. […] With the exception of slow-channel CMS, the inheritance pattern for the types of CMS described here is autosomal recessive. This means that it takes two copies of the defective gene one from each parent to cause the disease. […] Slow-channel CMS is inherited in an autosomal dominant manner. This means that one copy of a defective gene is enough to cause the disease, so an affected parent has a 50 percent chance of passing the disease on to a child. […] By identifying the genetic defects that cause CMS, MDA-funded scientists have improved the diagnosis of CMS and discovered drugs that are effective against it. Theyre pursuing better drug treatments, and eyeing techniques to fix or replace the underlying genetic defects by gene therapy.

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

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

  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. […] The most common causative genes are CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1. […] Most CMSs respond favourably to acetylcholine-esterase inhibitors, 3,4-diamino-pyridine, salbutamol, albuterol, ephedrine, fluoxetine, or atracurium. […] CMSs are an increasingly recognised group of genetically transmitted defects, which usually respond favorably to drugs enhancing the neuromuscular transmission. […] Currently, 8 pre-synaptic, 4 synaptic, 15 post-synaptic, and 5 glycosilation defects are known to cause CMS. […] The most frequently reported CMS subtypes are COLQ-, CHRNE-, RAPSN-, DOK7-, and CHAT-related CMS. […] Though CMS are congenital in the majority of the cases, it becomes increasingly evident that in some subtypes the onset may be in early or even late adulthood. […] However, severity of the disease is usually more pronounced in early-onset subtypes.

• #7 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/congenital-myasthenic-syndrome-treatment/31555/

  Congenital myasthenic syndromes (CMS) comprise a rare heterogeneous group of diseases that impair neuromuscular transmission (NMT) and are characterized by fatigability and transient or permanent weakness of ocular, facial, bulbar, or limb muscles. […] Caused by genetic mutations in any of the numerous genes encoding for components of the neuromuscular junction (NMJ), CMS are classified by where in the NMJ the mutated component is located: presynaptic, synaptic, or postsynaptic. […] Taken together, mutations in 30 genes have been implicated in CMS phenotype. […] Because of the large number of gene mutations that can cause CMS, clinical features, age of onset, symptoms, and response to treatment vary widely and can make diagnosis difficult. […] Diagnosis of CMS is established with clinical and electrodiagnostic features and identification of a causative mutation.

• #8 SciELO Brazil – Clinical and genetic basis of congenital myasthenic syndromes Clinical and genetic basis of congenital myasthenic syndromes

  https://www.scielo.br/j/anp/a/H4rKyTD8VDXhn4rswqQHmFH/?lang=en

  Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of rare inherited diseases in which the neuromuscular transmission in the motor plate is compromised by one or more genetic pathophysiological specific mechanisms. […] Currently, major defects involved in the etiology of CMS occur: (A) in the presynaptic terminal; (B) associated with the synaptic basal lamina membrane; (C) the acetylcholine receptor; (D) shortcomings in the maintenance and development of the neuromuscular junction; (E) congenital defects in glycosylation; and (F) other sites and mechanisms. […] To understand the pathophysiological mechanisms involved in CMS, it is essential to recognize key aspects of the neuromuscular junction structure and function. The neuromuscular junction has three basic components: (i) the presynaptic nerve terminal, where there is the biosynthesis process, storage and release of acetylcholine, the main neurotransmitter involved in primary muscular contraction process; (ii) the synaptic space or synaptic cleft, where acetylcholine is released by the presynaptic nerve terminal and where there is a complex network of local proteins responsible for maintenance of the structure of the neuromuscular junction; and (iii) the postsynaptic muscle membrane, where there are acetylcholine receptors responsible for the action potential deflagration, endplate potential and the acetylcholinesterase enzyme, involved with the breakdown of acetylcholine and subsequent restoration of the resting potential of the membrane postsynaptic potential.

• #9 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/congenital-myasthenic-syndrome-treatment/31555/

  Congenital myasthenic syndromes (CMS) comprise a rare heterogeneous group of diseases that impair neuromuscular transmission (NMT) and are characterized by fatigability and transient or permanent weakness of ocular, facial, bulbar, or limb muscles. […] Caused by genetic mutations in any of the numerous genes encoding for components of the neuromuscular junction (NMJ), CMS are classified by where in the NMJ the mutated component is located: presynaptic, synaptic, or postsynaptic. […] Taken together, mutations in 30 genes have been implicated in CMS phenotype. […] Because of the large number of gene mutations that can cause CMS, clinical features, age of onset, symptoms, and response to treatment vary widely and can make diagnosis difficult. […] Diagnosis of CMS is established with clinical and electrodiagnostic features and identification of a causative mutation.

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

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

  The amplitude of the EPP is a function of the number of acetylcholine (ACh) molecules per synaptic vesicle, the number of synaptic vesicles released by nerve impulse, and the efficacy of the released quanta. […] Quantal efficacy is determined by the EP geometry, the density and functional state of AChE in the synaptic space, the density, affinity for ACh, and kinetic properties of AChR, and the density and kinetic properties of Nav1.4. […] The current classification takes into account the CMS caused by defects in protein glycosylation where the abnormal proteins are located at any EP site, and assigns a separate group to the CMS caused by defects of EP development and maintenance. […] The genetic diagnosis of a specific CMS is greatly facilitated when clinical, and EMG studies point to a candidate gene.

