Ophthalmologic Manifestations of Facioscapulohumeral Dystrophy

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This article will focus on ophthalmologic manifestations of facioscapulohumeral dystrophy.

Disease Entity

Facioscapulohumeral dystrophy; facio-scapulo-humeral dystrophy; facioscapulohumeral atrophy; facioscapulohumeral type progressive dystrophy; FSH muscular dystrophy; FSHD.

Disease

Facioscapulohumeral dystrophy (FSHD) is one of the most common muscular dystrophies, characterized by a progressive and descending pattern of muscle weakness and atrophy. The muscles of the face (facio-), shoulders (scapula-) and upper arms (humeral-) are affected first, followed by distal lower extremities and pelvic girdle muscles, typically with a considerable side-to-side asymmetry [1-4].

The term muscular dystrophy refers to the progressive degeneration of muscle, accompanied by loss of muscle bulk and increasing weakness. Although muscular involvement is the hallmark of the disease, other systemic manifestations such as retinal vasculopathy, hearing impairment, cardiac arrhythmia, epilepsy, cognitive disability, and chronic pain can occur [2, 4]. Rates of progression of this condition may vary considerably, and later in the course of the disease more proximal muscles can become affected. Life expectancy is normal for individuals with FSHD as it rarely affects the respiratory system or heart, however it can result in significant morbidity, with approximately 20% of people requiring a wheelchair by age 50 [2, 4].

Three types of FSHD have been described so far: type 1 (FSHD1), type 2 (FSHD2) and type 3 (FSHD3). Despite their different genetic mechanisms, they are clinically indistinguishable [4,5,7].

Genetics

FSHD is a complex genetic disorder in which a cascade of epigenetic mechanisms culminates in DNA hypomethylation and the expression of the normally silenced DUX4 gene, whose transcripts are toxic to the adult muscle cells [4-9].

FSHD1 is caused by a deletion of a variable number of tandemly repeated elements, called D4Z4, located in the subtelomeric region of the long arm of chromosome 4 (4q35). Instead of 11 to 100 D4Z4 repeat units normally present in healthy individuals, patients with FSHD1 have less than 10 D4Z4 repeat units on one of their chromosomes 4. These shortened fragments lead to DNA hypomethylation and a consequent opening of the chromatin structure, affecting the expression of the distal DUX4 gene [7, 8, 10, 11].

Patients with FSHD2, on the other hand, have a normal number of D4Z4 repeats, and DNA hypomethylation results from a mutation in the SMCHD1 gene in chromosome 18. Rare cases present with mutations in DNMT3B and LRIF1 genes [4, 12, 13]. However, DNA hypomethylation by itself is not sufficient to cause DUX4 gene derepression. Both FSHD1 and FSHD2 solely occur in the presence of a 4qA allele, a polymorphic segment, that contains a polyadenylation signal that stabilizes otherwise unstable DUX4 transcripts, resulting in translation of a toxic protein and consequent muscular disease [4, 14, 15].

All cases that have not yet been traced to a genetic cause are referred to as facioscapulohumeral muscular dystrophy 3 (FSHD3).

The precise pathogenic mechanisms underlying the development of retinal vasculopathy in FSHD are not entirely clear. It is thought that inadequate derepression of genes involved in vascular smooth muscle or endothelial cells function (such as cellular growth and angiogenesis) plays a dominant role [2, 7, 16, 17].

Inherence pattern

In 1886, FSHD was first described by two French physicians after monitoring a family for 11 years. FSHD was later confirmed to be inherited in an autosomal dominant pattern in 1950, after a detailed description of the condition in multiple generations of a family [7].  FSHD1 is inherited by an autosomal dominant pattern, although sporadic disease can occur in about 10 to 30% of cases [4, 11, 18, 19]. FSHD2 is a digenic disease involving a mutation in SMCHD1 on chromosome 18 and a permissive A allele on chromosome 4q. Around 60% of FSHD2 cases are estimated to be sporadic [4, 11, 20].

Epidemiology

FSHD is the third most frequent type of muscular dystrophy, sharing the podium with the dystrophinopathies and myotonic dystrophy [4, 7, 11]. It is estimated to affect 1 in 20 000 individuals, with a reported incidence of 0,3 per 100 000 people in a Dutch study [2, 21].

FSHD1 represents more than 95% of all cases, and a minority of patients (less than 5%) have FSHD2 [4, 11].

The age of disease onset varies, and FSHD can be diagnosed from childhood to old age. However, symptoms typically start by the second decade. Both genders are equally affected, although women are usually diagnosed later in life and appear to be less severely affected [4, 11].

Diagnosis

The diagnosis of FSHD is suggested by typical clinical features and positive family history. The definitive diagnosis is established by genetic testing [4]. Testing for a D4ZA contraction is performed with a Southern blot and has a 93% sensitivity and 98% specificity [4]. Methylation studies may alternatively be used to confirm a diagnosis. Low methylation in the context of a 4qA allele is sufficient for diagnosis.

