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1.
Handb Clin Neurol ; 203: 69-88, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39174255

RESUMO

The neuromuscular junction is a prototypic synapse that has been extensively studied and provides a model for smaller and less accessible central synapses. Central to transmission at the neuromuscular synapse is the muscle acetylcholine receptor cation channel. Studies of the genetic disorders affecting the neuromuscular junction, termed congenital myasthenic syndromes, have illustrated how impaired signal transmission may be caused by a variety of mutations both within the ion channel itself and by the context of the ion channel within the synapse. Thus, multiple pathogenic mutations are also identified in proteins affecting the clustering, location, and density of the receptor within the overall synaptic structure. Disease severity ranges from death in childhood to mild disability throughout life. In addition, in utero, fetal akinesia due to impaired neuromuscular transmission may cause developmental abnormalities. Early studies identified mutations in the genes encoding the acetylcholine receptor subunits that impair ion channel gating or reduce the number of endplate receptors or a combination of the two, giving rise to "slow channel," "fast channel," or deficiency syndromes. Subsequently, it became clear that myasthenic syndromes also stem from mutations in proteins involved in neurotransmitter release, the formation and maintenance of the neuromuscular synapse, or glycosylation. This chapter describes the patient phenotypes, the diverse range of molecular mechanisms for synaptic dysfunction, and the corresponding therapeutic strategies, including drug combinations, that can be tailored to the many subtypes.


Assuntos
Síndromes Miastênicas Congênitas , Junção Neuromuscular , Humanos , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/fisiopatologia , Mutação/genética , Receptores Colinérgicos/metabolismo , Receptores Colinérgicos/genética , Animais
2.
Curr Opin Neurol ; 37(5): 493-501, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39051439

RESUMO

PURPOSE OF REVIEW: Congenital myasthenia syndromes (CMS) are treatable, inherited disorders affecting neuromuscular transmission. We highlight that the involvement of an increasing number of proteins is making the understanding of the disease mechanisms and potential treatments progressively more complex. RECENT FINDINGS: Although early studies identified mutations of proteins directly involved in synaptic transmission at the neuromuscular junction, recently, next-generation sequencing has facilitated the identification of many novel mutations in genes that encode proteins that have a far wider expression profile, some even ubiquitously expressed, but whose defective function leads to impaired neuromuscular transmission. Unsurprisingly, mutations in these genes often causes a wider phenotypic disease spectrum where defective neuromuscular transmission forms only one component. This has implications for the management of CMS patients. SUMMARY: Given the widening nonneuromuscular junction phenotypes in the newly identified forms of CMS, new therapies need to include disease-modifying approaches that address not only neuromuscular weakness but also the multisystem involvement. Whilst the current treatments for CMS are highly effective for many subtypes there remains, in a proportion of CMS patients, an unmet need for more efficacious therapies.


Assuntos
Síndromes Miastênicas Congênitas , Humanos , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/fisiopatologia , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/terapia , Junção Neuromuscular/genética , Junção Neuromuscular/fisiopatologia , Mutação/genética , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
4.
Cell Mol Life Sci ; 81(1): 129, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38472514

RESUMO

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G > A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR.


Assuntos
Receptores Nicotínicos , Humanos , Acetilcolinesterase/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Membrana Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptores Nicotínicos/genética , Fala
5.
bioRxiv ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38405691

RESUMO

Congenital myasthenic syndromes (CMS) are a group of inherited disorders characterised by defective neuromuscular transmission and fatigable muscle weakness. Mutations in DOK7 , a gene encoding a post-synaptic protein crucial in the formation and stabilisation of the neuromuscular junction (NMJ), rank among the leading three prevalent causes of CMS in diverse populations globally. The majority of DOK7 CMS patients experience varying degrees of disability despite receiving optimised treatment, necessitating the development of improved therapeutic approaches. Here we executed a dose escalation pre-clinical trial using a DOK7-CMS mouse model to assess the efficacy of Amp-101, an innovative AAV gene replacement therapy. Amp-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. We show that at doses 6x10 13 vg/kg and 1x10 14 vg/kg, Amp-101 generated enlarged NMJs and rescued the very severe phenotype of the model. Treated mice became at least as strong as WT littermates and the diaphragm and tibialis anterior muscles displayed robust expression of DOK7. This data suggests that Amp-101 is a promising candidate to move forward to clinic trials.

6.
Genome Med ; 15(1): 94, 2023 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-37946251

RESUMO

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.


Assuntos
Variação Genética , Doenças Raras , Humanos , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Genoma , Testes Genéticos , Mutação , Proteínas de Ciclo Celular
7.
Brain Commun ; 5(6): fcad299, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38035366

RESUMO

Respiratory problems are a major cause of morbidity and mortality in patients with congenital myasthenic syndromes, a rare heterogeneous group of neuromuscular disorders caused by genetic defects impacting the structure and function of the neuromuscular junction. Recurrent, life-threatening episodic apnoea in early infancy and childhood and progressive respiratory failure requiring ventilation are features of certain genotypes of congenital myasthenic syndromes. Robb et al. published empirical guidance on respiratory management of the congenital myasthenic syndromes, but other than this workshop report, there are little published longitudinal natural history data on respiratory outcomes of these disorders. We report a retrospective, single-centre study on respiratory outcomes in a cohort of 40 well characterized genetically confirmed cases of congenital myasthenic syndromes, including 10 distinct subtypes (DOK7, COLQ, RAPSN, CHAT, CHRNA1, CHRNG, COL13A1, CHRNE, CHRNE fast channel syndrome and CHRNA1 slow channel syndrome), with many followed up over 20 years in our centre. A quantitative and longitudinal analysis of key spirometry and sleep study parameters, as well as a description of historical hospital admissions for respiratory decompensation, provides a snapshot of the respiratory trajectory of congenital myasthenic syndrome patients based on genotype.

8.
Artigo em Inglês | MEDLINE | ID: mdl-37582613

RESUMO

BACKGROUND AND OBJECTIVES: Up to 50% of patients with myasthenia gravis (MG) without acetylcholine receptor antibodies (AChR-Abs) have antibodies to muscle-specific kinase (MuSK). Most MuSK antibodies (MuSK-Abs) are IgG4 and inhibit agrin-induced MuSK phosphorylation, leading to impaired clustering of AChRs at the developing or mature neuromuscular junction. However, IgG1-3 MuSK-Abs also exist in MuSK-MG patients, and their potential mechanisms have not been explored fully. METHODS: C2C12 myotubes were exposed to MuSK-MG plasma IgG1-3 or IgG4, with or without purified agrin. MuSK, Downstream of Kinase 7 (DOK7), and ßAChR were immunoprecipitated and their phosphorylation levels identified by immunoblotting. Agrin and agrin-independent AChR clusters were measured by immunofluorescence and AChR numbers by binding of 125I-α-bungarotoxin. Transcriptomic analysis was performed on treated myotubes. RESULTS: IgG1-3 MuSK-Abs impaired AChR clustering without inhibiting agrin-induced MuSK phosphorylation. Moreover, the well-established pathway initiated by MuSK through DOK7, resulting in ßAChR phosphorylation, was not impaired by MuSK-IgG1-3 and was agrin-independent. Nevertheless, the AChR clusters did not form, and both the number of AChR microclusters that precede full cluster formation and the myotube surface AChRs were reduced. Transcriptomic analysis did not throw light on the pathways involved. However, the SHP2 inhibitor, NSC-87877, increased the number of microclusters and led to fully formed AChR clusters. DISCUSSION: MuSK-IgG1-3 is pathogenic but seems to act through a noncanonical pathway. Further studies should throw light on the mechanisms involved at the neuromuscular junction.


Assuntos
Miastenia Gravis , Receptores Proteína Tirosina Quinases , Humanos , Agrina/farmacologia , Imunoglobulina G , Proteínas Musculares/metabolismo , Miastenia Gravis/tratamento farmacológico , Fosforilação , Receptores Colinérgicos
10.
Neuromuscul Disord ; 33(2): 161-168, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36634413

RESUMO

Primary acetylcholine receptor deficiency is the most common subtype of congenital myasthenic syndrome, resulting in reduced amount of acetylcholine receptors expressed at the muscle endplate and impaired neuromuscular transmission. AChR deficiency is caused mainly by pathogenic variants in the ε-subunit of the acetylcholine receptor encoded by CHRNE, although pathogenic variants in other subunits are also seen. We report the clinical and molecular features of 13 patients from nine unrelated kinships with acetylcholine receptor deficiency harbouring the CHRNA1 variant NM_001039523.3:c.257G>A (p.Arg86His) in homozygosity or compound heterozygosity. This variant results in the inclusion of an alternatively-spliced evolutionary exon (P3A) that causes expression of a non-functional acetylcholine receptor α-subunit. We compare the clinical findings of this group to the other cases of acetylcholine receptor deficiency within our cohort. We report differences in phenotype, highlighting a predominant pattern of facial and distal weakness in adulthood, predominantly in the upper limbs, which is unusual for acetylcholine receptor deficiency syndromes, and more in keeping with slow-channel syndrome or distal myopathy. Finally, we stress the importance of including alternative exons in variant analysis to increase the probability of achieving a molecular diagnosis.


