myasthenic syndrome

Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected. The aim of this study was to identify changes in the hypothalamic-pituitary axis in mouse models for both disorders and to examine mitochondrial function in skin fibroblasts of patients and knockout cell lines...

Voltage gated calcium channels (VGCCs) play a critical role in neural transmission. Antibodies that target these ion channels can disrupt cellular signal transmission resulting in various clinical presentations. VGCC antibodies are most commonly associated with paraneoplastic syndromes such as Lambert-Eatons myasthenic syndrome. Here, we report a 47-year-old female with Stage IV appendiceal adenocarcinoma status post appendectomy and right hemicolectomy, who presented with progressive memory impairment, aphasia, ataxia, weakness, and headache...

BACKGROUND: SCN4A mutations account for a diverse array of clinical manifestations, encompassing periodic paralysis, myotonia, and newly recognized symptoms like classical congenital myopathy or congenital myasthenic syndromes. We describe the initial occurrence of myopathic features mimic with recessive classical CM in a Korean infant presenting with novel compound heterozygous SCN4A mutations. The infant exhibited profound hypotonia after birth, thereby expanding the spectrum of SCN4A -related channelopathy...

BACKGROUND: Collagen XIII is a transmembrane collagen associated with neuromuscular junction development, and in humans its deficiency results in congenital myasthenic syndrome type 19 (CMS19), which leads to breathing difficulties. CMS19 patients usually have restricted lung capacity and one patient developed chronic lung disease. In single-cell RNA sequencing studies, collagen XIII has been identified as a marker for pulmonary lipofibroblasts, which have been implicated in the resolution of pulmonary fibrosis...

Biallelic loss of function variants in the MUSK gene result in two allelic disorders: 1) congenital myasthenic syndrome (CMS; OMIM 616325), a neuromuscular disorder which has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness and 2) fetal akinesia deformation sequence (FADS; OMIM 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction...

OBJECTIVE: To explore the clinical and genetic characteristics of a fetus diagnosed with Congenital myasthenic syndrome type 16 (CMS16). METHODS: A couple who had visited Tianjin Medical University General Hospital in February 2018 due to "adverse outcome of two pregnancies" was selected as the study subject. Clinical data was gathered. Peripheral blood and amniotic fluid samples were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing...

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...

BACKGROUND: Congenital myasthenic syndrome is a heterogeneous group of inherited neuromuscular transmission disorders. Variants in RAPSN are a common cause of CMS, accounting for approximately 14%-27% of all CMS cases. Whether preimplantation genetic testing for monogenic disease (PGT-M) could be used to prevent the potential birth of CMS-affected children is unclear. METHODS: Application of WES (whole-exome sequencing) for carrier testing and guidance for the PGT-M in the absence of a genetically characterized index patient as well as assisted reproductive technology were employed to prevent the occurrence of birth defects in subsequent pregnancy...

A 79-year-old woman who presented ptosis and dysphagia were admitted to our hospital. Anti-acetylcholine receptor antibodies and anti-P/Q-type VGCC antibodies were both positive. Electrophysiological examination showed postsynaptic pattern which supported myasthenia gravis. She did not meet the diagnostic criteria for Lambert-Eaton myasthenic syndrome (LEMS). In cases which these antibodies coexist, careful electrophysiological evaluation is required for the diagnosis. In addition, although anti-P/Q-type VGCC antibodies have been specific to LEMS, patients with these antibodies represent various symptoms other than LEMS...

Lambert-Eaton myasthenic syndrome (LEMS) is a rare paraneoplastic neurological syndrome of the neuromuscular transmission. The symptoms often progress slowly and can be misdiagnosed in early stage. Seropositive SOX-1 antibodies are support for the diagnosis of LEMS and have high specificity for small cell lung cancer (SCLC). In this paper, we report a case of a 56-year-old man with smoking history who was admitted to hospital with progressive muscle weakness of the proximal legs. LEMS was diagnosed by repetitive nerve stimulation (RNS) testing and seropositive SOX-1 antibodies...

Treatment strategies in paraneoplastic neurological syndromes rely on the three pillars of tumor treatment, immunotherapy, and symptomatic treatment, the first one being by far the most important in the majority of patients and syndromes. Classically, antibodies against extracellular antigens are directly pathogenic, and patients with these syndromes are more responsive to immunomodulatory or immunosuppressive treatments than the ones with antibodies against intracellular targets. This chapter first discusses some general principles of tumor treatment and immunotherapy, followed by a closer look at specific treatment options for different clinical syndromes, focusing on symptomatic treatments...

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the gastro-entero-pancreatic system and respiratory tract. The classification was recently revised in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. NENs can rarely spread to the central or peripheral nervous systems. Neurologic involvement is determined by the rare development of paraneoplastic syndromes, which are remote effects of cancer...

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease characterized by proximal muscle weakness, loss of tendon reflexes, and autonomic dysfunction. Muscle weakness usually starts in the upper legs and can progress to oculobulbar and in severe cases respiratory muscles. P/Q-type voltage-gated calcium channels (VGCCs) localized in the presynaptic motor nerve terminal and in the autonomic nervous system are targeted by antibodies in LEMS patients. These antibodies can be detected in about 90% of patients, and the presence of decrement and increment upon repetitive nerve stimulation is also a highly sensitive diagnostic test...

Paraneoplastic neurologic syndromes are a group of rare disorders that have fascinated neurologists for more than a century. The discovery in the 1980s that many of these disorders occurred in association with antibodies against neuronal proteins revived the interest for these diseases. This chapter first traces the history of the paraneoplastic neurologic syndromes during the era that preceded the discovery of immune mechanisms and then reviews the immunologic period during which many of these syndromes were found to be associated with antibodies against intracellular onconeuronal proteins and pathogenic cytotoxic T-cell mechanisms...

We describe the case of a 19-month-old girl presenting with gross motor delays, hypotonia, diminished deep tendon reflexes, hyperCKaemia, extensive white matter changes on MRI brain, and electromyography studies consistent with myopathy. The differential diagnosis for infantile-onset hypotonia and muscle weakness is broad. It includes numerous subtypes of genetic disorders, including congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, spinal muscular atrophy, single-gene genetic syndromes, and inborn errors of metabolism...

BACKGROUND: Congenital myasthenic syndrome (CMS) is a group of neuromuscular disorders caused by abnormal signal transmission at the motor endplate. Mutations in the collagen-like tail subunit gene (COLQ) of acetylcholinesterase are responsible for recessive forms of synaptic congenital myasthenic syndromes with end plate acetylcholinesterase deficiency. Clinical presentation includes ptosis, ophthalmoparesis, and progressive weakness with onset at birth or early infancy. METHODS: We followed 26 patients with COLQ-CMS over a mean period of 9 years (ranging from 3 to 213 months) and reported their clinical features, electrophysiologic findings, genetic characteristics, and therapeutic management...

Myasthenia gravis (MG) is often complicated by respiratory failure, an exacerbation known as myasthenic crisis. However, most patients with MG develop respiratory symptoms during the late course of the disease. Respiratory failure as an exclusive initial and primary complaint in patients with MG is rare and seldom reported. We herein describe a woman in her late 50s who presented with respiratory failure and was diagnosed with obesity hypoventilation syndrome at a local hospital. Her condition gradually worsened during the next 4 months and became accompanied by dysphagia...

BACKGROUND: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disorder leading to muscle weakness, autonomic dysregulation and hyporeflexia. Psychosocial well-being is affected. Previously, we assessed burden of disease for Myasthenia gravis (MG). Here, we aim to elucidate burden of disease by comparing health-related quality of life (HRQoL) of patients with LEMS to the general population (genP) as well as MG patients. METHODS: A questionnaire-based survey included sociodemographic and clinical data along with standardized questionnaires, e...

Guanosine diphosphate-mannose pyrophosphorylase B (GMPPB) catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, which is required as a mannose donor for the biosynthesis of glycan structures necessary for proper cellular functions. Mutations in GMPPB have been associated with various neuromuscular disorders such as muscular dystrophy and myasthenic syndromes. Here, we report that GMPPB protein abundance increases during brain and skeletal muscle development, which is accompanied by an increase in overall protein mannosylation...

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. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics...