ABSTRACT
OBJECTIVE: To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency. BACKGROUND: The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ. The authors report three novel COLQ mutations in eight kinships. METHODS: Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed. RESULTS: Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms. CONCLUSIONS: 1) After mutations in the AChR epsilon subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.
Subject(s)
Acetylcholinesterase/genetics , Amino Acid Substitution/genetics , Collagen/genetics , Genetic Variation/genetics , Glycine/genetics , Muscle Proteins , Mutation/genetics , Acetylcholinesterase/biosynthesis , Acetylcholinesterase/deficiency , Action Potentials/genetics , Adolescent , Adult , Animals , COS Cells/metabolism , Child , Child, Preschool , Collagen/biosynthesis , Collagen/deficiency , Female , Humans , Male , Middle Aged , Motor Endplate/genetics , Motor Endplate/metabolism , Motor Endplate/pathology , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/metabolism , Myasthenic Syndromes, Congenital/pathology , Pedigree , PhenotypeABSTRACT
A full-term neonate was born to a 41-year-old woman via elective primary cesarean section for frank breech presentation after a 41-week pregnancy. Starting at 6 hr of age the infant presented with multiple episodes of apnea and cyanosis, in association with moderate hypotonia, subsequently requiring assisted ventilatory support for 2 days. Computerized axial tomography of the brain revealed infarction in the distribution of the left middle cerebral artery. Magnetic resonance imaging of the brain showed a left middle cerebral artery territory infarct and also a small right posterior-temporal infarct. Magnetic resonance angiography of the head and neck was normal, however, inferring that the vascular infarction was peripheral in location. Maternal anticardiolipin antibodies were elevated. This is only the fifth reported case of cerebral infarction in a newborn in association with elevated maternal anticardiolipin antibodies.