• #11 SciELO Brazil – Clinical and genetic basis of congenital myasthenic syndromes Clinical and genetic basis of congenital myasthenic syndromes

  https://www.scielo.br/j/anp/a/H4rKyTD8VDXhn4rswqQHmFH/?lang=en

  Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of rare inherited diseases in which the neuromuscular transmission in the motor plate is compromised by one or more genetic pathophysiological specific mechanisms. […] Currently, major defects involved in the etiology of CMS occur: (A) in the presynaptic terminal; (B) associated with the synaptic basal lamina membrane; (C) the acetylcholine receptor; (D) shortcomings in the maintenance and development of the neuromuscular junction; (E) congenital defects in glycosylation; and (F) other sites and mechanisms. […] To understand the pathophysiological mechanisms involved in CMS, it is essential to recognize key aspects of the neuromuscular junction structure and function. The neuromuscular junction has three basic components: (i) the presynaptic nerve terminal, where there is the biosynthesis process, storage and release of acetylcholine, the main neurotransmitter involved in primary muscular contraction process; (ii) the synaptic space or synaptic cleft, where acetylcholine is released by the presynaptic nerve terminal and where there is a complex network of local proteins responsible for maintenance of the structure of the neuromuscular junction; and (iii) the postsynaptic muscle membrane, where there are acetylcholine receptors responsible for the action potential deflagration, endplate potential and the acetylcholinesterase enzyme, involved with the breakdown of acetylcholine and subsequent restoration of the resting potential of the membrane postsynaptic potential.

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

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

  The amplitude of the EPP is a function of the number of acetylcholine (ACh) molecules per synaptic vesicle, the number of synaptic vesicles released by nerve impulse, and the efficacy of the released quanta. […] Quantal efficacy is determined by the EP geometry, the density and functional state of AChE in the synaptic space, the density, affinity for ACh, and kinetic properties of AChR, and the density and kinetic properties of Nav1.4. […] The current classification takes into account the CMS caused by defects in protein glycosylation where the abnormal proteins are located at any EP site, and assigns a separate group to the CMS caused by defects of EP development and maintenance. […] The genetic diagnosis of a specific CMS is greatly facilitated when clinical, and EMG studies point to a candidate gene.

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

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

  The amplitude of the EPP is a function of the number of acetylcholine (ACh) molecules per synaptic vesicle, the number of synaptic vesicles released by nerve impulse, and the efficacy of the released quanta. […] Quantal efficacy is determined by the EP geometry, the density and functional state of AChE in the synaptic space, the density, affinity for ACh, and kinetic properties of AChR, and the density and kinetic properties of Nav1.4. […] The current classification takes into account the CMS caused by defects in protein glycosylation where the abnormal proteins are located at any EP site, and assigns a separate group to the CMS caused by defects of EP development and maintenance. […] The genetic diagnosis of a specific CMS is greatly facilitated when clinical, and EMG studies point to a candidate gene.

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

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

  The CMS have been recognized as distinct clinical entities since the 1970s, after the autoimmune origin of myasthenia gravis and of the Lambert-Eaton myasthenic syndromes had been established. […] The study of the CMS gained further impetus when sequences of genes coding for EP-associated proteins were determined and with the advent of Sanger sequencing. […] In the past three years, whole exome sequencing facilitated discovery of novel CMS at an accelerated pace and by now no fewer than 20 CMS disease gene have been identified. […] In this review we consider the factors that affect the safety margin of neuromuscular transmission, classify the CMS identified to date, describe their distinguishing features and pathogenesis, and consider available therapies. […] The safety margin of neuromuscular transmission (NMT) is a function of the difference between the depolarization caused by the EP potential (EPP) and the depolarization required to activate the voltage gated Nav1.4 channels deployed on the postsynaptic membrane.

• #15 Reduced safety factor in the pathogenesis of autoimmune and congenital myasthenic syndromes – VJNeurology

  https://www.vjneurology.com/video/mllhxcwu6xa-reduced-safety-factor-in-the-pathogenesis-of-autoimmune-and-congenital-myasthenic-syndromes/

  Hakan Cetin, MD, PhD, Medical University of Vienna, Vienna, Austria, discusses the reduction of the safety factor seen in myasthenic syndromes. Impairment of the safety factor, measured as the ratio of the endplate potential to the threshold potential necessary to trigger an action potential, leads to dysfunction in neuromuscular transmission. […] The safety factor is also impacted in congenital syndromes via mutations in synaptic membrane proteins. […] Dr Cetin explains how these factors lead to a reduced safety factor and why identifying the specific defect at fault has important clinical implications.

• #16

  https://journals.lww.com/co-neurology/fulltext/2019/10000/the_congenital_myasthenic_syndromes__expanding.8.aspx

  Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. […] Recent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. […] The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. […] It has become apparent that the presynaptic forms of CMS can be subdivided into two main categories; first, those involved in the synthesis and recycling of acetylcholine (ACh) and second, those involved in vesicle docking and transmitter release from the nerve terminal. […] Mutations in the collagen-like tail subunit (COLQ) that anchors the asymmetric form of acetylcholinesterase (AChE) to the basal lamina in the synaptic cleft of the neuromuscular junction are an established major cause of CMS.

• #17

  https://www.omim.org/entry/254210

  A number sign (#) is used with this entry because presynaptic congenital myasthenic syndrome-6 (CMS6) is caused by homozygous or compound heterozygous mutation in the choline acetyltransferase gene (CHAT; 118490) on chromosome 10q11. […] Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS6 is an autosomal recessive CMS resulting from a presynaptic defect; patients have onset of symptoms in infancy or early childhood and tend to have sudden apneic episodes. Treatment with acetylcholinesterase inhibitors may be beneficial (summary by Engel et al., 2015).

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

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

  This approach works best in inbred populations or multiplex families. […] Exome sequencing with the bioinformatics analysis is still expensive and the putative mutations must be confirmed by Sanger sequencing. […] The analysis can miss pathogenic noncoding variants and large deletions or duplications but the latter can be identified by array based comparative genomic hybridization. […] The agrin-LRP4-MuSK-Dok-7 signaling system is also essential for maintaining the structure of the adult neuromuscular junction. […] The safety margin of NMT is compromised by incomplete filling of the synaptic vesicles with ACh. […] The mechanisms by which these agents improve neuromuscular transmission is not understood. […] Finally, it is important to note that agents that benefit one type of CMS can be ineffective or harmful in another type. […] Therefore it is essential that a molecular diagnosis should inform the choice of therapy. […] The safety margin of NMT is compromised because most Nav1.4 channels are inexcitable in the resting state.

• #19

  https://www.omim.org/entry/254210

  A number sign (#) is used with this entry because presynaptic congenital myasthenic syndrome-6 (CMS6) is caused by homozygous or compound heterozygous mutation in the choline acetyltransferase gene (CHAT; 118490) on chromosome 10q11. […] Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS6 is an autosomal recessive CMS resulting from a presynaptic defect; patients have onset of symptoms in infancy or early childhood and tend to have sudden apneic episodes. Treatment with acetylcholinesterase inhibitors may be beneficial (summary by Engel et al., 2015).

• #20 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

  The translation product of SLC5A7 is the CHT1, which is responsible for choline reuptake in the presynaptic terminal after the cleavage of ACh by the enzyme acetylcholinesterase in the synaptic cleft. […] We describe here the first two cases of CMS with episodic apnea caused by mutations in the SLC5A7 gene in Latin America and emphasize the frequent association of this genetic disorder with serious manifestations of central nervous system (CNS) involvement. […] We present two cases of presynaptic CMS, caused by pathogenic variants of the SLC5A7 gene. […] Congenital Myasthenic Syndromes are a rare entity, with an estimated prevalence of 9 to 10 per million. From the pathophysiological point of view, the defect is found in the postsynaptic level in 75% of cases. The rest of the cases correspond 15% to synaptic forms and 68% to presynaptic variants. Among the later, CHT1 deficiency due to SLC5A7 gene mutations are in second place in prevalence of presynaptic CMS after ChAT deficiency, which represents about 5% of CMS.

• #21

  https://journals.lww.com/co-neurology/fulltext/2019/10000/the_congenital_myasthenic_syndromes__expanding.8.aspx

  Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. […] Recent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. […] The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. […] It has become apparent that the presynaptic forms of CMS can be subdivided into two main categories; first, those involved in the synthesis and recycling of acetylcholine (ACh) and second, those involved in vesicle docking and transmitter release from the nerve terminal. […] Mutations in the collagen-like tail subunit (COLQ) that anchors the asymmetric form of acetylcholinesterase (AChE) to the basal lamina in the synaptic cleft of the neuromuscular junction are an established major cause of CMS.

• #22 Congenital myasthenic syndromes | MedLink Neurology

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

  The safety margin is compromised by a decreased probability of channel openings, which decreases the synaptic response to ACh, and by the accelerated decay of the synaptic response. […] The safety margin of neuromuscular transmission is compromised by decrease in the number of readily releasable quanta, loss of AChR from degenerating junctional folds, altered endplate geometry, and desensitization of AChR from overexposure to ACh. […] Pathogenic mutations residing in different subunits of the AChR prolong opening events of the AChR by increasing the rate at which the channel opens, or by decreasing the rate at which it closes, or by increasing the receptors affinity for ACh that allows it to reopen repeatedly during a single ACh occupancy. […] The safety margin is compromised by the AChR deficiency and by simplification of the junctional folds.

• #23 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/congenital-myasthenic-syndrome-treatment/31555/

  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. […] Mutations in RAPSN, COLQ, and DOK7 comprise another 35% to 50% of cases. […] The CMS are distinguished electrodiagnostically by defective NMT. […] Synaptic transmission is a complex cascade of events that requires fine-tuned expression and function of a number of NMJ components. […] First-line therapy for CMS is typically pyridostigmine, which has been shown effective for symptom management for many. […] In those with synaptic CMS or with DOK7, LRP4, or MUSK mutations, however, pyridostigmine is ineffective and alternative first-line therapies, usually albuterol, are used. […] The more we understand the gene functions underlying CMS, the greater are the chances of identifying novel treatments for this rare disorder.

• #24 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/congenital-myasthenic-syndrome-treatment/31555/

  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. […] Mutations in RAPSN, COLQ, and DOK7 comprise another 35% to 50% of cases. […] The CMS are distinguished electrodiagnostically by defective NMT. […] Synaptic transmission is a complex cascade of events that requires fine-tuned expression and function of a number of NMJ components. […] First-line therapy for CMS is typically pyridostigmine, which has been shown effective for symptom management for many. […] In those with synaptic CMS or with DOK7, LRP4, or MUSK mutations, however, pyridostigmine is ineffective and alternative first-line therapies, usually albuterol, are used. […] The more we understand the gene functions underlying CMS, the greater are the chances of identifying novel treatments for this rare disorder.

