IMPORTANCE: Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy. OBJECTIVES: To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy. DESIGN, SETTINGS, AND PARTICIPANTS: Two sisters with CMS affecting the limb-girdle muscles were investigated between 2012 and 2014 at an academic medical center by clinical observation, in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS7 cells, and for response to therapy, and they were compared with 15 historical control participants. MAIN OUTCOMES AND MEASURES: We identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. RESULTS: Quantitative analysis of single EP regions was done for all 15 control participants and microelectrode studies of neuromuscular transmission and α-bgt binding sites per EP was conducted for 13 control participants. Examination of the older sister's intercostal muscle end plates (EPs) showed them to be abnormally small, with attenuated reactivities for the acetylcholine receptor and acetylcholinesterase. Most EPs had poorly differentiated or degenerate junctional folds, and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in low-density lipoprotein receptor-related protein 4 (LRP4), a coreceptor for agrin to activate muscle-specific tyrosine kinase (MuSK), which is required for EP development and maintenance. Expression studies indicate that the mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Treatment with albuterol sulfate improved the patients' symptoms. A previously identified patient harboring 2 heterozygous mutations in LRP4 had structurally abnormal intercostal EPs but no identifiable defect of neuromuscular transmission at these EPs. CONCLUSIONS AND RELEVANCE: We identified a second CMS kinship harboring mutations in LRP4, identified the mechanisms that impair neuromuscular transmission, and mitigated the disease by appropriate therapy.
IMPORTANCE: Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy. OBJECTIVES: To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy. DESIGN, SETTINGS, AND PARTICIPANTS: Two sisters with CMS affecting the limb-girdle muscles were investigated between 2012 and 2014 at an academic medical center by clinical observation, in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS7 cells, and for response to therapy, and they were compared with 15 historical control participants. MAIN OUTCOMES AND MEASURES: We identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. RESULTS: Quantitative analysis of single EP regions was done for all 15 control participants and microelectrode studies of neuromuscular transmission and α-bgt binding sites per EP was conducted for 13 control participants. Examination of the older sister's intercostal muscle end plates (EPs) showed them to be abnormally small, with attenuated reactivities for the acetylcholine receptor and acetylcholinesterase. Most EPs had poorly differentiated or degenerate junctional folds, and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in low-density lipoprotein receptor-related protein 4 (LRP4), a coreceptor for agrin to activate muscle-specific tyrosine kinase (MuSK), which is required for EP development and maintenance. Expression studies indicate that the mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Treatment with albuterol sulfate improved the patients' symptoms. A previously identified patient harboring 2 heterozygous mutations in LRP4 had structurally abnormal intercostal EPs but no identifiable defect of neuromuscular transmission at these EPs. CONCLUSIONS AND RELEVANCE: We identified a second CMS kinship harboring mutations in LRP4, identified the mechanisms that impair neuromuscular transmission, and mitigated the disease by appropriate therapy.
Authors: V Mihaylova; M A M Salih; M M Mukhtar; H A Abuzeid; S M El-Sadig; M von der Hagen; A Huebner; G Nürnberg; A Abicht; J S Müller; H Lochmüller; V Guergueltcheva Journal: Neurology Date: 2009-12-01 Impact factor: 9.910
Authors: Ricardo A Maselli; Jose M Fernandez; Juan Arredondo; Carmen Navarro; Maian Ngo; David Beeson; Orla Cagney; D Colette Williams; Robert L Wollmann; Vladimir Yarov-Yarovoy; Michael J Ferns Journal: Hum Genet Date: 2011-12-29 Impact factor: 4.132
Authors: Olivier Leupin; Elke Piters; Christine Halleux; Shouih Hu; Ina Kramer; Frederic Morvan; Tewis Bouwmeester; Markus Schirle; Manuel Bueno-Lozano; Feliciano J Ramos Fuentes; Peter H Itin; Eveline Boudin; Fenna de Freitas; Karen Jennes; Barbara Brannetti; Nadine Charara; Hilmar Ebersbach; Sabine Geisse; Chris X Lu; Andreas Bauer; Wim Van Hul; Michaela Kneissel Journal: J Biol Chem Date: 2011-04-06 Impact factor: 5.157
Authors: Adi Aran; Reeval Segel; Kota Kaneshige; Suleyman Gulsuner; Paul Renbaum; Scott Oliphant; Tomer Meirson; Ariella Weinberg-Shukron; Yair Hershkovitz; Sharon Zeligson; Ming K Lee; Abraham O Samson; Stanley M Parsons; Mary-Claire King; Ephrat Levy-Lahad; Tom Walsh Journal: Neurology Date: 2017-02-10 Impact factor: 9.910