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1.
BMC Neurol ; 24(1): 211, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38907197

ABSTRACT

BACKGROUND: Congenital myasthenic syndromes (CMS) are among the most challenging differential diagnoses in the neuromuscular domain, consisting of diverse genotypes and phenotypes. A mutation in the Docking Protein 7 (Dok-7) is a common cause of CMS. DOK7 CMS requires different treatment than other CMS types. Regarding DOK7's special considerations and challenges ahead of neurologists, we describe seven DOK7 patients and evaluate their response to treatment. METHODS: The authors visited these patients in the neuromuscular clinics of Tehran and Kerman Universities of Medical Sciences Hospitals. They diagnosed these patients based on clinical findings and neurophysiological studies, which Whole Exome Sequencing confirmed. For each patient, we tried unique medications and recorded the clinical response. RESULTS: The symptoms started from birth to as late as the age of 33, with the mean age of onset being 12.5. Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2 3-Hz RNS was decremental in 5 out of 6 patients. Salbutamol was the most effective. c.1124_1127dupTGCC is the most common variant; three patients had this variant. CONCLUSION: 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.


Subject(s)
Muscle Proteins , Myasthenic Syndromes, Congenital , Humans , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/diagnosis , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/physiopathology , Male , Female , Muscle Proteins/genetics , Adult , Young Adult , Adolescent , Child , Mutation
2.
Neuropediatrics ; 55(3): 200-204, 2024 06.
Article in English | MEDLINE | ID: mdl-38531369

ABSTRACT

Congenital myasthenic syndrome-25 (CMS-25) is an autosomal recessive neuromuscular disorder caused by a homozygous mutation in VAMP1 gene. To date, only eight types of allelic variants in VAMP1 gene have been reported in 12 cases of CMS-25. Here, we report on an 8-year-old boy with motor developmental delay, axial hypotonia, myopathic face, muscle weakness, strabismus, ptosis, pectus carinatum, kyphoscoliosis, joint contractures, joint laxity, seizures, and recurrent nephrolithiasis. He also had feeding difficulties and recurrent aspiration pneumonia. Brain magnetic resonance imaging at 20 months of age showed left focal cerebellar hypoplasia. Genetic analysis revealed a homozygous missense variant of c.202C > T (p.Arg68Ter) in the VAMP1 gene. Treatment with oral pyridostigmine was started, which resulted in mild improvement in muscle strength. Salbutamol syrup was added a few months later, but no significant improvement was observed. This case report presents novel findings such as focal cerebellar hypoplasia and nephrolithiasis in VAMP1-related CMS-25. Consequently, this case report extends the clinical spectrum. Further studies are needed to expand the genotype-phenotype correlations in VAMP1-related CMS-25.


Subject(s)
Myasthenic Syndromes, Congenital , Vesicle-Associated Membrane Protein 1 , Humans , Male , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/physiopathology , Myasthenic Syndromes, Congenital/diagnosis , Child , Vesicle-Associated Membrane Protein 1/genetics , Mutation, Missense
4.
Neurotherapeutics ; 21(2): e00318, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38233267

ABSTRACT

Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including congenital myasthenic syndromes (CMS). Germline mutations in CHRNE encoding the acetylcholine receptor (AChR) ε subunit are the most common cause of CMS. An active form of vitamin D, calcitriol, binds to vitamin D receptor (VDR) and regulates gene expressions. We found that calcitriol enhanced MuSK phosphorylation, AChR clustering, and myotube twitching in co-cultured C2C12 myotubes and NSC34 motor neurons. RNA-seq analysis of co-cultured cells showed that calcitriol increased the expressions of Rspo2, Rapsn, and Dusp6. ChIP-seq of VDR revealed that VDR binds to a region approximately 15 â€‹kbp upstream to Rspo2. Biallelic deletion of the VDR-binding site of Rspo2 by CRISPR/Cas9 in C2C12 myoblasts/myotubes nullified the calcitriol-mediated induction of Rspo2 expression and MuSK phosphorylation. We generated Chrne knockout (Chrne KO) mouse by CRISPR/Cas9. Intraperitoneal administration of calcitriol markedly increased the number of AChR clusters, as well as the area, the intensity, and the number of synaptophysin-positive synaptic vesicles, in Chrne KO mice. In addition, calcitriol ameliorated motor deficits and prolonged survival of Chrne KO mice. In the skeletal muscle, calcitriol increased the gene expressions of Rspo2, Rapsn, and Dusp6. We propose that calcitriol is a potential therapeutic agent for CMS and other diseases with defective neuromuscular signal transmission.


