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Figure.  Immunohistochemical Staining
Immunohistochemical Staining

Phosphorylated Tau-positive globose tangles and tufted astrocytes in the spinal cord C1 vertebra (phospho-Tau [AT8]; original magnification ×40) (A), cerebellum (phospho-Tau [AT8]; original magnification ×50) (B), hippocampus (phospho-Tau [AT8]; original magnification ×45) (C), and frontal cerebral cortex (phospho-Tau [AT8]; original magnification ×100) (D). Inset in the upper right of each image shows the location of the image in the brain.

1.
Kim  JM, Hong  S, Kim  GP,  et al.  Importance of low-range CAG expansion and CAA interruption in SCA2 Parkinsonism.  Arch Neurol. 2007;64(10):1510-1518.PubMedGoogle ScholarCrossref
2.
Koga  S, Josephs  KA, Ogaki  K,  et al.  Cerebellar ataxia in progressive supranuclear palsy: an autopsy study of PSP-C.  Mov Disord. 2016;31(5):653-662.PubMedGoogle ScholarCrossref
3.
Estrada  R, Galarraga  J, Orozco  G, Nodarse  A, Auburger  G.  Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies.  Acta Neuropathol. 1999;97(3):306-310.PubMedGoogle ScholarCrossref
4.
Ross  OA, Rutherford  NJ, Baker  M,  et al.  Ataxin-2 repeat-length variation and neurodegeneration.  Hum Mol Genet. 2011;20(16):3207-3212.PubMedGoogle ScholarCrossref
5.
McNeill  N, Nasca  A, Reyes  A,  et al.  Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo.  Neurol Genet. 2017;3(4):e162.PubMedGoogle ScholarCrossref
Research Letter
August 2018

An Autopsy Case of Progressive Supranuclear Palsy With Incidental ATXN2 Expansion

Author Affiliations
  • 1Department of Neurology, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
  • 2Department of Pathology, College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
  • 3Department of Neurology, College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
JAMA Neurol. 2018;75(8):1025-1027. doi:10.1001/jamaneurol.2018.0652

A case of multiple system atrophy with predominant parkinsonism (MSA-P) with ATXN2 (OMIM 601517) expansion was previously reported.1 However, the autopsy in that patient showed tauopathy without evidence of spinocerebellar ataxia type 2 (SCA2). Herein, we present the pathologic findings to correct the previous misdiagnosis. This patient is case 3 in the previous report,1 which details clinical history and examination. He died when he was in his late 60s due to pneumonia, 9 years after onset of the disease. A rare chance to examine MSA-P with low-range ATXN2 expansion prompted us to perform an autopsy.

Methods

General autopsy was carried out with routine procedure. The time from death to the postmortem examination was 17 hours. The half brain was stored in a deep freezer (−80°C) and the remaining half brain was fixed in 10% neutral formalin for 4 weeks. After fixation, formalin-fixed paraffin embedded blocks were cut as 5-μm thickness. Hematoxylin-eosin, glial fibrillary acidic protein (1:200 dilution; Dako), phosphorylated tau (1:300 dilution AT8; ThermoFisher), 3 repeat tau (1: 40 000 dilution; Merck), 4 repeat tau (1:10 000 dilution; Millipore), α-synuclein (phospho S129, 1: 200 dilution; Abcam), phosphorylated TDP43 (1:10 000 dilution; Cosmo Bio), phosphorylated neurofilaments (1:10 000 dilution; Milipore), NeuN (1:500 dilution; Milipore), and 1C2 (1:200 dilution; Milipore) immunohistochemistry and Luxol fast blue staining were carried out. Permission for autopsy was granted by the family, and the study was approved by the institutional review board of the Seoul National University Hospital.

Results

The weight of the fresh brain was 1450 g. Gross autopsy findings showed mild cortical atrophy with sulcus widening. Prominent pontine atrophy with cerebellar involvement was seen. The globus pallidus was atrophic. The putamen, caudate nucleus, and hippocampus were preserved. Depigmentation was observed in the substantia nigra and locus coeruleus. Microscopic examination showed widespread neuronal loss with reactive gliosis in the globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, and the dentate nucleus of the cerebellum. Numerous tau-positive, ubiquitin-negative globose tangles, and tufted astrocytes were seen in the brainstem, thalamus, basal ganglia, hippocampus, cortex, cerebellum, and cervical spinal cord (Figure). There was no Lewy body, neurite, or senile plaque pathology. No positive reaction, except for a few areas of weak granular staining in neuronal soma, was observed in 1C2 (antibody specific for polyglutamine) immunostaining.

Discussion

In the previous report,1 possible MSA-P was diagnosed based on rapidly progressive parkinsonism, poor response to levodopa, recurrent falling, erectile dysfunction, and hyperreflexia. In retrospect, this patient showed clinical characteristics of progressive supranuclear palsy. Mild limitation of downward eye movement was suspected. He showed no prominent ataxia and urinary dysfunction, which was not sufficient for MSA criteria. There was a cognitive bias of anchoring toward parkinsonism with cerebellar ataxia that is MSA because of ATXN2 expansion. We thought that mild cerebellar atrophy was suggestive of MSA, but mild cerebellar atrophy may be found in progressive supranuclear palsy.2 We conclude that our patient had progressive supranuclear palsy, and ATXN2 expansion is incidental. Pathologic changes in this case involved dentate nucleus, which is commonly spared in most patients with SCA2.3 Moreover, the rarity of polyglutamine staining in this patient suggested that SCA2 did not contribute to the pathologic effects. In addition, 2 of his children (even though they are only in their late 30s) with same expansion number of 32 are neurologically normal. Ross et al4 observed a significant association of expanded ATXN2 repeats with progressive supranuclear palsy. They also reported that repeats of 32 were found in a control population.4 Our case highlights that rigorous examination of clinical relevance is critical in the interpretation of genetic test results, as shown in a previous report.5

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Article Information

Accepted for Publication: February 6, 2018.

Corresponding Author: Beomseok Jeon, MD, PhD, Department of Neurology, College of Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Korea (brain@snu.ac.kr).

Published Online: May 7, 2018. doi:10.1001/jamaneurol.2018.0652

Author Contributions: Drs Park and Jeon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jeon.

Acquisition, analysis, or interpretation of data: Kim, Park.

Drafting of the manuscript: Kim, Park.

Critical revision of the manuscript for important intellectual content: Jeon.

Administrative, technical, or material support: Park, Jeon.

Study supervision: Jeon.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Prof Shigeo Murayama, Tokyo Metropolitan Institute of Gerontology, reviewed the microscopic findings.

References
1.
Kim  JM, Hong  S, Kim  GP,  et al.  Importance of low-range CAG expansion and CAA interruption in SCA2 Parkinsonism.  Arch Neurol. 2007;64(10):1510-1518.PubMedGoogle ScholarCrossref
2.
Koga  S, Josephs  KA, Ogaki  K,  et al.  Cerebellar ataxia in progressive supranuclear palsy: an autopsy study of PSP-C.  Mov Disord. 2016;31(5):653-662.PubMedGoogle ScholarCrossref
3.
Estrada  R, Galarraga  J, Orozco  G, Nodarse  A, Auburger  G.  Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies.  Acta Neuropathol. 1999;97(3):306-310.PubMedGoogle ScholarCrossref
4.
Ross  OA, Rutherford  NJ, Baker  M,  et al.  Ataxin-2 repeat-length variation and neurodegeneration.  Hum Mol Genet. 2011;20(16):3207-3212.PubMedGoogle ScholarCrossref
5.
McNeill  N, Nasca  A, Reyes  A,  et al.  Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo.  Neurol Genet. 2017;3(4):e162.PubMedGoogle ScholarCrossref
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