Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Mar;44(1):2-10.
doi: 10.36185/2532-1900-1047.

Deciphering Facioscapulohumeral Dystrophy in the clinical trials era: where are we now?

Francesca Torri  1 , Beatrice Ciurli  2 , Mariaconcetta Rende  2 , Arianna Votta  3 , Emanuele Mocciaro  4 , Frida Karakashi  4 , Matteo Lencioni  5 , Elisabetta Ferraro  3 , Massimiliano Filosto  6 , Davide Gabellini  4 , Gabriele Siciliano  2 , Giulia Ricci  2
Affiliations
Review

Deciphering Facioscapulohumeral Dystrophy in the clinical trials era: where are we now?

Francesca Torri et al. Acta Myol. 2025 Mar.

Abstract

Objectives: Facioscapulohumeral muscular dystrophy (FSHD) is a common genetic disorder characterized by progressive muscle weakness, especially in the face, shoulders, and upper limbs. Despite extensive research, the underlying pathogenesis and clinical variability remain incompletely understood. This review aims to summarize recent advances in FSHD research, focusing on genetic and epigenetic factors and the potential for precision medicine.

Methods: A comprehensive review of recent literature was conducted, examining molecular mechanisms such as mutations in the D4Z4 region, DUX4 expression, RNA interference (RNAi) and antisense oligonucleotides (AOs). Clinical variability was analyzed to assess different disease phenotypes. Clinical trials investigating potential treatments, especially those targeting DUX4, were also reviewed.

Results: FSHD shows significant clinical variability, with different progression rates across phenotypes. The 4qA allele is linked to more typical forms of the disease, but epigenetic factors, including DNA methylation and miRNA expression, also influence disease severity. Despite progress, the exact molecular mechanisms driving disease expression remain unclear. Clinical trials, such as Losmapimod, show promise in slowing muscle degeneration, though results remain inconsistent.

Conclusions: FSHD presents significant challenges for therapy development due to its genetic complexity and clinical variability. Ongoing research is needed to clarify pathogenesis and identify reliable biomarkers. Future therapeutic strategies should focus on precision medicine, integrating genetic, clinical, and imaging data to optimize patient stratification and treatment efficacy.

Keywords: Clinical trials; Clinical variability; DUX4; Facioscapulohumeral muscular dystrophy (FSHD); Therapeutic strategies.

PubMed Disclaimer

Conflict of interest statement

All authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
The D4Z4 repeat array on chromosome 4q in healthy individuals and patients with facioscapulohumeral muscular dystrophy .
See this image and copyright information in PMC

References

    1. Giardina E, Zampatti S. The Future of Pharmacogenomics Requires New Discoveries and Innovative Education. Genes (Basel). 2022. Sep 2;13(9):1575. https://doi.org/10.3390/genes13091575. PMID: 36140743; PMCID: PMC9498360 10.3390/genes13091575 . - DOI - PMC - PubMed
    1. Snider L, Geng LN, Lemmers RJ, et al. . Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet. 2010. Oct 28;6(10):e1001181. https://doi.org/10.1371/journal.pgen.1001181. PMID: 21060811; PMCID: PMC2965761 10.1371/journal.pgen.1001181 . - DOI - PMC - PubMed
    1. Das S, Chadwick BP. Influence of Repressive Histone and DNA Methylation upon D4Z4 Transcription in Non-Myogenic Cells. PLoS One. 2016. Jul 28;11(7):e0160022. https://doi.org/10.1371/journal.pone.0160022. PMID: 27467759; PMCID: PMC4965136 10.1371/journal.pone.0160022 . - DOI - PMC - PubMed
    1. Lemmers RJ, van der Vliet PJ, Klooster R, et al. . A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010. Sep 24;329(5999):1650-3. https://doi.org/10.1126/science.1189044. Epub 2010 Aug 19. PMID: 20724583; PMCID: PMC4677822 10.1126/science.1189044 . - DOI - PMC - PubMed
    1. Lemmers RJ, Wohlgemuth M, van der Gaag KJ, et al. . Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2007. Nov;81(5):884-94. https://doi.org/10.1086/521986. Epub 2007 Sep 7. PMID: 17924332; PMCID: PMC2265642 10.1086/521986 - DOI - PMC - PubMed

MeSH terms