Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy

Abstract

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

“…While this is not surprising based on their necessity in neurotransmission, more recent mapping studies have shown that molecules regulating NMJ development can also cause CMS. These include agrin (200,283,323), MuSK (89), Lrp4 (331), and Dok-7 (32). Likewise, sporadic MG, where the majority is caused by autoantibodies to AChRs, can also be caused by antibodies directed against MuSK (193), Lrp4 (189,342,479), and agrin (150,478).…”

“GAG-ing with the neuron”: The role of glycosaminoglycan patterning in the central nervous system

“…Lrp4 −/− mice fail to form neuromuscular synapses and die; however, rescuing muscular Lrp4 expression enables survival and the mice have a low spine density on primary apical dendrites, developing deficits in cognitive tasks including learning and memory (Gomez et al, 2014). Moreover, recently agrin mutations have been shown to lead to the rare condition called congenital myasthenic syndrome, which results from impaired neuromuscular transmission with distal muscle weakness and atrophy (Nicole et al, 2014). Syndecan-2 is involved in the induction of mature dendritic spines, modulated by eph-ephrin signaling (Ethell and Yamaguchi, 1999;Irie and Yamaguchi, 2004).…”

GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice

“…These findings correspond to the pathological changes observed in muscle biopsies from DPAGT1 -CMS patients (6). Whilst minor myopathic changes are sometimes seen in some subtypes of CMS, secondary to neurotransmission failure (24,25), more recently, patient muscle MRI studies revealed pronounced myopathic changes in patients with mutations in GFPT1 and DPAGT1 , with dystrophic changes reflected by fatty infiltration of the muscle in patients with GMPPB mutations (26). …”