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From the Friedrich Baur Institute (Drs. Müller–Felber, Stucka, Lochmüller, and Abicht, J.S. Müller, G. Mildner, and S. Petrova), Department of Neurology, and Gene Center, Ludwig Maximilians University, Munich; Department of Pediatrics and Pediatric Neurology (Drs. Schara and Mortier), Ruhr University of Bochum; Department of Neurology (Drs. Krampfl and Bufler), Medical University, Hannover; Department of Neuropediatrics (Dr. Petersen), University of Kiel; Department of Pediatrics (Dr. Kurlemann), University of Münster; and Department of Pediatrics (Dr. Huebner), Technical University of Dresden, Germany; and Neuromuscular Unit (Dr. Merlini), Istituto Ortopedico Rizzoli, Bologna, Italy.
Address correspondence and reprint requests to Dr. H. Lochmüller, Genzentrum München, Feodor-Lynen-Str. 25, 81377 München, Germany; e-mail: hanns{at}lmb.uni-muenchen.de
Background: Mutations in various genes of the neuromuscular junction may cause congenital myasthenic syndromes (CMS). Most mutations identified to date affect the 
-subunit gene of the acetylcholine receptor (AChR), leading to end-plate AChR deficiency. Recently, three different mutations in the RAPSN gene have been identified in four CMS patients with AChR deficiency.
Objective: To perform mutation analysis of the RAPSN gene in patients with sporadic or autosomal recessive CMS.
Methods: One hundred twenty CMS patients from 110 unrelated families were analyzed for the RAPSN mutation N88K by restriction fragment length polymorphism and sequence analysis.
Results: In 12 CMS patients from 10 independent families, RAPSN N88K was identified either homozygous or heteroallelic to another missense mutation. Symptoms usually started perinatally or in the first years of life. However, one patient did not show any myasthenic symptoms before the third decade. Clinical symptoms typically included bilateral ptosis, weakness of facial, bulbar, and limb muscles, and a favorable response to anticholinesterase treatment. Crisis-like exacerbations with respiratory insufficiency provoked by stress, fever, or infections in early childhood were frequent. All RAPSN N88K families originate from Central or Western European countries. Genotype analysis indicated that they derive from a common ancestor (founder).
Conclusions: The RAPSN mutation N88K is a frequent cause of rapsyn-related CMS in European patients. In general, patients (RAPSN N88K) were characterized by mild to moderate myasthenic symptoms with favorable response to anticholinesterase treatment. However, severity and onset of symptoms may vary to a great extent.
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