RAPSN – Postsynaptic Congenital Myasthenic Syndrome

Postsynaptic congenital myasthenic syndrome (CMS) is an autosomal recessive disorder of neuromuscular transmission characterized by fatigable muscle weakness and impaired acetylcholine receptor (AChR) clustering at the motor endplate. RAPSN encodes rapsyn, a peripheral membrane protein essential for anchoring and clustering AChRs. Biallelic RAPSN mutations result in reduced AChR density and synaptic response, leading to early‐onset hypotonia, arthrogryposis, bulbar involvement, respiratory distress, and neck muscle weakness.

Seven independent cohorts have described a total of 58 patients with RAPSN‐related CMS: six patients in the original report (PMID:12929188), three patients with arthrogryposis and bulbar symptoms (PMID:15328566), ten patients with long‐term follow‐up (PMID:26782015), and 39 patients in a multicenter series (PMID:19620612). All patients carried at least one p.Asn88Lys allele (c.264C>G (p.Asn88Lys)) with compound heterozygosity or homozygosity for second alleles including missense, frameshift, splice‐site, and promoter mutations.

Segregation analysis across multiple families demonstrated recessive inheritance; compound heterozygotes and homozygotes segregated with disease, although asymptomatic homozygous p.Asn88Lys carriers suggest modifier effects (PMID:12929188). No additional affected relatives beyond index cases were reported.

Functional studies have elucidated pathogenic mechanisms: promoter E-box mutations (c.-38A>G, c.-27C>G) reduce RAPSN transcription in patient muscle and reporter assays (PMID:12651869). In vitro expression of RAPSN missense and deletion alleles (e.g., p.Arg91Leu, p.Leu361Arg, p.Lys373del) in TE671 cells and rapsyn–/– myotubes revealed impaired rapsyn stability, self-association, and agrin-induced AChR clustering (PMID:16945936).

Clinically, patients respond favorably to cholinesterase inhibitors and 3,4-diaminopyridine, with marked improvement in bulbar and respiratory symptoms (PMID:15328566; PMID:26782015). Early diagnosis and targeted therapy result in stable long-term outcomes in most cases.

RAPSN deficiency represents a well‐validated autosomal recessive CMS subtype with definitive genetic and functional evidence. Molecular testing for p.Asn88Lys and other RAPSN variants is essential for diagnostic confirmation and guiding cholinergic therapy or adjunctive agents.

References

• Muscle & nerve • 2003 • Rapsyn mutations in myasthenic syndrome due to impaired receptor clustering. PMID:12929188
• Neuropediatrics • 2004 • Congenital myasthenic syndrome due to rapsyn deficiency: three cases with arthrogryposis and bulbar symptoms. PMID:15328566
• Neuromuscular disorders : NMD • 2016 • Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations. PMID:26782015
• Neurology • 2009 • Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients. PMID:19620612
• Human molecular genetics • 2003 • E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. PMID:12651869
• Brain : a journal of neurology • 2006 • Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. PMID:16945936

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