LANDOUZY-DEJERINE MUSCULAR DYSTROPHY FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY, INFANTILE, INCLUDED
FSHD1A
FACIOSCAPULOHUMERAL DYSTROPHY WITH SENSORINEURAL HEARING LOSS AND TORTUOSITY OF RETINAL ARTERIOLES, INCLUDED
MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1
MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1A
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY
FSHD
FMD
FSHD1
Facioscapulohumeral muscular dystrophy is the third most common hereditary disease of muscle after Duchenne (DMD; 310200) and myotonic (160900) dystrophy. It is a highly variable disorder with weakness appearing from infancy to late life but typically in the ... Facioscapulohumeral muscular dystrophy is the third most common hereditary disease of muscle after Duchenne (DMD; 310200) and myotonic (160900) dystrophy. It is a highly variable disorder with weakness appearing from infancy to late life but typically in the second decade. In general, the disease initially involves the face and the scapulae followed by the foot dorsiflexors and the hip girdles. Typical features are striking asymmetry of muscle involvement from side to side and sparing of bulbar extraocular and respiratory muscles (Tawil et al., 1998). Richards et al. (2012) provided a detailed review of FSHD. See also FSHD2 (158901), which is phenotypically indistinguishable from FSHD1, but not associated with contraction of the D4Z4 microsatellite repeat. Evidence suggests, however, that epigenetic changes in this region are associated with both FSHD1 and FSHD2 (Zeng et al., 2009).
Justin-Besancon et al. (1964) added 3 affected generations to the 4 described by Landouzy and Dejerine (1885) and gave autopsy findings in 1 of the original patients who died at age 86 years. Some cases show congenital absence ... Justin-Besancon et al. (1964) added 3 affected generations to the 4 described by Landouzy and Dejerine (1885) and gave autopsy findings in 1 of the original patients who died at age 86 years. Some cases show congenital absence of part or all of certain muscles such as a pectoral muscle. The relationship of the congenital defect of muscle to the dystrophy is unclear. Tyler and Stephens (1950) and Tyler (1953) reported 17 families. In 1 kindred 150 members were affected over 6 generations. A girl, whose face alone was affected at age 9 when examined by Landouzy and Dejerine (1885), did not develop weakness of the arms until age 60 and of the legs until age 70, and survived to age 85 years. In her family, affected members were distributed through 8 generations. Meyerson et al. (1984) reported sensorineural hearing loss in 2 sibs with FSH muscular dystrophy which affected other members of the family in typical manner. The studies of Brouwer et al. (1991) suggest that a 'change of hearing function is part of the disease and may lead to severe hearing loss in some patients.' Deafness and abnormalities of retinal vessels (see later) are probably integral parts of the disorder. Sayli et al. (1984) found at least 53 affected persons in a Turkish kindred originating in the village of Cullar. Initial signs and symptoms seemed to appear early in infancy in many. The disorder progressed slowly without interfering significantly with survival and reproduction. Symptoms first involved the face, upper arms, and shoulder muscles. Creatine kinase levels were 1.5 to 2 times normal. Many of the affected persons were identified on examination; only 13 reported complaints and their mean age was 40.1 years. After the kindred reported by Tyler and Stephens (1950), this is the most extensively affected family studied to date. Awerbuch et al. (1990) found that the Beevor sign was present in 27 of 30 patients with FSHD but absent in all 40 patients with other neuromuscular disorders. They concluded that it is a common finding in FSHD patients even before functional weakness of abdominal wall muscles is apparent. Because of weakness of the lower rectus abdominis muscles, the umbilicus moves upward when the subject in the supine position raises his or her head, producing the Beevor sign. (This sign was originally proposed by English neurologist Charles E. Beevor as an indication of the level of involvement in spinal cord lesions.) Bodensteiner and Schochet (1986) suggested the supraspinatus muscle as the site of choice for biopsy in this disorder. Reardon et al. (1991) pointed out the difficulties in some cases in distinguishing FSHD from the Becker type of muscular dystrophy (300376). Calf hypertrophy, although rare, has been reported in FSHD. Jardine et al. (1993) reexamined the 3 affected members in the family reported by Reardon et al. (1991) and demonstrated that they had a rearrangement in the region of the FSHD gene as indicated by studies with probe p13E-11. Shen and Madsen (1991) described symptomatic atrial tachycardia, for which an antitachycardic pacing device was implanted, in a 44-year-old woman. Her severe scapular and shoulder weakness led to recurrent dislodgment of the atrial pacemaker lead. According to Bailey et al. (1986), infantile facioscapulohumeral muscular dystrophy was recognized by Duchenne (1862) and differentiated from pseudohypertrophic muscular dystrophy over 20 years before the description of the usual form of facioscapulohumeral muscular dystrophy by Landouzy and Dejerine (1885). Whereas FSHD is generally a benign, slowly progressive myopathy that begins in late childhood or adolescence and leads to disability only late in its course, occasional families contain individuals with a severe infantile form of the disorder who have 1 asymptomatic or minimally affected parent. Bailey et al. (1986) reported a family in which the severe infantile presentation predominated. They suggested 'that the gene coding for this disorder may be different from that responsible for conventional facioscapulohumeral muscular dystrophy.' The genes for the 2 forms of the disease may, of course, be allelic. In 56 of 75 persons with clinical or genetic evidence of FSH muscular dystrophy, Fitzsimons et al. (1987) found peripheral retinal capillary abnormalities including telangiectasia, closure, leakage, and microaneurysm formation. They were prompted to do this study by the occasional reports of exudative retinal detachment and deafness with this disorder. The study included 1 FSH family in which the proband was treated for exudative retinopathy and 13 other members had retinal telangiectasia. There were 8 cases, including 3 parents of apparently 'sporadic' FSH cases, in which fluorescein angiography 'confirmed the abnormal genotype, even though clinical examination of skeletal muscle revealed no clear abnormality.' Fitzsimons et al. (1987) concluded that retinal capillary abnormalities are an integral part of FSH muscular dystrophy and raised the question as to whether analogous capillary abnormalities may be implicated in the pathogenesis of the muscle disease. Padberg et al. (1992) came to similar conclusions on the basis of studies using fluorescein retinal angiography in 32 patients from 19 families. In 16 of the 32, representing 11 families, retinal capillary changes were found consisting of telangiectasia, microaneurysms, vessel occlusions, and small exudates and hemorrhages in the macular as well as in the peripheral retina. In addition, tone audiometry was performed, with the finding that 20 sibs from 14 families had some degree of high-tone deafness. Similar findings were observed in 8 sporadic cases: 4 had retinal vasculopathy and 5 had high-tone deafness. Combined with linkage data, these observations demonstrated that retinal vasculopathy and high-tone sensorineural deafness are part of the clinical picture of FSHD and are no grounds for assuming genetic heterogeneity. Small (1968) described 4 sibs with facioscapulohumeral dystrophy and bilateral retinal exudative telangiectasia, labeled Coats disease (see 300216). Neurosensory deafness and mental retardation were present in all 4. Taylor et al. (1982) and Voit et al. (1986) described the same association. Yasukohchi et al. (1988) described a brother and sister with facioscapulohumeral dystrophy. The brother, aged 13 years, also had sensorineural hearing loss, marked tortuosity of retinal arterioles, early onset and progression of severe restrictive pulmonary dysfunction, and cor pulmonale. The 8-year-old sister had only muscle manifestations. Bilateral sensorineural hearing loss in the high frequency range was described in the above patients. In some, the hearing loss was clearly progressive and with time tended to involve lower frequencies (Voit et al., 1986). As noted from the cases cited, autosomal dominant inheritance was not always clear; recessive inheritance was possible and might point to this being an entity separate from FSHD. Brouwer et al. (1991) performed screening audiometry in 56 patients with autosomal dominant FSHD and in 72 healthy family members, and found that the difference in hearing levels between 4,000 Hz and 6,000 