A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome

Estephan, Eduardo de Paula; Sobreira, Cláudia Ferreira da Rosa; Santos, André Clériston José dos; Tomaselli, Pedro J.; Marques, Wilson; Ortega, Roberta Paiva Magalhães; Costa, Marcela Câmara Machado; Silva, André Macedo Serafim; Mendonça, Rodrigo Holanda; Caldas, Vitor Marques; Zambon, A A; Neto, Osório Abath; Marchiori, Paulo Eurípedes; Heise, Carlos Otto; Reed, Umbertina Conti; Azuma, Yoshiteru; Töpf, Ana; Lochmüller, Hanns; Zanoteli, Edmar

doi:10.1007/s00415-018-8736-8

Cited by 20 publications

(20 citation statements)

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“…Patients with isolated ptosis have also been reported as in our patient. 6,12 The CHRNA1 gene encodes the α-subunit of acetylcholine receptor with homozygous mutations resulting in receptor deficiency and a severe phenotype with decreased fetal movements, growth retardation, and contractures with symptomatic response to pyridostigmine as seen in our patient. 6,13 CHRNB1 gene mutations affecting the β-subunit of acetylcholine receptor have rarely been reported in a few patients with congenital myasthenic syndrome, with at least 1 showing a severe phenotype of reduced fetal movements, polyhydramnios, hypotonia, ophthalmoplegia, bulbar weakness, and respiratory failure at birth as in our reported patient.…”

Section: Discussionmentioning

confidence: 62%

Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features

Prior

Ghosh

2021

J Child Neurol

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Background: Congenital myasthenic syndrome is a group of rare genetic disorders affecting transmission across the neuromuscular junction. Patients present with variable ocular, bulbar, respiratory, and extremity weakness that may respond to symptomatic therapies. Methods: We identified 18 patients with congenital myasthenic syndrome from a pediatric neuromuscular center over a decade. Through a retrospective chart review, we characterize demographic profile, clinical features, genetic variants, treatment, and follow-up of these patients. Results: Patients had the following genetic subtypes: CHRNE (6), CHAT (2), MUSK (2), DOK7 (2), COLQ (1), RAPSN (1), PREPL (1), GFPT1 (1), CHRBB1 (1), and CHRNA1 (1). The phenotype varied based on the genetic variants, though most patients have generalized fatigable weakness affecting ocular, bulbar, and extremity muscles. There was a significant delay in the diagnosis of this condition from the onset of symptoms. Although most patients improved with pyridostigmine, some subtypes showed worsening with pyridostigmine and others benefited from albuterol, ephedrine, or 3,4-diaminopyridine treatment. Conclusion: Increasing recognition of this rare syndrome will lead to early diagnosis and prompt treatment. Prompt utilization of genetic testing will identify novel variants and the expanding phenotype of this condition.

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Section: Discussionmentioning

confidence: 62%

Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features

Prior

Ghosh

2021

J Child Neurol

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“…Although it is known that congenital myasthenia patients do not usually have pure ocular symptoms, this phenotype has sometimes been reported [25]. Actually, our patient 7 was previously reported as a pure ocular syndrome at 19 years old [18], and now, aged 23 years, it was possible to see limb weakness. However, all DOK7 and COL13A1 patients were found in group B, as these cases do not respond to pyridostigmine, and COL13A1 patients often do not present fluctuations of symptoms [22,26], both characteristics included in group A criteria.…”

Section: Discussionmentioning

confidence: 75%

Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis

Estephan

Zambon

Thompson

et al. 2021

Euro J of Neurology

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Objectives To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. Methods Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non‐CMS molecular diagnosis. Results Seventy‐nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty‐one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non‐CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS. Conclusions Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.

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“…This was not an unexpected result, given the rarity of the condition and the fact that most pharmacological treatments for CMS are commonly available drugs prescribed in an off-label manner after rational selection based on their putative ability to correct the specific defect of neuromuscular transmission. While this means that there is a lack of evidence meeting the CEBM’s higher level evidence categories, the review clearly shows that there is a substantial body of both expert opinion and case-based analysis available and that in many cases, significant efforts have been made to gather substantially sized cohorts for prospective or retrospective analysis [37,38,41,42]. This demonstrates that it is valuable to systematically assess and categorize the evidence that does exist: clinicians make daily treatment decisions that involve giving patients with CMS a pharmacological therapy, and providing better access to the evidence in support of those decisions is not only of practical benefit to those making the prescribing decisions, but also provides a gap analysis and guidance towards possible future options for clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Targeted therapies for congenital myasthenic syndromes: systematic review and steps towards a treatabolome

Thompson

Bonne

Missier

et al. 2019

Emerging Topics in Life Sciences

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Despite recent scientific advances, most rare genetic diseases — including most neuromuscular diseases — do not currently have curative gene-based therapies available. However, in some cases, such as vitamin, cofactor or enzyme deficiencies, channelopathies and disorders of the neuromuscular junction, a confirmed genetic diagnosis provides guidance on treatment, with drugs available that may significantly alter the disease course, improve functional ability and extend life expectancy. Nevertheless, many treatable patients remain undiagnosed or do not receive treatment even after genetic diagnosis. The growth of computer-aided genetic analysis systems that enable clinicians to diagnose their undiagnosed patients has not yet been matched by genetics-based decision-support systems for treatment guidance. Generating a ‘treatabolome’ of treatable variants and the evidence for the treatment has the potential to increase treatment rates for treatable conditions. Here, we use the congenital myasthenic syndromes (CMS), a group of clinically and genetically heterogeneous but frequently treatable neuromuscular conditions, to illustrate the steps in the creation of a treatabolome for rare inherited diseases. We perform a systematic review of the evidence for pharmacological treatment of each CMS type, gathering evidence from 207 studies of over 1000 patients and stratifying by genetic defect, as treatment varies depending on the underlying cause. We assess the strength and quality of the evidence and create a dataset that provides the foundation for a computer-aided system to enable clinicians to gain easier access to information about treatable variants and the evidence they need to consider.

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A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome

Cited by 20 publications

References 20 publications

Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features

Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features

Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis

Targeted therapies for congenital myasthenic syndromes: systematic review and steps towards a treatabolome

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