Original article
Prevalence and genetic subtypes of congenital myasthenic syndromes in the pediatric population of Slovenia

https://doi.org/10.1016/j.ejpn.2020.02.002Get rights and content

Highlights

  • The prevalence of CMS in Slovenian children exceeds previously reported data by more than two-fold.

  • CMS is often a missed diagnosis and prevalence is likely to be underestimated.

  • Electrophysiological testing (RNS-EMG) often gave false negative results in the first year of life in our cohort.

  • Genetic molecular testing has improved diagnostics and enabled more targeted treatment.

  • Disease awareness among healthcare professionals and reliable diagnostic tests are important.

Abstract

Aim

Congenital myasthenic syndromes (CMS) are rare, genetically and phenotypically diverse disorders of neuromuscular transmission. Data on prevalence among children are scarce. Whole exome sequencing facilitated discovery of novel CMS mutations and enabled targeted treatment. Our aim was to identify the prevalence, genetic subtypes and clinical characteristics of CMS in pediatric population of Slovenia.

Methods

In this observational, national, cross-sectional study, medical records were retrospectively reviewed. Children with genetically confirmed CMS, referred over a 19 – year period (2000–2018) to the University Medical Centre, Ljubljana, Slovenia, were included in the study. Genetic and phenotypic characteristics were collected and prevalence of CMS in children was calculated.

Results

Eight children with a confirmed genetic mutation in 5 different genes (CHRNE, CHRND, RAPSN, CHAT, MUSK) causative of the CMS were identified. Calculated prevalence of genetically confirmed CMS was 22.2 cases per 1.000.000 children at the end of 2018.

Interpretation

The prevalence of genetically confirmed CMS in Slovenian children at the end of 2018 exceeds previously reported prevalence by more than two-fold, which suggests that prevalence in the literature is likely to be underestimated. Two extremely rarely detected mutations in MUSK and CHRND gene were detected and patient's clinical descriptions add important information on genotype-phenotype correlation.

Introduction

Congenital myasthenic syndromes (CMS) are rare, genetically and phenotypically diverse genetic disorders of neuromuscular transmission. The disease usually presents during the first and second year of life with fluctuating weakness, fatigability and exercise intolerance, typically involving ocular, bulbar, and limb muscles [1,2]. Episodic apneas in neonates, which can be the presenting symptom in certain subtypes, can result in brief resolved unexplained events (BRUE) [3].

Up to the last decade, typical clinical picture, positive family history, abnormal neuro-physiology tests, namely repetitive 3 Hz nerve stimulation (RNS) or single fiber electromyography (SF-EMG) and negative ACh and Musk antibodies have been hallmarks of the diagnosis [4]. In the last few years, next generation sequencing (NGS) and whole exome sequencing have become important and more readily available methods of confirming the diagnosis and the genetic subtype. The genetic landscape of CMS has been expanding fast in the past few years. In 2012, a total of 14 different genes known to cause CMS were reported and to date over 30 genes have been implicated [5].

Correct diagnosis is especially important because of treatment possibilities for certain subtypes [[6], [7], [8]]. Drugs with a positive effects for a specific CMS subtype may worsen other forms of CMS, depending on the underlying genetic defect. That is why the genetic subtyping of CMS is key to rational and optimized pharmacological treatment [2,[9], [10], [11]].

The aim of this study was to identify the prevalence and the genetic subtypes of childhood CMS in Slovenia. Knowledge on the most common genetic subtypes and corresponding phenotypes in our region could assist the physicians with establishing correct diagnosis and management of patients with CMS locally and globally.

Section snippets

Methods

In this retrospective, national, cross sectional study, all pediatric patients with genetically confirmed diagnosis of CMS obtained by December 31, 2018, and referred over a 19 – year period (2000–2018) to the Department of Child, Adolescent and Developmental Neurology, University Medical Centre, Ljubljana, Slovenia, were included. Considering ours is the only tertiary centre for child neurology and the only specialized pediatric centre for treatment of children with neuromuscular diseases in

Prevalence

We have identified 8 children (3 males, 5 females) with a confirmed genetic CMS who were born between January 1, 2000 and December 31, 2018. All 8 children were included in the study and none of the identified children died in the study period.

The population of children (age less than 19 years) in Slovenia at the end of 2018 was obtained from the Statistical Office of the Republic of Slovenia and was 360.161. All eight identified children included in the study were still under 19 years of age

Discussion

Despite the fact that CMS is considered to be a very rare disease, the possibility of effective treatment adds to the importance of early diagnosis of CMS.

Data on prevalence of CMS are scarce, the studies were mostly conducted in non-European regions [9,[15], [16], [17], [18]]. In Europe, the reported prevalence was between 1.8 cases per million total population in Spain to 9.2 per million children in UK [15,17]. Our study revealed the prevalence of 22.2 cases per million children, which

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