Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[FSH Muscular Dystrophy]
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Authors:
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Denise A Figlewicz, PhD
Rabi Tawil, MD |
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Initial Posting:
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Last Update:
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Disease characteristics. Facioscapulohumeral muscular dystrophy (FSHD) typically presents before age 20 years with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. Severity is highly variable. Weakness is slowly progressive and about 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened.
Diagnosis/testing. FSHD is diagnosed by a molecular genetic test showing a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4. Molecular genetic testing detects about 95% of affected individuals and is clinically available.
Genetic counseling. FSHD is inherited in an autosomal dominant manner. Approximately 70-90% of individuals have inherited the disease-causing deletion from a parent, and approximately 10-30% of affected individuals have FSHD as the result of a de novo deletion. Offspring of an affected individual have a 50% chance of inheriting the deletion. Prenatal testing is available.
FSHD is suspected in individuals with muscle weakness that predominantly involves the facial, scapular stabilizer, and foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Most individuals with FSHD show signs by age 20 years; more mildly affected individuals show signs at a later age and some remain asymptomatic [Tawil et al 1994 , Tawil et al 1998].
Serum 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 [Padberg 1982]. Rarely, the inflammatory reaction is intense enough to suggest an inflammatory myopathy [Rothstein et al 1971]. Muscle biopsy is now performed only in those individuals in whom FSHD is suspectedf but not confirmed by molecular genetic testing.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Critical region. Ninety-five to one hundred percent of individuals affected with FSHD have a deletion within the D4Z4 repeat region (chromosome 4q35) [Wijmenga et al 1992]. However, studies have failed to identify a gene within the region of the D4Z4 repeats or distal to the D4Z4 repeat region.
Allele sizes. Each D4Z4 repeat is 3.3 kb. The chromosome 4-derived diagnostic EcoRI fragment contains approximately 5 kb of sequence centromeric to the D4Z4 repeats. Therefore, the number of D4Z4 repeats in a given EcoRI fragment = allele size kb - 5 kb / 3.3 kb.
Normal alleles: Fragments of 42 or more kb are considered normal.
Borderline alleles: Fragments of 38-41 kb (i.e., 10-11 D4Z4 repeats) require reconciliation with clinical findings. In a study of 39 unrelated individuals, Butz et al (2003) identified individuals representing the complete phenotypic spectrum, (typical and atypical FSHD, facial-sparing FSHD, non-FSHD myopathy, and healthy controls) having a chromosome 4q35 allele falling in this size range. To date, it has not been possible to establish a definitive diagnostic cut-off size for the D4Z4 repeats. Caution should be exercised in assigning the diagnosis of FSHD to persons whose clinical findings are atypical and whose molecular genetic test results fall within this borderline ("gray") zone.
Abnormal alleles: About 95% of abnormal alleles are 34 kb or smaller [Upadhyaya et al 1997]. In the study of Lemmers et al (2003), three of 100 families with FSHD did not exhibit a small EcoRI fragment. This resulted from chromosome 4q35 deletions that extended centromerically and included the region of p13E-11 probe binding. Use of additional restriction digests and the telomeric probe 4qA allow resolution of D4Z4 fragment size on an allele with this type of deletion.
Mosaicism: An individual may be mosaic as a result of a de novo mitotic mutation at the D4Z4 locus, believed to occur fairly early in embryogenesis. In such cases, some cells contain the original chromosome 4q35 allele, while other cells derived from the first mutation-containing embryonic cell have the deleted D4Z4 allele. Approximately half of de novo FSHD cases result from such a mitotic event [Lemmers, van der Wielen et al 2004].
Other loci. A small group of affected families do not map to the FSHD1A locus at 4q35 [Gilbert et al 1993]; the location of a second FSHD locus is as yet unknown.
Molecular genetic testing: Clinical uses
Molecular genetic testing: Clinical method
Targeted mutation analysis. Pulsed-field electrophoresis (PFGE) of restriction enzyme-digested DNA is used to detect changes in fragment size (measured in kilobases [kb]) that indicate the presence or absence of a D4Z4 deletion. The probe used in testing identifies DNA fragments from both chromosome 4 (4q35) and chromosome 10 (10q26). For this reason, it is necessary to perform a "double" restriction enzyme digest (including an enzyme that digests chromosome 10 material into small fragments undetectable by PFGE) in addition to a "single" restriction enzyme digest to differentiate between chromosome 4 and 10 fragments [Deidda et al 1996].
Laboratories vary in their designation of allele size; clinicians are advised to consult with the laboratory before ordering testing.
Table 1
summarizes molecular genetic testing for this disorder.
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Test Method
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Mutation Detected
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Mutation Detection Rate
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Test Availability
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95%
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Clinical
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Interpretation of test results
Molecular genetic test results should always be interpreted within the context of clinical findings.
