This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited muscular dystrophy. It is the most common inherited myopathy after Duchenne muscular dystrophy and myotonic dystrophy. The clinical characteristics of this disease include asymmetric muscular involvement, a stuttering course, and variable severity of involvement within the same family. FSHD results from the ectopic expression of a normally silenced DUX4 gene that codes for a transcription factor which is expressed in early embryonic development and then is epigenetically silenced. The gene is present in a large macrosatellite repetitive sequence of units called D4Z4 repeats. Each unit carries a copy, the DUX4 gene, although DUX4 is expressed only from the last D4Z4 repeat.1 What we still do not know is which of the multiple pathways turned on by DUX4 results in muscle damage. Unaffected individuals typically have 11–150 D4Z4 repeats. In FSHD type 1 (FSHD1), reduction of repeat numbers (1–10 repeats) results in hypomethylation of the distal D4Z4 loosening the epigenetic silencing mechanism, resulting in ectopic expression of the most distal DUX4 gene, which turns on the DUX4 program and is toxic to skeletal muscles. FSHD type 2 (FSHD2), which accounts for about 5% of all FSHD, is clinically identical to FSHD1 and is also caused by ectopic activation of the DUX4 program. This activation, however, is not from contraction of the DUX4 repeat number but from mutations in genes disrupting the regulation of DNA methylation in the most distal DUX4 gene. Mutations in 3 genes result in FSHD2 including SMCHD1, which account for about 95% of FSHD2, as well as DNMT3B and LRIF1.2-5
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.
See page 100
- Received April 5, 2023.
- Accepted in final form May 11, 2023.
- © 2023 American Academy of Neurology
AAN Members
We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page.
AAN Non-Member Subscribers
Purchase access
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
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.
