. 2020 Sep;7(9):1716-1725.

doi: 10.1002/acn3.51151. Epub 2020 Aug 10.

Neuronal intranuclear inclusion disease is genetically heterogeneous

Zhongbo Chen^{1

2}, Wai Yan Yau², Zane Jaunmuktane³, Arianna Tucci⁴, Prasanth Sivakumar², Sarah A Gagliano Taliun⁵, Chris Turner⁶, Stephanie Efthymiou², Kristina Ibáñez⁴, Roisin Sullivan², Farah Bibi⁷, Alkyoni Athanasiou-Fragkouli², Thomas Bourinaris², David Zhang¹, Tamas Revesz³, Tammaryn Lashley^{1

3}, Michael DeTure⁸, Dennis W Dickson⁸, Keith A Josephs⁹, Ellen Gelpi^{10

11}, Gabor G Kovacs^{11

12}, Glenda Halliday^{13

14

15}, Dominic B Rowe¹⁶, Ian Blair¹⁶, Pentti J Tienari^{17

18}, Anu Suomalainen^{19

20

21}, Nick C Fox²², Nicholas W Wood²³, Andrew J Lees^{3

24}, Matti J Haltia²⁵; Genomics England Research Consortium^{26

27}; John Hardy^{1

24

28

29

30}, Mina Ryten¹, Jana Vandrovcova², Henry Houlden²

Affiliations

¹ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK.
² Department of Neuromuscular Disease, Queen Square Institute of Neurology, UCL, London, UK.
³ Queen Square Brain Bank, Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, UCL, UK.
⁴ Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁵ Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
⁶ Queen Square Institute of Neurology, UCL and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
⁷ University Institute of Biochemistry & Biotechnology, PMAS - Arid Agriculture University, Rawalpindi, Pakistan.
⁸ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
⁹ Mayo Clinic, Neurodegenerative Research Group, Rochester, Minnesota.
¹⁰ Neurological Tissue Bank of the Hospital Clinic-Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) Biobank, Barcelona, Spain.
¹¹ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Austria.
¹² University of Toronto, Tanz Centre for Research in Neurodegenerative Disease, Toronto, Canada.
¹³ Neuroscience Research Australia, Sydney, Australia.
¹⁴ School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
¹⁵ Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
¹⁶ Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.
¹⁷ Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
¹⁸ Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁹ Research Programs Unit, Stem Cells and Metabolism, University of Helsinki, Helsinki, 00290, Finland.
²⁰ Neuroscience Center, HiLife, University of Helsinki, Helsinki, 00290, Finland.
²¹ HUSlab, Helsinki University Hospital, Helsinki, 00290, Finland.
²² Dementia Research Centre, UCL, London, Queen Square, UK.
²³ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, UCL, London, UK.
²⁴ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, Wakefield Street, London.
²⁵ Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁶ Genomics England, London, UK.
²⁷ William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
²⁸ UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL, London, UK.
²⁹ NIHR University College London Hospitals Biomedical Research Centre, London, UK.
³⁰ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.

PMID: 32777174
PMCID: PMC7480908
DOI: 10.1002/acn3.51151

Neuronal intranuclear inclusion disease is genetically heterogeneous

Zhongbo Chen et al. Ann Clin Transl Neurol. 2020 Sep.

. 2020 Sep;7(9):1716-1725.

doi: 10.1002/acn3.51151. Epub 2020 Aug 10.

Authors

Affiliations

¹ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK.
² Department of Neuromuscular Disease, Queen Square Institute of Neurology, UCL, London, UK.
³ Queen Square Brain Bank, Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, UCL, UK.
⁴ Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁵ Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
⁶ Queen Square Institute of Neurology, UCL and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
⁷ University Institute of Biochemistry & Biotechnology, PMAS - Arid Agriculture University, Rawalpindi, Pakistan.
⁸ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
⁹ Mayo Clinic, Neurodegenerative Research Group, Rochester, Minnesota.
¹⁰ Neurological Tissue Bank of the Hospital Clinic-Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) Biobank, Barcelona, Spain.
¹¹ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Austria.
¹² University of Toronto, Tanz Centre for Research in Neurodegenerative Disease, Toronto, Canada.
¹³ Neuroscience Research Australia, Sydney, Australia.
¹⁴ School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
¹⁵ Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
¹⁶ Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.
¹⁷ Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
¹⁸ Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁹ Research Programs Unit, Stem Cells and Metabolism, University of Helsinki, Helsinki, 00290, Finland.
²⁰ Neuroscience Center, HiLife, University of Helsinki, Helsinki, 00290, Finland.
²¹ HUSlab, Helsinki University Hospital, Helsinki, 00290, Finland.
²² Dementia Research Centre, UCL, London, Queen Square, UK.
²³ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, UCL, London, UK.
²⁴ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, Wakefield Street, London.
²⁵ Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁶ Genomics England, London, UK.
²⁷ William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
²⁸ UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL, London, UK.
²⁹ NIHR University College London Hospitals Biomedical Research Centre, London, UK.
³⁰ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.