Assuntos
Síndromes Miastênicas Congênitas , Receptores Nicotínicos , Humanos , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/patologia , Éxons/genética , Fenótipo , Mutação , Receptores Nicotínicos/genética
11.
J Neurol Sci ; 443: 120494, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36403297

RESUMO

This study aimed to evaluate the diagnostic usefulness of motor end-plate (MEP) analysis along with clustered acetylcholine receptor (AChR) antibody (Ab) assays in patients with myasthenia-like symptoms but negative routine AChR and muscle-specific kinase (MuSK) Ab tests. MEP analysis of muscle biopsies of the biceps brachii was performed in 20 patients to try to differentiate between those with or without immune-mediated myasthenia gravis (MG). Using a quantitative method, complement C3 deposition and AChR densities in MEPs were examined. Independently, cell-based assays were used to detect serum clustered-AChR Abs. Only five of 20 patients had complement deposition at MEPs; four of these patients had reduced AChR densities similar to those in patients with typical AChR Ab positive MG, and distinct from those in the remaining 15 patients. Two of the four serum samples from these patients had clustered-AChR Abs. All complement-positive patients were considered as having immune-mediated MG and improved with appropriate treatments; although one patient presented with MG 3 years later, the remaining patients had other diagnoses during over 10 years of follow-up. These results suggest the usefulness of MEP analysis of muscle biopsies in diagnosing immune-mediated MG in seronegative patients with myasthenia-like symptoms but, due to the invasiveness of the muscle biopsy procedure, clustered AChR Abs should, if possible, be tested first.


Assuntos
Placa Motora , Miastenia Gravis , Humanos , Miastenia Gravis/diagnóstico , Autoanticorpos , Biópsia , Projetos de Pesquisa
12.
Eur J Paediatr Neurol ; 40: 5-10, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35835035

RESUMO

Juvenile myasthenia gravis (JMG) is a rare, antibody-mediated disorder of the neuromuscular junction. Treatment strategies in JMG are largely informed by adult MG treatments as the pathophysiology is similar. Rituximab is increasingly considered as a treatment option in refractory JMG but has not yet been systematically investigated in this patient group We conducted a retrospective study from five international centres with expertise in paediatric myasthenia. 10 JMG patients treated with rituximab were identified. Following rituximab treatment all patients had a reduction in JMG-related hospital admissions. At 24 month follow up, 6 patients (60%) had achieved complete stable remission or pharmacological remission and 7 patients were able to reduce immunomodulatory treatment(s). The main side-effect was infusion-related reactions (30%) which resolved in all patients with symptomatic treatment. We compared our cohort to previously reported JMG cases treated with rituximab and noted similar response rates but a slightly higher side-effect profile. Rituximab is a safe and effective treatment option in moderate to severe JMG and most patients have an improvement in MG symptoms post treatment.


Assuntos
Miastenia Gravis , Adulto , Criança , Estudos de Coortes , Humanos , Miastenia Gravis/tratamento farmacológico , Estudos Retrospectivos , Rituximab/efeitos adversos , Resultado do Tratamento
13.
Muscle Nerve ; 66(3): 345-348, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35661384

RESUMO

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.


Assuntos
Síndromes Miastênicas Congênitas , Cesárea , Feminino , Humanos , Mutação , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/genética , Junção Neuromuscular , Gravidez , Resultado da Gravidez , Receptores Colinérgicos
14.
Neuromuscul Disord ; 32(1): 80-83, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34980536

RESUMO

ALG2 mutations are extremely rare causes of congenital myasthenic syndromes (CMS). The clinical phenotype and treatment response is therefore not well described. We present the case of a baby who immediately after birth presented with pronounced truncal hypotonia, proximal muscle weakness and feeding difficulties. Single fibre electromyography showed neuromuscular transmission failure and salbutamol and ephedrine treatment improved both muscle weakness and neuromuscular transmission. Genetic analysis revealed a likely pathogenic variant c.1040del, p.(Gly347Valfs*27) in exon 2 and a variant of uncertain significance, c.239G>A, p.(Gly80Asp) in exon 1 of the ALG2 gene. Western blot in whole cell lysates of HEK293 cells transfected with p.Gly80Asp, or p.Gly347Valfs*27 expression constructs indicated that p.Gly347Valfs*27 is likely a null allele and p.Gly80Asp is pathogenic through marked reduction of ALG2 expression. This case highlights the utility of functional studies in clarifying variants of unknown significance, in suspected cases of CMS.


