Background
Facioscapulohumeral dystrophy (FSHD) is one of the most common types of muscular dystrophy. It has distinct regional involvement and progression. Landouzy and Dejerine first described FSHD in 1884. Tyler and Stephens described an extensive family from Utah in which 6 generations were affected. Walton and Nattrass established FSHD as a distinct muscular dystrophy with specific diagnostic criteria.
Pathophysiology
The facioscapulohumeral dystrophy (FSHD) phenotype encompasses two genetically distinct entities: FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2).
FSHD1, which accounts for 95% of all FSHD, is inherited as an autosomal dominant disease in 70–90% of patients, whereas in the remaining 10–30%, it is the result of a de novo defect. One of the FSHD genes has been localized to chromosome band 4q35, but the precise gene or genes that are affected in FSHD are still unknown. Patients with FSHD1 have a shorter Eco RI digestion fragment detected by the chromosome-4qter DNA marker p13E-11. [1]
The probe p13E-11 identifies 2 polymorphic loci at 4q35 and 10q26. The Eco R1 fragment of 4q is composed of repetitive DNA sequences that are 3.3-kilobase (kb) Kpn I tandem repeats identified as D4Z4. In control subjects, the D4Z4 repeat consists of 11–100 KpnI units, each 3.3 kb, whereas in FSHD this is shortened; the shortened Eco RI fragment in FSHD is 1–10 units. Diagnostic difficulties arise as these fragments also may come from chromosome 10, as already described. 4-type units are resistant to Bln I and 10-type units are resistant to Xap I. The combined use of EcoRI, BlnI, and XapI in pulsed-field gel electrophoresis–based DNA separation techniques allows detection of 4q fragments.
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FSHD1 is caused by a contraction mutation of D4Z4 macrosatellite repeats in the subtelomeric region of the 4qA161 haplotype of chromosome 4 in 95% of patients.
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Those without FSHD have approximately 11–100 D4Z4 units, whereas patients with FSHD have 1–10 D4Z4 units. [2]
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At least 1 copy of D4Z4 is required to develop FSHD.
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Mosaic males are mostly affected, where as mosaic females with an equal complement of affected cells are more often asymptomatic carriers.
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A bi-allelic variation of chromosome 4qter is known, designated as 4qA and 4qB. FSHD alleles are exclusively of the 4qter type (4qA161).
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Although the genetic lesion is well described in FSHD, the causal gene and the protein products are not known.
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Additional testing may be needed in patients without D4Z4 contraction for a deletion encompassing the region.
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The most extensively studied candidate genes for FSHD on 4q35 are ANT1, PDLIM3, FRG1, TUBB4q, FRG2, and DUX4
FSHD2, seen in 5% patients, has digenic inheritance and is chararterized by DNA hypomethylation in the presence of preserved D4Z4 macrosatellite repeat numbers. This may be seen as a likely result of mutation of SMCHD1 or DNMT3B genes.
Disease mechanisms
Possible disease mechanisms include the following:
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Both FSHD1 and FSHD2 have inappropriate (increased) expression of the double homeobox 4 (DUX4) gene.
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DUX4 is a retrogene contained within D4Z4 repeats and is normally epigenetically silenced in somatic cells. D4Z4 contraction leads to loss of DNA methylation and heterochromatin markers in the D4Z4 region, resulting in relaxation of chromatin structure and release of DUX4 repression. [4]
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Position variegation effect on a proximal candidate gene or genes
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Direct and indirect evidence points to epigenetic modifications in the DNA. A local deficit of a repressor complex due to the contraction of D4Z4 may cause inappropriate expression of genes. This may account for upregulation of FRG2, FRG1, and ANT1 in FSHD muscle.
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The most common modification of mammalian DNA is cytosine methylation that is necessary for many regulatory processes. D4Z4 is found to be hypomethylated in both forms of FSHD.
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Myoblasts from patients with FSHD also demonstrate increased susceptibility to oxidative stress.
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Misexpression of FRG1 (FSHD region gene 1) may lead to the development of FSHD. Knockdown of FRG1 in Xenopus led to the decreased angiogenesis and reduced expression of DAB2 (angiogenic regulator). Of patients with FSHD, 50-75% exhibit retinal vasculopathy and increased expression of vascular or endothelial-related FRG1 transcripts in the muscle. Thus FRG1 may be at least crucial for angiogenesis.
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Deletion of D4Z4 macrosatellites results in aberrant gene expression. DUX4 transcript from the last D4Z4 (most telomeric) unit generates small si/miRNA-sized fragments; uncapped, polyadenylated 3-prime fragments encoding C-terminal portion of DUX4; capped and polyadenylated mRNAs containing the double-homeobox domain of DUX4, but splice-out the C-terminal polypeptide. C-terminal polypeptide produced by transfection studies inhibits myogenesis. [3]
Epidemiology
Frequency
Facioscapulohumeral dystrophy (FSHD) is considered one of the more common hereditary muscular disorders, with it being recognized as the third most common muscular dystrophy. Estimated prevalence of FSHD in the United States is 1 case per 20,000 persons. [5] Estimated worldwide prevalence is between 4 and 10 cases per 100,000 people. [6, 7]
Mortality/morbidity
Most patients with FSHD have a normal life expectancy.
Gender differences
Frequency of FSHD is higher in males; however, asymptomatic cases are more common in females.
Age
The usual presentation is between the first and third decades of life. Ninety-five percent of patients show clinical features before age 20 years. As many as one third of patients are asymptomatic.
Infantile onset has been described, but is rare.
Prognosis
Size of deletion affects disease severity and thus prognosis. Ricci studied 122 Italian families affected by FSHD and 230 healthy control subjects. An Eco RI fragment shorter than 30 kb that was resistant to Bln I restriction was found in 114 of 122 families (93%) with FSHD. Fifteen percent of the control group showed Eco RI fragments smaller than 30 kb that were Bln I sensitive, suggesting that these were 10 qter alleles. Prognosis varied with the length of the fragment size and the remaining Kpn I units. [17] The probabilities of developing the severe form of the disease were as follows:
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100% with very short segment length of 10-13 kb (1-2 Knp I repeats left)
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54% in patients with fragment length of 16-20 kb (3-4 Knp I repeats left)
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19% in patients with fragment length greater than 21 kb (more than 4 Knp I repeats left)
Age of onset is variable. The disease tends to progress from the face downwards. Asymmetry and selective muscle group involvement distinguish FSHD from other muscular dystrophies. Many authors describe stepwise deterioration with prolonged periods of apparent arrest. Extraocular muscles, bulbar muscles, deltoids, and respiratory muscles usually are spared. Ventilatory impairment is seen in fewer than 10% of patients.
Approximately 20% of patients may require wheelchair assistance.
Life expectancy is normal in most patients.