Subject(s)
Myasthenic Syndromes, Congenital , Animals , Mice , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/metabolism , Calcitriol/metabolism , Neuromuscular Junction/metabolism , Receptors, Cholinergic/genetics , Receptors, Cholinergic/metabolism , Motor Neurons/metabolism
5.
Acta Neurol Belg ; 123(6): 2325-2335, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37656362

ABSTRACT

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


Subject(s)
Myasthenia Gravis , Myasthenic Syndromes, Congenital , Child , Female , Humans , Myasthenic Syndromes, Congenital/diagnosis , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/drug therapy , Turkey , Myasthenia Gravis/diagnosis , Myasthenia Gravis/genetics , Myasthenia Gravis/complications , Muscle Weakness , Receptors, Cholinergic/genetics
6.
Adv Pediatr ; 70(1): 81-90, 2023 08.
Article in English | MEDLINE | ID: mdl-37422299

ABSTRACT

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


Subject(s)
Myasthenia Gravis , Myasthenic Syndromes, Congenital , Infant, Newborn , Infant , Child , Humans , Myasthenia Gravis/therapy , Myasthenia Gravis/drug therapy , Myasthenic Syndromes, Congenital/therapy , Myasthenic Syndromes, Congenital/drug therapy , Fatigue
7.
J Am Assoc Nurse Pract ; 35(8): 519-523, 2023 Aug 01.
Article in English | MEDLINE | ID: mdl-37141567

ABSTRACT

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


Subject(s)
Myasthenia Gravis , Myasthenic Syndromes, Congenital , Humans , Male , Mutation/genetics , Myasthenia Gravis/diagnosis , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/diagnosis , Pyridostigmine Bromide/therapeutic use , Adult , Treatment Outcome
8.
J Neurol ; 270(6): 3112-3119, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36869887

ABSTRACT

OBJECTIVES: Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between peripheral neuropathies and congenital myasthenic syndromes (CMS). The beta-2 adrenergic receptor agonist salbutamol has been shown to provide symptomatic benefit in CMS, while improving structural defects at the NMJ. Based on these findings, we identified cases of motor neuropathy with NMJ dysfunction and assessed the effect of salbutamol on motor function. METHODS: Cases of motor neuropathy with significant NMJ dysfunction, were identified using repetitive nerve stimulation and single fibre electromyography. Oral salbutamol was administered for 12 months. Repeat neurophysiological and clinical assessments were undertaken at baseline, 6 months and 12 months. RESULTS: Significant defects of neuromuscular transmission were identified in 15 patients harbouring a range of genetic defects, including mutations in GARS1, DNM2, SYT2 and DYNC1H. No clear benefit on motor function was seen following the administration of 12 months of oral salbutamol; however, there was a significant improvement in patient reported fatigue. In addition, no clear effect on neurophysiological parameters was seen in patients treated with salbutamol. Side-effects due to off-target beta-adrenergic effects were significant in the patient cohort. CONCLUSION: These results highlight the involvement of the NMJ in several subtypes of motor neuropathies, including subtypes of neuropathy due to deficits in mitochondrial fusion-fission, synaptic vesicle transport, calcium channels and tRNA synthetases. Whether the NMJ dysfunction is simply due to muscle reinnervation or a pathology unrelated to denervation is unknown. The involvement of the NMJ may represent a novel therapeutic target in these conditions. However, treatment regimens will need to be more targeted for patients with primary inherited defects of neuromuscular transmission.


