title: PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome.
abstract: OBJECTIVE
  To investigate the genetic and physiologic basis of the neuromuscular symptoms of hypotonia-cystinuria syndrome (HCS) and isolated PREPL deficiency, and their response to therapy.
  
  
  METHODS
  We performed molecular genetic, histochemical, immunoblot, and ultrastructural studies, investigated neuromuscular transmission in vitro in a patient with isolated PREPL deficiency, and evaluated the effect of pyridostigmine in this patient and in 3 patients with the HCS.
  
  
  RESULTS
  HCS is caused by recessive deletions involving the SLC3A1 and PREPL genes. The major clinical features of HCS are type A cystinuria, growth hormone deficiency, muscle weakness, ptosis, and feeding problems. The proband with isolated PREPL deficiency had myasthenic symptoms since birth and a positive edrophonium test but no cystinuria. She and 1 of 3 patients with HCS responded transiently to pyridostigmine during infancy. The proband harbors a paternally inherited nonsense mutation in PREPL and a maternally inherited deletion involving both PREPL and SLC3A1; therefore, the PREPL deficiency determines the phenotype. We detected no PREPL expression in the patient's muscle and endplates. Electrophysiology studies revealed decreased quantal content of the endplate potential and reduced amplitude of the miniature endplate potential without endplate acetylcholine receptor deficiency or altered endplate geometry.
  
  
  CONCLUSIONS
  Isolated PREPL deficiency is a novel monogenic disorder that causes a congenital myasthenic syndrome with pre- and postsynaptic features and growth hormone deficiency. The myasthenic symptoms in PREPL deficiency with or without cystinuria may respond to pyridostigmine in early life. We attribute the myasthenia to abrogated interaction of PREPL with adaptor protein 1.
authors.affiliation: From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
authors.forename: Luc
authors.initials: L
authors.lastname: Régal
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Shen
authors.forename: Duygu
authors.initials: D
authors.lastname: Selcen
authors.forename: Chantal
authors.initials: C
authors.lastname: Verhille
authors.forename: Sandra
authors.initials: S
authors.lastname: Meulemans
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003555:Cystinuria / Q000150:complications / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D018908:Muscle Weakness / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D020294:Myasthenic Syndromes, Congenital / Q000175:diagnosis* / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases