title: Spectrum of neuropathophysiology in spinal muscular atrophy type I.
abstract: Neuropathologic findings within the central and peripheral nervous systems in patients with spinal muscular atrophy type I (SMA-I) were examined in relation to genetic, clinical, and electrophysiologic features. Five infants representing the full clinical spectrum of SMA-I were examined clinically for compound motor action potential amplitude and SMN2 gene copy number; morphologic analyses of postmortem central nervous system, neuromuscular junction, and muscle tissue samples were performed and SMN protein was assessed in muscle samples. The 2 clinically most severely affected patients had a single copy of the SMN2 gene; in addition to anterior horn cells, dorsal root ganglia, and thalamus, neuronal degeneration in them was widespread in the cerebral cortex, basal ganglia, pigmented nuclei, brainstem, and cerebellum. Two typical SMA-I patients and a milder case each had 2 copies of the SMN2 gene and more restricted neuropathologic abnormalities. Maturation of acetylcholine receptor subunits was delayed and the neuromuscular junctions were abnormally formed in the SMA-I patients. Thus, the neuropathologic findings in human SMA-I are similar to many findings in animal models; factors other than SMN2 copy number modify disease severity. We present a pathophysiologic model for SMA-I as a protein deficiency disease affecting a neuronal network with variable clinical thresholds. Because new treatment strategies improve survival of infants with SMA-I, a better understanding of these factors will guide future treatments.
authors.affiliation: From the Departments of Pathology (BNH), Pediatrics (BNH, MB, SWY, GT, RSF), and Neurology (SWY, GT, RSF), The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and Center for Motor Neuron Biology and Disease (SK, URM) and the Departments of Pathology and Cell Biology (SK, URM), Neurology (URM), and Pediatrics (WKC), Columbia University Medical Center, New York, New York.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Harding
authors.forename: Shingo
authors.initials: S
authors.lastname: Kariya
authors.forename: Umrao R
authors.initials: UR
authors.lastname: Monani
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Maryjane
authors.initials: M
authors.lastname: Benton
authors.forename: Sabrina W
authors.initials: SW
authors.lastname: Yum
authors.forename: Gihan
authors.initials: G
authors.lastname: Tennekoon
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
mesh_terms: D002490:Central Nervous System / Q000473:pathology*; D002648:Child; D005727:Ganglia, Spinal / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010525:Peripheral Nerves / Q000473:pathology*; D011978:Receptors, Nicotinic / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: C539275:CHRNG protein, human; D011978:Receptors, Nicotinic; D055540:Survival of Motor Neuron 2 Protein; D064569:alpha7 Nicotinic Acetylcholine Receptor