BACKGROUND: Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted.
METHODS: We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria.
RESULTS: Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0-4.3) in Austria. The most frequent genetic etiology was CHRNE (n = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 (n = 4), RAPSN (n = 3), COLQ (n = 2), GMPPB (n = 2), CHAT (n = 1), COL13A1 (n = 1), MUSK (n = 1) and AGRN (n = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients.
CONCLUSIONS: Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype-phenotype correlations that may help to improve the diagnostic approach and patient management.

This study was designed to analyze the sensitivity, specificity, and accuracy of jitter parameters combined with repetitive nerve stimulation (RNS) in congenital myasthenic syndrome (CMS), chronic progressive external ophthalmoplegia (CPEO), and congenital myopathies (CM). Jitter was obtained with a concentric needle electrode during voluntary activation of the Orbicularis Oculi muscle in CMS (n = 21), CPEO (n = 20), and CM (n = 18) patients and in controls (n = 14). RNS (3 Hz) was performed in six different muscles for all patients (Abductor Digiti Minimi, Tibialis Anterior, upper Trapezius, Deltoideus, Orbicularis Oculi, and Nasalis). RNS was abnormal in 90.5% of CMS patients and in only one CM patient. Jitter was abnormal in 95.2% of CMS, 20% of CPEO, and 11.1% of CM patients. No patient with CPEO or CM presented a mean jitter higher than 53.6 µs or more than 30% abnormal individual jitter (> 45 µs). No patient with CPEO or CM and mild abnormal jitter values presented an abnormal decrement. Jitter and RNS assessment are valuable tools for diagnosing neuromuscular transmission abnormalities in CMS patients. A mean jitter value above 53.6 µs or the presence of more than 30% abnormal individual jitter (> 45 µs) strongly suggests CMS compared with CPEO and CM.

Congenital myasthenic syndromes (CMSs) are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. Even though CMSs are genetic disorders, they are highly treatable, and the appropriate drug treatment depends on the underlying genetic defect. This highlights the importance of genetic testing in CMS. In recent years, the molecular basis of CMS has constantly broadened and disease-associated mutations have been identified in 14 genes encoding proteins of the neuromuscular junction. In the dawn of novel sequencing strategies, we report on our 14-year experience in traditional Sanger-based mutation screening of a large cohort of 680 independent patients with suspected CMS. In total, we identified disease-causing mutations in 299 patients (44%) of patients in various known CMS genes, confirming the high degree of genetic heterogeneity associated with the disease. Apart from four known founder mutations, and a few additional recurrent mutations, the majority of variants are private, found in single families. The impact of previously reported genotype-phenotype correlations on efficiency of genetic testing was analyzed in our population. Taking our experiment into account, we present our algorithm for genetic testing in CMS.

Slow-channel congenital myasthenic syndrome (CMS) is a rare subtype of CMS caused by dominant \"gain of function\" mutations in the acetylcholine receptor. Clinically, the cervical and forearm extensor muscles seem to be preferentially weaker; and conventional treatment with anticholinesterases fails to improve symptoms. In contrast, open channel blockers such as fluoxetine and quinidine have been shown to be of benefit. The objectives of our study were to provide further insight into the clinical features of slow-channel CMS and evaluate response to recommended therapy. We carried out a retrospective clinical follow up study of 15 slow-channel CMS patients referred to the Munich CMS Centre. Detailed clinical data were collected by clinicians involved in the care of each patient, with a particular focus on response and tolerability to recommended therapy. Patients varied widely as regard onset of symptoms, severity of disease and mutations involved. Patients received up to four different medications and some had none. Our results strengthen previous reported findings in terms of clinical phenotype variability and the poor response to pyridostigmine. Although treatment with fluoxetine was beneficial in most patients, a number of our patients suffered significant adverse effects that hindered optimum dose titration or led to treatment cessation. Slow-channel CMS is rare and exhibits distinct clinical and genetic characteristics. Our study suggests that fluoxetine, despite being effective in most patients, can be associated with significant side effects, thus reducing treatment effectiveness in clinical practice.

暂无摘要。

The slow-channel syndrome is one of the congenital myasthenic syndromes attributed to inherited kinetic disorders of the ion channel of the acetylcholine receptor of the neuromuscular junction. This is a case report of 25-years-old man with progressive ptosis and limitation of ocular movements since infancy, presented a 6-years history of worse of the external ophthalmoparesis and muscular weakness in the shoulders and hands. The motor nerve conduction studies after a supramaximal single stimulus disclosed a double compound muscle action potential (CMAP) that disappeared after a voluntary contraction of 30 seconds. Repetitive stimulation of facial and spinal accessory nerves showed a CMAP decrement greater than 10% with disappeared of the second potential. The patient received fluoxetine with mild improvement of muscular weakness, but persisted with: ptosis, limitation of ocular movements and repetitive CMAP in the motor nerve conduction study. The characteristic of disease are discussed.