ReviewEarly onset facioscapulohumeral dystrophy – a systematic review using individual patient data
Introduction
Facioscapulohumeral dystrophy (FSHD) is one of the most frequent hereditary muscular diseases with an estimated prevalence of 5–13 in 100,000 [1], [2]. In 3–21% of patients the symptoms start at an early age [3], [4]. Currently, two genetically distinct types of FSHD, called FSHD1 and FSHD2, are known. In both types, inefficient epigenetic repression of the retrogene DUX4 plays a key role in the pathogenesis [5], [6]. FSHD1 accounts for 95% of all patients and almost all early onset cases [7], it is associated with contraction of the D4Z4-repeat at chromosome 4q35 in combination with a disease-permissive 4qA allele [8], [9]. In the general population, the number of D4Z4 repeat units varies between 11 to more than 100, while patients with FSHD1 have only 1–10 repeat units. There is a roughly inverse correlation between repeat size and disease severity; most patients with short repeats have a severe disease phenotype [10], [11].
Historically, infantile FSHD was considered a distinct disease based on clinical onset before the age of two years (Brooke criteria, 1977 [12]). This concept evolved to early onset FSHD and was regarded a subgroup of FSHD, defined by signs or symptoms of facial weakness before the age of 5 and signs or symptoms of scapular weakness before the age of 10 (Brouwer criteria, 1994 [13]). Whereas the typical, classic form of FSHD is characterized by slowly progressive, often asymmetrical muscle weakness of facial- and shoulder muscles starting in the second decade of life [3], [14], the subgroup of early onset FSHD patients is characterized by severe muscle weakness, faster disease progression and systemic features. These systemic features include epilepsy, mental retardation, hearing loss, retinal vasculopathy, spinal deformities, respiratory problems and cardiac arrhythmias [3], [13], [15], [16], [17], [18], [19]. It should be noted that clinical variability in terms of age at onset and disease severity is typical of FSHD. Age at onset ranges from birth to 70 years of age and disease severity may vary from asymptomatic carriers to patients with severe muscle weakness causing functional dependence.
Our current understanding of disease severity, systemic features and prognosis in early onset FSHD is based on small case-series. Consequently, many questions about the clinical phenotype and natural history of early onset FSHD remain unanswered, thus limiting evidence based clinical management. Here, we systematically review the literature using individual patient data to gain insight into the clinical spectrum of early onset FSHD. The ultimate goals are to improve recognition and understanding of early onset FSHD and to advance clinical management.
Section snippets
Search strategy
We searched Embase (index period 1970–2016) and PubMed (index period 1970–2016) for articles reporting early onset FSHD cases (Supplementary Appendix A). We applied a sensitive search strategy using search terms as described in Table 1. Additional studies of potential interest were searched via cross-referencing.
Eligibility screening
We included articles presenting empirical data on early onset FSHD patients. We excluded conference abstracts, posters, publications not reporting original data (e.g. reviews, book
Search and selection results
The combined searches yielded 953 records, of which 303 were duplicates, leaving a total of 650 unique articles (Figure 1). This resulted in 43 articles including 1683 patients of which 227 are early-onset FSHD patients (Table 2).
Clinical description of early onset FSHD
Mean age at assessment was 18.8 years (range 2–72 years, SD 11.9 years). Symptoms started at a mean age of 2.8 years (range 0–5 years, SD 2.8 years). 56/227 of patients (25%) showed symptoms in the first year of life, mainly facial weakness resulting in feeding
Discussion
Based on data from 227 early onset FSHD cases, we conclude that early onset FSHD is on the severe end of the FSHD spectrum. The genetic defect, the distribution pattern of muscular weakness and the type of systemic features are similar to the classical FSHD phenotype. Early onset FSHD distinguishes itself from the adult-onset patients by a more severe muscle weakness, more rapid progression and more frequently occurring systemic features. Some systemic features (cognitive disability, epilepsy)
Acknowledgements
We would like to acknowledge Wiebe Pestman (Department for Health Evidence, Radboudumc, Nijmegen, the Netherlands) who has contributed to the statistical analysis in the study.
This project is supported by grants from the Prinses Beatrix Spierfonds [grant number W.OR14-22, 2014]. The funder has no role in the design, conduct of this study, or the decision if and when to submit for publication.
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2021, Molecular TherapyCitation Excerpt :Around 15%–20% of patients are wheelchair-bound.3 In certain cases, often in early-onset FSHD, patients present with additional extra-muscular features, e.g., hearing loss, retinal vasculopathy, and cognitive impairment.4–6 Surgery and physical therapy, among others, are available to help manage symptoms and improve patient quality of life.7
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Authors contributed equally.