Subject(s)
Charcot-Marie-Tooth Disease , Myasthenic Syndromes, Congenital , Humans , Albuterol/pharmacology , Albuterol/therapeutic use , Genetic Heterogeneity , Neuromuscular Junction/pathology , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/pathology , Charcot-Marie-Tooth Disease/genetics
9.
Int J Mol Sci ; 24(3)2023 Jan 23.
Article in English | MEDLINE | ID: mdl-36768582

ABSTRACT

PURA-related neurodevelopmental disorders (PURA-NDDs) are a rare genetic disease caused by pathogenic autosomal dominant variants in the PURA gene or a deletion encompassing the PURA gene. PURA-NDD is clinically characterized by neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements, and epilepsy. It is generally considered to be central nervous system disorders, with generalized weakness, associated hypotonia, cognitive and development deficits in early development, and seizures in late stages. Although it is classified predominantly as a central nervous syndrome disorder, some phenotypic features, such as myopathic facies, respiratory insufficiency of muscle origin, and myopathic features on muscle biopsy and electrodiagnostic evaluation, point to a peripheral (neuromuscular) source of weakness. Patients with PURA-NDD have been increasingly identified in exome-sequenced cohorts of patients with neuromuscular- and congenital myasthenic syndrome-like phenotypes. Recently, fluctuating weakness noted in a PURA-NDD patient, accompanied by repetitive nerve stimulation abnormalities, suggested the disease to be a channelopathy and, more specifically, a neuromuscular junction disorder. Treatment with pyridostigmine or salbutamol led to clinical improvement of neuromuscular function in two reported cases. The goal of this systematic retrospective review is to highlight the motor symptoms of PURA-NDD, to further describe the neuromuscular phenotype, and to emphasize the role of potential treatment opportunities of the neuromuscular phenotype in the setting of the potential role of PURA protein in the neuromuscular junction and the muscles.


Subject(s)
Epilepsy , Learning Disabilities , Myasthenic Syndromes, Congenital , Nervous System Malformations , Neurodevelopmental Disorders , Humans , Neuromuscular Junction , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Muscle Hypotonia/genetics , DNA-Binding Proteins/genetics , Transcription Factors/genetics
10.
Hum Mol Genet ; 32(9): 1552-1564, 2023 04 20.
Article in English | MEDLINE | ID: mdl-36611016

ABSTRACT

Congenital myasthenic syndrome (CMS) is a heterogeneous condition associated with 34 different genes, including SLC5A7, which encodes the high-affinity choline transporter 1 (CHT1). CHT1 is expressed in presynaptic neurons of the neuromuscular junction where it uses the inward sodium gradient to reuptake choline. Biallelic CHT1 mutations often lead to neonatal lethality, and less commonly to non-lethal motor weakness and developmental delays. Here, we report detailed biochemical characterization of two novel mutations in CHT1, p.I294T and p.D349N, which we identified in an 11-year-old patient with a history of neonatal respiratory distress, and subsequent hypotonia and global developmental delay. Heterologous expression of each CHT1 mutant in human embryonic kidney cells showed two different mechanisms of reduced protein function. The p.I294T CHT1 mutant transporter function was detectable, but its abundance and half-life were significantly reduced. In contrast, the p.D349N CHT1 mutant was abundantly expressed at the cell membrane, but transporter function was absent. The residual function of the p.I294T CHT1 mutant may explain the non-lethal form of CMS in this patient, and the divergent mechanisms of reduced CHT1 function that we identified may guide future functional studies of the CHT1 myasthenic syndrome. Based on these in vitro studies that provided a diagnosis, treatment with cholinesterase inhibitor together with physical and occupational therapy significantly improved the patient's strength and quality of life.


