title: Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Duygu
authors.initials: D
authors.lastname: Selcen
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Bisei
authors.initials: B
authors.lastname: Ohkawara
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Shen
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kathleen
authors.initials: K
authors.lastname: McEvoy
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000328:Adult; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D009157:Myasthenia Gravis / Q000235:genetics / Q000503:physiopathology*; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology*; D055815:Young Adult
chemical_list: D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human