title: Synaptic defects in type I spinal muscular atrophy in human development.
abstract: Childhood spinal muscular atrophy is an autosomal recessive neuromuscular disorder caused by alterations in the Survival Motor Neuron 1 gene that triggers degeneration of motor neurons within the spinal cord. Spinal muscular atrophy is the second most common severe hereditary disease of infancy and early childhood. In the most severe cases (type I), the disease appears in the first months of life, suggesting defects in fetal development. However, it is not yet known how motor neurons, neuromuscular junctions, and muscle interact in the neuropathology of the disease. We report the structure of presynaptic and postsynaptic apparatus of the neuromuscular junctions in control and spinal muscular atrophy prenatal and postnatal human samples. Qualitative and quantitative data from confocal and electron microscopy studies revealed changes in acetylcholine receptor clustering, abnormal preterminal accumulation of vesicles, and aberrant ultrastructure of nerve terminals in the motor endplates of prenatal type I spinal muscular atrophy samples. Fetuses predicted to develop milder type II disease had a similar appearance to controls. Postnatal muscle of type I spinal muscular atrophy patients showed persistence of the fetal subunit of acetylcholine receptors, suggesting a delay in maturation of neuromuscular junctions. We observed that pathology in the severe form of the disease starts in fetal development and that a defect in maintaining the initial innervation is an early finding of neuromuscular dysfunction. These results will improve our understanding of the spinal muscular atrophy pathogenesis and help to define targets for possible presymptomatic therapy for this disease.
authors: Department of Genetics, Hospital de la Santa Creu i Sant Pau and IIB Sant Pau, Avda Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors: Rebeca
authors: R
authors: Martínez-Hernández
authors: Sara
authors: S
authors: Bernal
authors: Eva
authors: E
authors: Also-Rallo
authors: Laura
authors: L
authors: Alías
authors: María Jesús
authors: MJ
authors: Barceló
authors: Marta
authors: M
authors: Hereu
authors: Josep E
authors: JE
authors: Esquerda
authors: Eduardo F
authors: EF
authors: Tizzano
mesh_terms: D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009024:Morphogenesis; D009045:Motor Endplate / Q000473:pathology; D009046:Motor Neurons / Q000737:chemistry / Q000473:pathology* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000196:embryology / Q000294:innervation / Q000473:pathology* / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000196:embryology / Q000473:pathology* / Q000648:ultrastructure; D010641:Phenotype; D017729:Presynaptic Terminals / Q000737:chemistry / Q000473:pathology; D011950:Receptors, Cholinergic / Q000032:analysis; D012720:Severity of Illness Index; D014897:Spinal Muscular Atrophies of Childhood / Q000196:embryology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D011950:Receptors, Cholinergic