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Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I

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Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I J Neuropathol Exp Neurol Vol. 74, No. 1 Copyright Ó 2014 by the American Association of Neuropathologists, Inc. January 2015 pp. 15Y24 ORIGINAL ARTICLE Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I Brian N. Harding, MD, PhD, Shingo Kariya, MD, PhD, Umrao R. Monani, PhD, Wendy K. Chung, MD, PhD, Maryjane Benton, BSN, Sabrina W. Yum, MD, Gihan Tennekoon, MD, and Richard S. Finkel, MD Downloaded from https://academic.oup.com/jnen/article/74/1/15/2614215 by guest on 24 September 2021 protein deficiency disease affecting a neuronal network with variable Abstract clinical thresholds. Because new treatment strategies improve survival Neuropathologic findings within the central and peripheral ner- of infants with SMA-I, a better understanding of these factors will vous systems in patients with spinal muscular atrophy type I (SMA-I) guide future treatments. were examined in relation to genetic, clinical, and electrophysiologic features. Five infants representing the full clinical spectrum of SMA-I Key Words: Genetics, Neuromuscular junction, Neuronal degeneration, were examined clinically for compound motor action potential ampli- Pathophysiology, Spinal muscular atrophy, Threshold hypothesis model. tude and SMN2 gene copy number; morphologic analyses of post- mortem 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 INTRODUCTION single copy of the SMN2 gene; in addition to anterior horn cells, Proximal recessively inherited spinal muscular atrophy dorsal root ganglia, and thalamus, neuronal degeneration in them ([SMA] OMIM No. 253300) is the most frequent lethal ge- was widespread in the cerebral cortex, basal ganglia, pigmented netic disorder in infancy (1), with an estimated incidence of nuclei, brainstem, and cerebellum. Two typical SMA-I patients and 1:11,000 births (2). Spinal muscular atrophy is characterized a milder case each had 2 copies of the SMN2 gene and more re- by progressive degeneration of lower motor neurons in the stricted neuropathologic abnormalities. Maturation of acetylcholine spinal cord, which, in severe cases, extends to bulbar motor receptor subunits was delayed and the neuromuscular junctions nuclei and in which there is concomitant skeletal muscle at- were abnormally formed in the SMA-I patients. Thus, the neuro- rophy (3). The degeneration results in a phase of plateau in pathologic findings in human SMA-I are similar to many findings in motor development, followed by a progressive decline, and, animal models; factors other than SMN2 copy number modify dis- in the more severe cases, feeding and breathing difficulties ease severity. We present a pathophysiologic model for SMA-I as a that lead to premature demise (4). In addition to muscle weakness, fatigue in motor function has also been character- ized clinically in SMA patients (5). Prior observations have From the Departments of Pathology (BNH), Pediatrics (BNH, MB, SWY, supported the hypothesis that SMA is a motor neuronal dis- GT, RSF), and Neurology (SWY, GT, RSF), The Children’s Hospital of order with developmental arrest (6, 7); this has been demon- Philadelphia and the Perelman School of Medicine at the University of strated in the zebra fish model of SMA (8). Spinal muscular Pennsylvania, Philadelphia, Pennsylvania; and Center for Motor Neuron atrophy is caused by abnormally low levels of the ubiquitous Biology and Disease (SK, URM) and the Departments of Pathology and protein survival of motor neuron (SMN), resulting from a Cell Biology (SK, URM), Neurology (URM), and Pediatrics (WKC), Columbia University Medical Center, New York, New York. combination of homozygous deletions or mutations of the Dr Richard S. Finkel is now with the Division of Neurology, Nemours telomeric copy of the SMN gene (SMN1) on chromosome 5q Children’s Hospital, Orlando, Florida. and the presence of 1 or more copies of SMN2 (9), an almost Send correspondence and reprint requests to: Brian N. Harding, MD, De- identical but partially functional centromeric copy, which is partment of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, 324 South 34th St, Philadelphia, PA 19104; E-mail: unique to humans (10). The difference between these 2 genes, [email protected] a single nucleotide transition at exon 7, affects a splice site The Spinal Muscular Atrophy Foundation provided support to The Children’s enhancer such that approximately 90% of transcripts of SMN2 Hospital of Philadelphia (Richard Finkel, Gihan Tennekoon) and Columbia lack exon 7 (SMN$7), resulting in greatly reduced levels of University (Wendy Chung and Umrao Monani) as well as sponsorship of normal