Hz was significantly greater in FSHD patients than in their unaffected relatives. This led them to conclude that a change in hearing function is part of the disease and may lead to severe hearing loss in some patients. Gieron et al. (1985) described a mother and 3 children with FSHD, sensorineural hearing loss, and marked tortuosity of retinal vessels. The deafness, which varied from mild to moderate, was bilateral and early in onset. Audiologic studies indicated the cochlea as the site of the abnormality. Matsuzaka et al. (1986) reported a sporadic case of this constellation of manifestations plus mental retardation and suggested that these cases constitute a nosologically specific form of FSHD. Shields et al. (2007) noted that retinal telangiectasia compatible with Coats disease (300216) can be an extramuscular manifestation of FSHD but that most affected patients have asymptomatic retinal telangiectasia found at ocular screening after diagnosis of FSHD. They described a young child who had advanced eye findings of unilateral neovascular glaucoma from bilateral retinal telangiectasia 3 years before FSHD became apparent. See 182970 for a form of spinal muscular atrophy simulating FSH muscular dystrophy. Miura et al. (1998) reported 2 sporadic cases of early-onset scapulohumeral muscular dystrophy with mental retardation and epilepsy in unrelated, severely affected females. In both cases, Southern blot analysis of the EcoRI-digested genomic DNA, using 2 probes, detected 10-kb EcoRI fragments, the shortest reported to that time. Patient 1 showed infantile spasms at the age of 4 months and localization-related epilepsy at the age of 2.5 years. Muscular atrophy in the face, shoulder girdle, and upper arms was observed from the age of 4 years. In patient 2, lack of facial expression was noticed since the age of 1 year, and at 4 years she was noted to have loss of upward gaze bilaterally. She developed localization-related epilepsy at the age of 9 years. From the age of 10 years, weakness of the lower limbs progressed and she became wheelchair-bound at the age of 14 years. She had moderate sensorineural hearing loss, a loss of upward gaze bilaterally, and tongue atrophy. Their IQs were 33 and 45, respectively. Miura et al. (1998) suggested that mental retardation and epilepsy may be part of the clinical spectrum of FSHD, especially in very early-onset patients with large deletions. Among 151 Japanese patients with FSHD, Yamanaka et al. (2001) reported 7 patients with tongue atrophy with abnormal tongue MRI findings (disorganized architecture) and typical myogenic patterns of electromyography. All patients were classified as having early-onset FSHD with large gene deletions within the 4q35 gene region. Krasnianski et al. (2003) described atypical features in 6 of 41 patients with FSHD and the 4q35 deletion. Three patients from 1 family showed the typical phenotype with the additional feature of chronic progressive external ophthalmoplegia. Three patients, 2 from 1 family, showed sparing of the facial muscles, and 2 of these patients had severe, diffuse myalgia. There was no correlation between the atypical features and the DNA fragment size due to the deletion. Wohlgemuth et al. (2006) found that 10 of 87 individuals with FSHD had signs of weakness in the jaw, lips, or tongue. Oropharyngeal evaluation in 8 of these patients detected mild to moderate swallowing abnormalities in 7 patients and tongue atrophy in 6. - Pathologic Features In a 20-year-old woman who had inherited FSHD from her father and who also had an affected brother, Slipetz et al. (1991) found that muscle biopsy showed fiber atrophy with patchy staining for oxidative enzymes; that electron microscopy of liver showed many enlarged mitochondria with paracrystalline inclusions; and that skin fibroblasts showed decreased oxidation of the respiratory substrates alanine and succinate, suggesting deficiency of complex III of the electron-transport chain. Cytochrome c oxidase activity (complex IV) was normal. Biochemical analysis of liver supported the fibroblast data, since succinate oxidase activity (electron-transport activity through complexes II-IV) was reduced and complex IV activity was normal. Cytochrome b, a component of complex III, was undetectable in liver, although typical peaks were found for other cytochromes. Southern blot analysis of fibroblast mtDNA showed no major deletions or rearrangements. Using confocal microscopy, Reed et al. (2006) found that some of the structures at the sarcolemma in FSHD skeletal muscle biopsies were misaligned with respect to the underlying contractile apparatus. Electron microscopy showed a significant increase in the distance between the sarcolemma and the nearest myofibrils, from less than 100 nm in controls to 550 nm in FSHD. Reed et al. (2006) concluded that the pathophysiology of FSHD includes novel changes in the organization of the sarcolemma and the subsarcolemmal membrane cytoskeleton.
As indicated earlier, FSHD is associated with a short (less than 35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3-kb repeat located at 4q35. Vitelli et al. (1999) determined fragment sizes ... As indicated earlier, FSHD is associated with a short (less than 35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3-kb repeat located at 4q35. Vitelli et al. (1999) determined fragment sizes separated by pulsed field gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38-kb fragment was detected in the proband, in his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. Thus, whereas in healthy individuals the size of the 4q35 polymorphic fragment varies from 48 to 300 kb, and most patients with FSHD show fragments less than 35 kb, fragment sizes between 35 and 48 kb must be interpreted with caution. An inverse correlation between fragment size and severity was described by Lunt et al. (1995) and Tawil et al. (1996). In familial cases, although the size of the inherited fragment remains constant, FSHD seems to become more severe with each generation (anticipation), according to the findings of Griggs et al. (1993), Lunt et al. (1995), Nakagawa et al. (1996), and Tawil et al. (1996). Wohlgemuth et al. (2003) reported 2 unrelated families with FSHD in which the probands were compound heterozygous for 2 FSHD-sized alleles: a severely affected woman had chromosome 4-type arrays of 17 and 24 kb, and in the other family, a man had arrays of 33 and 36 kb. All of these alleles resided on 4qA. In the first family, 1 unaffected member had the 24-kb allele and 1 affected member had the 17-kb allele; in the second family, 3 unaffected children of the proband carried either the 33-kb allele or the 36-kb allele. Wohlgemuth et al. (2003) noted that the findings showed that having 2 disease alleles is not lethal, and proposed that the phenotype in both probands reflected a dosage effect. In 21 FSHD1 patients who had 1 translocated chromosome 10-type array on chromosome 4, referred to as 'monosomic,' van Overveld et al. (2005) found D4Z4 hypomethylation compared to monosomic controls. Further analysis delineated 2 classes of clinical severity: patients with repeat sizes of 10 to 20 kb were severely affected and showed pronounced hypomethylation, whereas patients with repeat sizes of 20 to 31 kb showed variation in clinical severity and in hypomethylation. However, the authors could not establish a linear relationship between methylation and disease severity. Sacconi et al. (2013) found that the SMCHD1 gene (614982), mutation in which causes FSHD2, is a modifier of disease severity in families affected by FSHD1. Three unrelated families with intrafamilial clinical variability of the disorder were studied. In 1 family, a mildly affected man with FSHD1 carried a 9-unit D4Z4 repeat on a 4A allele with no SMCHD1 mutations, whereas his mildly affected wife carried a SMCHD1 mutation (T527M; 614982.0006) on a normal-sized 4A allele, consistent with FSHD2. Their more severely affected son and grandson each carried the 9-unit D4Z4 repeat on a 4A allele as well as the T527M SMCHD1 mutation, consistent with having both FSHD1 and FSHD2. In a second family, a man with a severe early-onset phenotype had both a 9-unit D4Z4 repeat on a 4A permissive allele and a mutation in the SMCHD1 gene. Each of his children, who had milder symptoms, inherited 1 of the genetic defects. In a third family, a man with a severe phenotype was also found to carry a 9-unit D4Z4 repeat on a 4A permissive allele with a SMCHD1 mutation. No information from his parents was available. Transduction of SMCHD1 shRNA into FSHD1 myotubes caused increased levels of DUX4 mRNA as well as transcriptional activation of known DUX4 target genes. These findings were consistent with further chromatin relaxation of the contracted FSHD1 repeat upon knockdown of SMCHD1. Sacconi et al. (2013) concluded that FSHD1 and FSHD2 share a common pathophysiologic pathway converging on transcriptional derepression of DUX4 in skeletal muscle.