Intermediate results. Dynamic, subtelomeric translocations between chromosomes 4q35 and 10q26 occur relatively frequently in the general population [Van Deutekom, Bakker et al 1996]. A D4Z4 deletion results in disease if the deletion occurs on chromosome 4. However, if the deletion occurs on chromosome 10, it is not pathogenic. Therefore, the finding of a deletion in an individual with a 4;10 translocation must be interpreted with caution and reconciled with clinical findings. Additional testing (e.g., a third restriction enzyme digest) may also be performed to determine if the deletion is located on chromosome 10 or chromosome 4 [van der Maarel et al 1999 , Lemmers et al 2001].
Normal results in symptomatic individuals. Approximately 5% of individuals with FSHD do not have identifiable D4Z4 deletions. The following are possible explanations:
Shortened fragment in individuals without FSHD. Lemmers et al (2002) observed two 4q subtelomere variants. These variants, named A and B, differ in their sequence in the subtelomeric region distal to the D4Z4 repeats. Deletion of a critical number of repeats on 4qA but not 4qB results in FSHD. Routine molecular diagnostic testing does not distinguish between deletions on the A variant or the B variant. Therefore a "positive" test result in an individual with symptoms that are not consistent with FSHD should be interpreted with caution.
No other phenotypes are associated with deletion of the D4Z4 motif.
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a pattern of 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 [Padberg 1982].
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, more 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. They 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, which is 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. Sensation is preserved; reflexes are often diminished.
Respiratory function is usually normal [Tawil & Griggs 1997], but occasionally compromised [Kilmer et al 1995].
The most common early sign of FSHD in a child is sleeping with the eyes open. Scapular winging, foot drop, and difficulty whistling are also frequent. Early onset may also be associated with sensorineural hearing loss [Korf et al 1985 , Brouwer et al 1994].
Atypical presentations. Clinical variants of typical FSHD in individuals with the FSHD-associated chromosome 4q35 deletion have been reported. In addition to scapulohumeral dystrophy with facial sparing, which has been previously observed by others, Krasnianski et al (2003) describe a family with slowly progressive FSHD accompanied by progressive external ophthalmoplegia. This latter kindred presents a clear 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.
Other manifestations [Small 1968 , Fitzsimons et al 1987 , Brouwer et al 1991]
A correlation has been reported between the size of the disease-associated 4q35-EcoRI fragment 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, Passos-Bueno et al 2004]. Individuals with small EcoRI fragments tend to have earlier-onset disease and more rapid progression. However, others have not been able to confirm a correlation between disease severity and small fragment size [Butz et al 2003].
De novo mutations are associated with smaller EcoRI fragments (on average) than those segregating in families; hence, individuals with de novo mutations tend to have findings at the more severe end of the phenotypic spectrum.
Zatz et al (1998) have reported reduced penetrance in females with the FSHD small fragment, compared to the penetrance in males with the FSHD small fragment; these results support their previous findings.
Mosaicism. The phenotypic severity of individuals with mosaicism, which is typically less than that of individuals without mosaicism, may reflect the proportion of mutation-containing cells in addition to the size of the deletion at D4Z4 in those cells.
Compound heterozygosity. Two unrelated affected individuals, each having two copies of chromosome 4 FSHD-associated deletions, were reported by Wohlgemuth et al (2003), confirming that the presence of two disease 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 might be a lethal condition. This is also a possibility in light of the fact that the authors report a phenotypic dosage effect in both of the compound heterozygotes in comparison to other family members.
Homozygosity. Tonini, Pavello et al (2004) report the existence of a true FSHD homozygote whose clinical phenotype is not more severe than some of his heterozygous relatives. Within the same family, Tonini, Pavanello et al (2004) also observed a large number of asymptomatic or minimally affected heterozygotes, reflecting the wide range of clinical variability that can occur among affected individuals in a given kindred.
In one study, penetrance of FSHD was found to vary by age and gender; it was 83% by age 30 years, but significantly greater for males (95%) than for females (69%) [Zatz et al 1998]. This finding was confirmed by Tonini, Passos-Bueno et al (2004). The sex difference in penetrance is unexplained [Zatz et al 1998].
Penetrance is less than 2% in individuals over 50 years of age who have an FSHD chromosome 4q35 deletion. Tonini, Passos-Bueno et al (2004) suggest that non-penetrance may cluster in families, with other genetic factors contributing to the severity of clinical presentation. Goto et al (2004) drew similar conclusions in an analysis of penetrance in 85 kindreds.
The existence and putative mechanism for anticipation in FSHD remains controversial. Anticipation in FSHD was originally suggested by Zatz et al (1995) based on the observation in multigenerational families that parents were frequently less affected than their offspring. Substantiation for this idea can be found in the reports of Lunt et al (1995) and Tawil et al (1996). More recently, data suggest that this apparent anticipation may be the result of the gender differences in penetrance described above [Zatz et al 1998]. Thus, affected male offspring of affected mothers are likely to be more severely affected as a function of gender difference rather than anticipation. It has also been suggested that late ascertainment bias among maternal relatives contributed to the apparent anticipation [Padberg et al 1995]. Absence of anticipation in large multigenerational families has also been reported [Flanigan et al 2001].
