Materiały źródłowe

• #1 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. […] There are many types of congenital myasthenic syndromes, depending on which gene is affected. The changed gene also determines many of the signs and symptoms and severity of the condition. […] Caused by any one of more than 30 identified genes, the type of congenital myasthenic syndrome depends on which gene is affected. […] 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.

• #1 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 most commonly inherited in an autosomal recessive pattern. That means both parents must be carriers, but they do not typically show signs of the condition. The affected child inherits two copies of the abnormal gene one from each parent. […] Rarely, congenital myasthenic syndromes can be inherited in an autosomal dominant pattern, meaning that only one parent passes on the affected gene. In some cases, the affected gene occurs randomly and is not inherited. In other cases, no gene can be identified.

• #2 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. […] 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. […] 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.

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

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

  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. […] 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. […] Whole exome sequencing has been used to identify CMS mutations. […] Current therapies for the CMS include cholinergic agonists, namely pyridostigmine and 3,4-diaminopyridine (3,4-DAP), long-lived open-channel blockers of the AChR ion channel, and adrenergic agonists.

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

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

  The adrenergic agonists albuterol and ephedrine were empirically found to be effective in the CMS caused by mutations in the ColQ component of AChE, Dok-7, and laminin-2 as well as in some patients harboring low-expressor mutations of the AChR. […] Finally, it is important to note that agents that benefit one type of CMS can be ineffective or harmful in another type.

• #3 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. A large number of cases are also caused by mutations in the RAPSN, CHAT, COLQ, and DOK7 genes. All of these genes provide instructions for producing proteins that are involved in the normal function of the neuromuscular junction. […] 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. Disrupted signaling between these cells results in an impaired ability to move skeletal muscles, muscle weakness, and delayed development of motor skills. 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.

• #4 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. […] 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.

• #5 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. […] The main risk factor for CMS is having a positive family history, but most CMS-associated mutations are inherited in an autosomal recessive pattern and a family history may not be identified. […] 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. […] The most common of the 32 genes associated with CMS are CHAT, CHRNE, COLQ, DOK7, GFPT1, and RAPSN.

• #6 Congenital myasthenic syndromes | MedLink Neurology

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

  Congenital myasthenic syndromes are inherited disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. […] The genetic basis of more than 30 congenital myasthenic disorders has now been identified. […] To date, no fewer than 30 genetically distinct congenital myasthenic syndromes have been recognized. […] The congenital myasthenic syndromes caused by defects in Dok7, LRP4, and ColQ respond to ephedrine or albuterol. […] Because medications that benefit one type of syndrome can worsen another type, a correct genetic diagnosis is essential before treatment is initiated. […] The syndromes are caused by defects in presynaptic, synaptic basal lamina, and postsynaptic proteins as well as in proteins subserving glycosylation of proteins at the neuromuscular junction or in endplate development.

• #6 Congenital myasthenic syndromes | MedLink Neurology

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

  The postsynaptic syndromes and those associated with endplate development and maintenance account for 77% of the cases. […] Most congenital myasthenic syndromes are caused by loss of function mutations transmitted by autosomal recessive inheritance. […] The safety margin of neuromuscular transmission is compromised by one or more mechanisms. […] The safety margin is a function of the difference between the postsynaptic depolarization caused by the endplate potential (EPP) and the depolarization required to activate Nav1.4. […] The amplitude of the EPP depends on the number of quanta released by nerve impulse and the miniature endplate potential (MEPP) amplitude that represents the depolarization caused by a single quantum. […] 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.

• #6 Congenital myasthenic syndromes | MedLink Neurology

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

  Most mutations in AChR causing myasthenia reside in the epsilon subunit and are associated with compensatory expression of the fetal gamma subunit. […] This notion has now been confirmed by reports of lethal fetal akinesia syndromes due to biallelic null mutations in the AChR alpha, beta, and delta subunits, as well as in rapsyn and Dok-7.

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

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

  A genetic change (mutation) causes congenital myasthenic syndrome. Some of the gene changes responsible include, but arent limited to, the following: CHRNE, RAPSN, CHAT, COLQ, DOK7. […] Yes, you can inherit congenital myasthenic syndrome. It usually happens in an autosomal recessive pattern. This means that both biological parents need to have the gene and pass it on to their child for the child to develop the condition. […] Anyone can develop congenital myasthenic syndrome. Youre more at risk if it runs in your biological family history. […] Congenital myasthenic syndrome complications may include: Feeding difficulties, Stiff muscles, Delayed developmental milestones (motor skills), Inability to walk, Pauses when breathing (apnea), Seizures, Intellectual disability, Neuropathy, Metabolic abnormalities.

