CHRNE Mutations Research Articles

Independent CHRNE mutations at serine 503 in English Springer Spaniels and a Smooth Fox Terrier having congenital myasthenic syndrome.

Independent CHRNE mutations at serine 503 in English Springer Spaniels and a Smooth Fox Terrier having congenital myasthenic syndrome.

Divergent Phenotypes with Same CHRNE Mutation in Two Siblings with Congenital Myasthenic Syndrome

Background: Congenital myasthenic syndrome is a rare inherited neuromuscular disorder resulting in abnormal weakness and fatigue on exertion with onset at or shortly after birth or in early childhood. Clinical Description: A 2-year-old boy presented to us with respiratory failure, having a history of recurrent respiratory tract infections and underlying isolated motor delay. His 7-year-old elder sister had undiagnosed generalized weakness. Management and Outcome: While the index case was being stabilized with mechanical ventilation, his elder sibling was evaluated. Ptosis was noted in her, which improved with neostigmine. Examination and laboratory investigations ruled out other differentials. Clinical exome sequencing was sent which showed homozygous CHRNE ENST00000649488.2.c.1367_1369del. (p.Asn456del) resulting in acetylcholine receptor deficiency. Both siblings were started on oral pyridostigmine and salbutamol, resulting in improvement in muscle weakness over 3 months and 4 months in younger and older sibling, respectively. Conclusion: Recurrent respiratory insufficiency when associated with motor delay may be suggestive of a neuromuscular disorder. Even siblings with the same mutation may have different levels of severity of clinical manifestation.

Calcitriol ameliorates motor deficits and prolongs survival of Chrne-deficient mouse, a model for congenital myasthenic syndrome, by inducing Rspo2

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.

Congenital Myasthenic Syndrome: case study from a tertiary care institute of Western India

Objective. To describe clinical characteristics, genetic details and management of patients of congenital myasthenic syndrome. Methods. A retrospective study was carried out from 2020 to 2023. Patient who presented with ptosis, ophthalmoplegia, proximal limb weakness with genetically confirmed mutations for CMS were included in the study. Patients who were positive for Acetylcholine receptor antibody (AChRAb) or Muscle specific kinase (MuSK) antibody or any other antibodies suggestive of acquired myasthenia were excluded from the study. Outcome. 6 genetically proven patients were identified out of which 4 patients had CHRNE mutation, 1 patient had CHRNA1 mutation and 1 patient had Dok7 mutation. Mean delay in diagnosis was 15 years. Patient with Dok 7 mutation responded to salbutamol, 1 patient of CHRNE mutation required combination of pyridostigmine, fluoxetine and salbutamol, rest all patient responded to pyridostigmine. It took 4 weeks for improvement after starting salbutamol in patient with Dok7 mutation. Conclusion. Although rare, CMS is potentially treatable group of disease. Patient presenting with early onset muscular weakness should be evaluated thoroughly and CMS should be considered in presence of eyelid ptosis, ophthalmoplegia and proximal weakness with diurnal fluctuations. RNS and genetic testing are paramount in achieving an early diagnosis.

Homozygous Duplication in the CHRNE in a Family with Congenital Myasthenic Syndrome 4C: 18-Year Follow Up.

Congenital myasthenic syndromes (CMSs) are rare inherited diseases characterized by muscle weakness and fatigability on exertion resulting from defects in the neuromuscular junctions. Mutations in 32 genes have been reported as the underlying causes of CMS, with mutations in the cholinergic receptor nicotinic epsilon subunit (CHRNE) being the most common cause of the disease. Methodology and Materials: This study investigated a large consanguineous family with multiple individuals suffering from abnormal fatigue and muscle weakness in the ocular and limb regions. Moreover, the affected individuals were followed up for 18 years to observe the clinical course of the disease. High-quality exome sequencing followed by bidirectional Sanger sequencing revealed a homozygous duplication variant (NM_000080.4: c.1220-8_1227dup) in the splice acceptor site of exon 11 of the CHRNE gene. This variant is predicted to cause frameshift and premature termination (p.Cys410ProfsTer51). Both parents had heterozygous duplication variants with no clinical symptoms. The personalized treatment of the affected individuals resulted in a marked improvement in the clinical symptoms. More than 80% of the disease symptoms in the affected individuals subsided after the use of pyridostigmine and salbutamol (4 mg). This is the first report of long-term follow up of cases with homozygous insertion (c.1220-8_1227dup) in the CHRNE gene. Furthermore, this report expands the phenotypic symptoms associated with the CHRNE mutation.