All patients with a confirmed diagnosis of FSHD and for whom detailed molecular studies have been performed carry a chromosomal rearrangement within the subtelomeric region of 4q (4q35). This subtelomeric region is composed mainly of a polymorphic repeat ... All patients with a confirmed diagnosis of FSHD and for whom detailed molecular studies have been performed carry a chromosomal rearrangement within the subtelomeric region of 4q (4q35). This subtelomeric region is composed mainly of a polymorphic repeat structure consisting of 3.3-kb repeated elements, designated D4Z4 (see 606009). The number of repeat units varies from 10 to more than 100 in the population, and, in FSHD patients, an allele of 1 to 10 residual units is observed because of the deletion of an integral number of these units (Wijmenga et al., 1992; Hewitt et al., 1994). - D4Z4 Macrosatellite Repeat For a full discussion of the D4Z4 macrosatellite repeat, see 606009. Lemmers et al. (2004) summarized the relationship of the D4Z4 repeat to FSHD. The polymorphic D4Z4 repeat is highly recombinogenic, since somatic mosaicism for rearrangement of D4Z4 is found in as much as 3% of the general population (van Overveld et al., 2000). The D4Z4 repeat consists of identical units defined by the restriction enzyme KpnI, each 3.3 kb, ordered in a head-to-tail fashion, and varying between 11 and 100 units on 'healthy' chromosomes (van Deutekom et al., 1993). Patients with FSHD carry a repeat of 1 to 10 units on one of their chromosomes 4 (Wijmenga et al., 1992). A rough and inverse correlation has been observed between the severity and age at onset of the disease and the residual repeat unit number. In a review of genetic disorders associated with aberrant chromatin structure, Bickmore and van der Maarel (2003) noted that FSHD represents a potential example of gene activation through loss of repression complexes. A review of the D4Z4 repeat-mediated pathogenesis of FSHD was provided by van der Maarel and Frants (2005). They pointed out that in contrast to most monogenic disorders, in which the genetic lesion typically affects the structure or function of a specific disease gene, evidence suggested that FSHD is caused by a complex epigenetic mechanism involving the contraction of a subtelomeric macrosatellite repeat. It is likely not the structure but rather the (spatiotemporal-restricted) transcriptional control of one or more disease genes that is perturbed in FSHD as a result of repeat-contraction-mediated chromatin alterations. Their review focused on the cause and consequence of the repeat-array contraction. Van der Maarel and Frants (2005) designated FSHD a macrosatellite repeat-contraction disease. Van Overveld et al. (2003) showed that contraction of the D4Z4 repeat array causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with FSHD clinically identical to other cases but with an unaltered D4Z4 (FSHD2; 158901) also have hypomethylation of D4Z4. These results strongly suggested that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1. Using chromatin immunoprecipitation (ChIP) in HeLa cells, Zeng et al. (2009) found SUV39H1 (300254)-mediated trimethylation of histone H3 (see 602810) at lysine-9 (H3K9), as well as trimethylation at H3 at lysine-27 (H3K27), both at D4Z4, representing transcriptionally repressive heterochromatin. There was also H3K4 dimethylation and H3 acetylation at proximal D4Z4 repeat regions, marking transcriptionally permissive euchromatin. The methylation signal at H3K9, at both the 4q and the 10q locus, was significantly decreased in cell lines derived from patients with FSHD1 (myoblasts and fibroblasts) and FSHD2 (fibroblasts) compared to controls. Contraction of D4Z4 at 1 allele showed a dominant effect on methylation of H3K9 at the other allele, as well as at the 10q locus, suggesting a spreading effect of histone modification. DNA hypomethylation was not observed in FSHD cells, and the decrease in H3K9 methylation was not observed in cells from patients with other forms of muscular dystrophy. Immunoprecipitation studies showed that loss of methylation at H3K9 interrupted binding of CBX3 (604477) and the cohesin complex (see, e.g., SCC1, 606462) at this region. Zeng et al. (2009) hypothesized that loss of H3K9 methylation, and thus loss of CBX3 and cohesion, results in the disruption of chromatin regulation, thereby causing abnormal derepression of distant target genes that leads to the dystrophic phenotype specific to muscle tissue. - DUX4 Expression Dmitriev et al. (2008) noted that the DUX4 gene (606009) found within the D4Z4 repeat was initially considered to be nonfunctional because it lacked introns and polyadenylation signals. Furthermore, expression of DUX4 could not be detected despite the efforts of several groups using various methods including screening of cDNA libraries, RT-PCR, microarray, and Pol II ChIP. Subsequently, work by Dixit et al. (2007) and Clapp et al. (2007) confirmed expression of DUX4 in human and mouse, respectively, and showed conservation of the DUX4 ORF for more than 100 million years. Bosnakovski et al. (2008) conditionally expressed cDNAs for FSHD candidate genes within the D4Z4 repeat, DUX4, FRG1 (601278), FRG2 (609032), and ANT1 (SLC25A4; 103220), in mouse C2C12 myoblasts at both high and low expression levels and found that only DUX4 was overtly toxic, as indicated by cellular ATP content, morphologic changes, and apoptosis. DUX4 showed variable toxicity when expressed in mouse fibroblasts or embryoid bodies. DUX4 localized to C2C12 cell nuclei within 2 hours of induction. Microarray analysis revealed altered expression in a broad range of genes, with greatest changes in those involved in growth and development and signal transduction. Expression of Myod was also downregulated at an early time point. Oxidative stress and heat shock genes were downregulated at later time points, suggesting that they may be secondary targets. The DUX4 homeodomains are most similar to those of PAX3 (606597) and PAX7 (167410), and overexpression of these genes rescued viability and proliferation in DUX4-expressing C2C12 cells. Bosnakovski et al. (2008) concluded that DUX4 may cause FSHD by interfering with normal PAX3 or PAX7 function in muscle satellite cells. Lemmers et al. (2010) showed that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonic polyadenylation signal for transcripts derived from DUX4, a double homeobox gene that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. This particular chromosomal setting containing the pathogenic sequences was named 4APAS (4A polyadenylation signal; Scionti et al., 2012). Lemmers et al. (2010) concluded that their findings suggested that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript. By RT-PCR, Snider et al. (2010) found that full-length DUX4 (DUX4-fl) was aberrantly expressed in 5 of 10 FSHD muscle biopsy specimens, but not in normal muscle specimens. PCR analysis of myoblast cultures of varying pool size, and immunohistochemical analysis of cultured myoblasts revealed that only about 0.1% of FSHD muscle nuclei expressed a relatively abundant amount of DUX4-fl mRNA and protein. DUX4-fl was also aberrantly expressed in differentiated FSHD embryoid bodies. A short variant of DUX4 (DUX4-s) was expressed in both FSHD and control tissues and cells. Aberrant DUX4-fl was often associated with apoptotic changes, and in all cases was associated with the FSHD permissive 4qA haplotype (see below). Snider et al. (2010) concluded that repressive chromatin associated with D4Z4 in differentiated cells may facilitate usage of the noncanonical splice donor site to generate DUX4-s, and the more permissive chromatin in FSHD may favor polymerase progression through to the consensus splice donor and generate DUX4-fl. Wallace et al. (2011) showed that apoptotic changes observed in DUX4-expressing HEK293 cells were eliminated by inactivating mutation of the first DNA-binding homeobox domain of DUX4. The development of lesions in DUX4-injected mouse muscle was also abrogated by mutation of the DUX4 homeobox domain. Pharmacologic inhibition of p53 (TP53; 191170) mitigated DUX4 toxicity in HEK293 cells, and muscle from p53-null mice were resistant to DUX4-induced damage. Wallace et al. (2011) concluded that DUX4-induced myopathy is dependent on p53-induced apoptosis. - 4qA and 4qB Polymorphic Segment Human 4qter and 10qter share a high degree of similarity, including the D4Z4 repeat array; however, contractions affecting the 10qter repeat are nonpathogenic. Van Geel et al. (2002) detected a polymorphic segment of 10 kb directly distal to D4Z4, which they called alleles 4qA and 4qB. Lemmers et al. (2002) reported that although the 2 alleles are equally common in the general population, FSHD is associated solely with the 4qA allele. They suggested that this was the first example of an intrinsically benign subtelomeric polymorphism predisposing to the development of human disease. Lemmers et al. (2004) concluded that contractions of D4Z4 on 4qB subtelomeres do not cause FSHD. The 2 allelic variants of 4q, 4qA