The clinical and molecular landscape of congenital myasthenic syndromes in Austria: a nationwide study

Abstract

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.

Keywords: Austria; CHRNE; Congenital myasthenic syndrome; Myasthenia.

Fig. 1

Clinical and genetic spectrum of patients with CMS in Austria. A Frequency of phenotypic features compared between patients with CHRNE-associated CMS and the remaining molecular etiologies. The CHRNE subgroup is predominantly characterized by ocular features (ophthalmoparesis/ophthalmoplegia and ptosis) and the absence of respiratory symptoms, while limb and bulbar weakness was more commonly observed in patients with other CMS forms. B The identification of nine different molecular etiologies within the cohort reflects the remarkable genetic heterogeneity of CMS. CHRNE and DOK7 are the two most commonly mutated genes together accounting for more than 60% of the whole cohort