Subject(s)
Mutant Proteins , Mutation , Myasthenic Syndromes, Congenital , Symporters , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/metabolism , Myasthenic Syndromes, Congenital/rehabilitation , Humans , Male , Child , HEK293 Cells , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Half-Life , Cell Membrane/metabolism , Protein Transport , Staurosporine/pharmacology , Pyridostigmine Bromide/therapeutic use , Quality of Life , Symporters/chemistry , Symporters/genetics , Symporters/metabolism
11.
Curr Neuropharmacol ; 21(7): 1594-1605, 2023.
Article in English | MEDLINE | ID: mdl-36703579

ABSTRACT

BACKGROUND: Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) is the second-most common cause of CMS. However, data on pharmacological treatments are limited. OBJECTIVE: In this study, we reviewed related reports to determine the most appropriate pharmacological strategy for CMS caused by COLQ mutations. A literature review and meta-analysis were also performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched to identify studies published in English before July 22, 2022. RESULTS: A total of 42 studies including 164 patients with CMS due to 72 different COLQ mutations were selected for evaluation. Most studies were case reports, and none were randomized clinical trials. Our meta-analysis revealed evidence that ß-adrenergic agonists, including salbutamol and ephedrine, can be used as first-line pharmacological treatments for CMS patients with COLQ mutations, as 98.7% of patients (74/75) treated with ß-adrenergic agonists showed positive effects. In addition, AChEIs should be avoided in CMS patients with COLQ mutations, as 90.5% (105/116) of patients treated with AChEIs showed either no or negative effects. CONCLUSION: (1) ß-adrenergic agonist therapy is the first pharmacological strategy for treating CMS with COLQ mutations. (2) AChEIs should be avoided in patients with CMS with COLQ mutations.


Subject(s)
Myasthenic Syndromes, Congenital , Humans , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Muscle Proteins/therapeutic use , Mutation , Adrenergic beta-Agonists/therapeutic use , Collagen/genetics , Collagen/therapeutic use
12.
Acta Neurol Belg ; 123(5): 1841-1847, 2023 Oct.
Article in English | MEDLINE | ID: mdl-36094697

ABSTRACT

INTRODUCTION: Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders affecting the safety factor which required for neuromuscular transmission. Here we reported our experience in children with CMS. METHODS: We retrospectively collected the data of 18 patients with CMS who were examined in our outpatient clinic between January 2021 and January 2022. The diagnosis of CMS was based on the presence of clinical symptoms such as abnormal fatigability and weakness, absence of autoantibodies against acetylcholine receptor and muscle-specific kinase, electromyographic evidence of neuromuscular junction defect, molecular genetic confirmation, and response to treatment. RESULTS: The most common mutations were in the acetylcholine receptor (CHRNE) gene (8/18) and choline acetyltransferase (ChAT) (2/18) gene. Despite targeted gene sequencing and whole exome sequencing (WES) were underwent, we couldn't detect a genetic mutation in three out of patients. The most commonly determined initial finding was eyelid ptosis, followed by fatigable weakness, and respiratory insufficiency. Although the most commonly used drug was pyridostigmine, we have experienced that caution should be exercised as it may worsen some types of CMS. DISCUSSION: We reported in detail the phenotypic features of very rare gene mutations associated with CMS and our experience in the treatment of this disease. Although CMS are rare genetic disorder, the prognosis can be very promising with appropriate treatment in most CMS subtypes.


