Abstract Details

Title Expanding the Clinical Phenotype of Agrin-Associated Congenital Myasthenic Syndrome

Topic Muscle Disease/Neuromuscular Junction

Presentation(s) S45 - (-)

Poster/Presentation
Number 003

Objective

Background Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders associated with impaired neuromuscular transmission. The clinical hallmark is fatigable weakness. An interesting group to recognise is patients presenting with distal muscle weakness, which can be misdiagnosed as neuropathy or myopathy. In our study, we report a novel mutation in the N-terminal of agrin which results in a distal pattern of muscle involvement in two affected siblings.

Design/Methods We performed whole-exome sequencing in two individuals presenting with progressive muscle weakness of both hands and feet who had evidence of a neuromuscular junction disorder on neurophysiology. Extensive investigations excluded mutations in known CMS genes. We also carried in vitro functional studies to prove pathogenicity of our candidate variants.

Results Both affected individuals shared a clinical predilection for distal limb muscles and lack of response to cholinesterase inhibitors. Neurophysiological studies revealed decrement on repetitive nerve stimulation and post exercise facilitation. We show that both siblings are compound heterozygous for a missense mutation and a paternal deletion in agrin. Mutation c.G226A:p G76S is positioned in the N-terminal domain of agrin. Using in vitro functional studies, we analysed the impact of this mutation on laminin binding as well as acetylcholine receptor clustering at the post synaptic membrane.

Conclusions Agrin is a key player in neuromuscular junction organisation and maintenance and has been implicated in two cases of congenital myasthenic syndromes so far. The phenotype of these individual was much more severe than our patients who exhibit slowly progressive distal muscle weakness and wasting. Our findings emphasize the importance of agrin in maintaining the integrity of neuromuscular transmission as well as expand the clinical phenotype associated with mutations in this protein.

Authors/Disclosures
Amina Chaouch, MD PRESENTER	No disclosure on file
TORBERG TORBERGSEN	No disclosure on file
	No disclosure on file
Kate Bushby, MD	Dr. Bushby has nothing to disclose.
	No disclosure on file
Angela Abicht, MD	No disclosure on file
Elsdon Storey, FRACP, DPhil (Monash University, ASPREE, SPHPM)	No disclosure on file
Hanns Lochmuller, MD, FAAN (Childrens Hospital of Eastern Ontario)	Dr. Lochmuller has nothing to disclose.

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