Homozygous Duplication in the CHRNE in a Family with Congenital Myasthenic Syndrome 4C: 18-Year Follow Up
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SUBMITTER: Almatrafi A
PROVIDER: S-EPMC10668953 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:RationaleCongenital myasthenic syndrome (CMSs) are a group of rare genetic disorders of the neurological junction, which can result in structural or functional weakness. Here, we characterized a case of CMS in order to clarify the diagnosis and expand the understanding of it. The molecular diagnosis had implications for choice of treatment and genetic counseling.Patient concernsA 3-year-old male patient with CMS had ptosis and limb weakness for 2 months after birth. Clinical course and electrophysiological, imaging, and genetic findings were assessed. Protein structure/function was predicted. A novel mutation of c.295C>T (exon 4) and another known mutation of c.442T>A (exon 5) were found in CHRNE. Both mutations localized in conserved sequences. The c.442T>A (p.C148S) missense mutation in CHRNE was predicted to be damaging/deleterious. The iterative threading assembly refinement (I-TASSER) server generated vastly different 3-dimensional (3D) atomic models based on protein sequences from wide-type and novel nonsense mutation of c.295C>T (p.R99X) in CHRNE.DiagnosesThe diagnosis of CMS with CHRNE mutations in Han Chinese was confirmed.InterventionsThe patient was given prednisone (10 mg, once daily, taken orally) and pyridostigmine (15 mg, three times a day, taken orally).OutcomesThe patient had a moderate response to prednisone and pyridostigmine.LessonsWe expanded the genotype and phenotype of CMS with CHRNE mutations in Han Chinese and provided new insights into the molecular mechanism of CMS and help to the diagnosis and treatment of CMS.
| S-EPMC5944527 | biostudies-literature
Project description:Mutations in CHRNE encoding the epsilon subunit of acetylcholine receptor result in impaired neuromuscular transmission and congenital myasthenic syndrome (CMS) with variying severity of symptoms. Although the pathophysiology is well-known, blood biomarker signatures enabling a patient-stratification are lacking. This retrospective two-center-study includes 19 recessive CHRNE-patients (AChR deficiency; mean age 14.8 years) from 13 families which were clinically characterized according to disease severity. 15 patients were classified as mildly and 4 patients as moderate to severely affected. Seven known pathogenic and one unreported variant (c.1032 + 2_1032 + 3delinsGT) were identified. Biomarker discovery was carried out on blood samples: proteomics was performed on white blood cells (WBC; n = 12) and on extracellular vesicles (EV) purified from serum samples (n = 7) in addition to amino acid profiling (n = 9) and miRNA screening (n = 18). For miRNA studies, 7 patients with other CMS-subtypes were moreover included. WBC-proteomics unveiled a significant increase of 7 and a decrease of 36 proteins. In silico studies of these proteins indicated affection of secretory granules and the extracellular space. Comparison across patients unveiled increase of two vesicular transport proteins (SCAMP2 and SNX2) in severely affected patients and indeed EV-proteomics revealed increase of 7 and decrease of 13 proteins. Three of these proteins (TARSH, ATRN & PLEC) are known to be important for synaptogenesis and synaptic function. Metabolomics showed decrease of seven amino acids/ amino acid metabolites (aspartic and glutamic acids, phosphoserine, amino adipate, citrulline, ornithine, and 1-methyhistidine). miRNA-profiling showed increase miR - 483 - 3p, miR-365a-3p, miR - 365b - 3p and miR-99a, and decrease of miR-4433b-3p, miR-6873-3p, miR-182-5p and let-7b-5p in CHRNE-patients whereas a comparison with other CMS subtypes showed increase of miR - 205 - 5p, miR - 10b - 5p, miR-125a-5p, miR-499-5p, miR-3120-5p and miR - 483 - 5p and decrease of miR - 1290. Our combined data introduce a molecular fingerprint on protein, metabolic and miRNA level with some of those playing different roles along the neuromuscular axis.
