TY - JOUR
T1 - Impaired synaptic development, Maintenance, and neuromuscular transmission in LRP4-related myasthenia
AU - Selcen, Duygu
AU - Ohkawara, Bisei
AU - Shen, Xin Ming
AU - McEvoy, Kathleen
AU - Ohno, Kinji
AU - Engel, Andrew G.
N1 - Publisher Copyright:
© 2015 American Medical Association. All rights reserved.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - Importance Congenitalmyasthenic 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 á-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 receptorrelated 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.
AB - Importance Congenitalmyasthenic 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 á-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 receptorrelated 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.
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U2 - 10.1001/jamaneurol.2015.0853
DO - 10.1001/jamaneurol.2015.0853
M3 - Article
C2 - 26052878
AN - SCOPUS:84938936453
SN - 2168-6149
VL - 72
SP - 889
EP - 896
JO - JAMA neurology
JF - JAMA neurology
IS - 8
ER -