Assuntos
Artrogripose , Humanos , Artrogripose/genética , Artrogripose/diagnóstico , Artrogripose/complicações , Feminino , Gravidez , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/complicações , Adulto , Anormalidades Múltiplas , Hipertermia Maligna , Anormalidades da PeleRESUMO
AIM: Respiratory insufficiency can be a presenting symptom of congenital myasthenic syndromes (CMS) but is rarely recognised as such. In this study, we aim to raise awareness of CMS to paediatricians. METHODS: We performed a retrospective case study of infants and preschool children treated in the past 5 years in Amalia Children's Hospital, Radboud University Medical Center in Nijmegen, the Netherlands for respiratory insufficiency as presenting symptom of CMS. RESULTS: Five children aged 2 weeks to 5 years experienced severe to life-threatening episodes of respiratory insufficiency, especially during viral infections, due to respiratory muscle weakness. During infections, they often also had progression of their otherwise mild ocular, facial, and limb muscle weakness. They were eventually diagnosed with genetically proven CMS. In these five children, treatment with pyridostigmine, an acetylcholinesterase inhibitor, resulted in clinical improvement. CONCLUSION: CMS should be considered in every patient with unexplained recurrent respiratory insufficiency, or with an unusually severe course of a normally mild respiratory infection, especially in combination with mild muscle weakness outside periods of illness. Early diagnosis of CMS is crucial for early treatment, which may help avoiding sudden infant death, severe respiratory insufficiency and further deterioration of the muscle strength.
Assuntos
Síndromes Miastênicas Congênitas , Insuficiência Respiratória , Lactente , Pré-Escolar , Humanos , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Estudos Retrospectivos , Acetilcolinesterase/genética , Acetilcolinesterase/uso terapêutico , Proteínas Musculares/genética , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Debilidade Muscular , MutaçãoRESUMO
Congenital myasthenic syndromes (CMS) is a group of diseases that causes abnormalities at the neuromuscular junction owing to genetic anomalies. The pathogenic variant in ALG14 results in a severe pathological form of CMS causing end-plate acetylcholine receptor deficiency. Here, we report the cases of two siblings with CMS associated with a novel variant in ALG14. Immediately after birth, they showed hypotonia and multiple joint contractures with low Apgar scores. Ptosis, low-set ears, and high-arched palate were noted. Deep tendon reflexes were symmetrical. They showed worsening swallowing and respiratory problems; hence, nasal feeding and tracheotomy were performed. Cranial magnetic resonance imaging scans revealed delayed myelination and cerebral atrophy. Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14. Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential. After treatment with pyridostigmine, the time off the respirator increased. Their epileptic seizures were well controlled by anti-epileptic drugs. Their clinical course is stable even now at the ages of 5 and 2 years, making them the longest reported survivors of a severe form of CMS with the ALG14 variant thus far.
Assuntos
Síndromes Miastênicas Congênitas , Éxons , Humanos , Mutação , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Irmãos , Sobreviventes , Sequenciamento do ExomaRESUMO
Congenital myasthenic syndrome (CMS) describes a group of rare inherited disorders caused by impaired neuromuscular transmission at the motor endplate. Common ophthalmic manifestations associated with CMS include ptosis and ophthalmoplegia. A 19-year-old female presented with variable day-to-day ptosis secondary to CMS that was refractory to medical therapy. Bilateral silicone frontalis slings were used to stabilise the upper lid height and reduce fluctuation in severity of ptosis. Blepharoptosis surgery has been performed in patients with chronic myasthenia gravis (MG), but rarely in the setting of CMS. Blepharoptosis surgery in CMS patients with variable ptosis is difficult due to the risk of upsetting the original lid position and developing post-operative exposure keratopathy. Our case demonstrates that the frontalis sling procedure may be considered as an option in the management of variable blepharoptosis secondary to CMS.
Assuntos
Blefaroplastia , Blefaroptose , Miastenia Gravis , Síndromes Miastênicas Congênitas , Adulto , Blefaroplastia/métodos , Blefaroptose/congênito , Blefaroptose/cirurgia , Feminino , Humanos , Miastenia Gravis/complicações , Miastenia Gravis/cirurgia , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/cirurgia , Período Pós-Operatório , Estudos Retrospectivos , Silicones , Adulto JovemRESUMO
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 JovemRESUMO
Purpose: To report a patient with Pierson syndrome who presented with neovascular glaucoma (NVG) after cataract surgery.Methods: Retrospective case report.Results: A 17-year old monocular female presented with sudden onset of pain and decreased vision in the right eye. On examination, she had intraocular pressure (IOP) of 50 mmHg, aggressive iris neovascularization (NVI) and 3-piece IOL. Fundus examination revealed pale disc with tessellated fundus and parapapillary atrophy. Vascular arcades were vertically stretched with avascular ischemic retina starting from the near periphery. Macula appeared thin and atrophic. An intravitreal injection of 0.05 mg/0.1 ml bevacizumab was given to the right eye followed by Ahmed glaucoma valve (AGV) implantation. Assessment of her brother revealed similar posterior segment changes. A subsequent urine analysis showed proteinuria and high albumin to creatinine ratio. Next-generation sequencing for LAMB2 gene revealed a homozygous c.4573 + 1 G > A variant confirming the diagnosis of Pierson syndrome.Conclusion: This case expands our knowledge on retinal ischemia in the setting of Pierson syndrome. Close monitoring after intraocular surgery is recommended to look for the development of NVG.
Assuntos
Glaucoma Neovascular/etiologia , Laminina/genética , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/genética , Síndrome Nefrótica/complicações , Síndrome Nefrótica/genética , Facoemulsificação/efeitos adversos , Distúrbios Pupilares/complicações , Distúrbios Pupilares/genética , Adolescente , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Terapia Combinada , Feminino , Implantes para Drenagem de Glaucoma , Glaucoma Neovascular/diagnóstico , Glaucoma Neovascular/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pressão Intraocular , Implante de Lente Intraocular/efeitos adversos , Masculino , Síndromes Miastênicas Congênitas/diagnóstico , Síndrome Nefrótica/diagnóstico , Distúrbios Pupilares/diagnóstico , Estudos Retrospectivos , Irmãos , Tonometria Ocular , Adulto JovemRESUMO
Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.
Assuntos
Predisposição Genética para Doença , Hipotonia Muscular/genética , Síndromes Miastênicas Congênitas/genética , Sinaptotagmina II/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Hipotonia Muscular/complicações , Hipotonia Muscular/patologia , Debilidade Muscular/genética , Debilidade Muscular/patologia , Mutação de Sentido Incorreto/genética , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/patologia , Linhagem , Fenótipo , Transmissão Sináptica/genéticaAssuntos
Doenças Renais Císticas/diagnóstico , Síndromes Miastênicas Congênitas/diagnóstico , Síndrome Nefrótica/diagnóstico , Distúrbios Pupilares/diagnóstico , Evolução Fatal , Humanos , Recém-Nascido , Doenças Renais Císticas/etiologia , Doenças Renais Císticas/patologia , Masculino , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/patologia , Síndrome Nefrótica/complicações , Síndrome Nefrótica/patologia , Distúrbios Pupilares/complicações , Distúrbios Pupilares/patologiaAssuntos
Epidermólise Bolhosa Simples/genética , Síndromes Miastênicas Congênitas/genética , Plectina/genética , Criança , Pré-Escolar , Inibidores da Colinesterase/uso terapêutico , Epidermólise Bolhosa Simples/complicações , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/tratamento farmacológico , Brometo de Piridostigmina/uso terapêutico , IrmãosRESUMO
Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co-occurrence of myasthenia gravis or Lambert-Eaton myasthenic syndrome with an immune-mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.
Assuntos
Músculo Esquelético/fisiopatologia , Doenças Musculares/fisiopatologia , Síndromes Miastênicas Congênitas/fisiopatologia , Junção Neuromuscular/fisiopatologia , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Eletrodiagnóstico , Eletromiografia , Humanos , Músculo Esquelético/patologia , Doenças Musculares/complicações , Doenças Musculares/patologia , Distrofias Musculares/complicações , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Miastenia Gravis/complicações , Miastenia Gravis/patologia , Miastenia Gravis/fisiopatologia , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/patologia , Miopatias Congênitas Estruturais/complicações , Miopatias Congênitas Estruturais/patologia , Miopatias Congênitas Estruturais/fisiopatologia , Transtornos Miotônicos/complicações , Transtornos Miotônicos/patologia , Transtornos Miotônicos/fisiopatologia , Condução NervosaAssuntos
Colágeno Tipo XIII/genética , Síndromes Miastênicas Congênitas/genética , Blefaroptose/etiologia , Transtornos de Deglutição/etiologia , Dispneia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Mutação , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/fisiopatologia , Condução Nervosa , Insuficiência Respiratória/etiologiaRESUMO
In this case report, we describe an adult male with congenital myasthenic syndrome due to mutations in muscle-specific receptor tyrosine kinase (MuSK, c.79+2 T>G; IVS1 +2 T>G, c.2368 G>A, Val790Met) presenting with sleep apnoea and hypercapnic respiratory failure. In the intensive care unit, he required intubation followed by tracheostomy which resolved obstructive sleep apnoea. Later, due to persistent sleep-associated hypoventilation, he required nocturnal mechanical ventilation. His case illustrates how respiratory muscle weakness due to mutations in MuSK can lead to various forms of sleep disordered breathing.
Assuntos
Hipoventilação/etiologia , Síndromes Miastênicas Congênitas/complicações , Apneia Obstrutiva do Sono/etiologia , Humanos , Hipoventilação/terapia , Intubação Intratraqueal , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Apneia Obstrutiva do Sono/terapia , TraqueostomiaRESUMO
A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1, SEPN1, and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development.
