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.

Figure 1

Neuropathology of the brain and spinal cord. (A-F) Findings in all 5 cases. The anterior roots were very thin compared with the posterior roots (A, C). There was neurogenic atrophy of skeletal muscle with group atrophy and hypertrophy (B). There was degeneration (ballooning/chromatolysis) and loss of anterior horn cells at all levels of the spinal cord (D). Similar changes included neuronophagia identified in the thalamus (E), and degenerating neurons in dorsal root ganglia and residual nodules of Nageotte (F). (G-J) Unusual features in cases 1 and 5. In case 1 there was more widespread neuronal degeneration included: locus ceruleus (G), nuclei pontis (H), cerebellar dentate nucleus (I), and motor cortex (arrow = affected Betz cell) (J). (K) In case 4 when the spinal theca was reflected at postmortem, a retroverted sacral cord and anomalous course of the lowest anterior roots were observed. Panels B-J, hematoxylin and eosin. Original magnifications: B, D, F, J, x100; C, x10; E, H, x400; G, I, x200

Figure 1

Neuropathology of the brain and spinal cord. (A-F) Findings in all 5 cases. The anterior roots were very thin compared with the posterior roots (A, C). There was neurogenic atrophy of skeletal muscle with group atrophy and hypertrophy (B). There was degeneration (ballooning/chromatolysis) and loss of anterior horn cells at all levels of the spinal cord (D). Similar changes included neuronophagia identified in the thalamus (E), and degenerating neurons in dorsal root ganglia and residual nodules of Nageotte (F). (G-J) Unusual features in cases 1 and 5. In case 1 there was more widespread neuronal degeneration included: locus ceruleus (G), nuclei pontis (H), cerebellar dentate nucleus (I), and motor cortex (arrow = affected Betz cell) (J). (K) In case 4 when the spinal theca was reflected at postmortem, a retroverted sacral cord and anomalous course of the lowest anterior roots were observed. Panels B-J, hematoxylin and eosin. Original magnifications: B, D, F, J, x100; C, x10; E, H, x400; G, I, x200

Figure 2

Impaired development of neuromuscular junctions (NMJs) in severe (type 1) spinal muscular atrophy (SMA). (A) Immunohistochemistry of NMJs in the diaphragm muscle from controls (A17, 5 months old; A18, 4 years old) and an SMA patient (case 5, 10 years old) depicting relatively small, non-perforated, acetylcholine receptor (AChR)-expressing endplates in the affected individual. While A17 continues to express the γ-AchR isoform, the endplates from this individual and A18 are relatively elaborately structured (perforated). (B) Quantification of endplate area in the 3 human samples. Cm (D) The complexity of the NMJs was assessed by quantifying the number of perforations (C) and the proportion of endplates expressing the γ-AchR isoform (D). Scale bar, 35 μm.

Figure 3

Western blot analysis of muscle tissue from severe spinal muscular atrophy (SMA) patients and a control. Patients express reduced SMN protein vs. the loading control glyceraldehyde 3-phosphate dehydrogenase (GAPDH).

Figure 4

Pathophysiologic model of spinal muscular atrophy type I (SMA-I). Clinically relevant pathological findings are represented in larger boxes with clear background; pathologic findings without clear clinical correlates are represented in smaller boxes with a grey background. *Other: see text for other neurons involved.