• #7 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. It happens when your nerve and muscle cells dont communicate as expected. Treatment is available, but theres no cure for this genetic condition. […] Congenital myasthenic syndrome (CMS) is a group of conditions that cause muscle weakness that gets worse with physical activity (exertion). Congenital means the condition is present at birth. […] There are multiple types of congenital myasthenic syndromes. Healthcare providers group them into categories based on what part of the neuromuscular junction the condition affects. This is where your nerve and muscle cells meet. CMS affects how your nerve cells communicate with your muscle cells at this junction. […] Congenital myasthenic syndrome and myasthenia gravis are similar conditions that cause weakness due to problems where nerve cells and muscle cells meet (neuromuscular junction). CMS is a genetic condition caused by a genetic change.

• #8 Congenital myasthenic syndrome | Myasthenia Gravis NewsEnvelope icon

  https://myastheniagravisnews.com/congenital-myasthenia/

  Congenital myasthenic syndrome (CMS), also known as congenital myasthenia, is a group of rare genetic disorders marked by muscle weakness that worsens with physical activity, similar to myasthenia gravis (MG). […] In contrast, CMS results from genetic mutations that patients are born with, which impair neuromuscular communication. […] Despite their similarities, CMS and MG are considered different disease entities, each with distinct underlying causes and treatment approaches. […] The CHAT gene, needed to produce acetylcholine, is the most common cause of presynaptic CMS, found in about 5% of patients. […] The genes most commonly involved in postsynaptic CMS are CHRNA1, CHRNB1, CHRND, and CHRNE. These four genes code for the five subunits that make up nicotinic acetylcholine receptors, which are the primary mediators of muscle contraction at the neuromuscular junction.

• #8 Congenital myasthenic syndrome | Myasthenia Gravis NewsEnvelope icon

  https://myastheniagravisnews.com/congenital-myasthenia/

  Mutations in these genes collectively account for about half of all CMS cases. […] Mutations in the COLQ gene, which codes for a protein needed for anchoring acetylcholinesterase to the neuromuscular junction’s basal lamina, account for most cases of synaptic CMS. […] Congenital myasthenic syndrome usually is inherited in an autosomal recessive manner, meaning that the disease only develops if both copies of a person’s gene — one from each biological parent — contain a mutation. […] More rarely, such as in some cases of slow-channel CMS, the disease is inherited in an autosomal dominant manner. […] Some of the medications named here may also be used to treat MG. However, because CMS is caused by genetic mutations rather than an autoimmune attack, treatments that suppress the immune system and are widely used to manage MG are not effective in CMS.

• #9 Congenital Myasthenic Syndrome Treatment

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

  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. […] 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.

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

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

  Most CMS patients show autosomal recessive inheritance or require biallelic pathogenic variants. An autosomal dominant inheritance or a de novo hemiallelic pathogenic variant is observed in slow-channel CMS (SCCMS), SNAP25-CMS, PURA-CMS, and 4 out of 11 patients with SYT2-CMS. […] In the 35 causative genes for CMS, pathogenic variants have been frequently observed in genes for AChR ε subunit (CHRNE), collagen Q (COLQ), rapsyn (RAPSN), Dok-7 (DOK7), and glutamine–fructose-6-phosphate transaminase 1 (GFPT1). […] Pathogenic variants in CHRNA1, CHRNB1, CHRND, and CHRNE have been repeatedly reported since 1996. […] ChEIs are generally effective for endplate AChR deficiency irrespective of defective genes. […] The spectrum of mutations causing endplate acetylcholinesterase deficiency.

• #10 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 (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. […] 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.

• #11 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.

• #12 Congenital myasthenic syndromes // Middlesex Health

  https://middlesexhealth.org/learning-center/diseases-and-conditions/congenital-myasthenic-syndromes

  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. […] Congenital myasthenic syndromes are most commonly inherited in an autosomal recessive pattern. That means both parents must be carriers, but they do not typically show signs of the condition. The affected child inherits two copies of the abnormal gene one from each parent. […] Rarely, congenital myasthenic syndromes can be inherited in an autosomal dominant pattern, meaning that only one parent passes on the affected gene. In some cases, the affected gene occurs randomly and is not inherited. In other cases, no gene can be identified.

