Abstract

Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Methods: Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. Results: ES unraveled compound heterozygous missense and nonsense variants (c.315G>A, p.Trp105* and c.1192G>C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to a more severe effect of the nonsense variant. Therapy with pyridostigmine was only partially effective while 3,4 diaminopyridine showed no effect. Microscopic investigation of the muscle biopsy revealed reduced fibre size and a significant accumulation of lipid droplets. Conclusions: We suggest that nonsense variants have a more detrimental impact on the clinical manifestation of SLC18A3-associated CMS. The impact of pathogenic SLC18A3 variants on muscle fibre integrity beyond the effect of denervation is suggested by the build-up of lipid aggregates. This in turn implicates the importance of proper VAChT-mediated synthesis and recycling of ACh for lipid homeostasis in muscle cells. This hypothesis is further supported by the pathological observations obtained in previously published VAChT-animal models.

Highlights

  • Congenital myasthenic syndromes (CMS) are a heterogeneous group of rare genetic diseases characterized by impaired neuromuscular transmission

  • The male patient presented in this study was born prematurely at 36 + 2 weeks of gestation due to pathological cardiotocographical findings as the 2nd child of nonconsanguineous healthy parents after an uneventful pregnancy

  • Due to respiratory insufficiency with recurrent apnoeas, cardiopulmonary reanimations with short periods of assisted ventilation were necessary during the first month post-partum

Read more

Summary

Introduction

Congenital myasthenic syndromes (CMS) are a heterogeneous group of rare genetic diseases characterized by impaired neuromuscular transmission. Missense variants and whole gene deletions have been previously identified in CMS-patients, defining SLC18A3 as a CMS-causative gene (CMS subtype 21; MIM: #617239), a molecular genetic observation in agreement with the above-mentioned function of the corresponding protein These patients presented with features seen in presynaptic CMS forms, including ptosis, ophthalmoplegia, bulbar symptoms, fatigable weakness, decrement on low-frequency repetitive stimulation followed by a prolonged period of post-activation exhaustion, and apnoeic crises with moderate clinical improvement upon treatment with pyridostigmine (PS) [6,7]. Given that one patient showed learning difficulties and left ventricular dysfunction [3], a phenotypical variability of pathogenic SLC18A3-mutations is likely Along this line, a recent publication reported on a severe prenatal phenotype defined by akinesia, arthrogryposis, edema, and partial cleft palate based on a homozygous nonsense variant

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call