To describe a novel compound heterozygous agrin (AGRN) gene variant associated with a congenital myasthenic syndrome (CMS).

Congenital myasthenic syndromes are a heterogeneous group of diseases caused by genetic defects of proteins involved in neuromuscular transmission. Nearly 30 unique genes coding for proteins in the neuromuscular junction have been identified in the literature. One such gene is agrin, a large proteoglycan critical for the formation of the neuromuscular junction. Limited case reports and small case series have demonstrated that loss-of-function agrin genetic variants result in pathogenic phenotypes. 

We present a 48-year-old white man presumed to have seronegative myasthenia gravis. He had normal motor milestones, but always felt weaker than his peers. He also reported life-long exertional dyspnea with several episodes of respiratory failure requiring intubation. However, no underlying cardiac or pulmonary etiology was identified. He was subsequently referred to the neuromuscular clinic for evaluation of nocturnal hypoventilation requiring BiPAP support. Upon interview, he reported intermittent diplopia, dysarthria, dysphonia, difficulty with chewing, head drop, difficulty with stairs, exertional dyspnea, and dependence on a wheelchair for long distances. His exam was notable for bilateral ptosis, facial weakness, prominent distal tongue atrophy, reduced bulk in the hands and calves, and diffuse motor weakness in the arms greater than the legs. Acetylcholine and MUSK antibodies were negative. EMG with repetitive nerve stimulation was suggestive of myasthenia gravis. Muscle biopsy showed mild type II muscle fiber atrophy. Treatment with IVIG and plasmapheresis did not provide sustained benefit. A CeGat CMS diagnostic panel identified a deletion variant (c.3842_4014del; p.Pro1315Serfs*88) and missense variant (c.5063G>A; p.Gly1688Glu) of AGRN. Both variants previously have not been reported, but likely result in a loss-of-function variant of AGRN.

It is important to consider genetic testing for CMS in patients with seronegative myasthenia gravis and a history suggestive of childhood weakness.