Abstract
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.
Highlights
Congenital myasthenic syndromes (CMS) refer to a heterogenic group of neuromuscular transmission disorders
We retrospectively studied the clinical characteristics and medication data of 32 children with genetically proven forms of CMS
At the University Hospital of Essen (Department for Neuropediatrics), a retrospective chart review was performed for all patients diagnosed with CMS who were at regular follow up between January 2010 and December 2015
Summary
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. Congenital myasthenic syndromes (CMS) are a phenotypic heterogeneous group of hereditary diseases caused by disturbed or impaired neuromuscular transmission, resulting in clinical symptoms such as muscle weakness and increased muscle fatigue. Clinical presentation and severity may vary enormously and depend on the underlying genetic mutation and the regular localization of the responding protein. Smooth and heart muscles are generally not affected (Abicht et al, 2017). The patients present their first symptoms usually at birth or in the first 2 years of life. Initial manifestations are known, albeit much less frequently, up to advanced age and are frequently misdiagnosed as seronegative MG (especially mutations in the RAPSN, DOK7, and slow-channel syndrome; Croxen et al, 1997; Burke et al, 2003; Durmus et al, 2018; Kao et al, 2018)
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