In addition, the work-up for diagnosing FSHD often includes electromyography (EMG) and serology. EMG would demonstrate findings of a myopathic disorder. Serology of a patient with FSHD would likely show elevated creatine kinase levels [4]. If genetic or electrodiagnostic testing is nonconfirmatory but FSHD is still suspected, a muscle biopsy may be performed. FSHD is known to cause changes in the organization of the sarcolemma and increase the distance between the sarcolemma and the nearest myofibrils [7].

Clinical Features

There is a large phenotypic heterogeneity among individuals with FSHD [9]. The following features could support a diagnosis of FSHD:

  •    Difficulty with raising arms over shoulder level (most common initial presenting symptom)[2]
  •   Winging of scapula
  •   Progressive weakness of facial muscles (more pronounced in lower facial muscles)
  •   Typically progresses from upper to lower extremities
  •    Affects distal musculature first, and later progresses more proximally (hamstrings and quadriceps)
  •   Muscle involvement can be asymmetric
  •   Eyes may not fully close while sleeping and may not be able to bury eyelashes during forced eye closure
  •   Presence of retinal vasculopathy (can usually be seen with fluorescein angiography)
  •   Hearing loss of high-frequency sounds occurs in approximately 65% of patients[3]
  •   Atrophy of upper arm muscles (such as biceps, triceps, serratus anterior) with sparing of forearm muscles
  •   Lumbar lordosis or bent spine syndrome
  •   Musculoskeletal pain
  •   Previous family history of FSHD


The following features would support an alternate diagnosis:

  •  Dysphagia or lingual involvement
  •  Cardiomyopathy
  •  Ptosis or weakness of ocular muscles
  • Contractures
  • Creatine kinase values persistently five times above the upper limit


Clinical Ophthalmologic Findings

Facial muscles involvement is an early sign in patients with FSHD. Orbicularis oculi weakness hampers adequate eyelid closure especially during sleep time, resulting in potential exposure keratitis and corneal ulceration. Extra-ocular muscles are usually spared, but a few cases of progressive external ophthalmoplegia have been reported. Ptosis is rare [1, 2, 4].

Retinal vasculopathy is one of the most frequent extra-muscular findings in FSHD, affecting around 50-70% of patients [22]. Retinal vascular changes are usually bilateral and include vascular tortuosity, capillary telangiectasias and microaneurysms, commonly found in an asymptomatic patient at a screening visit [1, 2, 26]. Most of these alterations are subtle and can be easily overlooked without a fluorescein angiogram [2]. Peripheral retinal avascularity can be seen on the FA. A minority of FSHD patients develop a Coats-like syndrome, with significant telangiectasias and exudative retinopathy, ultimately progressing to retinal detachment, retinal neovascularization and neovascular glaucoma [1, 2, 9, 23]. The most severe end of the clinical spectrum is typically associated with a smaller number of D4Z4 repeat units [4, 9, 11, 23].

Rosa N. et al reported that patients with FSHD have thinner central corneas and lower intraocular pressure measurements in comparison with healthy controls [24].

Differential diagnosis

Myotonic dystrophy type 1 and 2 and Limb-girdle muscular dystrophies may present with similar pathologic findings and a similar distribution of weakness. Regarding retinal microvascular findings more common diseases such as diabetic retinopathy, venous occlusive disease, hypertensive retinopathy or sickle-cell anemia, should be included in the differential diagnosis of a retinal microvascular disorder [2]. Also, familial exudative vitreoretinopathy, retinopathy of prematurity, Norrie’s disease, hemangioma and Eales’ disease can all lead to retinal telangiectasias and exudation and should be considered when such findings are present.

Genotype-Phenotype Correlations

American Academy of Neurology guidelines (2015) advise that a large contraction of D4Z4 (D4ZA fragments of 10-20 kb) increases the likelihood of an earlier onset of symptoms, and increases the chance of significant disability and extramuscular manifestations [25].

Management

There is no curative treatment for FSHD and disease management is based on supportive care focusing on screening, rehabilitation and symptomatic control [4, 25]. Future potential therapies include small molecule drugs, gene therapy and antisense oligonucleotides. An ophthalmological exam with dilated fundus examination is recommended for all patients with FSHD at the time of diagnosis to screen for reversible and potentially sight-threatening complications. When identified in an early stage, Coats-like syndrome manifestations can be treated with photocoagulation and/or intravitreal injections of anti-angiogenic agents, preventing further retinal damage [2, 4, 25]. The regularity of subsequent follow-up visits varies according to the severity of initial eye findings. Adults without retinal vasculopathy at the first visit should be evaluated again by an ophthalmologist if they develop visual complaints. Patients with the smallest D4Z4 repeats, as well as children with the infantile form of the disease should have at least an annual ophthalmological examination [2, 23, 25].

