Facioscapulohumeral Muscular Dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive dystrophic myopathy with predominant involvement of facial and shoulder girdle musculature (94). There are two subtypes of FSHD: FSHD1 observed in 95% of FSHD patients and linked to the chromosome 4q35 locus, and FSHD2 genetically distinct with a more complex digenic (2 gene) inheritance pattern (chromosomes 10 and 18). Approximately 10% to 30% of FSHD cases are caused by sporadic mutations. To date, based on a relatively small study, FSHD1 and 2 appear to be clinically indistinguishable; however, larger studies are needed to confirm this observation.

FSHD is the third most common of the dystrophies, behind Duchenne and myotonic dystrophies with an incidence of between 10 and 20 per million live births (7). The age of presentation is generally before 20 years. Changes on muscle biopsy are relatively slight, with the most consistent finding being the presence of isolated small atrophic fibers. Other fibers may be hypertrophied. Serum CK levels are normal or slightly elevated in the majority of patients. Diagnosis is confirmed in over 90% of cases by molecular genetic testing.

Facial weakness is an important clinical feature of FSHD muscular dystrophy. The initial weakness affects the facial muscles, especially the orbicularis oculi, zygomaticus, and orbicularis oris. These patients often have difficulty with eye closure but not ptosis. An individual may assume an expressionless appearance and exhibit difficulty whistling, pursing the lips, drinking through a straw, or smiling (Figure 18.7). Even in the very early stages, forced closure of the eyelids can be easily overcome by the examiner. Masseter, temporalis, extraocular, and pharyngeal muscles characteristically are spared in FSHD.

Scapular stabilizers, shoulder abductors, and shoulder external rotators may be significantly affected, but at times the deltoids are surprisingly spared if tested with the scapulae stabilized. Both the biceps and triceps may be more affected than the deltoids. Patients with FSHD show characteristic patterns of muscle atrophy and scapular displacement. Involvement of the latissimus dorsi, lower trapezius, rhomboids, and serratus anterior results in a characteristic appearance of the shoulders, with the scapula positioned more laterally and superiorly, giving the shoulders a forward-sloped appearance (Figure 18.8). The upper border of the scapula rises into the trapezius, falsely giving it a hypertrophied appearance. From the posterior view, the medial border of the scapula may exhibit profound posterior and lateral winging. The involvement of shoulder girdle musculature may be quite asymmetric. Some authors have found asymmetric weakness in the dominant upper extremity (95).

A sensory neural hearing deficit was originally observed in Coates syndrome (early-onset FSHD). These

Facial weakness and expressionless facies in FSHD muscular dystrophy. Both father and daughter demonstrate difficulty whistling and pursing their lips.

FIGURE 18.7 Facial weakness and expressionless facies in FSHD muscular dystrophy. Both father and daughter demonstrate difficulty whistling and pursing their lips.

individuals have a myopathy that presents in infancy. The disease progression is fairly rapid with most individuals becoming wheelchair reliant by the late second or third decade. These individuals also have a progressive exudative telangiectasia of the retina. Early recognition and photocoagulation of the abnormal retinal vessels may prevent loss of vision. Several audiometry studies have demonstrated hearing deficits in many later-onset FSHD patients in addition to those with Coates syndrome, suggesting that impaired hearing function is more common than expected in FSHD muscular dystrophy (96). Thus, all patients with FSHD should have screening audiometry and ophthalmologic evaluation. Contractures are relatively uncommon in FSHD muscular dystrophy. FSHD patients with scoliosis have mild and nonprogressive curves. Rarely, severe and progressive hyperlordosis is associated with FSHD. The patients with severe hyperlordosis may utilize their lordotic posturing to compensate for hip extensor weakness.

Posterior and lateral scapular winging and high riding scapula.

FIGURE 18.8 Posterior and lateral scapular winging and high riding scapula.

Mild restrictive lung disease has been reported in nearly one-half of FSHD patients (94). The expiratory muscles involved in respiration appear to be more affected than inspiratory muscles in FSHD (95). Patients rarely require nocturnal ventilatory support.

