Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients

Abstract

Background: Pathogenic mutations in rapsyn result in endplate acetylcholine receptor (AChR) deficiency and are a common cause of postsynaptic congenital myasthenic syndromes.

Methods: Clinical, electrophysiologic, pathologic, and molecular studies were done in 39 patients.

Results: In all but one patient, the disease presented in the first 2 years of life. In 9 patients, the myasthenic symptoms included constant or episodic ophthalmoparesis, and 1 patient had a pure limb-girdle phenotype. More than one-half of the patients experienced intermittent exacerbations. Long-term follow-up was available in 25 patients after start of cholinergic therapy: 21 became stable or were improved and 2 of these became asymptomatic; 3 had a progressive course; and 1 died in infancy. In 7 patients who had endplate studies, the average counts of AChR per endplate and the synaptic response to ACh were less reduced than in patients harboring low AChR expressor mutations. Eight patients were homozygous and 23 heterozygous for the common p.N88K mutation. Six mutations, comprising 3 missense mutations, an in-frame deletion, a splice-site mutation, and a nonsense mutation, are novel. Homozygosity for p.N88K was associated with varying grades of severity. No genotype-phenotype correlations were observed except in 8 Near-Eastern patients homozygous for the promoter mutation (c.-38A>G), who had a mild course.

Conclusions: All but 1 patient presented early in life and most responded to cholinergic agonists. With early diagnosis and therapy, rapsyn deficiency has a benign course in most patients. There was no consistent phenotype-genotype correlation except for an E-box mutation associated with jaw deformities.

Figure 1 Genetic analysis of rapsyn (A) Rapsyn domains and interactions. (B) Schematic representations of the RAPSN mutations identified in the 39 patients investigated at the Mayo Clinic. The novel mutations are indicated in red. (C) The mutated residues in the coding region are conserved across species.

Figure 2 Structural features of rapsyn-deficient endplates (EPs) (A) Small cholinesterase reactive EP regions are dispersed over an extended length of the muscle fiber. These synaptic contacts differ from the compact pretzel-shaped contacts at normal EPs. (B, C) Multiple small nerve terminals are apposed against highly simplified postsynaptic regions with no (B) or few (C) junctional folds. In (B), the distribution of AChR on the postsynaptic membrane, visualized with peroxidase-labeled α-bungarotoxin, is patchy. Bars 50 μm in (A) and 1 μm in (B) and (C).