• #13 Causes/Inheritance – Congenital Myasthenic Syndromes (CMS) – Diseases | Muscular Dystrophy Association

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

  At the normal neuromuscular junction, a nerve cell tells a muscle cell to contract by releasing the chemical acetylcholine (ACh). […] CMS results from flaws in genes necessary for making the ACh receptor or other components of the neuromuscular junction. […] Presynaptic CMS is caused by insufficient release of ACh; postsynaptic CMS (ACh receptor deficiency, fast-channel CMS) is caused by ACh receptors that are missing or don’t stay open long enough; postsynaptic CMS (slow-channel CMS) is caused by ACh receptors that stay open too long; and synaptic CMS is caused by a deficiency of acetylcholinesterase, an enzyme that breaks down ACh.

• #14 Myasthenic Syndromes | PM&R KnowledgeNow

  https://now.aapmr.org/myasthenic-syndromes/

  CMS results from defective or absent presynaptic, synaptic or post-synaptic proteins required for neuromuscular transmission or maintenance of neuromuscular junction structure. Approximately 75% of cases are due to post-synaptic (acetylcholine receptor) defects; these are classified further into AChR deficiency, kinetic defects of AChR (fast and slow channel syndromes), defective AChR clustering, and glycosylation defects. Pre-synaptic deficiency (impaired ACh synthesis, storage, release, or recycling) and synaptic basal lamina associated dysfunction also occur. […] In CMS, AChR antibodies are absent, and the specific diagnosis instead depends on genetic testing (single gene testing, multiple gene panel testing, and comprehensive genetic testing such as whole genome sequencing and next generation sequencing). […] CMS has a variable prognosis depending on the subtype. Genes related to receptor deficiency tend to have better outcomes compared to abnormalities in the synapse or presynapse.

• #15

  https://link.springer.com/article/10.1007/s11910-002-0057-7

  Congenital myasthenic syndromes (CMS) stem from defects in presynaptic, synaptic, and postsynaptic proteins. […] The presynaptic CMS are associated with defects that curtail the evoked release of acetylcholine (ACh) quanta or the resynthesis of ACh. Insufficient resynthesis of ACh is now known to be caused by mutations that reduce the expression, catalytic efficiency, or both of choline acetyltransferase. […] The synaptic CMS are caused by mutations in the collagenic tail subunit (ColQ) of the endplate species of acetylcholinesterase that prevent ColQ from associating with catalytic subunits or from insertion into the synaptic basal lamina. […] With one exception, postsynaptic CMS identified to date are associated with a kinetic abnormality or decreased expression of the acetylcholine receptor (AChR).

• #15

  https://link.springer.com/article/10.1007/s11910-002-0057-7

  Numerous mutations have now been identified in subunits of AChR that alter the kinetics or surface expression of the receptor. […] The kinetic mutations increase or decrease the synaptic response to ACh and result in slow- and fast-channel syndromes, respectively. […] Most mutations that reduce surface expression of AChR reside in the receptors subunit and are partially compensated by residual expression of the fetal-type subunit. […] Null mutations in both alleles of other AChR subunits are likely lethal, owing to absence of a substituting subunit.

• #16 Congenital myasthenic syndrome | PPT

  https://www.slideshare.net/slideshow/congenital-myasthenic-syndrome-39338481/39338481

  Congenital myasthenic syndromes (CMS) are genetic diseases characterized by dysfunction of neuromuscular transmission. […] Causes include mutations in genes encoding choline acetyltransferase (ChAT), acetylcholinesterase, acetylcholine receptor subunits, rapsyn, and sodium channels. […] Congenital myasthenic syndromes caused by ChAT mutations manifest at birth or in the neonatal period with bulbar disorders and respiratory insufficiency with apnoea or even sudden death. […] CHAT gene encoding ChAT, located on 10q11.2. […] Mutations lead to a reduction or even abolition of the catalytic capacity of the enzyme. […] Genetics- Mutations in the COLQ gene coding for the collagenic tail of acetylcholinesterase. […] Broadly categorized in 2 categories: 1. CMS in connection with a kinetic anomaly of the acetylcholine receptor 2. CMS with a decreased number of acetylcholine receptors at the neuromuscular junction.

• #17

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

  The underlying mechanism(s) giving rise to these sudden and recurrent apnoeas is yet to be characterised. […] The majority of mutations causing CMS-EA lead to pre-synaptic defects, which have important functions for both central and neuromuscular synaptic function. […] 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.