• #25 Congenital myasthenic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Congenital_myasthenic_syndrome

  Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. […] CMS is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). In the neuromuscular junction there is a vital pathway that maintains synaptic structure and results in the aggregation and localization of AChR on the postsynaptic folds. […] Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor (AChR) subunits. […] Another common underlying mechanism of CMS is the mutation of the rapsyn protein, coded by the RAPSN gene. […] Dok-7 is a postsynaptic protein that binds and activates MuSK protein, which then leads to AChR clustering and typical folding of the postsynaptic membrane. Mutations of Dok-7 are yet another underlying mechanism of postsynaptic CMS.

• #26 Congenital myasthenic syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/congenital-myasthenic-syndrome/

  Congenital myasthenic syndrome is a group of conditions characterized by muscle weakness (myasthenia) that worsens with physical exertion. […] Mutations in many genes can cause congenital myasthenic syndrome. Mutations in the CHRNE gene are responsible for more than half of all cases. […] Gene mutations lead to changes in proteins that play a role in the function of the neuromuscular junction and disrupt signaling between the ends of nerve cells and muscle cells. […] The respiratory problems in congenital myasthenic syndrome result from impaired movement of the muscles of the chest wall and the muscle that separates the abdomen from the chest cavity (the diaphragm). […] Some people with congenital myasthenic syndrome do not have an identified mutation in any of the genes known to be associated with this condition.

• #27 Congenital myasthenic syndromes | MedLink Neurology

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

  The safety margin is compromised by a decreased probability of channel openings, which decreases the synaptic response to ACh, and by the accelerated decay of the synaptic response. […] The safety margin of neuromuscular transmission is compromised by decrease in the number of readily releasable quanta, loss of AChR from degenerating junctional folds, altered endplate geometry, and desensitization of AChR from overexposure to ACh. […] Pathogenic mutations residing in different subunits of the AChR prolong opening events of the AChR by increasing the rate at which the channel opens, or by decreasing the rate at which it closes, or by increasing the receptors affinity for ACh that allows it to reopen repeatedly during a single ACh occupancy. […] The safety margin is compromised by the AChR deficiency and by simplification of the junctional folds.

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

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

  This approach works best in inbred populations or multiplex families. […] Exome sequencing with the bioinformatics analysis is still expensive and the putative mutations must be confirmed by Sanger sequencing. […] The analysis can miss pathogenic noncoding variants and large deletions or duplications but the latter can be identified by array based comparative genomic hybridization. […] The agrin-LRP4-MuSK-Dok-7 signaling system is also essential for maintaining the structure of the adult neuromuscular junction. […] The safety margin of NMT is compromised by incomplete filling of the synaptic vesicles with ACh. […] The mechanisms by which these agents improve neuromuscular transmission is not understood. […] Finally, it is important to note that agents that benefit one type of CMS can be ineffective or harmful in another type. […] Therefore it is essential that a molecular diagnosis should inform the choice of therapy. […] The safety margin of NMT is compromised because most Nav1.4 channels are inexcitable in the resting state.

• #29 Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia | Nature

  https://www.nature.com/articles/s41586-021-03672-3

  Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM. The most common disease-causing mutation (DOK7 1124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. […] The formation and maintenance of neuromuscular synapses requires the assembly of highly specialized presynaptic and postsynaptic membranes, which involves the coordinated action of several key molecules. AGRIN, which is released from motor nerve terminals, binds to the lipoprotein receptor-related protein 4 (LRP4) in muscle, stimulating the formation of a complex between LRP4 and muscle-specific kinase (MUSK), a receptor tyrosine kinase that acts as a master regulator of synaptic differentiation.

• #30

  https://insight.jci.org/articles/view/132023

  Congenital myasthenic syndromes (CMS) are caused by mutations in molecules expressed at the neuromuscular junction. […] We report clinical, structural, ultrastructural, and electrophysiologic features of 4 CMS patients with 6 heteroallelic variants in AGRN, encoding agrin. […] Mutations of agrin affect AChR clustering by enhancing agrin degradation or by suppressing MuSK phosphorylation and/or by compromising anchoring of agrin to the sarcolemma of the neuromuscular junction. […] Agrin encoded by AGRN is a heparan sulfate proteoglycan essential for differentiation and maintenance of the NMJ in skeletal muscle. […] The agrin-LRP4 complex binds to the postsynaptic receptor tyrosine kinase MuSK and activates its kinase domain. […] We here report 4 CMS patients harboring 6 different variants in AGRN.

• #31

  https://insight.jci.org/articles/view/132023

  Congenital myasthenic syndromes (CMS) are caused by mutations in molecules expressed at the neuromuscular junction. […] We report clinical, structural, ultrastructural, and electrophysiologic features of 4 CMS patients with 6 heteroallelic variants in AGRN, encoding agrin. […] Mutations of agrin affect AChR clustering by enhancing agrin degradation or by suppressing MuSK phosphorylation and/or by compromising anchoring of agrin to the sarcolemma of the neuromuscular junction. […] Agrin encoded by AGRN is a heparan sulfate proteoglycan essential for differentiation and maintenance of the NMJ in skeletal muscle. […] The agrin-LRP4 complex binds to the postsynaptic receptor tyrosine kinase MuSK and activates its kinase domain. […] We here report 4 CMS patients harboring 6 different variants in AGRN.

