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NI FEATURE: NEUROPATHOLOGY DISCUSSION
Year : 2020  |  Volume : 68  |  Issue : 4  |  Page : 882-885

Spinal Muscular Atrophy: Autopsy Based Neuropathological Demonstration


1 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication26-Aug-2020

Correspondence Address:
Dr. Kirti Gupta
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.293477

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 » Abstract 


Spinal muscular atrophy (SMA) encompasses a group of disorders with loss of spinal motor neurons.The report describes the neuropathological findings including brain and spinal cord at autopsy in a five-and-half-month-old boy with suspected type 1 SMA. The anterior motor neurons, Clarke's column at all the levels of spinal cord showed neuronal loss and degeneration while neurons at all the deep grey nuclei were preserved apart from variable degree anoxic changes. Skeletal muscle biopsy revealed features of neurogenic atrophy consistent with SMA. A differential diagnosis like storage disorders was excluded using electron microscopy. No extra-neural manifestations were seen. Neuropathological features at autopsy have seldom been reported in the literature.


Keywords: Neurogenic atrophy, spinal muscular atrophy, Werdnig–Hoffmann disease
Key Messages: Spinal muscular atrophy (SMA) encompasses a group of disorders with loss of spinal motor neurons. It is inherited in an autosomal recessive manner and is caused by a genetic mutation affecting the survival motor neuron (SMN) gene. Skeletal muscle biopsy reveals marked group atrophy of fibers with compensatory hypertrophy of adjacent fibers. There is predominant atrophy of type 2 fibers and hypertrophy of type 1 fibers. Diagnosis of SMA is confirmed by genetic test demonstrating homozygous SMN1 deletion.


How to cite this article:
Thirunavukkarasu B, Gupta K, Bansal A, Dhanasekaran N, Baranwal A. Spinal Muscular Atrophy: Autopsy Based Neuropathological Demonstration. Neurol India 2020;68:882-5

How to cite this URL:
Thirunavukkarasu B, Gupta K, Bansal A, Dhanasekaran N, Baranwal A. Spinal Muscular Atrophy: Autopsy Based Neuropathological Demonstration. Neurol India [serial online] 2020 [cited 2020 Oct 20];68:882-5. Available from: https://www.neurologyindia.com/text.asp?2020/68/4/882/293477




Spinal muscular atrophy (SMA) is characterized by progressive degeneration of lower motor neurons in the spinal cord, which, in severe cases, extends to bulbar motor nuclei and in which there is concomitant skeletal muscle atrophy.[1] The onset of weakness ranges from before birth to adolescence or young adulthood. The weakness is symmetric, with proximal more than distal, and progressive. It is the most common genetic cause of death in infants.[2] Based on the age of onset and clinical course, SMA is classified into four types of which type 1 is a severe form with infantile onset. We report the post-mortem neuropathological findings of a five-and-half month-old boy with type I SMA who succumbed to the illness.


 » Case Summary Top


A five-and-half month old boy was admitted with complaints of difficulty in breathing for five days associated with fever, cough, and poor feeding for two days duration. Developmental history was significant with history of paucity of limb movements since birth. No significant family history was present, and child was first-born of a non-consanguineous marriage. On examination, the baby had fast breathing with retraction, non-productive cough and altered sensorium. Bilateral crepitations were present. There was isolated motor development delay in the form of absent neck holding and rolling over. Language, social, and visual developments were appropriate for age. There was generalized floppiness, hypotonia and areflexia. Power was 1/5 in all four limbs. No gross wasting of muscle fibres was noted. Tongue fasciculations were present.

Arterial blood gas analysis revealed chronic respiratory acidosis with metabolic compensation with [pH of 7.25 (N: 7.36–7.44), PaO2 of 85 mmHg (N: 80-100 mmHg), PaCO2 of 58.9 mmHg (N: 35–45 mmHg), HCO3:32.9 mEq/L (N: 22-26 mEq/L)]. Chest X-ray showed mild cardiomegaly and heterogeneous opacity involving lower lobe of right lung. Electrocardiogram showed baseline fasciculations indicating a myopathy. The respiratory distress and shock worsened and the child succumbed within three days of admission despite intravenous antibiotics, respiratory support, correction of electrolyte disturbance and anti-shock measures.

Pathology findings

A complete autopsy including brain and spinal cord was performed on this baby with a clinical diagnosis of acute floppy infant likely to be SMA and a differential of glycogen storage disorder like Pompe's disease was kept. No facial dysmorphism was noted.

Brain weighed 630g (average normal weight for this age-644 g). The gyral pattern was normal. No focal lesions or infarcts were seen on coronal sectioning of entire brain. On microscopy, the cortical laminations of cortical neurons were preserved, however hypoxic changes were noted within the cortical neurons [Figure 1]a, [Figure 1]b, [Figure 1]c. The deep grey nuclei including basal ganglia, thalamus, granular and pyramidal neurons of dentate gyrus (CA4–CA1 areas), substantia nigra, pontine nuclei, medulla (inferior olivary nuclei) were normal [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. The cerebellar cortex including granular neurons, Purkinje cells, dentate nuclei were also normal. The nuclei of the cranial nerves including hypoglossal and vagus were unremarkable. The anterior spinal roots were thinner than the posterior roots.
Figure 1: (a) Coronal sections at the level of third ventricle and thalamus did not reveal any focal lesions; (b) Low magnification of the cortex represented in the box showing normal lamination of neurons (H&E ×40); (c) Cortical neurons showing hypoxic changes with pyknotic nuclei and hypereosinophilic cytoplasm (H&E ×400)

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Figure 2: (a) Coronal sections at the level of hippocampus; (b) Normal row of neurons forming the dentate gyrus at low magnification (H&E ×40); (c) Scanner view of section of hippocampus; (d) High magnification showing the row of granular neurons of the Ammons's horn (H&E ×400)

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Sections from spinal cord at upper and lower cervical levels, thoracic levels, and lumbar levels were sampled [Figure 3]a. The anterior motor neurons at cervical and thoracic levels demonstrated neuronal loss with few chromatolytic and ballooned neurons with peripheral condensation of Nissl granules [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e. Neuronophagia was rarely seen. No microglial nodules were identified. Neuronal loss was further highlighted by NeuNimmunostain. Neurons within the dorsal thoracic nuclei of Clarke's revealed variable degree of degeneration [Figure 4]a and [Figure 4]b. CD68 positive cells were not significantly increased. There was no neuronal loss noted in the posterior nerve root ganglion. No significant gliosis was evident in regions of neuronal loss [Figure 4]c. Sampled portions of anterior nerve roots attached to the spinal cord were atrophic with loss of myelinated fibres [Figure 4]d.
Figure 3: (a) Complete spinal cord removed at autopsy; (b) Low magnification highlighting the central canal and neurons of the anterior horn (bracket); inset showing the scanner view of the section at the level of cervical cord; (c) Degenerative changes (arrow) noted in the neurons of anterior horn associated with loss of neurons (H&E ×400); (d) Chromatolytic with peripheral condensation of Nissl granules (H&E ×400); (e) Ballooned neurons within the anterior horn neurons (H&E ×400)

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Figure 4: (a) Degenerative changes (arrow) noted in the neurons of Clarke's column (H&E ×200); (b) High magnification showing loss of neurons at Clarke's column (H&E ×400); (c) Glial fibrillary acidic protein did not reveal any significant gliosis in areas corresponding to anterior horn neurons (immunoperoxidase ×400); (d) Luxol fast blue stain reveals loss of myelinated fibres at the anterior nerve roots (Luxol fast blue ×200)

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Snap frozen section of psoas muscle biopsy revealed marked group atrophy of fibres with compensatory hypertrophy of adjacent fibres [Figure 5]a and b]. The atrophic fibres were predominantly rounded. No significant interstitial fibrosis or inflammatory infiltrate was seen. Immunohistochemistry performed for slow and fast myosin highlighted predominant atrophy of type 2 fibres and hypertrophy of type 1 fibres [Figure 5]c and d]. No ragged red fibres or sub-sarcolemmal accumulation of mitochondria was observed on Modified Gomori trichrome stain [Figure 5]e.
Figure 5: (a) Low magnification depicting group atrophy of muscle spindles (H&E x100); (b) High magnification depicts group atrophy of fibres with compensatory hypertrophy of adjacent fibres (H&E ×400); (c and d) Slow myosin (c) and fast myosin (d) depicting atrophy of type 2 and hypertrophy of type 1 fibres (immunoperoxidase ×200); (e) No sub-sarcolemmalcolections of mitochondria as seen on Modified Gomori trichrome stain, (MGT ×200)

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The heart weighed 38.5g (average normal weight for this age-31g). The shape of the heart was maintained and no congenital malformations were seen. Left ventricular wall thickness was 0.4 cm and right ventricular wall thickness was 0.2 cm. Microscopically, no significant interstitial fibrosis or inflammatory infiltrate was seen. Cardiac myocytes did not show any vacuolation which is a feature of Pompe's disease. Periodic acid Schiff (PAS) stain also did not highlight any glycogen deposition within the cells. Electron microscopy did not reveal any membrane bound vacuoles, thus ruling out clinically suspected glycogen storage disorder. Liver weighed 198g (average normal weight for this age is 200g) and on microscopy revealed maintained lobular architecture with diffuse microvesicular steatosis. PAS stain, however, did not show positivity in any of the vacuoles. Semi-thin section (1 μg) stained with toluidine blue confirmed the microvesicular steatosis and did not reveal any glycogen vacuoles. Lungs weighed 120 g (average normal weight for this age is 81g) and on cut surface revealed areas of consolidation and hemorrhage. On microscopy, there was extensive diffuse alveolar damage in exudative phase with hyaline membrane formation in alveoli. Bronchopneumonia was also seen with acute inflammatory infiltrate within the alveoli. Gram Twort stain failed to highlight any gram positive or negative organisms. Rest of the organs was unremarkable. Hence, a final autopsy diagnosis of neurogenic atrophy consistent with SMA type 1 along with bronchopneumonia and diffuse alveolar damage was rendered.


 » Discussion Top


SMA is characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The incidence of SMA is estimated to be 1:11,000 births.[3] Guido Werdnig in 1891 and Johann Hoffmann, between 1893 and 1900, described a total of nine cases of a disease where young people were affected by a new form of muscular atrophy. SMA has been classified traditionally into types 1–3, but some experts suggest an expanded classification that includes additional subtypes from type 0 to type 4 on the basis of age of onset and the highest motor function achieved. Type 1 or the Werdnig–Hoffmann disease is a very severe form representing 45% of cases; it is associated with onset after birth but before age six months. Affected infants have delayed milestones with impaired head control, weak cry and cough and inability to sit. Swallowing, feeding, and handling of oral secretion are affected before 1 year of age. Weakness and hypotonia in the limbs and trunks are eventually accompanied by intercostal muscle weakness. Paradoxical breathing is a characteristic feature with flattening of the chest wall (rather than expansion) and protrusion of the abdomen during inspiration. Their life expectancy usually does not exceed two years. Type 2 SMA is an intermediate form with onset is between 7 and 18 months, while patients with type 3 SMA (Kugelberg and Welander syndrome) have onset after 30th month of life. Type 4 has onset between the 10th and the 30th year of life and many have a normal lifespan.[4] The clinical features such as the age of onset, paucity of limb movements with absent neck control as well as pathological features in the index child were consistent of Type 1 SMA.

SMA is inherited in an autosomal recessive manner. The classical form of the disorder is caused by a genetic mutation in 5q11.2–q13.3, affecting the survival motor neuron (SMN) gene. This gene is duplicated with a telomeric copy (SMN1) and a centromeric analogue copy (SMN2). SMN2 predominantly produces a survival motor neuron protein that is lacking in exon 7, a less stable protein. SMA is caused by loss of SMN1 because SMN2 cannot fully compensate for loss of SMN1-produced protein. However, when the SMN2 (dosage) copy number is increased, the small amount of full-length transcript generated by SMN2 is often able to produce a milder type II or type III phenotype.[5]

In the index case, the atrophic fibres in the muscle biopsy were predominantly rounded in contrast to the angulated shape seen in other forms of neurogenic atrophy such as amyotrophic lateral sclerosis. Muscle biopsy cannot distinguish clearly between SMA subtypes, but certain histological features are associated with disease severity. Muscle biopsy in infants with types 1 and 2 shows large groups of atrophic fibres interspersed with fascicles of hypertrophied and normal fibres as demonstrated in this case. The hypertrophied fibres are usually type 1. In milder cases of type 2 and type 3 SMA, there are typically groups of uniformly atrophic fibres between groups of non-atrophic muscle fibres. Both the atrophic and non-atrophic groups may be of either type 1 or 2 muscle fibres. The groups of atrophic fibres vary in size. Muscle biopsy features in type 4 SMA are similar to type 3.[6] Harding et al.[7] had demonstrated the neuropathological findings in five genetically confirmed cases of Type 1 SMA. Similar to our case, degeneration of neurons was predominantly seen in the anterior horn cells and Clarke's column. However, unlike our case, two cases showed degenerative changes in the cerebral cortex, thalamus and brain stem and cranial nerve nuclei XII, X, VII, VI, III. The dorsal root ganglion showed residual nodules of Nageotte and frequent ballooned chromatolytic sensory neurons. Similar findings were reported by Ito et al.[8] In addition, there was expression of phosphorylated NFP in the ballooned neurons with prominent SMN immunostaining in the prenatal period and loss in the later stages. Autopsy pathology of SMA has been reported rarely in literature.[9],[10] Kuru and colleagues describe abundant gliosis in areas of neuronal loss and glial bundles in the nerve roots in anterior spinal roots. Long clinical course and late onset could explain the presence of these which were not evident in the present case.[10]

One of the interesting challenges in considering the pathogenesis of SMA is the selective vulnerability of certain cell populations. The current hypothesis is that there may be differential thresholds between different cell types, with spinal motor neurons the most sensitive to a reduction in SMN protein expression. Individuals with only 1 copy of the truncated SMN2 gene have the lowest level of SMN protein compatible with survival, which may unmask the vulnerability of cell types with lesser quantitative requirements for the protein.[7]

The diagnosis of SMA is confirmed by genetic test demonstrating homozygous SMN1 deletion which is 100% specific and 95% sensitive for SMA.[11] If mutational analysis is negative, laboratory investigations including electrophysiological tests such as electromyography and nerve conduction tests should be performed. If electromyography suggests a motor neuron disease, then further testing for SMN mutations should be undertaken. Mutational analysis for SMN1 gene could not be performed in the present case. However, the neuropathological features at autopsy are classical. Relatively few such reports are documented in the literature which prompted us to report this instructive case.

Until recently, treatment of SMA was primarily supportive. The identification of SMN2 as a molecular target and generation of animal models for preclinical testing has significantly transformed its therapeutics. Lately, the therapeutic strategies focus on increasing the amount of SMN protein through small molecules, oligonucleotides and gene replacement.

In conclusion, the report adds observational data to the literature as there are very few autopsy studies demonstrating the neuropathological findings of SMA leading to its complications. The case illustrates one such rare example with a brief review of the literature. Thus, in a child presenting with protean manifestation of delayed milestones, hypotonia and floppiness, genetic testing for SMN gene must be performed. Characteristics features of neurogenic atrophy in muscle biopsy if performed are helpful supportive clues for diagnosis. Lastly, role of genetic counselling is equally important as it has autosomal recessive inheritance.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord 1992;2:423-8.  Back to cited text no. 1
    
2.
Roberts DF, Chavez J, Court SD. The genetic component in child mortality. Arch Dis Child 1970;45:33-8.  Back to cited text no. 2
    
3.
Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of >72 400 specimens. Eur J Hum Genet 2012;20:27-32.  Back to cited text no. 3
    
4.
Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: Controversies and challenges. Lancet Neurol 2012;11:443-52.  Back to cited text no. 4
    
5.
Farrar MA, Kiernan MC. The Genetics of spinal muscular atrophy: Progress and challenges. Neurotherapeutics 2015;12:290-302.  Back to cited text no. 5
    
6.
Dubowitz V. Enzyme histochemistry of skeletal muscle. 3. Neurogenic muscular atrophies. J Neurol Neurosurg Psychiatry 1966;29:23-8.  Back to cited text no. 6
    
7.
Harding BN, Kariya S, Monani UR, Chung WK, Benton M, Yum SW, et al. Spectrum of neuropathophysiology in spinal muscular atrophy type I. JNeuropathol Exp Neurol 2015;74:15-24.  Back to cited text no. 7
    
8.
Ito Y, Shibata N, Saito K, Kobayashi M, Osawa M. New insights into the pathogenesis of spinal muscular atrophy. Brain Dev 2011;33:321-31.  Back to cited text no. 8
    
9.
Huang K, Luo Y. Adult spinal muscular atrophy. A report of four cases. J Neurol Sci 1983;61:249-59.  Back to cited text no. 9
    
10.
Kuru S, Sakai M, Konagaya M, Yoshida M, Hashizume Y, Saito K. An autopsy caseof spinal muscular atrophy type III (Kugelberg-Welander disease). Neuropathology 2009;29:63-7.  Back to cited text no. 10
    
11.
Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: Diagnosis and management in a new therapeutic era. Muscle Nerve 2015;51:157-67.  Back to cited text no. 11
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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