DISTROFIA FACIOESCAPULOUMERAL PDF

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder in which the muscles of the face, shoulder blades and upper arms are among the. Facioscapulohumeral muscular dystrophy (FSHD) is associated with the progressive weakening of the muscles starting in the face, shoulders, and upper arms. Facioscapulohumeral dystrophy (FSHD) is one of the most common types of muscular dystrophy. It has distinct regional involvement and.

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University of Washington, Seattle; March 8, ; Last Revision: 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. Life expectancy is not shortened. Although some controversy remains, FSHD is likely caused by inappropriate expression of the double homeobox-containing gene DUX4 in muscle cells.

DUX4 lies in the macrosatellite repeat D4Z4 on chromosome 4q35, which has a length between 11 and repeat units on normal alleles. Molecular genetic testing measures the length of the D4Z4 allele. Surgical fixation of the scapula to the chest wall may improve range of motion of the arms over the short term. Pain should be assessed at regular visits to the primary care physician or physical therapist; routine screening for hypoventilation and yearly forced vital capacity in those with moderate to severe disease; periodic hearing screening in affected children; annual dilated ophthalmoscopy in childhood.

FSHD1 is inherited in an autosomal dominant manner. Prenatal testing for pregnancies at increased risk is possible if the D4Z4 pathogenic contraction has been identified in the family. FSHD2 is inherited in a digenic manner. View in own window. For synonyms and outdated names see Nomenclature. 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.

Muscle biopsy most often shows nonspecific chronic myopathic changes. 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.

See Table A for chromosome locus and protein name for these genes. Evidence for locus heterogeneity. Organization and regulation of the D4Z4 locus is complex but critical to the understanding of genetic testing issues.

The DUX4 open reading frame is present in each 3. The pathologic contraction of the D4Z4 repeat array is associated with an opening of the chromatin structure at the D4Z4 locus. Genetic variation at D4Z4. Roughly, the present authors distinguish two different variants of D4Z4 on chromosome 4: This categorization is mainly based on sequence variations telomeric to D4Z4, which contribute to the pathogenicity of a contracted D4Z4 allele [ van Geel et alLemmers et al ].

Distal to the D4Z4 region on the 4A variant, the authors find an extra DUX4 exon that carries the polyadenylation signal of the gene required for stable expression of the gene from the most distal D4Z4 unit [ Dixit et alLemmers et al a ].

Chromosome variants 4A and 4B sometimes referred to as 4qA and 4qB are almost equally common in a control population see Molecular Genetics and can be further divided into at least nine distinct haplotypes i.

Number of D4Z4 repeat units in the subtelomeric region of chromosome 4q The D4Z4 array consists of single D4Z4 units of 3.

The normal D4Z4 allele has between 11 and units of the 3. Individuals with FSHD2 did not have a D4Z4 contraction but were shown to have an open chromatin structure at the D4Z4 locus that was marked by a loss of CpG methylation at all D4Z4 repeat arrays on chromosomes 4 and Individuals that carried both pathogenic variants were shown to be more affected than family members with either of the two pathogenic variants [ Sacconi et al ].

At the end of this meeting all participants came to a consensus regarding the molecular diagnosis of FSHD1; see Lemmers et al [a] full text and Figure 2. Best practice guidelines [Lemmers et al a] recommend standard analysis steps 1 and 2which can confirm or exclude a diagnosis for the majority of individuals tested.

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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.

Standard DNA diagnostic testing defined here as linear gel electrophoresis and Southern blot analysis uses the restriction enzyme EcoR I that recognizes the D4Z4 locus on chromosomes 4 and Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants. All individuals with FSHD carry a permissive haplotype.

Sequence analysis detects variants that are benign, likely benign, of uncertain significancelikely pathogenic, or pathogenic. For issues to consider in interpretation of sequence analysis results, click here.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family. Prenatal diagnosis and preimplantation genetic diagnosis PGD for at-risk pregnancies require prior identification of the pathogenic variant in the family. Facioscapulohumeral muscular dystrophy FSHD is characterized by progressive muscle weakness involving the face, scapular stabilizers, upper arm, lower leg peroneal musclesand hip girdle [ Tawil et al ].

Facioscapulohumeral muscular dystrophy: MedlinePlus Medical Encyclopedia

Typically, individuals with FSHD become symptomatic in their teens, but age of onset is variable. 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 facooescapuloumeral periods of rapid deterioration. 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 disgrofia 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.

Facioscapulohumeral Muscular Dystrophy (FSHD)

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. 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.