Prognosis

FSHD is the third most prevalent type of genetic neuromuscular disorder [7]. Classically, FSHD is a slowly progressive disease and patients usually have a normal lifespan [4, 11]. However, it can lead to significant disability and morbidity, ultimately resulting in wheelchair dependence in about 20% of patients. On the other hand, some patients can persist with mild or no symptoms for their entire lives [4, 5, 11]. It seems to be an association between the number of D4Z4 units and the severity of disease progression and phenotype, with patients with smaller repeat units (between 1 to 3 elements), having a faster progression to more severe manifestations [4, 9, 11, 23]. Men seem to have a more severe clinical phenotype [4]. Based on current guidelines, the best practice for treatment is supportive care.

References

1. Goselink RJM, Schreur V, van Kernebeek CR, Padberg GW, van der Maarel SM, van Engelen BGM, et al. Ophthalmological findings in facioscapulohumeral dystrophy. Brain Commun. 2019;1(1):fcz023.

2. Matos R, Beato J, Silva M, Silva S, Brandão E, Falcão-Reis F, et al. Combined treatment with intravitreal bevacizumab and laser photocoagulation for exudative maculopathy in facioscapulohumeral muscular dystrophy. Ophthalmic Genet. 2017;38(5):490-3.

3. Schätzl T, Kaiser L, Deigner HP. Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update. Orphanet J Rare Dis. 2021;16(1):129.

4. Statland JM, Tawil R. Facioscapulohumeral Muscular Dystrophy. Continuum (Minneap Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31.

5. DeSimone AM, Pakula A, Lek A, Emerson CP, Jr. Facioscapulohumeral Muscular Dystrophy. Compr Physiol. 2017;7(4):1229-79.

6. Krasnianski M, Neudecker S, Eger K, Schulte-Mattler W, Zierz S. [Facioscapulohumeral muscular dystrophy. The spectrum of clinical manifestations and molecular genetic changes]. Nervenarzt. 2003;74(2):151-8.

7. Man®) OOMIi. FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1; FSHD1 [updated August 12, 2021. Available from: https://www.omim.org/entry/158900#title

8. Nikolic A, Jones TI, Govi M, Mele F, Maranda L, Sera F, et al. Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies. Int J Mol Sci. 2020;21(7).

9. Ricci G, Mele F, Govi M, Ruggiero L, Sera F, Vercelli L, et al. Large genotype-phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis. Sci Rep. 2020;10(1):21648.

10. van Overveld PG, Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F, et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003;35(4):315-7.

11. Lemmers RJ MD, van der Maarel SM Facioscapulohumeral muscular dystrophy. : GeneReviews; 1999 [updated February 6, 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1443/.

12. Hamanaka K, Šikrová D, Mitsuhashi S, Masuda H, Sekiguchi Y, Sugiyama A, et al. Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy. Neurology. 2020;94(23):e2441-e7.

13. van den Boogaard ML, Lemmers R, Balog J, Wohlgemuth M, Auranen M, Mitsuhashi S, et al. Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy. Am J Hum Genet. 2016;98(5):1020-9.

14. Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ, Frants RR, et al. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet. 2002;32(2):235-6.

15. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010;329(5999):1650-3.

16. Wuebbles RD, Hanel ML, Jones PL. FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy. Dis Model Mech. 2009;2(5-6):267-74.

17. Fitzsimons RB. Retinal vascular disease and the pathogenesis of facioscapulohumeral muscular dystrophy. A signalling message from Wnt? Neuromuscul Disord. 2011;21(4):263-71.

18. Bakker E, Van der Wielen MJ, Voorhoeve E, Ippel PF, Padberg GW, Frants RR, et al. Diagnostic, predictive, and prenatal testing for facioscapulohumeral muscular dystrophy: diagnostic approach for sporadic and familial cases. J Med Genet. 1996;33(1):29-35.

19. Köhler J, Rupilius B, Otto M, Bathke K, Koch MC. Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occurring predominantly in oogenesis. Hum Genet. 1996;98(4):485-90.

20. de Greef JC, Lemmers RJ, Camaño P, Day JW, Sacconi S, Dunand M, et al. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology. 2010;75(17):1548-54.

21. Deenen JC, Arnts H, van der Maarel SM, Padberg GW, Verschuuren JJ, Bakker E, et al. Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology. 2014;83(12):1056-9.

22. Osborne RJ, Welle S, Venance SL, Thornton CA, Tawil R. Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy. Neurology. 2007;68(8):569-77.

23. Statland JM, Sacconi S, Farmakidis C, Donlin-Smith CM, Chung M, Tawil R. Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size. Neurology. 2013;80(13):1247-50.

24. Rosa N, Lanza M, de Bernardo M, Cecio MR, Passamano L, Politano L. Intraocular pressure in patients with muscular dystrophies. Ophthalmology. 2013;120(6):1306-7.e1.

25. Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;85(4):357-64.

26. Xia T, Bhagat N. Coats’-like Response in Facioscapulohumeral Muscular Dystrophy. Acta Scientific Ophthalmology. July 2018; Volume 1(1): 07-09.

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