Inherited disorders of the neuromuscular junction: an update

Abstract

Congenital myasthenic syndromes (CMSs) are a group of heterogeneous inherited disorders caused by mutations in genes affecting the function and structure of the neuromuscular junction. This review updates the reader on established and novel subtypes of congenital myasthenia, and the treatment strategies for these increasingly heterogeneous disorders. The discovery of mutations associated with the N-glycosylation pathway and in the family of serine peptidases has shown that causative genes encoding ubiquitously expressed molecules can produce defects at the human neuromuscular junction. By contrast, mutations in lipoprotein-like receptor 4 (LRP4), a long-time candidate gene for congenital myasthenia, and a novel phenotype of myasthenia with distal weakness and atrophy due to mutations in AGRN have now been described. In addition, a pathogenic splicing mutation in a nonfunctional exon of CHRNA1 has been reported emphasizing the importance of analysing nonfunctional exons in genetic analysis. The benefit of salbutamol and ephedrine alone or combined with pyridostigmine or 3,4-DAP is increasingly being reported for particular subtypes of CMS.

Clinical and genetic basis of congenital myasthenic syndromes

“…Congenital myasthenic syndromes should be suspected in cases of: (i) early-onset fatigable muscle weakness mainly involving ocular, bulbar and proximal limb musculature (generally varying from birth to late childhood); (ii) a positive family history of a specific disorder or sometimes only the history of a hypotonic infant; (iii) clinical and neurophysiological myasthenic findings with a negative antibody testing profile; (iv) electromyography (EMG) studies showing decremental responses of 10% or more in the amplitude or in the quarter of the area from the first evoked compound motor action potential (CMAP), or single-fiber EMG studies compatible with a neuromuscular junction dysfunction; and (v) the presence of a specific clinical syndromic phenotype (i.e. Escobar syndrome, Pierson syndrome) 2,3,4 . However, in some congenital myasthenic syndromes, the onset of clinical manifestations may be late with involvement in adolescence or adulthood, other family members may not have been affected by the disease and electromyography changes may not be present in all muscles or occur intermittently 4 .…”

“…Escobar syndrome, Pierson syndrome) 2,3,4 . However, in some congenital myasthenic syndromes, the onset of clinical manifestations may be late with involvement in adolescence or adulthood, other family members may not have been affected by the disease and electromyography changes may not be present in all muscles or occur intermittently 4 . Therefore, although some clinical, therapeutic and neurophysiological clues allow a high clinical suspicion for each CMS subtype (Tables 2 and 3), in many cases of rapsyn deficiency, primary deficiency of endplate acetylcholine receptor and fast-channel syndrome, there are frequently no specific hallmarks in presentations 2,3,4 .…”

“…However, in some congenital myasthenic syndromes, the onset of clinical manifestations may be late with involvement in adolescence or adulthood, other family members may not have been affected by the disease and electromyography changes may not be present in all muscles or occur intermittently 4 . Therefore, although some clinical, therapeutic and neurophysiological clues allow a high clinical suspicion for each CMS subtype (Tables 2 and 3), in many cases of rapsyn deficiency, primary deficiency of endplate acetylcholine receptor and fast-channel syndrome, there are frequently no specific hallmarks in presentations 2,3,4 . The list of differential diagnoses of CMS is huge and includes some of the following conditions: congenital myopathies, congenital muscular dystrophy, limb-girdle muscular dystrophy, mitochondrial myopathies, facioscapulohumeral dystrophy, myotonic dystrophy and autoimmune myasthenia gravis, motor neuron disease and peripheral neuropathies (Table 4) 2 .…”

“…Currently, major defects involved in the etiology of CMS occur 2,4 : (A) in the presynaptic terminal; (B) associated with the synaptic basal lamina membrane; (C) the acetylcholine receptor; (D) shortcomings in the maintenance and development of the neuromuscular junction; (E) congenital defects in glycosylation; and (F) other sites and mechanisms ( Figure).…”

“…Most cases occured as a consequence of postsynaptic defects (68%), and basal lamina defects (13.7%), development and maintenance of the end plate defects (12.5%), pure presynaptic defects (5.9-8%) and congenital myopathies with secondary neuromuscular junction transmission defects (0.3%) also represent other rare congenital myasthenic syndromes. Thus, postsynaptic forms represent up to 75-80% of all CMS cases 3,4,8 .…”