Facioescapulokmeral et al [] reported two sisters with infantile onset FSHD who had tortuous retinal vessels, small aneurysms, and yellow exudates. Both the exudative retinopathy and the sensorineural hearing loss are seen more commonly in people with small repeat arrays or in individuals with early onset disease [ Trevisan et al ]. Clinical variants of typical FSHD in individuals with a pathogenic contraction of the D4Z4 locus in the subtelomeric region of chromosome 4q35 include the following:.

A correlation has been reported between the degree of the pathogenic contraction of the D4Z4 locus and the age at onset of symptoms [ Zatz et al ], age at loss of ambulation [ Lunt et al ], faciiescapuloumeral muscle strength as measured by quantitative isometric myometry [ Tawil et al ], particularly in affected females [ Tonini et al facioesvapuloumeral ].

However, others have not been able to confirm a correlation between disease severity and degree of D4Z4 pathogenic contractions [ Butz et al ]. De novo pathogenic variants are associated with larger contractions of D4Z4 on average compared to the size of D4Z4 pathogenic contractions observed fackoescapuloumeral in families; hence, individuals with facioescapulooumeral novo pathogenic variants tend to have findings at the more severe end of the phenotypic spectrum.

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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 pathogenic variant in a family is suspected. Zatz et al [] have reported reduced penetrance in females with large pathogenic contractions of D4Z4, compared to the penetrance in facioescapuloumeraal with similar-sized pathogenic contractions; these results support their previous findings see Penetrance.

The phenotypic severity of individuals with mosaic distributions of one or more faciosecapuloumeral sizes, which is typically less than that of individuals without mosaicismmay reflect fcioescapuloumeral proportion of cells carrying the pathogenic contracted D4Z4 locus in addition to the degree of the contraction of the D4Z4 locus in those cells.

Two unrelated affected individuals homozygous for a D4Z4 pathogenic contraction were reported by Wohlgemuth et al []suggesting that the presence of two FSHD-associated alleles can be compatible with life. In support of this possibility, the authors report a phenotypic dosage effect in both of the compound heterozygotes in comparison to other family members.

Tonini et al [b] reported distrfoia individual homozygous for the contraction on two D4Z4 4qA alleles whose clinical phenotype is not more severe than those of some of his heterozygous relatives.

Within the same family, the authors also distrpfia a large number of asymptomatic or minimally affected heterozygotes, reflecting the wide range of clinical variability that can occur in a given racioescapuloumeral. This finding was confirmed by Tonini et al [a].

Facioescxpuloumeral sex difference in penetrance is unexplained [ Zatz et al ]. Tonini et al [a] suggest that non- penetrance may cluster in families, with other genetic factors contributing to the severity of clinical presentation. Goto et al [] drew similar conclusions in an analysis of penetrance in 85 kindreds. The existence and putative mechanism for anticipation in FSHD facioescwpuloumeral controversial.

Anticipation in FSHD was originally distrofiw by Zatz et al [] 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 [] and Tawil et al [].

However, further data suggest that this apparent anticipation may be the result of the gender differences in penetrance described above [ Zatz et al ]. Thus, affected male fafioescapuloumeral of affected mothers are likely to be more severely affected as a function of gender difference rather than ristrofia.

It has also been suggested that late ascertainment bias among maternal relatives contributed to the apparent anticipation. Absence of anticipation in large multigenerational families has also been reported [ Flanigan et al ]. The term Landouzy-Dejerine muscular dystrophy used in the past for a syndrome similar or identical to FSHD is no longer in use. Persons with FSHD are sometimes included under the descriptive terms of scapulo-humeral or scapulo-peroneal syndromes.

The estimated prevalence of FSHD is between four and ten perpopulation. Sposito et al [] found a prevalence in central Italy of 4. No phenotypes other than those discussed in this GeneReview are associated with mutation of SMCHD1 or with the pathogenic contraction of the D4Z4 locus in the subtelomeric region of chromosome 4q.

Disorders that are similar clinically to facioscapulohumeral muscular dystrophy FSHD but easily differentiated by their distinct muscle histopathology include the following:. More troublesome are the following disorders in which the distribution of weakness and pathologic findings can be difficult to distinguish easily from FSHD:.

To establish the extent of disease in an individual diagnosed with facioscapulohumeral muscular dystrophy FSHDthe following evaluations are recommended:. Standards of care and management of facioscapulohumeral muscular dystrophy were agreed upon at the st ENMC International Workshop. A consensus on the following topics and the recommendations from that conference [ Tawil et distofia ] are outlined below:.

Ventilatory support such as BiPAP should be considered as necessary for those with hypoventilation. Standard therapies for hearing loss, including amplification if necessary, are appropriate.