Congenital myasthenic syndromes: A study of 15 cases

AbstractBackgroundCongenital myasthenic syndromes (CMS) are rare inherited heterogeneous disorders of neuromuscular transmission.Aims and methodologyThis study aims to describe clinical and investigative characteristics including genetic aspects of patients with congenital myasthenic syndrome (CMS), in a cohort from western India. Retrospective analysis for the study period of 9 years (−January 2013 to December 2021) was performed. Patients were identified by predefined selection criteria using a combination of clinical, electrophysiological, and genetic studies.ResultsFifteen genetically evaluated CMS patients, 11 females, and 4 males were identified. Ten patients had a history of fatigable ptosis at an early age, whereas all patients had varying degrees of proximal weakness at the time of presentation. The mean age at onset was 16 years and the mean age at final diagnosis was 22 years, thereby representing a mean delay in diagnosis of 6 years. Among the total 13 different genetic mutations identified, 4 are not previously reported. The most common genetic mutations identified were CHRNE gene (in 7 patients) followed by DOK7 gene (in 6 patients), and the remaining 2 patients had mutation in MUSK gene. Roma founder mutation (c.1327delG, p.E443ter) was seen in 5 patients with CHRNE gene. Four patients responded to pyridostigmine alone, 7 patients to salbutamol, whereas 4 patients required a combination of pyridostigmine and salbutamol.ConclusionThis study, carried out in a small cohort of patients, highlights the frequent occurrence of Roma founder mutation in our population, and the predominance of CHRNE and DOK7 gene mutations, points of regional importance. Four novel variants were also identified in the genetic studies carried out.

Congenital myasthenic syndrome in a cohort of patients with 'double' seronegative myasthenia gravis.

Congenital myasthenic syndromes (CMS) have some phenotypic overlap with seronegative myasthenia gravis (SNMG). The aim of this single center study was to assess the minimum occurrence of CMS misdiagnosed as double SNMG in a Brazilian cohort. The genetic analysis of the most common mutations in CHRNE, RAPSN, and DOK7 genes was used as the main screening tool. We performed genetic analysis in 22 patients with a previous diagnosis of 'double' SNMG. In this study, one CMS patient was confirmed due to the presence of compound heterozygous variants in the CHRNE gene (c.130insG/p.Cys210Phe). This study confirmed that CMS due to CHNRE mutations can be mistaken for SNMG. In addition, our study estimated the prevalence of misdiagnosed CMS to be 4.5% in 'double' SNMG patients of our center. Based on our findings, genetic screening could be helpful in the diagnostic workup of patients with 'double' SNMG in whom differential diagnosis is recommended.

Congenital myasthenic syndrome in Turkey: clinical and genetic features in the long-term follow-up of patients.

Congenital Myasthenic Syndromes (CMS) are rare disorders that occur as a result of defects in the structure and in the function of neuromuscular junctions. Molecular genetic diagnosis is important to select the most suitable therapeutic option and treatment. Eight patients with congenital myasthenic syndromes who presented to the Çukurova University Pediatric Neurology Department Outpatient Clinic between June 2015 and May 2018 were reviewed. Mutations in the acetylcholine receptor (subunits in epsilon) (CHRNE) in three and mutations in the collagenic tail of endplate acetylcholinesterase (COLQ) gene in five patients were identified; p.W148 mutation was detected to be homozygous in four, c.1169A > G novel mutation in COLQ gene was homozygous in one, c452_454delAGG mutation was homozygous in the other patient, IVS7 + 2T > C(c.802 + 2T > C) mutation was homozygous in a patient and compound heterozygous mutations of c.865C > T(p.Leu289Phe) and c.872C > G(p.A2916)(p.Arg291Gly) in the CHRNE gene in the last patient. The parents of all the evaluated patients were consanguineous. Ptosis, ophthalmoplegia, generalized hypotonia, bulbar weakness, and respiratory crisis were the main findings at the time of presentation. Pyridostigmine is the first-line drug therapy in primary AChR deficiency. Beta adrenergic agonists, ephedrine, and albuterol are the other treatment options for CMS subtypes caused by mutations in COLQ. This study points out the genetic and phenotypic features of CMS patients in the Turkish population and it also reports previously unreported mutations in the literature. CHRNE and COLQ gene mutations are common in the Turkish population. Patients can get serious benefits and recover after the treatment. The treatment should be planned according to genetic tests and clinical findings.