| S-EPMC11823195 | biostudies-literature
Project description:BackgroundCongenital myasthenic syndromes (CMSs) are a heterogeneous group of neuromuscular disorders. Mutations of the nicotinic acetylcholine receptor epsilon subunit gene (CHRNE) are the most common causes of these disorders. CMSs are gaining increasing recognition by clinicians. However, pharmacological treatment of CMS with CHRNE mutations has only been discussed in a small number of case reports.ObjectiveThis study aims to determine how to choose an appropriate pharmacological strategy for CMS with CHRNE mutations.MethodsA meta-analysis was performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched for studies published in English prior to June 1, 2020. The extracted data included clinical information, gene mutations, pharmacological treatment, and treatment effects.ResultsA total of 48 studies and 208 CMS patients with CHRNE mutations were included in our meta-analysis. Ten different pharmacological strategies were used in these patients. Our research found that β2-adrenergic receptor agonists had the best treatment effect for CMS patients with CHRNE mutations, especially in patients with primary AChR deficiency. In addition, our analysis found no evidence that age at disease onset influences the treatment results.ConclusionThis meta-analysis provides evidence that (1) β2-adrenergic receptor agonist therapy could be the first choice of pharmacological strategy for treating CMS with CHRNE mutations; (2) a single-drug-regime, rather than a combination therapy, should be the first choice of treatment; and (3) it is never too late to initiate pharmacological treatment.
| S-EPMC8573743 | biostudies-literature
Project description:Congenital myasthenic syndromes (CMS) are rare and heterogeneous genetic diseases characterized by compromised neuromuscular transmission and clinical features of fatigable weakness; age at onset, presenting symptoms, distribution of weakness, and response to treatment differ depending on the underlying molecular defect. Mutations in one of the multiple genes, encoding proteins expressed at the neuromuscular junction, are currently known to be associated with subtypes of CMS. The most common CMS syndrome identified is associated with mutation in the CHRNE gene, causing principally muscle nicotinic acetylcholine receptor deficiency, that results in reduced receptor density on the postsynaptic membrane. We describe the clinical, neurophysiological and molecular features of two unrelated CMS Italian families with marked phenotypic variability, carrying the already reported p.T159P mutation in the CHRNE gene. Our report highlights clinical heterogeneity, intrafamily variability in spite of the same genotype and a possible gender effect; it confirms the efficacy and safety of salbutamol in patients who harbor mutations in the epsilon subunit of acetylcholine receptor.
| S-EPMC5479107 | biostudies-literature
Project description:We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597-603.
| S-EPMC5413866 | biostudies-literature
Project description:BackgroundEvidence on the role of co-occurring psychiatric disorders in mortality associated with psychotic depression is limited.AimsTo estimate the risk of cause-specific mortality in psychotic depression compared with severe non-psychotic depression while controlling for comorbid psychiatric disorders.MethodThis cohort study used routine data from nationwide health registers in Finland. Eligible participants had their first diagnosis for psychotic depression or for severe non-psychotic depression between the years 2000 and 2018, had no pre-existing diagnoses for schizophrenia spectrum disorders or bipolar disorder, and were aged 18-65 years at the index diagnosis. Causes of death were defined by ICD-10 codes. The follow-up time was up to 18 years.ResultsWe included 19 064 individuals with incident psychotic depression and 90 877 individuals with incident non-psychotic depression. Half (1199/2188) of the deaths in those with psychotic depression occurred within 5 years from the index diagnosis and the highest relative risk was during the first year after the diagnosis. Compared with individuals with non-psychotic depression, those with psychotic depression had a higher risk of all-cause mortality (adjusted hazard ratio, aHR = 1.59, 95% CI 1.48-1.70), suicides (aHR = 2.36, 95% CI 2.11-2.64) and fatal accidents (aHR 1.63, 95% CI 1.26-2.10) during the subsequent 5-year period after the index diagnosis.ConclusionsPsychotic symptoms markedly added to the mortality risk associated with severe depression after controlling for psychiatric comorbidity. Prompt treatment and enhanced monitoring for psychotic symptoms is warranted in all patients with severe depression to prevent deaths because of suicides and other external causes.
| S-EPMC10895511 | biostudies-literature
Project description:Pathogenic variants in CHRNE encoding the epsilon subunit of acetyl choline receptor (AChR) result in impaired neuromuscular transmission and congenital myasthenic syndromes (CMS). Clinical manifestations include facial, ocular and limb fatigability and weakness, whereby severity of symptoms may vary in patients harboring the same pathogenic variant. Although the underlying pathophysiology is well-known, blood biomarkers enabling a patient-stratification are lacking. Previous studies revealed CHRNE protein in white blood cells (WBC) rendering these cells suitable for the study of cellular and minimal-invasive marker proteins.