The estimated prevalence of FSHD is between four and ten per 100,000 population.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Disorders that are similar clinically to FSHD but easily differentiated by their distinct muscle histopathology [Hudgson et al 1972 , Bates et al 1973 , Askanas et al 1992 , McKee et al 1992] include:
More troublesome are the following disorders in which the distribution of weakness and pathologic findings can be difficult to distinguish easily from FSHD:
A physical evaluation to assess strength and limitations to functioning should be conducted at least annually.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
FSHD is inherited in an autosomal dominant manner.
Parents of a proband
Note: The family history may appear to be "negative" because of failure to recognize the disorder in family members, a parent who has a deletion within the D4Z4 subtelomeric DNA repeat region but is asymptomatic, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
Sibs of a proband
Offspring of a proband. Each offspring of an affected individual has a 50% chance of inheriting the deleted region within the D4Z4 repeat motif for FSHD.
Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected and/or has a deletion within the D4Z4 repeat motif, his or her family members are at risk.
Testing of at-risk individuals. Molecular genetic testing for asymptomatic at-risk adult family members is available. The testing of unaffected at-risk children under the age of 18 years is discouraged because no treatment is available. Testing of at-risk individuals who are under the age of 18 years is always appropriate when symptoms are present. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible nonmedical explanations including alternate paternity or undisclosed adoption could also be explored.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal testing is available for fetuses at 50% risk for FSHD [Bakker et al 1996] by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The size of the disease-causing allele of the affected parent must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal diagnosis of (typically) adult-onset diseases such as FSHD that do not usually affect intellect or life span are uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.
Critical Region | Chromosomal Locus | Protein Name |
D4Z4 | 4q35 | Unknown |
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Data are compiled from the following standard references: Gene symbol from HUGO;
chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
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Critical Region | Entrez Gene | HGMD | GeneCards | GDB |
D4Z4 |
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For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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Understanding of the molecular pathogenesis has been evolving as knowledge of affected individuals' genotype and phenotype and of the molecular architecture of the subtelomeric region of chromosome 4q35 emerges.
Each D4Z4 contains two regions of repeat sequences and a single open reading frame with two homeodomains. Although initially no D4Z4-related transcript was isolated from a number of cDNA libraries [Hewitt et al 1994 , Lyle et al 1995 , Van Deutekom et al 1995], more recent studies [Gabriels et al 1999 , Coppee et al 2002] suggest that the unconventional coding sequence in each repeat (named DUX4) may be expressed in FSHD, but not control, myoblasts.
The D4Z4 repeat region lies within a region of telomeric heterochromatin that is usually transcriptionally inactive [Fisher & Upadhyaya 1997]. No genes lie telomeric to the D4Z4 repeats [Dickson et al 1996]. However, recent studies demonstrated the presence of beta satellite repeats downstream of the D4Z4 repeats on the allele that is deleted in FSHD [Lemmers et al 2002 , Van Geel et al 2002]. This suggests that an additional parameter perhaps related to locus-specific chromatin folding or binding of factors plays a role in the connection between fewer than ten D4Z4 repeats and the disease phenotype.
The position effect hypothesis [Winokur et al 1994] proposes cis-interactions between the subtelomeric region of chromosome 4q35 and a gene (or genes) lying centromeric to the D4Z4 repeats. The phenomenon of position-effect variegation (PEV) refers to changes in the expression of a euchromatic gene when adjacent to a region of heterochromatin. In this model, a dominant-negative effect occurs as a result of the D4Z4 deletions in FSHD, possibly by de-repression of a silent gene(s) or maintenance of a gene(s) in a transcriptionally active state after expression should have been down-regulated.
Studies to quantify expression levels of 4q35 genes using RNA from normal control skeletal muscle samples and unrelated FSHD patient muscle samples [Figlewicz et al 2002 , Gabellini et al 2002] have confirmed a highly significant up-regulation of the expression of genes that lie immediately upstream of the D4Z4 repeats. However, another study using microarray analysis of muscle biopsy samples failed to show up-regulation of 4q35 genes in FSHD [Winokur et al 2003].
Recent reports describing somatic mosaicism in FSHD resulting from mitotic rearrangements of the 4q35 at a very early developmental stage may explain reduced penetrance, variable clinical phenotype, and frequent incidence of de novo mutations [Lemmers, van Overveld et al 2004].
In addition to the absolute number of the D4Z4 repeats, it is also likely that epigenetic phenomena such as the downstream (A vs. B) satellite sequence, binding of proteins that serve to act as transcriptional repressors [Tupler & Gabellini 2004], and methylation, which may affect heterochromatin packaging in the D4Z4 region, play a role in the the FSHD phenotype [van Overveld et al 2003]
Analysis of the equivalent FSHD region in other species such as pufferfish, rodents, and primates provide some insight into what may be a uniquely human disorder [Clapp et al 2003].
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