and 4qB, exist in the region distal to D4Z4. Although both variants are almost equally present in the population, FSHD is associated exclusively with the 4qA allele. Lemmers et al. (2004) identified 3 families with FSHD in which each proband carried 2 FSHD-sized alleles and was heterozygous for the 4qA/4qB polymorphism. Segregation analysis demonstrated that FSHD-sized 4qB alleles are not associated with disease, since these were present in unaffected family members. Thus, in addition to a contraction of D4Z4, additional cis-acting elements on 4qA may be required for the development of FSHD. Alternatively, 4qB subtelomeres may contain elements that prevent FSHD pathogenesis. Lemmers et al. (2007) hypothesized that allele-specific sequence differences among 4qA, 4qB, and 10q alleles underlie the 4qA specificity of FSHD. By examining sequence variations in the FSHD locus, they demonstrated that the subtelomeric domain of chromosome 4q can be subdivided into 9 distinct haplotypes, of which 3 carry the distal 4qA variation. They showed that repeat contractions in 2 of the 9 haplotypes, 1 of which is a 4qA haplotype, are not associated with FSHD. Lemmers et al. (2007) showed that each of these haplotypes has its unique sequence signature, and proposed that specific SNPs in the disease haplotype are essential for the development of FSHD. Thomas et al. (2007) measured the frequency of 4qA-defined and 4qB-defined subtelomeric sequences in 164 unrelated patients with FSHD from the UK and Turkey, all known to have large D4Z4 deletions. An almost complete association (162 of 164 patients) was found between large D4Z4 repeat array deletions located on 4qA-defined 4qter subtelomeres and disease expression. DNA samples from 50 controls displayed equivalent frequencies for 4qA and 4qB markers, as did the normal chromosome 4 in all 65 patients studied. The 4qA and 4qB probes failed to hybridize in 2 patients, confirming the presence of an additional rare type of 4qter subtelomeric sequence in humans. Wang et al. (2011) provided evidence that the 4qB-associated D4Z4 contraction is not pathogenic in Chinese individuals. Molecular reexamination of 3 unrelated Chinese patients originally diagnosed with FSHD on the basis of a D4Z4 contraction showed that all were nonpathogenic 4qB variants. All 3 patients were found to have different disorders with similar phenotypes, including LGMD2A (253600), LGMD2E (604286), and DM1 (160900), respectively. A fourth Chinese patient originally diagnosed with FSHD was found to have a pathogenic 18-kb D4Z4 4qA contraction that she inherited from her symptomatic mother. Her 2 daughters carried a paternally inherited 24-kb nonpathogenic contraction that was found to be a mixture of 4q and 10q. The daughters were thus considered unaffected, whereas previously they had been misdiagnosed as asymptomatic cases. Wang et al. (2011) concluded that the D4Z4 repeat length analysis alone is insufficient for the diagnosis of FSHD, and should be accompanied by 4qA/4qB variant determination. - Expression of Other Genes within the FSHD Candidate Region Van Deutekom et al. (1996) identified a novel gene, which they referred to as FRG1 (601278), that mapped 100 kb centromeric of the repeated units on chromosome 4q35 that are deleted in FSHD. They identified a polymorphism in exon 1 of this gene and used RT-PCR to amplify reverse transcribed mRNA from lymphocytes and muscle biopsies of patients and controls. These studies indicated that both alleles were transcribed and gave no evidence of 'position effect' variegation leading to repression of allelic transcription. Gabellini et al. (2002) found that in FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1, FRG2 (609032), and ANT1 (103220), are inappropriately overexpressed. They showed that an element within D4Z4 specifically binds a multiprotein complex consisting of transcriptional repressor YY1 (600013), HMGB2 (163906), and nucleolin (NCL; 164035). This multiprotein complex binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes. Gabellini et al. (2002) proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease. In normal individuals, the presence of a threshold number of D4Z4 repeats leads to repression of 4q35 genes by virtue of the DNA-bound multiprotein complex that actively suppresses gene expression. In FSHD patients, deletion of an integral number of D4Z4 repeats reduces the number of bound repressor complexes and consequently decreases or abolishes transcriptional repression of 4q35 genes. By oligonucleotide microarrays, Winokur et al. (2003) compared FSHD expression profiles with those from normal muscle and DMD and LGMD2D (608099). Several genes whose expression was altered in an FSHD-specific and highly significant manner are involved in myogenic differentiation, suggesting a partial block in the normal differentiation program. Many of the transcripts affected in FSHD were direct targets of the transcription factor MYOD1 (159970). Additional misexpressed genes confirmed a diminished capacity to buffer oxidative stress, as demonstrated in FSHD myoblasts. This enhanced vulnerability of proliferative stage myoblasts to reactive oxygen species was also disease-specific, further implicating a defect in FSHD muscle satellite cells. None of the genes localizing to the FSHD region at 4q35 were found to exhibit a significantly altered pattern of expression in FSHD muscle. Winokur et al. (2003) hypothesized that disruptions in FSHD myogenesis and oxidative capacity may not arise from a position effect mechanism, as has been previously suggested, but rather from a global effect on gene regulation. Jiang et al. (2003) found that H4 acetylation levels of a nonrepeated region adjacent to the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in unexpressed euchromatin, rather than like constitutive heterochromatin. The control and FSHD cells also displayed similar H4 hyperacetylation (like that of expressed genes) at the 5-prime regions of 4q35 candidate genes FRG1 (601278) and ANT1. There was no position-dependent increase in transcript levels from these genes in FSHD skeletal muscle samples compared with controls. Jiang et al. (2003) proposed a model for FSHD in which differential long-distance cis looping depends upon the presence of a 4q35 D4Z4 array with less than a threshold number of copies of the 3.3-kb repeat. Perini and Tupler (2006) suggested that FSHD might be considered a useful model for the study of position effect in humans. D4Z4 deletion might result in stochastic variation in gene expression in muscle cells and explain the asymmetric involvement of muscles, the great variability of clinical expression between and within families, and the apparent threshold effect whereby there is a requirement for the deletion of a certain number of copies of D4Z4 to develop FSHD. Osborne et al. (2007) detected no change in expression of the FRG1, FRG2, or ANT1 genes in muscle biopsies from 19 FSHD patients compared to controls. Further studies of the 8-Mb region proximal to the D4Z4 array showed no significant changes in gene expression, no evidence of a position effect, and no evidence of unequal allele-specific expression. However, microarray analysis of global gene expression in FSHD muscle identified 11 upregulated genes with a role in vascular smooth muscle or endothelial cells, suggesting a possible link between muscular dystrophy and vasculopathy in FSHD. Davidovic et al. (2008) found that myoblasts isolated from patients with FSHD showed an abnormal pattern of expression of isoforms of the FXR1P (600819) gene compared to controls. FXR1P encodes an RNA-binding protein involved in the metabolism of muscle-specific-mRNAs during myogenesis. The altered pattern of FXR1P expression was due to a specific reduced stability of muscle-specific FXR1 mRNA variants. The findings suggested that the molecular basis of FSHD not only involves splicing alterations, but may also involve a deregulation of mRNA stability. Using RNA-DNA FISH, Masny et al. (2010) found no change in gene transcription of 16 genes in cis in the 4q35 region in nuclei of differentiated myotubes derived from patients with FSHD compared to differentiated myotubes from controls. In particular, there was no change in expression in the FRG1, FRG2, or ANT1 genes, which had previously been implicated. Dmitriev et al. (2011) showed that KLF15 (606465) bound an enhancer element within the D4Z4 repeat unit. Binding of KLF15 to 2 sites within the D4Z4 enhancer drove expression of FRG2 and DUX4C (DUX4L9; 615581), which are located over 40 kb centromeric to the D4Z4 repeat array. KLF15 expression was upregulated following differentiation of normal human myoblasts and following expression of MYOD, and it was upregulated in FSHD myoblasts, myotubes, and muscle biopsies. FSHD cells also showed upregulated expression of MYOD and the KLF15 target gene PPARG (601487), in addition to DUX4C and FRG2. Dmitriev et al. (2011) concluded that MYOD-dependent KLF15 expression is involved in partial activation of the differentiation program in FSHD myoblasts.
In a population-based study in northeastern Italy, Mostacciuolo et al. (2009) identified 40 patients with a clinical diagnosis of FSHD. Thirty (76%) patients from 13 families had a family history of the disorder, whereas 10 had sporadic disease. ... In a population-based study in northeastern Italy, Mostacciuolo et al. (2009) identified 40 patients with a clinical diagnosis of FSHD. Thirty (76%) patients from 13 families had a family history of the disorder, whereas 10 had sporadic disease. Of the 40 patients, 33 (82.5%) had a contraction at chromosome 4q35 ranging from 14 to 35 kb, whereas 4 patients from 1 family had a borderline 38-kb fragment, and 3 had a fragment greater than 40 kb. The 4 patients with the 38-kb fragment had onset of slowly progressive mild proximal muscle weakness between age 15 and 35 years without facial weakness. In contrast, 2 related patients with the fragment greater than 40 kb had a typical FSHD phenotype with facial involvement and profound weakness in the lower and upper region muscles, but the fragment was also found in an unaffected family member, thus excluding it as disease-causing. One asymptomatic 43-year-old man with a 20-kb fragment was identified, yielding an overall penetrance of 97%. Mostacciuolo et al. (2009) estimated the prevalence of genetically confirmed FSHD in this population to be 44 in 1,000,000.
FSHD is suspected in individuals with the following [Tawil et al 1998, Tawil & Van Der Maarel 2006]:...
DiagnosisClinical DiagnosisFSHD is suspected in individuals with the following [Tawil et al 1998, Tawil & Van Der Maarel 2006]:Weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness Onset of signs typically by age 20 years. However, more mildly affected individuals show signs at a later age and some remain asymptomatic.TestingSerum concentration of creatine kinase (CK) is normal to elevated in individuals with FSHD and usually does not exceed three to five times the upper limit of the normal range. Serum concentration of CK over 1500 IU/L suggests an alternate diagnosis. EMG usually shows mild myopathic changes. Muscle biopsy most often shows nonspecific chronic myopathic changes. Mononuclear inflammatory reaction is present in muscle biopsies in up to 40% of individuals with FSHD. Rarely, the inflammatory reaction is intense enough to suggest an inflammatory myopathy. Muscle biopsy is now performed only in those individuals in whom FSHD is suspected but not confirmed by molecular genetic testing. Molecular Genetic TestingCritical region. Approximately 95% of individuals with FSHD have a contraction mutation of the D4Z4 macrosatellite array in the subtelomeric region of chromosome 4q35. Each D4Z4 macrosatellite repeat contains a gene with two homeoboxes, called DUX4 [Hewitt et al 1994, Gabriels et al 1999]. The pathologic contraction of the D4Z4 repeat array is associated with an opening of the chromatin structure and derepression of DUX4. The DUX4 open reading frame is present in each 3.3-kb D4Z4 unit, but only transcripts that are spliced with an exon at the distal end of the array are stabilized sufficiently for protein production. Recently, transcription analysis showed that transcripts from the most distal D4Z4 unit are present in cultured myoblasts from affected individuals, but not in control myoblasts [Dixit et al 2007, Snider et al 2009, Lemmers et al 2010a]. About 5% of individuals with FSHD do not have a D4Z4 contraction, yet they maintain an opening of the chromatin structure at the D4Z4 locus. Detection of this epigenetic FSHD variant, designated FSHD2, is still in the research phase and is not carried out in a diagnostic setting [Lemmers et al 2012].Evidence for locus heterogeneity. A repeat sequence almost identical to D4Z4 has been identified on chromosome 10q26 but contractions of this repeat have never been associated with FSHD. Genetic analysis showed that the distal DUX4-like gene in the D4Z4 array on chromosome 10 has nucleotide variants in the polyadenylation signal, which prevent the production of a stable DUX4 transcript from this locus [Lemmers et al 2010a]. Number of D4Z4 repeat units in the subtelomeric region of chromosome 4q35. The D4Z4 array consists of single D4Z4 units of 3.3 kilobases (kb) repeated in a head-to-tail array (depicted by triangles in Figure 1). FigureFigure 1. Schematic comparison of the structure of the normal D4Z4 allele and the contracted mutant D4Z4 allele that causes FSHD. The normal D4Z4 allele has between 11 and 100 units of the 3.3-kb repeat sequence (depicted by triangles), whereas the contracted (more...)Unaffected individuals. Both chromosome 4 D4Z4 alleles have 11-100 repeat units. Individuals with FSHDOne chromosome 4 D4Z4 allele has contracted to between one to ten repeat unitsOne chromosome 4 D4Z4 allele has the normal 11-100 repeat units Haplotypes telomeric to the D4Z4 region. Haplotypes telomeric to the D4Z4 locus, categorized into two haplotype groups 4A and 4B, contribute to the pathogenicity of a contracted D4Z4 mutant allele [van Geel et al 2002]. Chromosome haplotypes 4A and 4B (sometimes referred to as 4qA and 4qB) are almost equally common in a control population and can be further divided into at least nine distinct haplotypes (i.e., different combinations of single nucleotide variants at one locus that are inherited together) [Lemmers et al 2007]. In general, contractions of the D4Z4 allele on 4A haplotypes cause FSHD [Lemmers et al 2002]. 4A161 is the most common 4A haplotype; less common FSHD permissive haplotypes are 4A159, 4A163, 4A166H, and 4A168 [Lemmers et al 2007, Lemmers et al 2010a]. A study in two Dutch families showed that D4Z4 contraction in the less common 4A haplotype designated 4A166 is not associated with FSHD.Contractions of the D4Z4 allele on the 4B haplotypes are non-pathogenic [Lemmers et al 2004a, Lemmers et al 2007]. Note: In the European population, approximately 39% of the alleles on chromosome 4 have a 4A161 haplotype and 4% have a 4A166H haplotype (both permissive for FSHD). The most common non-permissive haplotypes are 4A166 (4%) 4B163 (33%) and 4B168 (13%) [Lemmers et al 2010b].Clinical testingThe guidelines for genetic diagnosis of FSHD were discussed at a Best Practice meeting held in The Netherlands in 2010. At the end of this meeting all participants came to a consensus for the molecular diagnosis of FSHD; see Lemmers et al [2012] (click for full text).Allele sizes. Molecular genetic testing to determine the length or number of repeat units of the D4Z4 locus relies on Southern blot analysis, typically with a probe (e.g., p13E-11) that is localized immediately proximal to the D4Z4 locus. Standard DNA diagnostic testing (linear gel electrophoresis and Southern blot analysis) uses the restriction enzyme EcoRI that recognizes the D4Z4 locus on chromosomes 4 and 10. Note: Pulsed-field gel electrophoresis and Southern blot analysis requires EcoRI/HindIII double digestion for a better resolution of DNA fragments between 20 and 50 kb. An EcoRI/BlnI double digestion further fragments the chromosome 10 array allowing one to distinguish D4Z4 arrays located on chromosome 4 from the similar benign arrays on chromosome 10. Normal alleles. A D4Z4 locus with 11 to 100 repeat units (i.e., fragments of 42 kb or greater using EcoRI and the p13E-11 probe) Borderline alleles. A D4Z4 locus with ten or 11 repeat units (i.e., fragments of 38-41 kb using the p13E-11 probe) Note: (1) To date, it has not been possible to establish a definitive diagnostic cut-off for the number of repeat units of the D4Z4 locus; thus, caution should be exercised in assigning the diagnosis of FSHD to persons whose clinical findings are atypical and whose molecular genetic test results are within this borderline ("gray") zone. (2) Interpretation of the significance of fragments of this length requires correlation with clinical findings: In a study of 39 unrelated individuals having a D4Z4 allele in this size range, Butz et al [2003] identified individuals representing the complete phenotypic spectrum, from typical and atypical FSHD, to facial-sparing FSHD, to non-FSHD myopathy, to healthy without signs or symptoms. The authors consider 35-40 kb fragments to be FSHD-associated if the person has clinical features of FSHD.FSHD-associated alleles. A D4Z4 locus with one to ten repeat units (i.e., fragments of 10-40 kb using the p13E-11 probe) AND on a chromosome 4A haplotype. When such a fragment is not visible in the DNA sample, the person is said to have tested negative for FSHD1.Mosaicism for FSHD-associated alleles. Approximately half of de novo cases of FSHD (i.e., affected offspring of an unaffected parent) show a mosaic distribution of array lengths in the peripheral blood. This mosaicism likely results from a postzygotic array contraction during mitotic cell divisions early in embryogenesis. In such cases, a proportion of cells have two normal-sized D4Z4 alleles, while the remaining cells have one normal-sized D4Z4 allele and one contracted mutant D4Z4 allele [Lemmers et al 2004b]. Depending on when in embryogenesis the contraction mutation occurs at the D4Z4 locus and what proportion of cells have the contracted DZ4Z mutation, individuals with mosaicism can be affected or asymptomatic. FSHD with somatic mosaicism of D4Z4 array lengths is more penetrant in males than in females [van der Maarel et al 2000]. Note: In the other half of cases of de novo FSHD, the contraction mutation of the D4Z4 array likely occurs within the germline, prior to fertilization.Translocated alleles. Approximately 20% of the general population carries either a chromosome 4q35-type D4Z4 repeat array on chromosome 10 or a D4Z4 array that consists of both 4q35- and 10q26-type sequence repeats on chromosome 4q35 [van Deutekom et al 1996, Lemmers et al 2010b]. Translocated arrays on chromosome 10q are non-permissive to FSHD, while the contractions on the hybrid arrays on chromosome 4q35 cause FSHD [Buzhov et al 2005, Lemmers et al 2010a]. Therefore, the finding of a D4Z4 array that appears to be contracted in an individual who carries these translocations must be interpreted with caution and reconciled with clinical findings [Lemmers et al 2010b, Lemmers et al 2012]. Note: Although these are commonly known as ‘translocated alleles,’ the mechanism is unknown. Haplotype analysis. The clinician should know whether the laboratory test can distinguish between contracted D4Z4 arrays that occur on either the permissive 4A161 haplotype or the non-permissive 4A166 and 4B haplotypes (see Molecular Genetic Testing), telomeric to the D4Z4 region. Haplotype analysis is important to prevent a false positive diagnosis. Sometimes a D4Z4 array from chromosome 4 that appears to have a contraction mutation is detected in unaffected control individuals. In such cases, the contracted D4Z4 array is on the non-permissive 4B haplotype and is therefore non-penetrant. Lemmers et al developed a diagnostic test to discriminate both haplotype variants using HindIII-digested DNA and specific probes for 4qA and 4qB [Lemmers et al 2002, Lemmers et al 2007]. Note: More specific genotyping to distinguish different 4A haplotypes is not yet possible.Deletion alleles. In approximately 3% of the European families with FSHD1 the D4Z4 contraction on chromosome 4q35 is not visible using the standard genetic test because a deletion encompasses the region of the molecular diagnostic probe p13E-11. These individuals require additional testing to visualize the contracted D4Z4 repeat and resolve the size of the repeat [Lemmers et al 2003, Ehrlich et al 2007].Research testingD4Z4 hypomethylation. CpG methylation analysis of people with FSHD revealed that contracted D4Z4 arrays have a significantly lower level of methylation than normal-sized arrays suggesting that hypomethylation of D4Z4 may play a role in pathogenicity. Further analysis showed that the fewer than 5% of persons with FSHD who do not have a contracted D4Z4 repeat on chromosome 4A have reduced CpG methylation levels on the normal-sized D4Z4 arrays on chromosomes 4q and 10q [van Overveld et al 2003, de Greef et al 2009]. In these cases, FSHD is caused by an opening of the chromatin structure at the D4Z4 locus by a mechanism that is independent of a D4Z4 contraction. This epigenetic FSHD variant is designated FSHD2 and is clinically indistinguishable from D4Z4-array contraction-dependent FSHD1 [de Greef et al 2009, de Greef et al 2010]. Both FSHD1 and FSHD2 require a permissive chromosome 4 haplotype for disease to develop. Detection of FSHD2 is still in the research phase and diagnostic testing for clinical purposes is not yet available [Lemmers et al 2012].Alternative diagnostic methods are being developed to improve detection of pathologic alleles (see Molecular Genetics).Table 1. Summary of Molecular Genetic Testing Used in Facioscapulohumeral Muscular DystrophyView in own windowTest MethodMutation DetectedMutation Detection Frequency 1Test Availability Deletion testingContraction mutation of D4Z4 locus95%ClinicalHaplotype analysisAnalysis to confirm that the D4Z4 contraction mutation occurred on a permissive haplotype 2Not applicableMethylation analysisD4Z4 hypomethylation<5%Research only1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 4A161 is most common permissive haplotype, but others are reported (4A159, 4A168, 4A166H) [Lemmers et al 2010a]. All individuals with FSHD carry a permissive haplotype. Because 66% of controls also carry a permissive haplotype, this analysis is often not informative. Test is available on a limited basis.Interpretation of test results Molecular genetic test results should always be interpreted within the context of clinical findings. Detection of the contracted mutation of the D4Z4 locus by Southern blot analysis requires a high DNA quality; in some cases a false negative test result can be caused by poor-quality DNA which has been sheared into small fragments.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. Molecular genetic testing to determine the size of the chromosome 4q-like D4Z4 repeat array is the preferred method of diagnosis. Additional standard and recommended testing methods are depicted in the flowchart (Figure 2).FigureFigure 2. Flowchart analysis of FSHD Standard analysis: Best practice guidelines [Lemmers et al 2012] recommend standard analysis (steps 1 and 2), which can confirm or exclude a diagnosis for the majority of individuals tested. Step (more...)Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo other phenotypes are associated with the contraction mutation of the D4Z4 locus in the subtelomeric region of chromosome 4q.
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness involving the face, scapular stabilizers, upper arm, lower leg (peroneal muscles), and hip girdle [Tawil et al 1998]. Asymmetry of limb and/or shoulder weakness is common [Kilmer et al 1995]. Typically, individuals with FSHD become symptomatic in their teens, but age of onset is variable. More than 90% of affected individuals demonstrate findings by age 20 years. Individuals with severe infantile FSHD have muscle weakness at birth. In contrast, some individuals remain asymptomatic throughout their lives. Progression is usually slow and continuous; however, many affected individuals describe a stuttering course with periods of disease inactivity followed by periods of rapid deterioration. Eventually 20% of affected individuals require a wheelchair....
Natural HistoryFacioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness involving the face, scapular stabilizers, upper arm, lower leg (peroneal muscles), and hip girdle [Tawil et al 1998]. Asymmetry of limb and/or shoulder weakness is common [Kilmer et al 1995]. Typically, individuals with FSHD become symptomatic in their teens, but age of onset is variable. More than 90% of affected individuals demonstrate findings by age 20 years. Individuals with severe infantile FSHD have muscle weakness at birth. In contrast, some individuals remain asymptomatic throughout their lives. Progression is usually slow and continuous; however, many affected individuals describe a stuttering course with periods of disease inactivity followed by periods of rapid deterioration. Eventually 20% of affected individuals require a wheelchair.Scapular winging is the most common initial finding; preferential weakness of the lower trapezius muscle results in characteristic upward movement of the scapula when attempting to flex or abduct the arms. The shoulders tend to slope forward with straight clavicles and pectoral muscle atrophy.Affected individuals show facial weakness, with symptoms more pronounced in the lower facial muscles than the upper. Some affected individuals recall having facial weakness before the onset of shoulder weakness. Earliest signs are often difficulty whistling or sleeping with eyes partially open in childhood. Individuals with FSHD are unable to purse their lips, turn up the corners of their mouth when smiling, or bury their eyelashes when attempting to close their eyelids tightly. Extraocular, eyelid, and bulbar muscles are spared.The deltoids remain minimally affected until late in the disease; however, the biceps and triceps are selectively involved, resulting in atrophy of the upper arm and sparing of the forearm muscles. The latter results in the appearance of ‘Popeye arms.’ Abdominal muscle weakness results in protuberance of the abdomen and exaggerated lumbar lordosis. The lower abdominal muscles are selectively involved, resulting in Beevor's sign (upward displacement of the umbilicus upon flexion of the neck in a supine position). The legs are variably involved, with peroneal muscle weakness with or without weakness of the hip girdle muscles, resulting in foot drop. Sensation is preserved; reflexes are often diminished.Respiratory function is usually normal [Tawil & Griggs 1997] but occasionally compromised [Kilmer et al 1995].Other manifestations. Retinal vasculopathy characterized by failure of vascularization of the peripheral retina, telangiectatic blood vessels, and microaneurysms can be demonstrated by fluorescein angiography in 40%-60% of affected individuals [Padberg et al 1995]. Vision is usually unaffected by this particular vascular malformation, but an exudative retinopathy clinically indistinguishable from Coats disease that can result in retinal detachment and vision loss has also been described. Bindoff et al [2006] reported two sisters with infantile onset FSHD who had tortuous retinal vessels, small aneurysms, and yellow exudates.Approximately 60% of individuals with FSHD have an abnormal audiogram with high-tone sensorineural hearing loss [Brouwer et al 1991, Padberg et al 1995]. Subclinical sensorinerural hearing loss occurs in up to 75% of affected individuals. Both the exudative retinopathy and the sensorineural hearing loss are seen more commonly in people with small (1-2 repeat) arrays or in individuals with early onset disease [Trevisan et al 2008]. A predilection for atrial tachyarrhythmias has been reported in about 5% of cases, but symptoms are rarely experienced [Laforet et al 1998, Galetta et al 2005, Trevisan et al 2006].Chronic pain is a frequent and likely under-recognized complaint in affected individuals, with a prevalence as high as 77% [van der Kooi et al 2007]. Atypical presentations. Clinical variants of typical FSHD in individuals with a contraction mutation of the D4Z4 locus in the subtelomeric region of chromosome 4q35 include the following: Scapulohumeral dystrophy with facial sparingSlowly progressive FSHD with progressive external ophthalmoplegia [Krasnianski et al 2003]. This kindred presents a departure from previously described atypical FSHD kindreds. Given the complexity of interpreting FSHD molecular genetic test results, more comprehensive molecular testing of this kindred is necessary before progressive external ophthalmoplegia can be included with certainty in the clinical spectrum of FSHD. Infantile onset with severe rapidly progressive disease and a large contraction mutation of D4Z4 (D4Z4 fragments in the 9-21 kb range) was observed in 4% of individuals studied [Klinge et al 2006]. Felice et al [2005] and Bindoff et al [2006] have also reported cases with infantile onset. Mild to moderate cognitive deficiency and possible epilepsy have been reported in early-onset cases often with associated deafness and retinopathy [Bindoff et al 2006, Hobson-Webb & Caress 2006, Quarantelli et al 2006].The affected parent frequently had mild disease and was mosaic for a contraction mutation of the D4Z4 locus.
A correlation has been reported between the degree of the contraction mutation of the D4Z4 locus and the age at onset of symptoms [Zatz et al 1995], age at loss of ambulation [Lunt et al 1995], and muscle strength as measured by quantitative isometric myometry [Tawil et al 1996], particularly in affected females [Tonini et al 2004a]. Individuals with a large contraction of the D4Z4 locus tend to have earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus [Bindoff et al 2006, Hobson-Webb & Caress 2006, Klinge et al 2006]. However, others have not been able to confirm a correlation between disease severity and degree of D4Z4 contraction mutations [Butz et al 2003]....
Genotype-Phenotype CorrelationsA correlation has been reported between the degree of the contraction mutation of the D4Z4 locus and the age at onset of symptoms [Zatz et al 1995], age at loss of ambulation [Lunt et al 1995], and muscle strength as measured by quantitative isometric myometry [Tawil et al 1996], particularly in affected females [Tonini et al 2004a]. Individuals with a large contraction of the D4Z4 locus tend to have earlier-onset disease and more rapid progression than those with smaller contractions of the D4Z4 locus [Bindoff et al 2006, Hobson-Webb & Caress 2006, Klinge et al 2006]. However, others have not been able to confirm a correlation between disease severity and degree of D4Z4 contraction mutations [Butz et al 2003].De novo mutations are associated with larger contractions of D4Z4 (on average) compared to the degree of D4Z4 contraction mutations observed segregating in families; hence, individuals with de novo mutations tend to have findings at the more severe end of the phenotypic spectrum. Caution must be noted as this correlation may represent an ascertainment bias where more mild forms of FSHD are detected when inheritance of a known mutation in a family is suspected. Zatz et al [1998] have reported reduced penetrance in females with large contraction mutations of D4Z4, compared to the penetrance in males with similar-sized contraction mutations; these results support their previous findings (see Penetrance).Mosaicism. The phenotypic severity of individuals with mosaic distributions of one or more array sizes, which is typically less than that of individuals without mosaicism, may reflect the proportion of cells carrying the contracted mutated D4Z4 locus in addition to the degree of the contraction of the D4Z4 locus in those cells. Compound heterozygosity. Two unrelated affected individuals homozygous for a D4Z4 contraction mutation were reported by Wohlgemuth et al [2003], suggesting that the presence of two FSHD-associated alleles can be compatible with life. However, both families demonstrated reduced penetrance for FSHD, leaving open the possibility that in other genetic/environmental settings, compound heterozygosity could be a lethal condition. In support of this possibility, the authors report a phenotypic dosage effect in both of the compound heterozygotes in comparison to other family members. Homozygosity. Tonini et al [2004b] reported an individual homozygous for the contraction on two 4qA alleles whose clinical phenotype is not more severe than those of some of his heterozygous relatives. Within the same family, the authors also observed a large number of asymptomatic or minimally affected heterozygotes, reflecting the wide range of clinical variability that can occur in a given kindred.
Disorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) but easily differentiated by their distinct muscle histopathology include the following:...
Differential DiagnosisDisorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) but easily differentiated by their distinct muscle histopathology include the following:Myofibrillar myopathy (previously called desmin-storage myopathy) Inclusion body myositis including inclusion body myopathy 2 (IBM2) Mitochondrial myopathies Congenital myopathies (see Congenital Muscular Dystrophy Overview) Polymyositis More troublesome are the following disorders in which the distribution of weakness and pathologic findings can be difficult to distinguish easily from FSHD:The limb-girdle muscular dystrophiesScapuloperoneal muscular dystrophy syndromes, including myotonic dystrophy type 1 and myotonic dystrophy type 2 (also known as PROMM), which have mild facial weakness and nonspecific histopathologic changes that cannot be differentiated from FSHD. Molecular genetic testing allows definitive diagnosis of these two conditions.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with facioscapulohumeral muscular dystrophy (FSHD), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with facioscapulohumeral muscular dystrophy (FSHD), the following evaluations are recommended:Physical examination to assess strength and functional limitations Evaluation for physical therapy and need for assistive devices Assessment of hearing if the individual has symptomatic hearing loss Ophthalmologic evaluation for the presence of retinal telangiectasias Genetics consultationTreatment of ManifestationsStandards of care and management of facioscapulohumeral muscular dystrophy were agreed upon at the 171st ENMC International Workshop. A consensus on the following topics and the recommendations from that conference [Tawil et al 2010] are outlined below: Physical therapy and rehabilitationConsultation with a physical therapist is indicated.Establishment of follow-up frequency is important at the time of diagnosis. Individuals with FSHD should be seen at a frequency based on their disease severity, which for some will be frequent initially, and may include occupational and speech therapy in infantile onset forms of FSHD. For others with mild involvement, annual visits would be appropriate. Physical therapy and rehabilitation consultations can help establish appropriate exercise regimens and assistive devices that may enhance mobility and reduce the risk of falls in home environments. Exercise in FSHD Exercise with moderate weights is not detrimental to individuals with FSHD [Milner-Brown & Miller 1988, van der Kooi et al 2004]. Aerobic training (when possible) has been beneficial to affected individuals [Olsen et al 2005]. Any type of exercise regimen should be instituted under the guidance of a physical therapist and personalized according to the individual’s disease symptoms, age, and cardiovascular status. PainChronic pain should be managed by physical therapy and medication as necessary.Respiratory dysfunctionVentilatory support such as BiPAP should be considered as necessary for those with hypoventilation.Hearing lossStandard therapies for hearing loss, including amplification if necessary, are appropriate.Ophthalmologic disease Exposure keratitis may occur in individuals who sleep with their eyes partially open. Use of lubricants to prevent drying of the sclera or in more severe cases taping the eyes shut during sleep may be required. Orthopedic interventionAnkle/foot orthoses can improve mobility and prevent falls in individuals with foot drop. Surgical fixation of the scapula to the chest wall often improves range of motion of the arms, although this gain can be short-lived in individuals with rapidly progressive disease [Diab et al 2005, Krishnan et al 2005, Giannini et al 2006]. Evaluation of such individuals prior to surgery is warranted to assure a functional and sustained benefit.Surveillance For those with a confirmed diagnosis of FSHD, the following surveillance applies:PainPain should be assessed at regular visits to primary care physicians and physical therapists.Respiratory dysfunctionAffected individuals with moderate to severe FSHD, defined as those with proximal lower extremity weakness, should be routinely screened for hypoventilation. Yearly forced vital capacity (FVC) measurements should be monitored for all affected individuals who are wheelchair bound, have pelvic girdle weakness and superimposed pulmonary disease, and/or have moderate to severe kyphoscoliosis, lumbar hyperlordosis, or chest wall deformities. Hearing lossAs in children who are at risk for hearing loss for other reasons, hearing can be followed routinely by periodic assessment as part of school-based testing.Hearing screens are particularly important in severe infantile onset forms of FSHD, as hearing loss can result in delayed language acquisition. Adults should have a formal hearing evaluation based purely on symptoms. No additional audiometry screening of asymptomatic individuals is necessary.Ophthalmologic diseaseAnnual dilated ophthalmoscopy in childhood is indicated. In adults, a dilated retinal exam should be performed at the time of diagnosis; if vascular disease is absent, follow-up exams are only necessary if visual symptoms develop. In children at risk for FSHD due to known inheritance within a family, but for whom the diagnosis has not yet been confirmed, annual dilated ophthalmoscopy is indicated.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementOutcome of 105 pregnancies in 38 women with FSHD was generally favorable [Ciafaloni et al 2006]. However, rates for low birth-weight infants, augmented extraction procedures such as forceps and vacuum assisted deliveries, delivery by Cesarean section, and anesthetic complications were higher than for the general population. Worsening of weakness occurred in 24% of the pregnancies, beginning during the pregnancy and generally not resolving after delivery.Therapies Under InvestigationMYO-029, an antibody designed to inhibit the activity of myostatin and enhance the growth and strength of muscles, has been developed. Because results in animal models of muscular dystrophy indicated that this could result in increased strength, a clinical trial was initiated in 2005 and completed in 2007. The study was designed primarily as a safety study for antibody injection into humans and identification of side effects. The study had four treatment groups on increasing doses of MYO-029 and a group that received a placebo for comparison. Side effects from the highest dose of MYO-029 caused that group to be discontinued from the study. The injections were fairly well tolerated; hypersensitivity reactions (rashes, itching, and occasionally more systemic reactions) limiting the dose that could be injected were the most common reactions. Such reactions are generally expected for the injection of biologically active proteins into the blood stream. With respect to FSHD, 22 people who received MYO-29 injections of various doses finished the study. A total of five withdrew voluntarily and four were in the high-dose cohort and were discontinued from the study. People who received the MYO-029 injections and placebo injections were evaluated for muscle strength (6 months of dosing and 3 months of follow-up for a total of 9 months). Using a number of both quantitative and subjective parameters, no difference in strength was measured or perceived by subjects in the study regardless of dose. The study authors [Wagner et al 2008] did state that many more subjects would have been necessary (160 with FSHD) to demonstrate a significant difference in strength, thus it cannot be concluded that the treatment was completely unsuccessful; further, the primary goal of the study was determination of safety rather than demonstration of increase in strength. Muscle biopsies from subjects who received MYO-029 showed no significant adverse effect by several measures. A dose-dependent increase in fiber size diameter (essentially an increase in muscle size) was observed (low dose: 2% increase; medium dose: 2.2% increase; high dose: 5.3% increase in size). Thus, the MYO-029 appeared to have an effect on muscle.The study also indicated that more potent inhibitors of myostatin are being developed [Wagner et al 2008]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherA 24-week trial of dilitazem did not improve findings in individuals with FSHD [Elsheikh et al 2007].Steroids, albuterol, and creatine have not proven effective [Tawil & van der Maarel 2006].Two controlled studies of oral albuterol in FSHD [Kissel et al 2001, van der Kooi et al 2004] did not show significant global improvement in strength despite a modest increase in muscle mass. A Cochrane review concluded that further study of albuterol in FSHD is needed [Rose & Tawil 2004]. Corticosteroids have been used in individuals who have evidence of inflammation on muscle biopsy. Although transient improvement in strength has been reported, a natural history-controlled study in eight individuals with FSHD revealed no improvement after 12 weeks of treatment with prednisone [Tawil et al 1997].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Facioscapulohumeral Muscular Dystrophy: Genes and DatabasesView in own windowCritical RegionGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDD4Z4Unknown4q35Unknown DUX44q35.2Double homeobox protein 4DUX4 homepage - Leiden Muscular Dystrophy pagesDUX4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Facioscapulohumeral Muscular Dystrophy (View All in OMIM) View in own window 158900FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1; FSHD1 158901FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2; FSHD2 601278FSHD REGION GENE 1; FRG1 606009DOUBLE HOMEOBOX PROTEIN 4; DUX4Molecular Genetic PathogenesisSee Molecular Genetic Testing.Alternative diagnostic methods. Because the current Southern blot based molecular diagnosis for FSHD is expensive and labor intensive, and requires large amounts of high molecular-weight DNA, some alternative molecular diagnostic methods are being investigated. For example, D4Z4 sizing can be performed by long-range polymerase chain reaction (LR-PCR), which is faster and requires less DNA than the Southern blot-based method [Goto et al 2006]. However, the method does not allow the identification of repeat arrays of more than six repeat units, making the LR-PCR method unsuitable for the identification of FSHD in a large proportion of European families with FSHD. False negative results are a significant concern, as a negative result could occur when the DNA available was unsuitable for PCR amplification due to protein and salt impurities or due to low DNA quality.Recently, molecular combing (MC) was developed for FSHD; MC is based on fluorescence in situ hybridization (FISH) of stretched DNA molecules [Nguyen et al 2011]. By this method D4Z4 fragments are visualized and sized with different fluorescence-labeled probes which enable discrimination between arrays on chromosomes 4 and 10 and the 4A and 4B haplotypes. Detection of the different chromosomes by MC is currently time consuming and the technology needs further automation to warrant replacing the Southern blot-based method. However, if D4Z4 repeat array sizing by MC proves to be accurate and if the microscopic analysis is further automated MC may become a useful diagnostic method for FSHD.