SMN protein (11, 12). SMN1 mutations have been the Pediatric Neuromuscular Clinical Research Network (Richard Finkel, Maryjane Benton, Wendy Chung). This support is gratefully acknowl- demonstrated in the 3 clinical forms of childhood-onset SMA: edged. Umrao Monani is the recipient of grant funding, which supported acute early-onset severe type I Werdnig-Hoffmann disease the work described here: NIH R01NS057482, MDA-USA and DoD (SMA-I); chronic intermediate type II; and chronic mild type W81XWH-09-1-0245. III or Kugelberg-Welander (13). Spinal muscular atrophy type All authors report no potential conflict of interest. Supplemental digital content is available for this article. Direct URL citations I has been further subdivided into a connatal form (SMA-IA, appear in the printed text and are provided in the HTML and PDF versions also termed Type 0 [14]), onset by 3 months of age (SMA-IB), of this article on the journal’s Web site. (www.jneuropath.com). and onset after 3 months of age (SMA-IC) (15). A less severe J Neuropathol Exp Neurol Volume 74, Number 1, January 2015 15 Copyright © 2014 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. Harding et al J Neuropathol Exp Neurol Volume 74, Number 1, January 2015 disease phenotype is associated with increased SMN2 copy fibrillary acidic protein (1:400, No. M0761; Dako, Carpinteria, number (16), which is thought to arise by gene conversion CA), phosphorylated neurofilament (NF-P, clone TA51, gift of rather than deletion (10). Unsurprisingly, these recent correl- Dr J. Trojanowski, Hospital of University of Pennsylvania, PA), ative studies evaluating the natural history of the disease diluted 1:10, and ubiquitin (No. Z0458; Dako), diluted 1:700. alongside genetic data generally lack detailed corroborative A variety of skeletal muscles from these cases were ex- neuropathology (17, 18). Indeed, much of our neuropatho- amined in paraffin and frozen sections stained with hematoxylin logic knowledge in this field predates the genetic era (19Y21). and eosin and by myosin immunocytochemistry for fiber typing Therefore, we have revisited the human neuropathology in using MHCf, MHCs, and MHCn, all at 1:80 (No. NCL-MHCf, selected cases of genetically characterized SMA-I, covering MHCs, MHCn; Leica Microsystems, Bannockburn, IL). Ten- the full clinical spectrum and including data regarding both micrometer-thick frozen muscle sections were cut onto charged SMN genes, to investigate further the relationship between glass slides. Immunohistochemistry was done on the Leica SMN2 copy number and the severity of the morphologic Bond III Autostainer using the Bond Polymer Refine Detection phenotype. These observations and current animal model data System (Leica Microsystems). No antigen retrieval methods Downloaded from https://academic.oup.com/jnen/article/74/1/15/2614215 by guest on 24 September 2021 are used to construct a model of the pathogenesis of SMA. were used. The detection reagents include a horseradish per- oxidase linked polymer, and 3,3¶-diaminobenzidine as chro- mogen. The sections were counterstained with Gill hematoxylin. MATERIALS AND METHODS Muscle tissue was sent for detailed analysis (Shingo Five patients with SMA-I were treated at the Children’s Kariya, Umrao Monani), where normal control tissue was also Hospital of Philadelphia (CHOP) and evaluated by a neuro- examined. SMN copy numbers were determined by a poly- muscular physician (Richard Finkel, Gihan Tennekoon). Cases 1 merase chain reactionYderived dose ratio of SMN2 to a control and 2, with SMA-IA, were seen only in the neonatal intensive gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH), care unit. Cases 3 (SMA-IB), 4 (SMA-IB), and 5 (SMA-IC) were as previously described (25). followed in the neuromuscular clinic and enrolled in an institu- Diaphragm muscle samples from control patients had tional review boardYapproved natural history study, in which the following characteristics: each parent signed a consent form and clinical data and DNA Control A17, aged 5 months with Williams syndrome; were collected. Cases 3, 4, and 5 were selected from among Control A18, aged 4 years with cerebellar degeneration but no approximately 60 SMA-I patients seen in the clinic during a motor neuron disease and no genetic diagnosis established; 10-year span; they were selected for the range of clinical pheno- and Control A-23, aged 20 years with cystic fibrosis. type and for the availability of postmortem material for study. Clinical evaluations were performed using the CHOP Neuromuscular Junction Immunohistochemistry Infant Test of Neuromuscular Disorders (INTEND) Motor To determine the size and the complexity of motor Scale, a 16-item scale with a maximum score of 64 (22). A endplates
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