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

• DOI: 10.1007/s00415-022-11440-0
• Publication Date: 2022-10-29T05:02:41Z
• Authors: Martin Krenn; Merve Sener; Jakob Rath; Gudrun Zulehner; Omar Keritam; Matias Wagner; Franco Laccone; Stephan Iglseder; Sonja Marte; Manuela Baumgartner; Astrid Eisenkölbl; Christian Liechte...; Sabine Rudnik; Stefan Quasthoff; Susanne Grinzinger; Johannes Spenger; Saskia B. Wortmann; Wolfgang N. Löscher; Fritz Zimprich; Anna Kellersmann; Mika Rappold; Günther Bernert; Michael Freilinger; Hakan Cetin
• Keywords: Myasthenic Syndromes, Congenital; Original Communication; Radboudumc 6: Metabolic Disorders Paediatrics; Radboud University Medical Center; 3. Good health; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Austria; Mutation; Acetylcholinesterase; Prevalence; Humans; Austria ; Chrne ; Congenital Myasthenic Syndrome ; Myasthenia

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.