• #18

  https://omim.org/entry/601462

  A number sign (#) is used with this entry because of evidence that slow-channel congenital myasthenic syndrome-1A (CMS1A) is caused by heterozygous mutation in the CHRNA1 gene (100690) on chromosome 2q31. […] 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, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) (summary by Engel et al., 2003; Engel et al., 2015). Approximately 10% of CMS cases are presynaptic, 15% are synaptic, and 75% are postsynaptic, the majority of which are caused by AChR deficiency (Engel et al., 2003).

• #18

  https://omim.org/entry/601462

  Recessive mutations in subunits of the acetylcholine receptor are the most common cause of CMS (Harper, 2004). CMS1A and CMS1B (608930) are caused by mutation in the CHRNA1 gene (100690); CMS2A (616313) and CMS2C (616314) are caused by mutation in the CHRNB1 gene (100710) on 17p12; CMS3A (616321), CMS3B (616322), and CMS3C (616323) are caused by mutation in the CHRND gene (100720) on 2q33; and CMS4A (605809), CMS4B (616324), and CMS4C (608931) are caused by mutation in the CHRNE gene (100725) on 17p13. […] In studies of muscle tissue from patients with SCCMS, Engel et al. (1996) found a decrease in the rate of AChR ion channel closure and an increase in apparent affinity of the receptor for ACh, resulting in a prolonged channel-opening time. Cationic overloading of the postsynaptic region results in an endplate myopathy with loss of AChR due to destruction of the junctional folds. The temporal summation of endplate potentials predicted a depolarization block, also suggesting desensitization in the presence of acetylcholinesterase inhibitors.

• #19 Myasthenic Syndrome in Children | IntechOpen

  https://www.intechopen.com/chapters/64857

  The postsynaptic CMS is considered the most common type of CMS and is caused by gene mutations that encode AChR subunits. […] AChR deficiency is inherited as autosomal recessive with mutation in genes that encode AChR subunits in the postsynaptic neuromuscular junction. […] The functional character and kinetic properties of AChR may be impaired as a result of mutation in AChR deficiency gene, particularly when AChR is not significantly reduced. […] AChR deficiency due to receptor-associated protein of the synapse (RAPSN) mutations may occur at any age; nevertheless, neonates are the most commonly affected and might need nasogastric tubes for feeding and mechanical ventilation due to severe hypotonia and significant bulbar involvement. […] Mutations in CHRNG neuromuscular transmission is caused by prenatal inherited myasthenia, which in consequence might result in fetal developmental abnormalities. […] The mutation impairs postsynaptic voltage-gated sodium channel (SCN4A) and might cause severe respiratory distress with fluctuation of disease severity.

• #20 The Neuromuscular Junction and Wide Heterogeneity of Congenital Myasthenic Syndromes

  https://www.mdpi.com/1422-0067/19/6/1677

  Congenital myasthenic syndromes (CMS) are genetic disorders characterised by impaired neuromuscular transmission. […] The genetic diagnosis of CMS is complex due to the existence of more than 30 CMS causative genes identified to date. […] The number of CMS subtypes caused by mutations in genes encoding presynaptic proteins has expanded in recent years thanks to the use of NGS. […] Recent insight has shown that patients with presynaptic CMS and with abnormalities within the glycosylation pathway may manifest with symptoms beyond the neuromuscular boundaries. […] The increasing number of presynaptic CMS exhibiting CNS manifestations along with neuromuscular weakness demonstrate that the myasthenia can be only a small part of a much more extensive disease phenotype. […] The discovery of COL13A1 mutations and laminin α5 deficiency has helped to draw attention to the role of extracellular matrix proteins for the formation and maintenance of muscle endplates. […] Mutations in components within this pathway produce a spectrum of severe multisystemic disorders known as congenital disorders of glycosylation. […] More recently, it was shown that mutations in GMPPB can also cause CMS and bridge myasthenic disorders with dystroglycanopathies.

• #21 Autism in a case of congenital myasthenic syndrome

  https://www.oatext.com/Autism-in-a-case-of-congenital-myasthenic-syndrome.php

  Congenital Myasthenic Syndromes (CMS) are a heterogeneous group of disorders affecting neuromuscular transmission which result from mutations in genes encoding proteins located at the presynaptic, synaptic, or postsynaptic regions of the neuromuscular junction. […] The association of CMS and ASD has previously been reported in CMS most commonly due to mutations in the Choline Acetyltransferase (CHAT) gene, and rarely due to mutations in the genes encoding the UDP-N-acetyl glucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 (DPAGT1) enzyme and the synaptosomal-associated protein 25B (SNAP25B). […] Genetic diagnostic testing for CMS revealed that the patient was compound heterozygous for mutations in the gene encoding the subunit of the Acetyl Choline Receptor (AChR) ion channel (CHRNE).

