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
    • Neurology Future Forecasting Series
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • 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
    • Neurology Future Forecasting Series
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Neurology Video Journal Club
  • Residents & Fellows

User menu

  • Subscribe
  • My Alerts
  • Log in

Search

  • Advanced search
Neurology
Home
The most widely read and highly cited peer-reviewed neurology journal
  • Subscribe
  • My Alerts
  • Log in
Site Logo
  • Home
  • Latest Articles
  • Current Issue
  • Past Issues
  • Neurology Video Journal Club
  • Residents & Fellows

Share

April 18, 2017; 88 (16 Supplement) April 25, 2017

Oral deoxynucleoside for the treatment of thymidine kinase 2 deficiency (P3.195)

Carlos Lopez Gomez, Rebecca Levy, Maria J Sanchez-Quintero, Marti Juanola-Falgarona, Emanuele Barca, Beatriz Garcia-Diaz, Saba Tadesse, Caterina Garone, Michio Hirano
First published April 17, 2017,
Carlos Lopez Gomez
1Columbia University Medical Center New York NY United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rebecca Levy
2Stanford University Stanford CA United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria J Sanchez-Quintero
1Columbia University Medical Center New York NY United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marti Juanola-Falgarona
1Columbia University Medical Center New York NY United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emanuele Barca
3University of Messina Messina Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Beatriz Garcia-Diaz
4Instituto de Investigación Biomédica de Málaga Malaga Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Saba Tadesse
1Columbia University Medical Center New York NY United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Caterina Garone
5Cambridge University Cambridge United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michio Hirano
1Columbia University Medical Center New York NY United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Citation
Oral deoxynucleoside for the treatment of thymidine kinase 2 deficiency (P3.195)
Carlos Lopez Gomez, Rebecca Levy, Maria J Sanchez-Quintero, Marti Juanola-Falgarona, Emanuele Barca, Beatriz Garcia-Diaz, Saba Tadesse, Caterina Garone, Michio Hirano
Neurology Apr 2017, 88 (16 Supplement) P3.195;

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
0

Share

  • Article
  • Info & Disclosures
Loading

Abstract

Objective: To test whether effects of dCMP+dTMP treatment are attributable to increased levels of dC+dT, we treated our TK2 mouse model with oral dC+dT.

Background: TK2 is a nuclear gene encoding the mitochondrial enzyme thymidine kinase 2 (TK2), which phosphorylates the nucleosides deoxycytidine (dC) and deoxythymidine (dT) to dCMP and dTMP. Mutations in this gene cause TK2 deficiency, which most frequently leads to mitochondrial DNA (mtDNA) depletion syndrome in infants and children, manifesting as severe reduction of mtDNA copy number in muscle leading to a rapidly progressive mitochondrial myopathy. To date, there is no approved disease-modifying therapy for TK2 deficiency. We have reported that molecular bypass therapy via oral administration of the TK2 products, dCMP and dTMP, to our mouse model of TK2 deficiency ameliorates the symptoms and prolongs the lifespan of the animals. Despite the clear benefits of this therapeutic strategy, we observed that after administration, dCMP and dTMP were rapidly converted to their respective nucleosides suggesting that dC and dT are the active therapeutic agents.

Design/Methods: .

Results: Both 260 and 520mg/kg/day of oral dC+dT prolonged the lifespans of TK2 mutant animals to durations comparable to those achieved using 200 and 400mg/kg/day of dCMP+dTMP. Both doses of deoxynucleosides were sufficient to partially restore mtDNA levels in brain and completely prevent mtDNA depletion in heart, liver, kidney, intestine and muscle at age 13 days. Activities and amounts of respiratory chain enzymes were also partially restored at 29 days. There were slightly higher levels of complexes I and IV in brain from mice treated with the 520mg dose of dC+dT, compared to those treated with 260mg, which likely accounts for the prolonged survival time observed with the higher dose.

Conclusions: Our results reveal a novel therapy for TK2 deficiency. Although not curative, this substrate enhancement therapy may delay or halt progression of this devastating disease.

Study Supported by: This work was supported by the NICHD

Disclosure: Dr. Lopez Gomez has nothing to disclose. Dr. Levy has nothing to disclose. Dr. Sanchez-Quintero has nothing to disclose. Dr. Juanola-Falgarona has nothing to disclose. Dr. Barca has nothing to disclose. Dr. Garcia-Diaz has nothing to disclose. Dr. Tadesse has nothing to disclose. Dr. Garone has nothing to disclose. Dr. Hirano has received (royalty or license fee or contractual rights) payments from MitoRainbow Therapeutics, Inc.

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
  • Info & Disclosures
Advertisement

Hemiplegic Migraine Associated With PRRT2 Variations A Clinical and Genetic Study

Dr. Robert Shapiro and Dr. Amynah Pradhan

► Watch

Related Articles

  • No related articles found.

Alert Me

  • Alert me when eletters are published
Neurology: 100 (5)

Articles

  • Ahead of Print
  • Current Issue
  • Past Issues
  • Popular Articles
  • Translations

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
  • Activate a Subscription
  • 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 | Print ISSN:0028-3878
Online ISSN:1526-632X

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise