Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
    • Topics A-Z
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
    • Topics A-Z
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

December 2021; 7 (6) Clinical/Scientific NoteOpen Access

Predominant Spastic Paraparesis Associated With the D178N Mutation in PRNP

Sebastian Thams, Martin Paucar, Louise Wingård, Håkan Thonberg, Colin Smith, Inger Nennesmo, Per Svenningsson
First published November 4, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000636
Sebastian Thams
From the Department of Neurology (S.T., M.P., P.S.), Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience (S.T., M.P., P.S.), Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry (L.W.), North West District in Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.T.), Center for Molecular Medicine, Karolinska Institutet; Department of Clinical Genetics (H.T.), Karolinska University Laboratory, Karolinska University Hospital; Colin Smith (C.S.), National CJD Research & Surveillance Unit, Edinburgh, United Kingdom; and Department of Pathology (I.N.), Karolinska University Hospital, Stockholm, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: sebastian.thams@ki.se
Martin Paucar
From the Department of Neurology (S.T., M.P., P.S.), Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience (S.T., M.P., P.S.), Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry (L.W.), North West District in Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.T.), Center for Molecular Medicine, Karolinska Institutet; Department of Clinical Genetics (H.T.), Karolinska University Laboratory, Karolinska University Hospital; Colin Smith (C.S.), National CJD Research & Surveillance Unit, Edinburgh, United Kingdom; and Department of Pathology (I.N.), Karolinska University Hospital, Stockholm, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Louise Wingård
From the Department of Neurology (S.T., M.P., P.S.), Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience (S.T., M.P., P.S.), Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry (L.W.), North West District in Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.T.), Center for Molecular Medicine, Karolinska Institutet; Department of Clinical Genetics (H.T.), Karolinska University Laboratory, Karolinska University Hospital; Colin Smith (C.S.), National CJD Research & Surveillance Unit, Edinburgh, United Kingdom; and Department of Pathology (I.N.), Karolinska University Hospital, Stockholm, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: louise.wingard@sll.se
Håkan Thonberg
From the Department of Neurology (S.T., M.P., P.S.), Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience (S.T., M.P., P.S.), Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry (L.W.), North West District in Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.T.), Center for Molecular Medicine, Karolinska Institutet; Department of Clinical Genetics (H.T.), Karolinska University Laboratory, Karolinska University Hospital; Colin Smith (C.S.), National CJD Research & Surveillance Unit, Edinburgh, United Kingdom; and Department of Pathology (I.N.), Karolinska University Hospital, Stockholm, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: hakan.thonberg@sll.se
Colin Smith
From the Department of Neurology (S.T., M.P., P.S.), Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience (S.T., M.P., P.S.), Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry (L.W.), North West District in Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.T.), Center for Molecular Medicine, Karolinska Institutet; Department of Clinical Genetics (H.T.), Karolinska University Laboratory, Karolinska University Hospital; Colin Smith (C.S.), National CJD Research & Surveillance Unit, Edinburgh, United Kingdom; and Department of Pathology (I.N.), Karolinska University Hospital, Stockholm, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: col.smith@ed.ac.uk
Inger Nennesmo
From the Department of Neurology (S.T., M.P., P.S.), Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience (S.T., M.P., P.S.), Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry (L.W.), North West District in Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.T.), Center for Molecular Medicine, Karolinska Institutet; Department of Clinical Genetics (H.T.), Karolinska University Laboratory, Karolinska University Hospital; Colin Smith (C.S.), National CJD Research & Surveillance Unit, Edinburgh, United Kingdom; and Department of Pathology (I.N.), Karolinska University Hospital, Stockholm, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: inger.nennesmo@sll.se
Per Svenningsson
From the Department of Neurology (S.T., M.P., P.S.), Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience (S.T., M.P., P.S.), Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry (L.W.), North West District in Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.T.), Center for Molecular Medicine, Karolinska Institutet; Department of Clinical Genetics (H.T.), Karolinska University Laboratory, Karolinska University Hospital; Colin Smith (C.S.), National CJD Research & Surveillance Unit, Edinburgh, United Kingdom; and Department of Pathology (I.N.), Karolinska University Hospital, Stockholm, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: per.svenningsson@ki.se
Full PDF
Citation
Predominant Spastic Paraparesis Associated With the D178N Mutation in PRNP
Sebastian Thams, Martin Paucar, Louise Wingård, Håkan Thonberg, Colin Smith, Inger Nennesmo, Per Svenningsson
Neurol Genet Dec 2021, 7 (6) e636; DOI: 10.1212/NXG.0000000000000636

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
202

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Spastic paraparesis is a very rare manifestation of prion diseases, occurring in both sporadic prion disease1 and inherited prion disease.2 The D178N mutation in the prion protein (PRNP) gene is associated with familial fatal insomnia (FFI) or familial Creutzfeldt-Jakob disease (fCJD),3 and in some cases, FFI and fCJD overlap.4,5 Herein, we describe a patient harboring the D178N mutation in PRNP with initially predominant spastic paraparesis.

Case Presentation

A 70-year-old woman was admitted due to increasing dyspnea starting 6 months before admission. Relatives reported progressive gait difficulties, personality change, and frequent falls starting 2 months before admission. There were no signs of insomnia, but apnea during sleep was reported. She was a former smoker, investigations demonstrated mild emphysema and reduced FEV1%, and the patient was diagnosed with mild COPD. Her saturation was normal (95%) during ambient air breathing. Recurrent desaturation during sleep was noticed, but polysomnography (PSG) was not performed. OSA was diagnosed on these grounds, and the patient was treated with bronchodilators and CPAP, which alleviated dyspnea. On examination, spastic paraparesis, hyperreflexia, clonus, Babinski and Hoffman signs, and abnormal Romberg test were found. The patient could stand up only with support and was prone to fall backward. Two months after motor onset, the patient became a wheelchair user. The patient had confusion and apraxia; the Montreal Cognitive Assessment yielded 11 points, but her rapid deterioration prevented further cognitive assessment. Dyspnea and dysarthria worsened; imperative auditory hallucinations and dysphagia appeared early on. MRI of the brain with contrast revealed widespread white matter hyperintensities (WMHs) in subcortical areas and an incidental anterior communicating artery aneurysm. The WMHs were interpreted as angiopathic. In the left cerebellar hemisphere, 2 older small infarctions were found; the thalamus and the spinal cord had a normal appearance. Neuronal autoantibodies were absent; in her CSF, both cell number and albumin levels were normal, but neurofilament light protein and tau were elevated. In CSF, level of phosphorylated tau (p-tau) was within the reference range, resulting in a ratio t-tau/p-tau of 12.8, β42-amyloid was reduced, protein 14-3-3 was absent, and real-time quaking-induced conversion (RT-QuIC) for prion protein was negative (eTable 1, links.lww.com/NXG/A488). Motor neuron disease was suspected, but repeated EMG and MEP studies performed twice were normal. The patient developed somnolence, became bedridden and anarthric, contracted recurrent pneumonias, and died 7 months after the onset of motor symptoms. The patient's next of kin authorized autopsy and provided consent for this report.

Family History and Genetic Analyses

The patient (III:4) belonged to a family from the Castile region in Spain (Figure, A). One of her siblings (III:3), had died of a rapidly progressive disease, with anarthria and cognitive decline starting around age 35 years. The total course of disease in III:3 was 6 months, with a neuropathologic diagnosis of neuronal ceroid lipofuscinosis (Kufs disease). The neuropathologic report or charts were not possible to retrieve. Another sibling (III:2) and the patient's mother (II:1) had a similar course of disease with age at onset around 35 years; neuropathologic examinations were, however, not made.

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure D178N Mutation in PRNP Associated With Predominant Spastic Paraparesis

(A) The index case in a Spanish family (arrowhead) was affected with a late-onset and fast progressive neurodegenerative disease with prominent paraparesis. A genetic study revealed that she harbored the D178N mutation in PRNP. In addition, the neuropathologic assessment was compatible with familial fatal insomnia. (B) NaPTA Western blot analysis. M: magic marker; lane 1: unspiked NaPTA (500 µL of 10% brain homogenate—non-CJD case); lane 2: spiked NaPTA (500 µL of 10% brain homogenate—non-CJD case, spiked with 5 µL vCJD 10% brain homogenate); lane 3: frontal cortex sample from case (500 µL of 10% brain homogenate); lane 4: frontal cortex sample—additional sample from case (500 µL of 10% brain homogenate); lane 5: positive control type 2B (3 µL vCJD 10% brain homogenate). (C) Immunostaining for glial fibrillary acidic protein (GFAP) on section from the medial part of the thalamus shows astrocytosis. (D) Luxol fast blue staining on a parallel section to 1B shows the presence of several neurons indicated by asterisks. (E) Immunohistochemistry using the 12F10 antibody shows fine granular staining (brown) focally in the entorhinal cortex from the case. (F) Severe loss of Purkinje cells in the cerebellar cortex. The Purkinje cell layer is located below the asterisk. PRNP = prion protein.

Whole-genome sequencing (WGS) was performed, which ruled out mutations in genes associated with lipofuscinosis but revealed the heterozygous D178N mutation in PRNP, polymorphism M/V at codon 129, and M in cis with the mutated allele (supplementary material, links.lww.com/NXG/A488).

