Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I

• Published in: Journal of neuropathology and experimental neurology Vol. 74; no. 1; pp. 15 - 24
• Main Authors: Harding, Brian N, Kariya, Shingo, Monani, Umrao R, Chung, Wendy K, Benton, Maryjane, Yum, Sabrina W, Tennekoon, Gihan, Finkel, Richard S
• Format: Journal Article
• Language: English
• Published: England by American Association of Neuropathologists, Inc 01.01.2015
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - metabolism; Central Nervous System - pathology; Child; Ganglia, Spinal - pathology; Humans; Infant; Infant, Newborn; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Mutation - genetics; Neuromuscular Junction - metabolism; Neuromuscular Junction - pathology; Neurons - metabolism; Neurons - pathology; Peripheral Nerves - pathology; Receptors, Nicotinic - metabolism; Spinal Cord - pathology; Spinal Muscular Atrophies of Childhood - genetics; Spinal Muscular Atrophies of Childhood - pathology; Spinal Muscular Atrophies of Childhood - physiopathology; Survival of Motor Neuron 2 Protein - genetics; Survival of Motor Neuron 2 Protein - metabolism
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0000000000000144

ABSTRACTNeuropathologic 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.