The presence of cardiac abnormalities in FSHD muscular dystrophy is debated. While diverse ECG abnormalities have been noted, one study showed no abnormalities on ECG, chest radiography, Holter monitoring, and echocardiography (97). Nuclear scanning with thallium-201 has demonstrated diffuse defects consistent with diffuse fibrosis (65). Abnormalities in systolic time intervals on echocardiography and elevations in atrial natriuretic peptide are consistent with subclinical cardiomyopathy. Cardiac complications in FSHD muscular dystrophy are rare and patients in general have normal longevity. There is usually no associated intellectual involvement in this dystrophic myopathy.

MOLECULAR GENETICS AND THERAPEUTIC TARGETS IN FSHD. The complex molecular genetics of FSHD is becoming increasingly understood (98). D4Z4 repeat contractions on chromosome 4 are consistently identified in FSHD1 patients, but not in persons with FSHD2. A DUX4 mRNA polyadenylation sequence (PAS) is necessary for FSHD, providing genetic proof that the DUX4 mRNA is necessary for FSHD. Normally DUX4 is repressed in unaffected individuals. Repression of DUX4 is lost in FSHD and resulted in a burst of DUX4 expression with either subsequent silencing or the death of the cell. Expression of DUX4 retrogene is harmful and causes FSHD pathogenesis. A retrogene is defined as a DNA gene copied back from RNA by reverse transcription. Normally there is repression of the DUX4 retrogene embedded in the D4Z4 repeat units. In FSHD1 there is a PAS region of D4Z4 distal to the final DUX4 retrogene which initiates transcripts in the antisense (opposite) direction. For FSHD1 to occur, (a) there needs to be a smaller D4Z4 repeat (1-10), (b) there needs to be inefficient epigenetic repression of the DUX4 retrogene (normally a silenced gene) in the D4Z4 repeat region, and the last repeat must be adjacent to a PAS in the subtelomeric region of chromosome 4. This results in abnormal expression of DUX4 protein (a transcription factor) in skeletal muscle nuclei in FSHD.

Within the control population, the size of the D4Z4 repeat array on chromosome 4 varies between 11 and 100 units, while the array on chromosome 10 can vary from 1 to 100 units. Most patients with FSHD1 have one array of 1 to 10 units on chromosome 4 (some with 11 reported). Symptomatic hearing loss and retinal vascular disease occur almost exclusively in FSHD individuals with only one to three residual D4Z4 repeats.

FSHD2 individuals have a classical FSHD phenotype and do not have a D4Z4 repeat array contraction, but do show a strong reduction of D4Z4 methylation suggesting that the common feature of FSHD1 and FSHD2 was decreased epigenetic repression of D4Z4 (increased DUX4 expression) (98). Subsequent whole exome sequencing in selected FSHD2 families identified mutations in the Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) gene. Analysis of a larger cohort confirmed that SMCHD1 mutations account for approximately 85% of FSHD2 families. Thus, in FSHD2 there is digenic inheritance of a normal-sized D4Z4 repeat array on a DUX4 PAS containing chromosome 4 and a heterozygous SMCHD1 mutation on chromosome 18.

The pathogenesis of FSHD is becoming increasingly understood (98). Skeletal muscle cell apoptosis is perhaps the most dramatic consequence of DUX4 expression. The expression of DUX4 might also inhibit normal muscle regeneration. DUX4-induced misexpression of genes in FSHD muscle would be expected to induce an immune response in some tissues. RNAs and novel protein encoding transcripts could have biologic activity related to FSHD pathophysiology. Finally there may be modifier gene loci that protect the muscle cell. This has led to the following therapeutic targets for FSHD: (a) drugs that enhance the epigenetic repression of the D4Z4 region (silence the region), (b) oligonucleotide-based therapies that target the DUX4 mRNA and prevent it from making the DUX4 protein, or small molecules that might alter

RNA splicing or polyadenylation of a specific transcript, (c) drugs that block the activity of the DUX4 protein and DUX4 transcriptional activity, and (d) drugs that build lean muscle mass such as myostatin inhibitors.

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