Congenital myasthenic syndrome withe chrne mutation clinical and electrophysiological aspects (in cosanguinous moroccan family)

Congenital myasthenic syndrome withe chrne mutation clinical and electrophysiological aspects (in cosanguinous moroccan family)

Late presented congenital myasthenic syndrome with novel compound heterozygous CHRNE mutations mimicking seronegative myasthenia gravis

AbstractWe found a late presented congenital myasthenic syndrome (CMS) patient with novel CHRNE gene mutations. Although our patient has shown blepharoptosis since youth, fatigable muscle weakness began at age 71. Genetic analysis revealed novel compound heterozygous CHRNE mutations (c.1032+2T>G, c.1306_1307 delGA). His myasthenic symptoms were well managed by oral anti‐cholinesterase drug until he died at 82‐year‐old. The present case showed mild myasthenic symptoms with very late presentation and slow progression. Late presented CMS is often underdiagnosed; therefore, genetic testing is important to distinguish it from other myasthenic disease.

A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome.

The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.

P.416 - A common CHRNE mutation (c.130dupG) in Brazilian patients with congenital myasthenic syndrome

P.416 - A common CHRNE mutation (c.130dupG) in Brazilian patients with congenital myasthenic syndrome

Molecular characterization of congenital myasthenic syndromes in Spain

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.

Congenital myasthenic syndrome in Israel: Genetic and clinical characterization

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.

Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE 1267delG mutation. A long-term follow-up

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders. Mutations in CHRNE are one of the most common cause of them and the ɛ1267delG frameshifting mutation is described to be present on at least one allele of 60% of patients with CHRNE mutations. We present a comprehensive description of the heterogeneous clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit in nine members of two large Gipsy kindreds. Our observations indicate that founder Roma mutation 1267delG leads to a phenotype further characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP; but also by facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness that sometimes entails the loss of ambulation. Interestingly, we found in our series a remarkable proportion of patients with a progressive or fluctuating course of the disease. This finding is in some contrast with previous idea that considered this form of CMS as benign, non progressive, and with a low impact on the capacity of ambulation.

G.P.83 - Congenital myasthenic syndromes in Israel: Genetic and clinical characterization

The genetic and clinical characteristics of Israeli patients with congenital myasthenic syndromes (CMS) evaluated in four medical centers are presented. Forty-one patients with CMS from thirty two independent families in whom genetic mutation was detected are described. Genetic evaluation was initially performed depending on patients' clinical symptoms and known CMS genes were sequenced. All patients' medical records were reviewed and their clinical data, electrophysiological studies, genetic mutation and outcome were recorded. Mutations in Rapsyn were detected in 15 patients of 13 families. The most common mutation was the Rap-38A>G, identified in patients of Iran–Iraq Jewish origin. Mutations in COLQ were confirmed in 11 patients of 8 families. Four different recessive mutations of COLQ were identified mostly in Arab patients. CHRNE mutations were confirmed in 15 patients of 13 families. The less common detected mutations were: CHRND, ChAT, GFTP1 and dok-7. The vast majority of children had clinical symptoms in infancy. Ptosis, ophthalmoplegia and feeding problems were the most common symptoms. RAPSYN, COLQ and CHRNE were the most common causes of CMS in our cohort. Specific mutations in these genes are detected in unique ethnic populations in Israel.

P164 – 2586: Congenital myasthenic syndrome in Israel: Genetic and clinical characterization

Objective Congenital myasthenic syndromes (CMS) are a rare heterogeneous group of inherited neuromuscular disorders associated with distinctive clinical, electrophysiological and genetic abnormalities. Mutations in various genes of the neuromuscular junction may cause presynaptic, synaptic or postsynaptic defects. In this study, the genetic and clinical characteristics of Israeli patients with CMS were evaluated. Methods Twentysix patients with CMS from 16 independent families in whom genetic mutation was detected were diagnosed in two Israeli medical centers. Genetic evaluation was initially performed depending on patients' clinical symptoms and known CMS genes were sequenced. Patients of Jewish Iranian or Iraqi ethnic origin were screened directly for a known 38 A-G mutation in RAPSYN. In two patients, whole exome sequencing was analyzed. All patients' medical records were reviewed and their clinical data, electrophysiological studies and outcome were recorded. Results The diagnosis of CMS was confirmed in 26 patients of 16 families. Among these patients, 8 patients of 4 families had recessive mutations in COLQ, eight patients of 5 families, mutations in CHRNE, and eight patients of 5 families, mutations in RAPSN. CHRND was diagnosed in 2 patients from one family. The mean age of onset of clinical symptoms was 6 months. Ptosis, ophthalmoplegia and feeding problems were the most common symptoms. Conclusions RAPSYN and CHRNE are the most common causes of CMS in our cohort. The second most common cause is COLQ. Specific mutations in RAPSYN, CHRNE and COLQ are detected in unique ethnic populations in Israel.