• #21 Autism in a case of congenital myasthenic syndrome

  https://www.oatext.com/Autism-in-a-case-of-congenital-myasthenic-syndrome.php

  In addition, varied degrees of intellectual impairment have been reported in patients with CMS caused by mutations in the CHAT gene, but not in CMS caused by mutations in CHRNE. […] Central Nervous System involvement has also been reported in UDP-N-acetyl glucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 (DPAGT1)-associated myasthenic syndrome, as DPAGT1 is highly expressed in muscles and brain. […] More recently, a study reported that the (p.Ile 67Asn) mutation in the synaptosomal-associated protein 25B (SNAP25B) gene causes a novel presynaptic CMS associated with cortical hyper excitability, cerebellar ataxia, intellectual disability, and autism. […] The recent explosion of genetic associations in ASD research has highlighted the diversity of the disorders etiology.

• #22 Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant | European Journal of Human Genetics

  https://www.nature.com/articles/s41431-019-0506-2

  Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. […] We previously identified a homozygous c.740GA; p.(Arg247Gln) missense variant in SLC25A1 in a British sib-pair presenting with a mild form of CMS with intellectual disability. […] Here, we report three additional unrelated CMS families carrying the same missense variant in SLC25A1, presenting with a similar phenotype, confirming the genotype-phenotype association. […] Pathogenic variants in SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA), a severe metabolic neurodevelopmental disorder with early lethality. […] We previously reported that the homozygous p.(Arg247Gln) missense variant caused a CMS phenotype but without systemic manifestations of a mitochondrial disease.

• #22 Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant | European Journal of Human Genetics

  https://www.nature.com/articles/s41431-019-0506-2

  Our findings suggest that SLC25A1 and in particular the p.(Arg247Gln) variant should also be considered in CMS cases with intellectual disability. […] In summary, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS, particularly with accompanying intellectual disability.

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

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

  Genetic testing can reveal changes, sometimes called mutations, in genes that cause congenital myasthenic syndromes. […] Medications aren’t a cure, but they can improve muscle contraction and muscle strength in people with congenital myasthenic syndromes. […] Which medications are effective depends on the type of affected gene. […] Genetic testing is recommended before starting medications.

• #24 DOK7 congenital myasthenic syndrome: case series and review of literature | BMC Neurology | Full Text

  https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-024-03713-0

  Amongst the DOK7 variants, c.1124_1127dupTGCC, leading to a frameshift mutation and premature termination of DOK7, is the most common mutation. […] In our study, the c.1124_1127dupTGCC variant is the most common; three patients had this variant. […] Salbutamol was the most effective. […] We strongly recommend that neurologists consider CMS in patients with these symptoms and a similar familial history. We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients.

• #25 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. […] 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. They are now recognised as one of the commonest causes of CMS in the UK, responsible for around 21% of cases. […] 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.

• #26 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. Different severity levels among patients presenting the same medical condition could be explained by characteristic relationships between diverse molecular entities (i.e. gene products, metabolites, etc) in each individual. 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. The inheritance of CMS is autosomal recessive in the majority of patients. Severe CMS is typically presented with reduced Forced Vital Capacity (FVC), severe generalized muscle fatigue and weakness, proximal and bulbar muscle fatigue and weakness, impaired myopathic gait and hyperlordosis. 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. These findings support our hypothesis that the severe patients might present disruptions in NMJ functionally related genes that, combined with the causative CHRNE alteration, may be responsible for the worsening of symptoms.

• #27

  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 this brief review, CMS are classified in six major groups: (1). presynaptic CMS, (2) synaptic CMS, (3) postsynaptic CMS; 4. CMS affecting the agrin-signal transduction pathway, (5) CMS linked to disorders of glycosylation, and (6) CMS associated with abnormalities of the cytoskeleton. […] One of the consequences of this transformation is a paradigm shift in the clinical practice of CMS that no longer requires, with rare exceptions, the use of special muscle biopsies that enable the analysis of the function and ultrastructure of the neuromuscular junction to determine the type of CMS.

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