Facioscapulohumeral dystrophy (FSHD) is one of the most common hereditary neuromuscular disorders (NMD), with an estimated prevalence of 2000 patients in the Netherlands. Magnetic resonance imaging (MRI) and muscle ultrasound have contributed to an enhanced understanding of the pathophysiology of Facioscapulohumeral Muscular Dystrophy (FSHD). Previously, our group demonstrated the potential presence of an intermediate factor between muscle fiber loss and clinical weakness in FSHD. The influence of disrupted muscle architecture in FSHD on muscle contractile efficiency is a likely candidate for this factor, and remains relatively unexplored. In this study, we aim to assess the use of ultrasound-defined contractile performance, in comparison with current measures including structural MRI, for monitoring disease progression in FSHD.

Rationale: Facioscapulohumeral dystrophy (FSHD) is a slowly progressive hereditary muscle dystrophy characterized by initial asymmetrical weakness of the facial and shoulder girdle muscles, frequently followed by weakness in the trunk and leg muscles.

Previously, our research group showed the potential presence of an intermediate factor between muscle fiber loss and clinical weakness in FSHD. The influence of disrupted muscle architecture in FSHD on muscle contractile efficiency is a likely candidate for this factor. However, there is currently still a lack of studies on how the disrupted muscle architecture in muscle dystrophies influences the contractile efficiency. We might establish a baseline for muscle contractile performance with muscle ultrasound, determined by muscle strain and displacement.

Muscle imaging has previously contributed to a better understanding of the pathophysiology of various neuromuscular disorders. Both MRI and ultrasound have proven their clinical relevance in neuromuscular dystrophy. With the current development of FSHD clinical trials, the extensive need for biomarkers to follow disease progression is growing. To investigate whether muscle contractile performance can help explain the loss in strength and thereby also has the potential to act as a future biomarker, will be explored in this project.

Objective(s): We aim to assess the use of ultrasound-defined contractile performance as a biomarker for monitoring disease progression and treatment effects in patients with FSHD.

Stage I:

To establish the feasibility, optimal protocol, and repeatability of quantifying ultrasound-defined muscle contractile performance in the upper and lower limb muscles in healthy volunteers and patients with FSHD.

Stage II:

1. To determine the differences in ultrasound-defined contractile performance between healthy individuals and patients with FSHD, and compare to conventional clinical measures, ultrasound measures and MRI measures.
2. To determine the responsiveness of ultrasound-defined contractile performance to disease progression in FSHD patients after 1 year, and compare to MRI measures and other ultrasound measures.

Study design: This prospective cohort study consists of two different stages. In Stage I, the feasibility and repeatability of quantifying ultrasound-defined muscle contractile performance will be assessed in 15 healthy volunteers and 10 patients with FSHD type 1 or 2. Each participant in stage I has to visit the hospital only once. In Stage II, the ultrasound-defined contractile performance, and other ultrasound and MRI outcome measures of healthy volunteers and FSHD patients (type 1 or 2) are compared. In addition, the responsiveness of the different measurements to disease progression after 1 year will be analyzed only in FSHD patients. 50 patients with FSHD will perform these measurements of stage II during the two scheduled visits at baseline (T0) and the two scheduled visits 1-year after the first visit. In stage II, 25 Healthy volunteers will be recruited and will undergo the muscle ultrasound assessment. Only 10 out of 25 healthy volunteers will also undergo the MRI measurements. None of the healthy volunteers will perform follow-up measurements after 1 year. Therefore, 15 healthy volunteers will perform the ultrasound assessment of stage II during 1 visit and 10 healthy volunteers will perform ultrasound measurements during visit 1 and MRI measurements during visit 2 at baseline. A total of 100 individuals will participate in this study.

Inclusion Criteria:

• Age between 18 and 70 years.
• Informed consent is given by the participant.
• Ability to read and understand written and spoken instruction in Dutch.
• Willingness and ability to understand nature and content of the study

Exclusion Criteria:

• BMI ≥ 35

• Other diseases that could diffusely affect muscle integrity or disturb the imaging appearance beyond that what can be extrapolated.

• Wheelchair dependence

• Pregnancy

• Stage II: Any contra-indications for MRI, including:

  • Claustrophobia
  • Pacemakers and defibrillators
  • Nerve stimulators
  • Intracranial clips
  • Intraorbital or intraocular metallic fragments
  • Cochlear implants and ferromagnetic implants (e.g. implant for scoliosis)
  • Inability to lie supine for 60 minutes
  • Necessity of (continuous) daytime ventilation
  • Scoliosis surgery

In the Netherlands, FSHD has an estimated prevalence of 2000 patients. All patients will be recruited from one of the largest longitudinal follow up database, FSHD-FOCUS, which is maintained at the Dutch Radboudumc expertise center. This FSHD-FOCUS cohortwas started in 2014 and includes around 200 patients with clinically and genetically proven FSHD type 1 and type 2. A 5-year-follow-up study (FSHD-FOCUS2) collected comprehensive data on the natural course of FSHD using multiple clinical outcome measures. Only patients who have given consent during the FSHD-FOCUS study to be contacted for subsequent research, will be contacted for this study.

All anonymized (imaging) data will be made available in a suitable open-source online repository after the study results are published in peer-reviewed journals. A DOI will be assigned to dataset published in the Donders Data Repository (soon: Radboud Data Repository).

Data will become available after publication for long-term. To guarantee the long-term accessibility of data files, the repository may perform data migration. Even if data is removed, audit trails of 'removed' collections are always retained. Likewise, the metadata of published or archived collections are never removed.

The data Donders Repository will be used to guarantee long-term accessibility of the research data from this project. The pseudonymized data will be accessible in Donders Repository (soon: Radboud repository (RDR)) under restricted access. Requests for access will be checked, against the conditions for sharing the data as described in the signed Informed Consent. This repository is classified as a highest security-grade data system suitable for preserving large volume, privacy sensitive (i.e. human) research data.