• #32 Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia | Nature

  https://www.nature.com/articles/s41586-021-03672-3

  Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM. The most common disease-causing mutation (DOK7 1124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. […] The formation and maintenance of neuromuscular synapses requires the assembly of highly specialized presynaptic and postsynaptic membranes, which involves the coordinated action of several key molecules. AGRIN, which is released from motor nerve terminals, binds to the lipoprotein receptor-related protein 4 (LRP4) in muscle, stimulating the formation of a complex between LRP4 and muscle-specific kinase (MUSK), a receptor tyrosine kinase that acts as a master regulator of synaptic differentiation.

• #33 Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia | Nature

  https://www.nature.com/articles/s41586-021-03672-3

  Activation of MUSK also depends on the adaptor protein DOK7. Mutations in Dok7 are responsible for 10-20% of all cases of CM. The disease is debilitating, causing weakness in limb, neck and facial muscles, and one-quarter of patients with DOK7 CM require non-invasive ventilation at some point during their lifetime. […] A failure of DOK7 to bind MUSK leads to a failure of AGRIN to stimulate MUSK phosphorylation, demonstrating that DOK7 is essential to stabilize phosphorylation of MUSK, probably by promoting its dimerization. […] The most common cause of Dok7 CM is a four-base-pair duplication (residues 1124-1127, TGCC), which leads to a frameshift and premature termination of DOK7. […] The truncated form of DOK7 retains the PH and PTB domains and binds to the tyrosine-phosphorylated JM region of MUSK, but lacks the two tyrosine residues that are phosphorylated and recruit CRK proteins, suggesting that the loss of these tyrosine residues is responsible for the synaptic deficits in this common form of Dok7 CM.

• #34 Congenital myasthenic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Congenital_myasthenic_syndrome

  Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. […] CMS is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). In the neuromuscular junction there is a vital pathway that maintains synaptic structure and results in the aggregation and localization of AChR on the postsynaptic folds. […] Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor (AChR) subunits. […] Another common underlying mechanism of CMS is the mutation of the rapsyn protein, coded by the RAPSN gene. […] Dok-7 is a postsynaptic protein that binds and activates MuSK protein, which then leads to AChR clustering and typical folding of the postsynaptic membrane. Mutations of Dok-7 are yet another underlying mechanism of postsynaptic CMS.

• #35 Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia | Nature

  https://www.nature.com/articles/s41586-021-03672-3

  Activation of MUSK also depends on the adaptor protein DOK7. Mutations in Dok7 are responsible for 10-20% of all cases of CM. The disease is debilitating, causing weakness in limb, neck and facial muscles, and one-quarter of patients with DOK7 CM require non-invasive ventilation at some point during their lifetime. […] A failure of DOK7 to bind MUSK leads to a failure of AGRIN to stimulate MUSK phosphorylation, demonstrating that DOK7 is essential to stabilize phosphorylation of MUSK, probably by promoting its dimerization. […] The most common cause of Dok7 CM is a four-base-pair duplication (residues 1124-1127, TGCC), which leads to a frameshift and premature termination of DOK7. […] The truncated form of DOK7 retains the PH and PTB domains and binds to the tyrosine-phosphorylated JM region of MUSK, but lacks the two tyrosine residues that are phosphorylated and recruit CRK proteins, suggesting that the loss of these tyrosine residues is responsible for the synaptic deficits in this common form of Dok7 CM.

• #36 Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia | Nature

  https://www.nature.com/articles/s41586-021-03672-3

  Thus, unexpectedly, loss of the two tyrosine residues in the C-terminal region of DOK7 is not the cause of the lethality and severe synaptic deficits in Dok7 CM mice. […] Because DOK7 functions as a dimer to dimerize MUSK, thereby stabilizing MUSK tyrosine phosphorylation, we determined whether MUSK tyrosine phosphorylation was diminished in Dok7 CM mice. MUSK phosphorylation was reduced sevenfold in Dok7 CM mice but was normal in Dok7 2YF mice. […] These findings suggest that CRK is recruited to a tyrosine phosphorylated synaptic protein(s) in addition to DOK7. […] Thus, this therapeutic strategy, which avoids the complex requirements for gene therapy, might be beneficial for humans with DOK7 CM or other neuromuscular diseases.

• #37 Congenital myasthenic syndromes – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/congenital-myasthenic-syndrome/symptoms-causes/syc-20354754

  Congenital myasthenic syndromes are a group of rare hereditary conditions caused by a gene change that results in muscle weakness, which worsens with physical activity. […] The changed gene also determines many of the signs and symptoms and severity of the condition. […] Congenital myasthenic syndromes are classified by which location is affected in the neuromuscular junction the area that provides signals (impulses) between the nerve cells and the muscle cells to trigger movement (synapses). Disrupted signals that cause loss of muscle function can occur in different locations: […] Some types of congenital myasthenic syndromes are the result of congenital disorders of glycosylation. Glycosylation is a complex chemical process that plays a role in regulating communication between cells. Glycosylation defects can adversely affect the transmission of signals from nerve cells to muscles.

• #38

  https://journals.lww.com/co-neurology/fulltext/2019/10000/the_congenital_myasthenic_syndromes__expanding.8.aspx

  The addition and processing of these glycans are crucial for the folding, assembly, stability and intracellular transport of proteins. […] The response to treatment depends upon the subtype of CMS and the underlying pathogenic molecular mechanism. […] Many cases of CMS can be given effective symptomatic treatment with the drugs that are currently available once an understanding of the disease mechanism resulting from the mutation(s) is known.

• #39 Congenital myasthenic syndromes – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/congenital-myasthenic-syndrome/symptoms-causes/syc-20354754

  Congenital myasthenic syndromes are a group of rare hereditary conditions caused by a gene change that results in muscle weakness, which worsens with physical activity. […] The changed gene also determines many of the signs and symptoms and severity of the condition. […] Congenital myasthenic syndromes are classified by which location is affected in the neuromuscular junction the area that provides signals (impulses) between the nerve cells and the muscle cells to trigger movement (synapses). Disrupted signals that cause loss of muscle function can occur in different locations: […] Some types of congenital myasthenic syndromes are the result of congenital disorders of glycosylation. Glycosylation is a complex chemical process that plays a role in regulating communication between cells. Glycosylation defects can adversely affect the transmission of signals from nerve cells to muscles.

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

  https://ouci.dntb.gov.ua/en/works/l1w1gkP7/

  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 (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). […] The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. […] Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. […] From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. […] This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

• #41 Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes | Nature Communications

  https://www.nature.com/articles/s41467-024-45099-0

  Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. […] While over 30 genes are known to be monogenic causes of different forms of CMS, these genes do not fully explain the ample range of observed severities, which has been suggested to be determined by additional factors involved in neuromuscular function.

• #42 Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes | Nature Communications

  https://www.nature.com/articles/s41467-024-45099-0

  Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. […] While over 30 genes are known to be monogenic causes of different forms of CMS, these genes do not fully explain the ample range of observed severities, which has been suggested to be determined by additional factors involved in neuromuscular function.

• #43 Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes | Nature Communications

  https://www.nature.com/articles/s41467-024-45099-0

  Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. […] While over 30 genes are known to be monogenic causes of different forms of CMS, these genes do not fully explain the ample range of observed severities, which has been suggested to be determined by additional factors involved in neuromuscular function.

• #44 Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes | Nature Communications

  https://www.nature.com/articles/s41467-024-45099-0

  The extensive analysis of the genomic information did not render any SNPs that could be considered a unique cause of disease severity by being common to all the cases. Nevertheless, a number of CNVs and compound heterozygous variants were found to appear exclusively in the different severity groups, in one or more patients. Moreover, the compound heterozygous variants of the severe group are enriched in pathways related to the extracellular matrix (ECM) receptors, which have been proposed as a target for CMS therapy. […] Our approach revealed major relationships at the protein-protein and pathway layers. The personalized analysis of these mutations further suggests that CMS severity can be ascribed to the damage of specific molecular functions of the NMJ which involve genes belonging to distinct classes and localizations, namely ECM components (proteoglycans, tenascins, chromogranins) and postsynaptic modulators of AChR clustering.

• #45 Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes | Nature Communications

  https://www.nature.com/articles/s41467-024-45099-0

  The extensive analysis of the genomic information did not render any SNPs that could be considered a unique cause of disease severity by being common to all the cases. Nevertheless, a number of CNVs and compound heterozygous variants were found to appear exclusively in the different severity groups, in one or more patients. Moreover, the compound heterozygous variants of the severe group are enriched in pathways related to the extracellular matrix (ECM) receptors, which have been proposed as a target for CMS therapy. […] Our approach revealed major relationships at the protein-protein and pathway layers. The personalized analysis of these mutations further suggests that CMS severity can be ascribed to the damage of specific molecular functions of the NMJ which involve genes belonging to distinct classes and localizations, namely ECM components (proteoglycans, tenascins, chromogranins) and postsynaptic modulators of AChR clustering.

• #46

  https://journals.lww.com/co-neurology/fulltext/2019/10000/the_congenital_myasthenic_syndromes__expanding.8.aspx

  The addition and processing of these glycans are crucial for the folding, assembly, stability and intracellular transport of proteins. […] The response to treatment depends upon the subtype of CMS and the underlying pathogenic molecular mechanism. […] Many cases of CMS can be given effective symptomatic treatment with the drugs that are currently available once an understanding of the disease mechanism resulting from the mutation(s) is known.

• #47

  https://journals.ku.edu/rrnmf/article/view/19552

  Acetylcholinesterase inhibitors, such as pyridostigmine, are the standard symptomatic treatment for myasthenia gravis, and so have naturally been applied to the genetic forms of myasthenia, termed congenital myasthenic syndromes (CMS). […] Now, with greater understanding of the mutations and molecular mechanisms underlying CMS, treatments can be tailored for the specific syndrome and depending on diseases severity and patient response this can include utilizing different combinations of the drugs. […] The molecular pathogenic mechanisms for many CMS subtypes are now established and this report will also discuss a hypothetical rationale for which forms of CMS are likely to benefit from the b2-adrenergic receptor agonists.

• #48

  https://journals.ku.edu/rrnmf/article/view/19552

  Acetylcholinesterase inhibitors, such as pyridostigmine, are the standard symptomatic treatment for myasthenia gravis, and so have naturally been applied to the genetic forms of myasthenia, termed congenital myasthenic syndromes (CMS). […] Now, with greater understanding of the mutations and molecular mechanisms underlying CMS, treatments can be tailored for the specific syndrome and depending on diseases severity and patient response this can include utilizing different combinations of the drugs. […] The molecular pathogenic mechanisms for many CMS subtypes are now established and this report will also discuss a hypothetical rationale for which forms of CMS are likely to benefit from the b2-adrenergic receptor agonists.

• #49 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/congenital-myasthenic-syndrome-treatment/31555/

  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. […] Mutations in RAPSN, COLQ, and DOK7 comprise another 35% to 50% of cases. […] The CMS are distinguished electrodiagnostically by defective NMT. […] Synaptic transmission is a complex cascade of events that requires fine-tuned expression and function of a number of NMJ components. […] First-line therapy for CMS is typically pyridostigmine, which has been shown effective for symptom management for many. […] In those with synaptic CMS or with DOK7, LRP4, or MUSK mutations, however, pyridostigmine is ineffective and alternative first-line therapies, usually albuterol, are used. […] The more we understand the gene functions underlying CMS, the greater are the chances of identifying novel treatments for this rare disorder.

• #50 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/congenital-myasthenic-syndrome-treatment/31555/

  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. […] Mutations in RAPSN, COLQ, and DOK7 comprise another 35% to 50% of cases. […] The CMS are distinguished electrodiagnostically by defective NMT. […] Synaptic transmission is a complex cascade of events that requires fine-tuned expression and function of a number of NMJ components. […] First-line therapy for CMS is typically pyridostigmine, which has been shown effective for symptom management for many. […] In those with synaptic CMS or with DOK7, LRP4, or MUSK mutations, however, pyridostigmine is ineffective and alternative first-line therapies, usually albuterol, are used. […] The more we understand the gene functions underlying CMS, the greater are the chances of identifying novel treatments for this rare disorder.

• #51 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

  Electrophysiology studies demonstrating impaired neuromuscular transmission and blood work showing absence of autoantibodies against proteins of the NMJ are useful. However, the key to the diagnosis lies in the finding of pathogenic variants in genes involved in the structure and function of the NMJ, which is usually achieved by performing a WES. […] 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.

• #52 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

  Electrophysiology studies demonstrating impaired neuromuscular transmission and blood work showing absence of autoantibodies against proteins of the NMJ are useful. However, the key to the diagnosis lies in the finding of pathogenic variants in genes involved in the structure and function of the NMJ, which is usually achieved by performing a WES. […] 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.

• #53 Diagnosing congenital myasthenic syndrome — Oxford Neuroscience

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

  Congenital myasthenic syndromes (CMS) are inherited diseases resulting in fatiguable muscle weakness. […] By the late early 2000s the genetic mutations giving rise to many cases had been discovered. […] In 2006 David Beesons team published a research paper reporting mutations in the gene encoding a crucial muscle protein called DOK7. These mutations affect the size and structure of the connection, known as the synapse, between the nerve ending and muscle at the neuromuscular junction. They also caused abnormal maturation and survival of these synapses. […] 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. […] DOK7 mutations were quickly confirmed in similar cases worldwide. […] During their research the team also noticed that patients with DOK7 mutations either did not respond, or got worse when standard treatments for CMS were given. However, they did respond to a class of drugs known as beta 2 adrenergic receptor agonists. […] They subsequently found that giving patients this type of drug resulted in a dramatic improvement in their myasthenic weakness. Other studies have confirmed these striking results.

• #54 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). […] In many cases the pathomechanisms behind the disease are still not well understood, and our lab generates and works with cell, zebrafish and mouse models of various CMS subtypes in order to investigate the disease processes and look for therapeutic targets and disease modifiers. […] 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 in Germany, we are currently working on the elucidation of the NMJ proteome and the establishment of a tailored assay enabling the robust quantification of NMJ-related proteins in various mouse models of this group of diseases.

• #55

  https://journals.ku.edu/rrnmf/article/view/19633

  Very few areas of medical genetics have been so profoundly impacted by the advent of next-generation sequencing (NGS) as the field of congenital myasthenic syndromes (CMS). […] A molecular diagnosis of CMS is fundamental not only to provide an appropriate therapy, but more importantly, to avoid potential deleterious treatments. […] This permits an in-depth analysis of the pathogenesis and treatments of CMS caused by specific gene mutations. […] In terms of therapy, in addition to the classical pharmacologic treatments of CMS, including pyridostigmine sulfate, albuterol and 3,4 diaminopyridine, AAV-based gene therapies are now at the preclinical stage for several types of CMS. […] The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations. […] Decoding pathogenesis of slow-channel congenital myasthenic syndromes using recombinant expression and mice models. […] Slow-channel syndrome caused by enhanced activation, desensitization, and agonist binding affinity due to mutation in the M2 domain of the acetylcholine receptor alpha subunit. […] Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia.

• #56 Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia | Nature

  https://www.nature.com/articles/s41586-021-03672-3

  Thus, unexpectedly, loss of the two tyrosine residues in the C-terminal region of DOK7 is not the cause of the lethality and severe synaptic deficits in Dok7 CM mice. […] Because DOK7 functions as a dimer to dimerize MUSK, thereby stabilizing MUSK tyrosine phosphorylation, we determined whether MUSK tyrosine phosphorylation was diminished in Dok7 CM mice. MUSK phosphorylation was reduced sevenfold in Dok7 CM mice but was normal in Dok7 2YF mice. […] These findings suggest that CRK is recruited to a tyrosine phosphorylated synaptic protein(s) in addition to DOK7. […] Thus, this therapeutic strategy, which avoids the complex requirements for gene therapy, might be beneficial for humans with DOK7 CM or other neuromuscular diseases.

• #57 Congenital Myasthenic Syndrome Treatment

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/congenital-myasthenic-syndrome-treatment/31555/

  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. […] Mutations in RAPSN, COLQ, and DOK7 comprise another 35% to 50% of cases. […] The CMS are distinguished electrodiagnostically by defective NMT. […] Synaptic transmission is a complex cascade of events that requires fine-tuned expression and function of a number of NMJ components. […] First-line therapy for CMS is typically pyridostigmine, which has been shown effective for symptom management for many. […] In those with synaptic CMS or with DOK7, LRP4, or MUSK mutations, however, pyridostigmine is ineffective and alternative first-line therapies, usually albuterol, are used. […] The more we understand the gene functions underlying CMS, the greater are the chances of identifying novel treatments for this rare disorder.

• #58 Congenital myasthenic syndromes | MedLink Neurology

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

  The safety margin is compromised by a decreased probability of channel openings, which decreases the synaptic response to ACh, and by the accelerated decay of the synaptic response. […] The safety margin of neuromuscular transmission is compromised by decrease in the number of readily releasable quanta, loss of AChR from degenerating junctional folds, altered endplate geometry, and desensitization of AChR from overexposure to ACh. […] Pathogenic mutations residing in different subunits of the AChR prolong opening events of the AChR by increasing the rate at which the channel opens, or by decreasing the rate at which it closes, or by increasing the receptors affinity for ACh that allows it to reopen repeatedly during a single ACh occupancy. […] The safety margin is compromised by the AChR deficiency and by simplification of the junctional folds.

• #59 Congenital myasthenic syndromes | MedLink Neurology

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

  The safety margin is compromised by a decreased probability of channel openings, which decreases the synaptic response to ACh, and by the accelerated decay of the synaptic response. […] The safety margin of neuromuscular transmission is compromised by decrease in the number of readily releasable quanta, loss of AChR from degenerating junctional folds, altered endplate geometry, and desensitization of AChR from overexposure to ACh. […] Pathogenic mutations residing in different subunits of the AChR prolong opening events of the AChR by increasing the rate at which the channel opens, or by decreasing the rate at which it closes, or by increasing the receptors affinity for ACh that allows it to reopen repeatedly during a single ACh occupancy. […] The safety margin is compromised by the AChR deficiency and by simplification of the junctional folds.

• #60 Congenital Myasthenic Syndromes – EyeWiki

  https://eyewiki.org/Congenital_Myasthenic_Syndromes

  Congenital myasthenic syndromes (CMS) result from a variety of mutations affecting the neuromuscular junction and are characterized by fatigability and weakness of different muscle groups, commonly including the ocular muscles. […] CMS is caused by a wide variety of inherited or de novo mutations in over 30 identified genes affecting presynaptic, synaptic, and postsynaptic components of the NMJ. […] Normal neuromuscular transmission involves presynaptic, synaptic, and post synaptic transmission, and CMS can involve pathologies in all three of these components, as well as abnormalities in glycosylation proteins. Pathophysiological mechanisms of CMS involving presynaptic elements include defects in acetylcholine synthesis and acetyltransferase and vesicular transport. Synaptic mechanisms include defects in synaptic vesicles exocytosis. Postsynaptic mechanisms include deficiency in agrin and defects in acetylcholine receptor function, ion channel function, and extracellular matrix proteins that help form motor endplates. […] Congenital defects in glycosylation, mitochondrial disorders, and congenital myopathies with secondary impairment of neuromuscular transmission can also cause subtypes of CMS. The most common of the 32 genes associated with CMS are CHAT, CHRNE, COLQ, DOK7, GFPT1, and RAPSN.

• #61

  https://journals.lww.com/co-neurology/fulltext/2019/10000/the_congenital_myasthenic_syndromes__expanding.8.aspx

  The addition and processing of these glycans are crucial for the folding, assembly, stability and intracellular transport of proteins. […] The response to treatment depends upon the subtype of CMS and the underlying pathogenic molecular mechanism. […] Many cases of CMS can be given effective symptomatic treatment with the drugs that are currently available once an understanding of the disease mechanism resulting from the mutation(s) is known.

• #62 Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/congenital-myasthenic-syndromes-spotlight-on-genetic-defects-of-neuromuscular-transmission/29EE8AA7FB018FC886C1B0CD8319F386

  However, the genetic background of many CMS forms is still unresolved. […] A precise molecular classification of CMS type is of paramount importance for the diagnosis, counselling and therapy of a patient, as different drugs may be beneficial or deleterious depending on the molecular background of the particular CMS.

• #63 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

  Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of disorders characterized by impaired neuromuscular transmission. […] 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. […] The importance of genetic diagnosis is particularly emphasized because the response to medical treatment varies depending on the molecular subtypes in CMS. […] 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. […] The response to treatment depends on the subtype of CMS. […] Our study suggested the importance of molecular diagnosis of CMS to warrant appropriate treatment.

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