PP09.7 – 2375: Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE1267delG mutation. A long-term follow-up

Objective Mutations in CHRNE are the cause of approximately 50% of CMS. ɛ1267delG frameshifting mutation is present on at least one allele of 60% of patients with CHRNE mutations. We here present a description of the clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR ɛ subunit in 13 members of two large Roma kindreds. Methods Thirteen patients from two unrelated families were followed up over a mean period of 9.9 years. Results We trace 65 and 108 members in six and seven generations of each family, respectively. We interviewed and examined 13 clinically affected family members, 9 women and 4 men. Disease onset ranged from first weeks after birth to 12 years (mean 3.7 years; median 2 years). Ophthalmoparesis was observed in nine patients and subjective diplopia was present in all thirteen cases. Bilateral symmetric ptosis was found in ten patients. Facial weakness was encountered in eleven patients. Mild bulbar symptoms were reported in ten patients. Proximal muscle weakness was found in ten patients. It entailed restricted ambulation in 8 patients. A rapid progression of the disease was noted in two patients. The disease course have remained stable in eight patients. Three patients had a significant fluctuation of their symptoms. All the thirteen patients responded positively to pyridostigmine. In 6 patients, addition of 3,4-diaminopyridine resulted in further clinical improvement. Conclusion Founder European Roma mutation 1267delG leads to an heterogeneous phenotype with a varying severity. It is further characterized by ophthalmoplegia and a good response to anticholinesterase drugs and 3,4-DAP; but also by ptosis, facial weakness, bulbar symptoms, neck muscle weakness, and proximal muscle weakness that entails the loss of ambulation in 63% of our adult patients. The disease course can be stable but also progressive in nearly 40%, with or without fluctuations.

P.12.3 Do congenital myasthenic syndromes in childhood have a common face? Clinical profile of slow channel, CHRNE and RAPSYN mutations

Congenital myasthenic syndromes (CMSs) form a group of hereditary disorders, which are clinically and genetically heterogeneous. The neuromuscular transmission cascade is disrupted at presynaptic, synaptic or postsynaptic level, the latter is the most common. As a large part of CMSs have their onset in childhood, performing diagnostic studies leading to diagnosis can be very challenging. CMSs are highly treatable but treatment depends on the mutation type, so clinicians are urged to perform tailored genetic testing guided by clinical features. This systematic review of the literature shows the clinical neurological features of published cases with CMS due to a slow channel syndrome, RAPSYN deficiency or acetylcholine receptor (AChR) deficiency. English and Dutch case reports and series describing patients with a genetically proven CHRNE, RAPSYN or slow channel CMS from 1980 to 2012 were collected. Clinical features were evaluated. Findings were mostly in line with clinical features mentioned in previous literature. Minor differences were encountered. Very common were ocular, bulbar and limb weakness for AChR deficiency (N = 100). Cervical and distal weakness was often seen in slow channel syndromes (N = 51). Bulbar symptoms, arthrogryposis multiplex congenita, respiratory difficulties and the N88K founder mutation occurred frequently in the RAPSYN deficient patients (N = 98). Opposed to earlier reports no early- and late-onset phenotype was identified in the latter group and ophthalmoparesis was rare. In slow channel syndromes bulbar (25%) and ocular weakness (50%) was more common than previously reported. Ethnicity was not always in line with previous literature but could still be helpful in more targeted genetic testing. Overall we think that detailed descriptions of clinical features could guide the clinician in the diagnostic process.

Slow channel congenital myasthenic syndrome responsive to a combination of fluoxetine and salbutamol

Slow channel congenital myasthenic syndrome is a dominant disorder characterized by prolonged acetylcholine receptor ion-channel activation. Molecular genetic techniques, electrophysiology, and binding studies in human embryonic kidney (HEK) 293 cells determined mutant function and expression levels. Patient response to treatment was measured by quantitative myasthenic gravis and Medical Research Council grade strength scores. We report an unusual case due to heteroallelic mutations in CHRNE. The slow channel mutation, p.εS278del, is accompanied by a severe low-expression mutation, p.εR217L, on the second allele. Expression studies and cosegregation of p.εS278del with the disorder in the patient's offspring demonstrate robust expression of the p.εS278del mutation. The patient showed modest benefits from standard treatment with fluoxetine, but there was dramatic improvement when salbutamol was combined with fluoxetine. This case suggests that salbutamol, which is beneficial in some other congenital myasthenic syndromes, might also be considered in addition to fluoxetine in slow channel syndrome.