Neuropathology

No macroscopic abnormalities were found on the cut surface except from prominent so-called Swiss cheese changes. The thalami were of normal size. Microscopically, astrogliosis in different thalamic nuclei (Figure, C), especially in the medial nuclei, was found without prominent neuronal loss (Figure, D). In the medulla oblongata, severe loss of neurons and severe astrogliosis were found in the inferior olivary nuclei. The pyramid tracts appeared to be of normal size, and the motor neurons of the hypoglossal nuclei were well preserved. Spongiform changes were not present in the brain. Immunohistochemistry with an antibody against prion protein, 12F10 (Bertin Bioreagent), showed weak synaptic staining in the entorhinal cortex (Figure, E). There was a marked loss of Purkinje cells in the cerebellum (Figure, F). The spinal cord was not available for examination. Western blot analysis of frozen brain tissue demonstrated a type 2B PrP isoform (Figure, B, lane 3) (supplementary document, links.lww.com/NXG/A488).

Discussion

Wide variability of age at onset and clinical features has been described for the D178N mutation.3,5,6,7,e1–e6 A polymorphism at codon 129, either being valine (V) or a methionine (M), has been proposed as a strong modulator of the D178N mutation, with 129V on the same allele of the mutation associated with fCJD, whereas 129M is associated with FFI.3 Our case displays the typical neuropathologic abnormalities for FFI. It is important that homozygosity 129M is usually associated with shorter disease duration compared with heterozygotes.e3 However, this association has been challenged.4,5,e5 Short disease duration, despite 129MV, and the initial predominant spastic paraparesis stand out in our case. Brain MRI studies may contribute when investigating prion phenotypes such as fCJD associated with E200Ke7 but not cases with the D178N mutation. Furthermore, 14-3-3 is rarely positive in patients with the D178N mutation.5 Negative RT-QuIC for prion protein in our case contrasts with the high yield (83.3%) in a previous study.e8 Only once has irregular sleep pattern, but no apnea, been reported in D178N.5 This work has some limitations; PSG and dysautonomia tests were not performed due to the absence of insomnia and because dyspnea was interpreted as a COPD manifestation. Thus, central apnea may have been missed in our case. Another limitation is that the spinal cord was not available for examination. Finally, our serendipitous diagnosis illustrates the utility of WGS when investigating familial neurodegenerative diseases.

Study Funding

No targeted funding reported.

Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures.

Acknowledgment

The authors are grateful to the patient's next of kin for consenting to this publication and to Dr. Rodrigo Bernaldo de Quirós in Spain. The authors are also grateful to Dr. Nicola Carrol in Edinburgh for performing allele analysis at codon 129.

Appendix Authors

Table

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • ↵* These authors contributed equally to this work.

  • Received November 8, 2020.
  • Accepted in final form September 15, 2021.
  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Jansen C,
    2. Head MW,
    3. van Gool WA, et al
    . The first case of protease-sensitive prionopathy (PSPr) in The Netherlands: a patient with an unusual GSS-like clinical phenotype. J Neurol Neurosurg Psychiatry. 2010;81(9):1052-1055.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Kitamoto T,
    2. Amano N,
    3. Terao Y, et al
    . A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesis. Ann Neurol. 1993;34(6):808-813.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Gambetti P,
    2. Parchi P,
    3. Petersen RB,
    4. Chen SG,
    5. Lugaresi E
    . Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features. Brain Pathol. 1995;5(1):43-51.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Zerr I,
    2. Giese A,
    3. Windl O, et al
    . Phenotypic variability in fatal familial insomnia (D178N-129M) genotype. Neurology. 1998;51(5):1398-1405.
    OpenUrl
  5. 5.↵
    1. Zarranz JJ,
    2. Digon A,
    3. Atarés B, et al.
    Phenotypic variability in familial prion diseases due to the D178N mutation. J Neurol Neurosurg Psychiatry. 2005;76(11):1491-1496.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Lugaresi E,
    2. Medori R,
    3. Montagna P, et al
    . Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med. 1986;315(16):997-1003.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Parchi P,
    2. Petersen RB,
    3. Chen SG, et al
    . Molecular pathology of fatal familial insomnia. Brain Pathol. 1998;8(3):539-548.
    OpenUrlPubMed
  8. eReferences e1–e10 are available at: links.lww.com/NXG/A488.

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Case Presentation
    • Discussion
    • Study Funding
    • Disclosure
    • Acknowledgment
    • Appendix Authors
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures
Advertisement

Preferences and User Experiences of Wearable Devices in Epilepsy A Systematic Review and Mixed-Methods Synthesis

Dr. Daniel Friedman and Dr. Sharon Chiang

► Watch

Related Articles

  • No related articles found.

Topics Discussed

  • All Genetics
  • Spastic paraplegia

Alert Me

  • Alert me when eletters are published
Neurology Genetics: 9 (2)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise