Facioscapulohumeral muscular dystrophy (FSHD) is a progressive hereditary muscle disease characterized by weakness of the facial, shoulder girdle, and upper arm muscles. It is the third most common muscular dystrophy after dystrophinopathies and myotonic dystrophy 1). The prevalence is approximately 1 in 20,000, with an incidence of 0.3 per 100,000 reported in a Dutch study. Some reports suggest a prevalence of at least 1:10,000 2).
First described in 1886 by two French physicians, FSHD typically presents by the second decade of life and affects males and females equally. Women are often diagnosed at an older age and tend to have milder symptoms. Life expectancy is generally normal 2), but about 20% of patients require a wheelchair by age 50.
FSHD primarily affects muscles, but can also involve extramuscular symptoms such as retinal vasculopathy, high-frequency hearing loss, cardiac arrhythmias, and epilepsy. This article focuses on the ophthalmic complications of FSHD.
There are three types: FSHD1 (over 95% of all cases), FSHD2 (less than 5%), and FSHD3 with unidentified genetic cause. All are clinically indistinguishable.
There are three types: FSHD1, FSHD2, and FSHD3. FSHD1 accounts for over 95% of all cases and is caused by a contraction of the D4Z4 repeat array at 4q35. FSHD2 is caused by mutations in the SMCHD1 gene and accounts for less than 5%. FSHD3 refers to cases where the genetic cause has not been identified.
The main subjective symptom of FSHD is progressive muscle weakness.
Ophthalmologically, retinal abnormalities are asymptomatic in many FSHD patients and lack subjective symptoms. Visual loss occurs when macular edema or exudative retinal detachment due to Coats-like disease develops 1). Dryness and foreign body sensation due to incomplete eyelid closure may be perceived.
The following findings support the diagnosis of FSHD.
Anterior Segment Findings
Lagophthalmos (incomplete eyelid closure): Due to atrophy of the orbicularis oculi muscle, the eyelids do not close completely, especially during sleep. This can cause exposure keratitis and corneal ulcers.
Band keratopathy: May occur secondary to chronic corneal damage from lagophthalmos1).
Thinning of central corneal thickness: Reports indicate that the cornea is thinner compared to healthy controls, leading to lower intraocular pressure measurements.
Retinal Findings
Retinal vascular tortuosity: The most common finding. Observed in 50–75% of patients. Primarily involves arterial tortuosity.
Telangiectasia and microaneurysms: Detected by fluorescein angiography (FA).
Peripheral retinal avascular zones: Ischemic changes confirmed by FA.
Foveal hypoplasia: Frequently observed.
Coats-like disease develops in a small number of patients, presenting with telangiectasia and exudative retinopathy. Progression may lead to retinal detachment, retinal neovascularization, and neovascular glaucoma. In adult-onset cases, males are more commonly affected, with onset typically within the first two decades of life; however, a case of Coats-like disease first manifesting at age 44 has been reported1).
Bruzzone et al. (2023) reported a case of a 44-year-old female FSHD1 patient who developed Coats-like disease despite a previously normal ophthalmic history 1). The left eye showed parafoveal telangiectasia, macular edema, punctate hemorrhages, hard exudates, and extensive peripheral retinal ischemia, and panretinal laser photocoagulation was performed. Corrected visual acuity remained 1.0 at 12 months, with no neovascular complications.
Extramuscular symptoms occur more frequently in early-onset FSHD. A literature review of 324 cases reported retinopathy in 18.2%, hearing loss in 39.1%, spinal deformity in 42.0%, and wheelchair dependence in 35.1% 4).
Most retinal abnormalities are subclinical and difficult for patients to notice on their own. Subtle changes are easily overlooked without fluorescein angiography (FA). Visual decline is noticed when the condition progresses to Coats-like disease. Regular ophthalmic examinations are important.
FSHD is an epigenetic disorder associated with D4Z4 repeat sequences on the long arm of chromosome 4 (4q35).
| Item | FSHD1 | FSHD2 |
|---|---|---|
| Frequency | 95% or more | Less than 5% |
| Cause | Shortening of D4Z4 repeats (1-10) | SMCHD1 gene mutation |
| Inheritance pattern | Autosomal dominant | Digenic |
In FSHD1, the D4Z4 repeat sequence, which normally has 11 to 100 copies in healthy individuals, is shortened to fewer than 10 copies. This shortening leads to DNA hypomethylation, causing ectopic expression of the usually suppressed DUX4 gene 1). DUX4 is toxic to adult skeletal muscle cells.
In FSHD2, the D4Z4 repeat count is normal, but DNA hypomethylation occurs due to mutations in the SMCHD1 gene on chromosome 18 3). Rarely, mutations in the DNMT3B or LRIF1 genes are involved.
In both types, the presence of a polyadenylation signal on the 4qA allele that stabilizes DUX4 mRNA is essential for disease onset.
There is a negative correlation between D4Z4 repeat count and disease severity. Patients with 1 to 3 repeats progress to more severe symptoms faster 4). The severity of retinal vascular tortuosity also correlates with D4Z4 size.
FSHD1 occurs as sporadic cases in 10-30% of instances. In FSHD2, approximately 60% are estimated to be sporadic. In the first reported FSHD2 case in South Korea, a novel SMCHD1 frameshift mutation (c.3801delG) was identified 3).
The diagnosis of FSHD is suggested by clinical features and family history. Definitive diagnosis is made by genetic testing.
Ophthalmic evaluation including dilated fundus examination is recommended at diagnosis for all FSHD patients.
The following should be considered in the differential diagnosis of retinal microvascular findings.
There is currently no curative treatment for FSHD. Disease management is based on supportive therapy centered on screening, rehabilitation, and symptomatic treatment.
Retinal treatment
Laser photocoagulation: Performed for ischemic retinal areas in Coats-like disease. The purpose is to prevent neovascular complications 1). It is actively performed in cases with strong exudative changes.
Intravitreal anti-VEGF injection: Used for retinal neovascularization.
Observation: Regular ophthalmologic follow-up is performed for subclinical retinal vascular abnormalities.
Anterior Segment Management
Prevention of exposure keratitis: Artificial tears are instilled to prevent corneal dryness. Taping at bedtime and use of eye ointments are also effective.
Management of lagophthalmos: Surgical intervention is considered for severe lagophthalmos.
Bruzzone et al. (2023) recommended regular ophthalmologic examinations including annual dilated fundus examination and retinal imaging for adult patients with FSHD1). They noted that peripheral retinal avascular areas can cause retinal neovascularization at any age, and that visiting only when symptoms appear is insufficient.
A dilated fundus examination should be performed at diagnosis, and follow-up intervals should be determined based on the severity of initial findings. Even in adults without retinopathy, at least annual examination is recommended 1). Patients with fewer D4Z4 repeats or early-onset forms require more careful follow-up.
The molecular pathology of FSHD is centered on ectopic expression of the DUX4 gene.
In FSHD1, contraction of the D4Z4 macrosatellite repeat array on 4q35 (1–10 repeats) leads to DNA hypomethylation. Hypomethylation relaxes chromatin structure, allowing transcription of the DUX4 gene contained in the last unit of the repeat array 1). DUX4 is normally a germline transcription factor and is suppressed in somatic cells. Ectopic expression of DUX4 in skeletal muscle cells causes cellular damage, leading to muscle degeneration and atrophy.
In FSHD2, mutations in the SMCHD1 gene lead to hypomethylation of D4Z4, similarly resulting in derepression of DUX4 3).
In both cases, the polyadenylation signal on the 4qA allele stabilizes unstable DUX4 mRNA, which is essential for disease onset. Without the 4qA allele, DUX4 protein is not translated, and clinical symptoms do not appear.
The toxic mechanisms of DUX4 are thought to involve impaired muscle differentiation, oxidative stress response, immune response, and abnormal protein turnover 4). Interestingly, DUX4 is also detected in muscle tissue of genetically diagnosed asymptomatic FSHD subjects 1). This suggests that epigenetic modifiers may influence the clinical impact of DUX4 expression.
The pathogenesis of retinal vasculopathy is not fully understood. Inappropriate derepression of genes involved in vascular smooth muscle and endothelial cell functions (such as cell proliferation and angiogenesis) is thought to play a dominant role. The exact mechanism of vascular complications associated with ectopic DUX4 expression remains unclear 1).
Future therapeutic strategies for FSHD can be broadly divided into two categories.
ACE-083 is a therapeutic agent targeting TGF-β-related proteins (activin and myostatin), and clinical trials are ongoing 4). It aims to increase muscle mass and restore muscle strength.
Gene silencing strategies aimed at knocking down DUX4 or suppressing its downstream targets are being evaluated 4). The application of antisense oligonucleotides such as eteplirsen and nusinersen is also being considered. Over 300 compounds that inhibit DUX4 protein production have been identified 4).
A wide range of approaches, including small-molecule drugs, gene therapy, and antisense oligonucleotides, are being explored, but none have yet reached clinical application.
