title: Salbutamol-responsive limb-girdle congenital myasthenic syndrome due to a novel missense mutation and heteroallelic deletion in MUSK.
abstract: Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. In recent years, causative mutations have been identified in atleast 15 genes encoding proteins of the neuromuscular junction. Mutations in MUSK are known as a very rare genetic cause of CMS and have been described in only three families, world-wide. Consequently, the knowledge about efficient drug therapy is very limited. We identified a novel missense mutation (p.Asp38Glu) heteroallelic to a genomic deletion affecting exons 2-3 of MUSK as cause of a limb-girdle CMS in two brothers of Turkish origin. Clinical symptoms included fatigable limb weakness from early childhood on. Upon diagnosis of a MUSK-related CMS at the age of 16 and 13years, respectively, treatment with salbutamol was initiated leading to an impressive improvement of clinical symptoms, while treatment with esterase inhibitors did not show any benefit. Our findings highlight the importance of a molecular diagnosis in CMS and demonstrate considerable similarities between patients with MUSK and DOK7-related CMS in terms of clinical phenotype and treatment options.
authors.affiliation: Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Gallenmüller
authors.affiliation: Haunersche Kinderklinik, Ludwig Maximilians University, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Müller-Felber
authors.affiliation: Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Dusl
authors.affiliation: Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stucka
authors.affiliation: Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany; Clinic of Neurology, University Hospital Alexandrovska, Sofia, Bulgaria.
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.affiliation: Haunersche Kinderklinik, Ludwig Maximilians University, Munich, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Blaschek
authors.affiliation: Children's Hospital, Technical University Dresden, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: von der Hagen
authors.affiliation: Children's Hospital, Technical University Dresden, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Müller
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany; Medical Genetics Center, Munich, Germany. Electronic address: Angela.Abicht@med.uni-muenchen.de.
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
mesh_terms: D000420:Albuterol / Q000627:therapeutic use*; D000483:Alleles; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D020294:Myasthenic Syndromes, Congenital / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000235:genetics*; D017384:Sequence Deletion; D035781:Siblings
chemical_list: D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000420:Albuterol
keywords: AChE; AChR; CK; CMAP; CMS; Congenital myasthenic syndromes; MUSK-related CMS; Neuromuscular transmission; Salbutamol treatment; acetylcholine esterase; acetylcholine receptor; compound muscle action potential; congenital myasthenic syndrome; creatine kinase