Assuntos
Mutação/genética , Síndromes Miastênicas Congênitas/genética , Albuterol/uso terapêutico , Eletromiografia , Efedrina/uso terapêutico , Feminino , Células HEK293 , Humanos , Recém-Nascido , Proteínas Musculares/genética , Fenótipo
15.
Ann Clin Transl Neurol ; 9(1): 4-15, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34908252

RESUMO

OBJECTIVE: A group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic clarification. This study aims to explore the genetic background of cases with TAs in order to improve our knowledge of the pathogenesis of these rare pathological structures. METHODS: Thirty-three patients including two family members with biopsy confirmed TAs were collected. Whole-exome sequencing was performed on 31 unrelated index patients and a candidate gene search strategy was conducted. The identified variants were confirmed by Sanger sequencing. The wild-type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot analysis was performed to quantify protein expression levels. RESULTS: Eleven index cases (33%) were found to have pathogenic variant or likely pathogenic variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them, the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in SCN4A were novel. Western blot analysis showed that the expression of ALG14 protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr) compared with wild type. The ALG14 variants might be associated with TAs in patients with complex multisystem disorders. INTERPRETATION: This study expands the phenotypic and genotypic spectrums of myopathies with TAs. Our findings further confirm previous hypothesis that genes related with calcium signalling pathway and N-linked glycosylation pathway are the main genetic causes of myopathies with TAs.


Assuntos
Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Adolescente , Adulto , Biópsia , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/fisiopatologia , Linhagem , Sequenciamento do Exoma , Adulto Jovem
16.
J Physiol ; 599(24): 5417-5449, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34748643

RESUMO

Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Some survivors develop a severe, acute or delayed myasthenic syndrome. In animal models, similar myasthenia has been associated with increasing plasma concentration of one insecticide solvent metabolite, cyclohexanol. We investigated possible mechanisms using voltage and current recordings from mouse neuromuscular junctions (NMJs) and transfected human cell lines. Cyclohexanol (10-25 mM) reduced endplate potential (EPP) amplitudes by 10-40% and enhanced depression during repetitive (2-20 Hz) stimulation by up to 60%. EPP decay was prolonged more than twofold. Miniature EPPs were attenuated by more than 50%. Cyclohexanol inhibited whole-cell currents recorded from CN21 cells expressing human postjunctional acetylcholine receptors (hnAChR) with an IC50 of 3.74 mM. Cyclohexanol (10-20 mM) also caused prolonged episodes of reduced-current, multi-channel bursting in outside-out patch recordings from hnAChRs expressed in transfected HEK293T cells, reducing charge transfer by more than 50%. Molecular modelling indicated cyclohexanol binding (-6 kcal/mol) to a previously identified alcohol binding site on nicotinic AChR α-subunits. Cyclohexanol also increased quantal content of evoked transmitter release by ∼50%. In perineurial recordings, cyclohexanol selectively inhibited presynaptic K+ currents. Modelling indicated cyclohexanol binding (-3.8 kcal/mol) to voltage-sensitive K+ channels at the same site as tetraethylammonium (TEA). TEA (10 mM) blocked K+ channels more effectively than cyclohexanol but EPPs were more prolonged in 20 mM cyclohexanol. The results explain the pattern of neuromuscular dysfunction following ingestion of organophosphorus insecticides containing cyclohexanol precursors and suggest that cyclohexanol may facilitate investigation of mechanisms regulating synaptic strength at NMJs. KEY POINTS: Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Survivors may develop a severe myasthenic syndrome or paralysis, associated with increased plasma levels of cyclohexanol, an insecticide solvent metabolite. Analysis of synaptic transmission at neuromuscular junctions in isolated mouse skeletal muscle, using isometric tension recording and microelectrode recording of endplate voltages and currents, showed that cyclohexanol reduced postsynaptic sensitivity to acetylcholine neurotransmitter (reduced quantal size) while simultaneously enhancing evoked transmitter release (increased quantal content). Patch recording from transfected cell lines, together with molecular modelling, indicated that cyclohexanol causes selective, allosteric antagonism of postsynaptic nicotinic acetylcholine receptors and block of presynaptic K+ -channel function. The data provide insight into the cellular and molecular mechanisms of neuromuscular weakness following intentional ingestion of agricultural organophosphorus insecticides. Our findings also extend understanding of the effects of alcohols on synaptic transmission and homeostatic synaptic function.