Assuntos
Músculo Esquelético/patologia , Síndromes da Apneia do Sono , Criança , Feminino , Humanos , Microscopia Eletrônica , Proteínas Musculares/genética , Músculo Esquelético/fisiopatologia , Músculo Esquelético/ultraestrutura , Mutação/genética , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/genética , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/patologia , Síndromes da Apneia do Sono/fisiopatologiaRESUMO
Los síndromes miasténicos congénitos son un conjunto de alteraciones hereditarias cuya patogenia en común es la disfunción de la transmisión neuromuscular. La clínica consiste en debilidad y fatigabilidad de la musculatura estriada, que puede debutar tras el nacimiento o primera infancia. En la mujer gestante, el síndrome miasténico congénito tiene un transcurso impredecible, y puede agravarse en algunos casos. La vía de parto de elección es la vaginal. La fase de dilatación no se ve alterada, pero sí la fase de expulsivo por afectación de la musculatura abdominal, por lo que será necesario el uso de la tocurgia y la administración de anestesia epidural desde el inicio del parto. Presentamos un caso de una gestante con síndrome miasténico congénito por mutación en el gen COLQ
The congenital myasthenic syndromes are a group of inherited disorders in wich neuromuscular transmission is impaired. The congenital myasthenic syndromes are characterized by fatigable weakness of skeletal muscle with onset at or shortly after birth or in early childhood. Some case reports have suggested possible worsening of the clinical condition during pregnancy. However, this risk has not yet been quantified in a significant number of patients. Vaginal delivery is the best one in a pregnant patient with myasthenic symptomatology. The first stage of labour isnt affected. Nevertheless, the use of the instrumental delivery and epidural analgesia is necessary in the last stage of delivery due to weakness of abdominal muscles from fatigue. We show a case of a pregnant woman with congenital myasthenic syndrome because of mutation in the gene COLQ
Assuntos
Humanos , Feminino , Gravidez , Adulto , Síndromes Miastênicas Congênitas/complicações , Complicações na Gravidez/diagnóstico , Debilidade Muscular/complicações , Acetilcolinesterase/uso terapêutico , Anestesia Caudal/métodosRESUMO
Objective: To investigate the clinical and genetic features of congenital myasthenia syndrome with episodic apnea (CMS-EA) caused by gene mutation of choline acetyltransferase (CHAT) Methods: The clinical data of 2 patients with congenital myasthenia syndrome were collected, and both were diagnosed from 2013 to 2015 in Beijing Children's Hospital, Capital Medical University. The clinical features and gene mutation characteristics were analyzed, and the patients were followed-up for therapeutic efficacy. Results: The two patients (case 1 and case 2) had the onset soon after birth and at 3 months after birth respectively. The two patients were admitted to the PICU due to dyspnea, cyanotic episodes that required intubation. The patients had repeated apnea and became ventilator dependent. Case 1 died due to refusal of any treatment. Case 2 had a tracheotomy, and gradually weaned from ventilator after using pyridostigmine. The hospitalization of case 2 lasted 162 days. Case 2 was followed up to the age of 3 years and 4 months, and was extubated and was maintained on oral neostigmine but still had fluctuating ptosis and minor physical and mental retardation. Both cases were negative for anti-AChR, anti-acetylcholinesterase, anti-MuSK antibodies. Neostigmine test was negative in case 1 and suspiciously positive in case 2. Low-frequency repetitive nerve stimulation testing of case 2 was negative. Cranial MRI scans of both cases showed brain atrophy-like change. Genetic testing showed compound heterozygous deletions (exon 4, 5, 6) and pathogenic variant c.914T>C (p.I305T) in CHAT in case 1, compound heterozygous variants c.1007T>C (p.I336T) and c.64C>T (p.Q22X) in CHAT in case 2. To our knowledge, compound heterozygous deletions (exon 4, 5, 6) and p.Q22X were novel, previously unreported variants. Conclusion: CMS-EA usually presents at birth or in the neonatal period with hypotonia, ptosis, dysphagia due to severe bulbar weakness, and respiratory insufficiency with cyanosis and apnea. Early treatment with pyridostigmine is helpful to the improvement of clinical symptoms and prognosis.
Assuntos
Mutação , Síndromes Miastênicas Congênitas/genética , Apneia , Criança , Colina O-Acetiltransferase , Éxons , Humanos , Síndromes Miastênicas Congênitas/complicações , Insuficiência RespiratóriaRESUMO
OBJECTIVE: To summarize the electrophysiological characteristics of two cases of endplate acetylcholinesterase deficiency (EAD) related congenital myasthenic syndrome (CMS) caused by COLQ mutation and to discuss the possible mechanism of these electrophysiological phenomena. METHODS: Electrophysiological examinations were conducted including nerve conduction studies, routine electromyography (EMG), repetitive nerve stimulation (RNS) and single fiber EMG (SFEMG). The ulnar nerve was also stimulated at 50â¯Hz followed by 0.5â¯Hz to record the recovery process of compound muscle action potential (CMAP). RESULTS: Repetitive CMAP (R-CMAP) was found in motor nerve conduction in both cases. Needle EMG showed myogenic damages and SFEMG showed remarkably increased jitter values. Of note, the amplitude of CMAP and R-CMAP showed regular changing trends, and so did their time intervals in RNS studies. CONCLUSIONS: The change patterns of CMAP and R-CMAP, in combination with other electrophysiological features are very useful for the diagnosis of EAD related CMS, especially in predicting the presence of correct gene mutations.