PMID: 32777174
PMCID: PMC7480908
DOI: 10.1002/acn3.51151

Abstract

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico-based screening using whole-genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Distribution of *NOTCH2NLC* repeat expansions. Panel A is that of Patient 1 ¹¹ : intranuclear p62 immunoreactive inclusions are present in the majority of the neurons across the neocortex (A, blue arrow), dentate gyrus in the hippocampus (B, blue arrow), deep grey nuclei, brainstem nuclei and cerebellar neurons (not shown). The inclusions are eosinophilic on routine haematoxylin and eosin stained sections (inset in A, blue arrow). The intranuclear inclusions are also frequently seen in the ependymal cells (C, red arrow) but only rarely observed in glial cells (D, red arrow). Scale bar: 20 µm in A‐D. The corresponding electropherogram confirms absence of the repeat expansion within this patient. Panel B shows the histogram distributions of the number of CGG repeats in the population (population) (estimated from ExpansionHunter based on 20,536 participants with neurological presentations enrolled into the 100,000 Genomes Project) compared with cases of neuropathologically confirmed NIID within our samples (NIID) and cases with evidence of pathological intranuclear inclusions (inclusions). Panel C summarizes the comparison of clinical characteristics between cases of NIID described within and outside of Japan. Panel D shows brightfield‐positive and brightfield‐negative images for p62 immunoreactivity in the skin biopsy of the patient identified from 100,000 Genomes Project (Case 12). The corresponding electropherogram infers presence of a repeat expansion as seen by the typical sawtooth pattern.

**Figure 2**
Proposed diagnostic criteria for neuronal intranuclear inclusion‐related diseases. The classification is based on clinical, pathological and genetic criteria. MRI: Magnetic resonance imaging. DWI: diffusion‐weighted imaging. CJD: Creutzfeldt‐Jakob disease. FXTAS: Fragile X‐associated tremor/ataxia syndrome. FTLD‐FUS: frontotemporal dementia‐fused in sarcoma subtype. FTLD‐TDP43: frontotemporal dementia with transactive response DNA binding protein 43 kDa‐positive inclusions.

See this image and copyright information in PMC

Comment in

Reply to: No evidence supports genetic heterogeneity of neuronal intranuclear inclusion disease.
Chen Z, Ryten M, Houlden H. Chen Z, et al. Ann Clin Transl Neurol. 2020 Dec;7(12):2544-2545. doi: 10.1002/acn3.51222. Epub 2020 Oct 30. Ann Clin Transl Neurol. 2020. PMID: 33124767 Free PMC article. No abstract available.
No evidence supports the genetic heterogeneity of Neuronal intranuclear inclusion disease.
Li H, Sun M, Wan B, Xu X. Li H, et al. Ann Clin Transl Neurol. 2020 Dec;7(12):2542-2543. doi: 10.1002/acn3.51223. Epub 2020 Oct 30. Ann Clin Transl Neurol. 2020. PMID: 33124781 Free PMC article. No abstract available.
Reply: Genetic heterogeneity of neuronal intranuclear inclusion disease. What about the infantile variant?
Yau WY, Chen Z, Sullivan R, Vandrovcova J, Houlden H. Yau WY, et al. Ann Clin Transl Neurol. 2021 Apr;8(4):1002-1004. doi: 10.1002/acn3.51330. Epub 2021 Mar 29. Ann Clin Transl Neurol. 2021. PMID: 33780167 Free PMC article. No abstract available.
Genetic heterogeneity of neuronal intranuclear inclusion disease: What about the infantile variant?
Sikora J, Jedlickova I, Pristoupilova A, Stranecky V, Honzik T. Sikora J, et al. Ann Clin Transl Neurol. 2021 Apr;8(4):994-1001. doi: 10.1002/acn3.51332. Epub 2021 Mar 29. Ann Clin Transl Neurol. 2021. PMID: 33780169 Free PMC article. No abstract available.

References

1. Sone J, Mori K, Inagaki T, et al. Clinicopathological features of adult‐onset neuronal intranuclear inclusion disease. Brain 2016;139(Pt 12):3170–3186. - PMC - PubMed
1. Lindenberg R, Rubinstein LJ, Herman MM, Haydon GB. A light and electron microscopy study of an unusual widespread nuclear inclusion body disease. Acta Neuropathol 1968;10(1):54–73. - PubMed
1. Ishiura H, Shibata S, Yoshimura J, et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet 2019;51(8):1222–1232. - PubMed
1. Sone J, Mitsuhashi S, Fujita A, et al. Long‐read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet 2019;51(8):1215–1221. - PubMed
1. Gelpi E, Botta‐Orfila T, Bodi L, et al. Neuronal intranuclear (hyaline) inclusion disease and fragile X‐associated tremor/ataxia syndrome: a morphological and molecular dilemma. Brain 2017;140(8):e51. - PubMed

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Neuronal intranuclear inclusion disease is genetically heterogeneous

Affiliations

Neuronal intranuclear inclusion disease is genetically heterogeneous

Authors

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Abstract

Conflict of interest statement

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