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.

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…RAPSN -CMS has been reported in 38 papers [ 39 , 40 , 46 , 47 , 49 , 50 , 77 , 112 , 113 , 114 , 115 , 116 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ]. A review of 10 patients with RAPSN -CMS showed similar clinical features with a neonatal onset, fluctuations of lid ptosis, bulbar signs, neck muscle weakness, mild limb muscle weakness, as well as with episodic worsening of muscle weakness in adults [ 134 ].…”

“…COLQ -CMS has been reported in 30 original articles since 1998 [ 62 , 73 , 78 , 140 , 141 , 221 , 222 , 225 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 ]. Interestingly, a grandmother and a father of two siblings with COLQ -CMS carried a heterozygous truncation variant of COLQ , and showed congenital ptosis [ 246 ].…”

“…COL13A1 -CMS has been reported in 41 patients in 19 pedigrees since 2015 [ 140 , 141 , 239 , 267 , 268 , 269 ]. All patients developed respiratory distress and weak sucking at birth.…”

Congenital myasthenic syndromes (CMS) a rare cause of uncommon fatigue

“…The prevalence of genetically confirmed CMS in Slovenia is 22.2 per million children under the age of 18 [2]. A similar study in Austria reported 3.1 cases of genetically confirmed CMS per million patients [3]. The severity and course of the disease are highly variable.…”

“…The prognosis depends on the underlying genetic defect [4]. Regardless of the subtype, the symptoms result from significant muscle weakness [3]. There are effective forms of therapy to improve NMJ transmission, but it happens that patients are underdiagnosed.…”