2025-05-07 | PXD054347 | Pride
Project description:Introduction: Congenital myasthenic syndromes (CMS) refer to a heterogenic group of neuromuscular transmission disorders. CMS-subtypes are diverse regarding exercise intolerance and muscular weakness, varying from mild symptoms to life-limiting forms with neonatal onset. Long-term follow-up studies on disease progression and treatment-response in pediatric patients are rare. Patients and Methods: We analyzed retrospective clinical and medication data in a cohort of 32 CMS-patients including the application of a standardized, not yet validated test (CMS-ST) to examine muscular strength and endurance in 21 patients at the last follow-up. Findings obtained in our cohort were compared with long-term follow-up studies of (adult) CMS-cohorts from the literature by considering the underlying molecular mechanisms. Outcomes of CMS-ST were compared to results of normal clinical assessment. Results: Thirty-two pediatric patients with defects in eight different CMS-genes were followed by a median time of 12.8 years. Fifty-nine percentage of patients manifested with first symptoms as neonates, 35% as infants. While 53% of patients presented a reduced walking distance, 34% were wheelchair-bound. Even under adequate therapy with pyridostigmine (PS) and 3,4-diaminopyridine, CHAT-mutations led to the progression of muscular weakness partly in combination with persistent respiratory and bulbar symptoms. RAPSN, CHRND, and CHRNB1 patients with neonatal manifestation, early respiratory problems, and bulbar symptoms showed a good and maintained treatment response. CHAT and CHRNE patients required higher PS dosages, whereas RAPSN patients needed a lower mean dosage at the last follow-up. The benefits of short-term medication and long-term progression of symptoms were highly dependent on the specific genetic defect. CMS-ST was carried out in 17/21 patients, determined affected muscle groups including bulbar and ocular symptoms, some of which were not reported by the patients. Conclusions: Our findings and comparison with the literature- suggest a better treatment-response and less severe progression of symptoms present in patients suffering from mutations in CMS-genes directly associated with receptor deficiency, while patients with defects leading to synaptopathy and presynaptic defects tend to have worse outcomes. Assessment of affected muscular groups and clinical symptoms by CMS-ST may be a useful tool for optimal therapeutic management of the patients, especially for future clinical studies.
| S-EPMC7750519 | biostudies-literature
Project description:This study compared mortality rates and decline in life expectancy of Iranian patients with type 2 diabetes (T2DM) with the general population. A retrospective study of 2451 patients with T2DM was conducted in the Isfahan Endocrine and Metabolism Research Center, Iran, between 1992 and 2010. The mean (SD) of diabetes duration and median (Q1,Q3) of follow-up period were 15.5(8.0) and 8(5, 10) years. The main outcome was all-cause mortality. 732(29.87%) of patients died during the follow-up. Overall mortality rates (95%CI) per 1000 person-years in men and women were 56.3(52.0-62.1) and 27.3(24.5-30.4), respectively. The relative risks (95%CI) of all-cause mortality in males vs. females with T2DM aged 45-49, 50-54, 55-59, 60-64, 65-69, 70-74 were [3.02(1.49-6.11) vs. 2.09(0.96-4.57)], [4.05(2.73-6.01) vs. 2.29(1.52-3.45)], [4.13(3.26-5.24) vs. 1.70(1.23-2.35)], [2.42(1.90-3.07) vs. 1.82(1.46-2.27)], [2.36(2.02-2.76) vs. 1.49(1.25-1.78)] and [1.71(1.50-1.95) vs. 1.04(0.88-1.23)] times more than the general population, respectively. Men and women living with diabetes lost an average of 13.2(6.3) and 13.9(6.0) life-years from the year of diagnosis, respectively (p = 0.101). The estimated life-years lost were greater in younger patients and a gradual decline was observed with increasing the age at diagnosis. In conclusion, Iranians with diabetes had higher risk of death and lower life expectancy compared to the general population.
| S-EPMC7035261 | biostudies-literature
Project description: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 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.
| S-EPMC10963930 | biostudies-literature