Assuntos
Cicloexanóis , Junção Neuromuscular , Animais , Células HEK293 , Humanos , Camundongos , Placa Motora , Receptores Colinérgicos , Transmissão Sináptica
17.
Neuromuscul Disord ; 31(10): 943-954, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34736634

RESUMO

Congenital myasthenia syndromes are rare but often treatable conditions affecting neuromuscular transmission. They result from loss or impaired function of one of a number of proteins secondary to a genetic defect. An estimate of the prevalence in the UK gave 9.2 cases per million, however, this is likely an underestimate since the adoption of next generation sequencing for diagnosis away from specialist centres is enhancing the 'pick up' rate. Next generation sequencing has helped identify a series of novel genes that harbour mutations causative for congenital myasthenic syndrome that include not only genes that encode proteins specifically expressed at the neuromuscular junction but also those that are ubiquitously expressed. The list of genes harbouring disease-causing mutations for congenital myasthenic syndrome continues to expand and is now over 30, but with many of the newly identified genes it is increasingly being recognised that abnormal neuromuscular transmission is only one component of a multifaceted phenotype in which muscle, the central nervous system, and other organs may also be affected. Treatment can be tailored to the underlying molecular mechanism for impaired neuromuscular transmission but treating the more complex multifaceted disorders and will require development of new therapies.


Assuntos
Síndromes Miastênicas Congênitas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Junção Neuromuscular/metabolismo , Fenótipo , Transmissão Sináptica/genética
18.
J Neuromuscul Dis ; 8(6): 1003-1005, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34120913

RESUMO

Congenital Myasthenic Syndromes (CMS) are a rare group of genetic disorders of neuromuscular transmission. Some subtypes of CMS can be associated with respiratory and bulbar weakness and these patients may therefore be at high risk of developing a severe disease from COVID-19. We screened 73 patients with genetically confirmed CMS who were attending the UK national referral centre for evidence of previous Severe Acute Respiratory Syndrome Corona Virus 2 infection and their clinical outcome. Of 73 patients, seven had history of confirmed COVID-19. None of the infected patients developed a severe disease, and there were no signals that CMS alone carries a high risk of severe disease from COVID-19.


Assuntos
COVID-19/complicações , Síndromes Miastênicas Congênitas/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Reino Unido , Adulto Jovem
19.
Neuromuscul Disord ; 31(3): 246-248, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33487521

RESUMO

Congenital myasthenic syndromes (CMS) are genetically determined heterogenous disorders of neuromuscular transmission. We report a rare mutation of COLQ causing CMS in an Asian man that remarkably improved with fluoxetine. A 51-year-old Sri Lankan man with slowly progressive fatigable muscle weakness since eight years of age, presented with type 2 respiratory failure that required mechanical ventilation in the acute crisis and subsequent home-based non-invasive ventilation. His birth and family histories were unremarkable. On examination, he had limb girdle type of muscle weakness with fatigability and normal tendon reflexes with no ocular or bulbar involvement. DNA sequencing revealed a pathogenic homozygous mutation in COLQ gene: ENST00000383788.10:exon16:c.1228C>T:p.R410W, the first report in an Asian. Treatment with fluoxetine resulted in remarkable improvement and regain of muscle power and independence from assisted ventilation.


Assuntos
Acetilcolinesterase/genética , Colágeno/genética , Fluoxetina/uso terapêutico , Proteínas Musculares/genética , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/genética , Povo Asiático/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNA , Sri Lanka
20.
Neuromuscul Disord ; 31(1): 21-28, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33250374

RESUMO

SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7. The individuals from family 1 and 2 were homozygous for c.320G>A; (p.Arg107His) and c.886G>A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T>A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and ß2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.


Assuntos
Proteínas de Membrana Transportadoras/genética , Síndromes Miastênicas Congênitas/genética , Simportadores , Acetilcolinesterase/genética , Antagonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Síndromes Miastênicas Congênitas/tratamento farmacológico , Linhagem , Fenótipo , Terminações Pré-Sinápticas , Sódio/metabolismo
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