Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil

Estephan, Eduardo de Paula; Zambon, A A; Marchiori, Paulo Eurípedes; Silva, André Macedo Serafim; Caldas, Vitor Marques; Moreno, Cristiane Araújo Martins; Reed, Umbertina Conti; Horvath, Rita; Töpf, Ana; Lochmüller, Hanns; Zanoteli, Edmar

doi:10.1016/j.nmd.2018.08.007

Cited by 15 publications

(16 citation statements)

References 22 publications

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“…Ocular movement impairment with relative sparing of downgaze was a frequent finding among confirmed cases, not only in CHRNE and RAPSN patients as was already described in previous studies [18,21], but also in COLQ, COLA13A1, SCN4A and CHAT . The absence of significance of ocular alterations, combined with the presence of significance regarding extra‐ocular symptoms, suggests that ocular symptoms are less specific for CMS phenotype than extra‐ocular symptoms.…”

Section: Discussionsupporting

confidence: 74%

“…The CHRNA1 patient and some of the CHRNE , COL13A1 and RAPSN patients were previously reported [18,21–23]. In the end, 16 families remained unsolved, and 5 were diagnosed as non‐CMS syndromes ( PTPN11 , VWA3B , LDB3 , DHCR7 , SCN8A ).…”

Section: Resultsmentioning

confidence: 99%

“…The CHRNA1 patient and some of the CHRNE, COL13A1 and RAPSN patients were previously reported [18,[21][22][23]. In the end, 16…”

Section: Re Sultsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

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Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis

Estephan

Zambon

Thompson

et al. 2021

Euro J of Neurology

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“…Interestingly, only patients with RAPSN mutations need a low mean dosage of AChE inhibitors, at last follow up, to have a stable/static disease condition compared to patients with mutations in other CMS-causative genes. This not only has advantages based on a lower potential to suffer from side effects but also can be an indicator for stabilization of the symptoms in the course of the disease (Natera-de Benito et al, 2016a;Estephan et al, 2018). Interestingly, with 7.6 mg/kg/day the mean dosage administered to patients from a Spanish cohort (total of 10 patients, partially adults) was higher than in our patients (Natera-de Benito et al, 2016a).…”

Section: General Therapy Responsementioning

confidence: 59%

Long Term Follow-Up on Pediatric Cases With Congenital Myasthenic Syndromes—A Retrospective Single Centre Cohort Study

Marina

Wibbeler

Schöser

et al. 2020

Front. Hum. Neurosci.

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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.

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“…For seronegative patients with no response with corticosteroids and immunosuppressants, it is important to keep in mind congenital myasthenic syndromes 38 . Receptor deficiency due to CHRNE mutations and cases related to RAPSN can be clinically very similar to acquired MG 39 , 40 . On the other hand, pure ocular symptoms are not expected to be congenital myasthenic syndromes 41 .…”

Section: Diagnostic Approachmentioning

confidence: 99%

Myasthenia gravis in clinical practice

Estephan

Baima

Zambon

2022

Arq. Neuro-Psiquiatr.

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Background: Myasthenia gravis is largely a treatable disease, but it can result in significant morbidity and even mortality, which can usually be avoided, or at least mitigated, with timely diagnosis and appropriate treatment of the disease. Objective: this review aims to summarize the main practical aspects of the diagnostic approach, treatment and care of myasthenic patients. Methods: The authors performed a non-systematic critical review summarizing the main practical aspects of myasthenia gravis. Results: Most patients with myasthenia have autoantibodies targeted at acetylcholine receptors or, less commonly, muscle-specific kinase - MuSK. Electrophysiology plays an important role in the diagnosis of neuromuscular junction dysfunction. The central clinical manifestation of myasthenia gravis is fatigable muscle weakness, which can affect eye, bulbar, respiratory, and limb muscles. With rare exceptions, patients have a good response to symptomatic treatment, but corticosteroids and/or immunosuppressants are usually also necessary to obtain good control of the manifestations of the disease. Conclusion: Knowledge of the peculiar aspects of their clinical and electrophysiological presentations is important for the diagnosis. Likewise, specific treatment and response time to each drug are crucial for proper care.

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Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil

Cited by 15 publications

References 22 publications

Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis

Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis

Long Term Follow-Up on Pediatric Cases With Congenital Myasthenic Syndromes—A Retrospective Single Centre Cohort Study

Myasthenia gravis in clinical practice

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