Subject(s)
Myasthenic Syndromes, Congenital , Child , Humans , Myasthenic Syndromes, Congenital/diagnosis , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/drug therapy , Retrospective Studies , Turkey , Receptors, Cholinergic/genetics , Mutation/genetics
13.
Muscle Nerve ; 66(3): 345-348, 2022 09.
Article in English | MEDLINE | ID: mdl-35661384

ABSTRACT

INTRODUCTION/AIMS: The congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders that affect neuromuscular junction transmission. Data on pregnancy outcomes in women with CMS are limited due to their infrequency. In this study we explored pregnancy with CMS in a large cohort of women attending a national specialty clinic in England. METHODS: All women with CMS who had a documented pregnancy were invited to complete a questionnaire assessing clinical status during pregnancy and postpartum, pregnancy outcomes, fetal outcomes, and medication use during pregnancy. RESULTS: Among 16 women with CMS (acetylcholine receptor deficiency [CHRNE], slow channel syndrome [CHRNA1], DOK7, RAPSYN and glycosylation [DPAGT1 and GFPT1]), 27 pregnancies were recorded: 26 single pregnancies and 1 twin pregnancy. Symptom worsening was reported in 63% of pregnancies, but recovery to baseline function was seen in all but one patient. Miscarriage and cesarean section occurred in 31% and 33% of the women, respectively. Over half of the patients continued taking their medication during pregnancy, which included pyridostigmine (n = 10), 3,4-diaminopyridine (n = 9), ephedrine (n = 3), salbutamol (n = 3), and quinidine (n = 1). No fetal malformations were recorded. DISCUSSION: Our results show that clinical worsening during pregnancy was common but rarely persistent. The majority of women with CMS can safely plan pregnancy, but close follow-up is required from their neurology and obstetric teams. Although we identified no safety concerns, continued medication use should be reviewed on a case-by-case basis.


Subject(s)
Myasthenic Syndromes, Congenital , Cesarean Section , Female , Humans , Mutation , Myasthenic Syndromes, Congenital/diagnosis , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Neuromuscular Junction , Pregnancy , Pregnancy Outcome , Receptors, Cholinergic
17.
J Clin Neurosci ; 96: 85-89, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34999496

ABSTRACT

The slow-channel congenital myasthenic syndrome is an autosomal dominant neuromuscular disorder caused by mutations in different subunits of the acetylcholine receptor. Fluoxetine, a common antidepressant and long-lived open-channel blocker of acetylcholine receptor, has been reported to be beneficial in the slow-channel congenital myasthenic syndrome. Here we report a prospective open label study of fluoxetine treatment in some affected members of a Thai family with slow-channel congenital myasthenic syndrome caused by a novel p.Gly153Ala (c.518G > C) mutation in CHRNA1 in the AChR α subunit. These patients showed significant clinical improvement following fluoxetine treatment but their respiratory function responded variably.


Subject(s)
Fluoxetine , Myasthenic Syndromes, Congenital , Fluoxetine/therapeutic use , Humans , Mutation , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Prospective Studies , Receptors, Cholinergic/genetics , Thailand
20.
Nature ; 595(7867): 404-408, 2021 07.
Article in English | MEDLINE | ID: mdl-34163073

ABSTRACT

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 CM1,2. The most common disease-causing mutation (DOK71124_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. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality.


Subject(s)
Muscle Proteins/genetics , Mutation , Myasthenic Syndromes, Congenital/drug therapy , Myasthenic Syndromes, Congenital/genetics , Aging , Agrin/genetics , Agrin/metabolism , Animals , Animals, Newborn , Antibodies/immunology , Disease Models, Animal , Female , LDL-Receptor Related Proteins/genetics , LDL-Receptor Related Proteins/metabolism , Male , Mice , Molecular Targeted Therapy , Muscle Fibers, Skeletal/chemistry , Muscle Fibers, Skeletal/metabolism , Muscle Proteins/chemistry , Muscle Proteins/metabolism , Myasthenic Syndromes, Congenital/immunology , Phosphorylation , Phosphotyrosine/genetics , Phosphotyrosine/metabolism , Proto-Oncogene Proteins c-crk/metabolism , Receptor Protein-Tyrosine Kinases/agonists , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/immunology , Receptor Protein-Tyrosine Kinases/metabolism , Recurrence , Synapses/metabolism
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