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Review
. 2016 Dec;22(6, Muscle and Neuromuscular Junction Disorders):1916-1931.
doi: 10.1212/CON.0000000000000399.

Facioscapulohumeral Muscular Dystrophy

Review

Facioscapulohumeral Muscular Dystrophy

Jeffrey M Statland et al. Continuum (Minneap Minn). 2016 Dec.

Abstract

Purpose of review: This article describes the clinical characteristics, diagnosis, molecular pathogenesis, and treatment of facioscapulohumeral muscular dystrophy (FSHD).

Recent findings: FSHD comprises two genetically distinct types that converge on a common downstream pathway of the expression of the toxic protein DUX4. Approximately 95% of patients have FSHD type 1 (FSHD1), in which loss of DNA repetitive elements (D4Z4 repeats) in the subtelomeric region of chromosome 4q causes decreased methylation and epigenetic derepression of DUX4, a gene contained within each D4Z4 repeat. FSHD type 2 (FSHD2) occurs through a deletion-independent mechanism but, similar to FSHD1, leads to decreased methylation and epigenetic derepression in the same region of chromosome 4q. Whereas FSHD1 is dominantly inherited, FSHD2 shows digenic inheritance, and about 80% of patients will have a mutation in the SMCHD1 gene. DUX4 lacks a polyadenylation signal, so both FSHD1 and FSHD2 only occur in the presence of permissive 4q polymorphisms, which provide a stabilizing polyadenylation sequence. FSHD is an epigenetic disease, and penetrance and severity are related to both the number of residual D4Z4 units and D4Z4 methylation.

Summary: Recent consensus guidelines outline standards for care for FSHD, and identification of potential therapeutic targets have shifted emphasis in the research community toward drug development and clinical trial planning.

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Figures

FIGURE 8-1
FIGURE 8-1
Pedigree of the patient in Case 8-1. The top line indicates the number of D4Z4 repeats on both copies of 4q and whether each has a permissive A or nonpermissive B polymorphism. The bottom line indicates the presence of an SMCHD1 mutation (SMD-) and percent of methylation (normal being greater than 20%) at the D4Z4 repeats. Note that the affected individual (arrow) has an SMCHD1 mutation and a permissive A allele while his father (asterisk) carries the same SMCHD1 mutation and is hypomethylated but is unaffected because he lacks a permissive A polymorphism.
FIGURE 8-2
FIGURE 8-2
Clinical features of facioscapulohumeral muscular dystrophy. A, Facial weakness with flattened pucker; B, chest wall showing asymmetric wasting of pectoral muscles with prominent axillary fold, upper arm wasting with sparing of forearms, and protruberant abdomen; C, Popeye arm appearance; D, both posterior and lateral winging of the scapula on shoulder forward flexion; E, Beevor sign demonstrating asymmetric abdominal weakness with intact upper abdominals pulling umbilicus upwards when the abdomen is tensed. Panel C reprinted with permission from Tawil R, Griggs RC, Butterworth-Heinemann. © 1997 R Tawil and RC Griggs. Panel E modified with permission from Griggs RC, et al, Muscle Nerve. © 1995 John Wiley & Sons, Inc. onlinelibrary.wiley.com/doi/10.1002/mus.880181311/full.
FIGURE 8-3
FIGURE 8-3
Muscle culture from a patient with facioscapulohumeral muscular dystrophy type 1 (FSHD1) showing a myotube (green) with a row of nuclei (blue) showing bursts of DUX4 expression (pink). Muscle tissue from patients with both FSHD1 and FSHD2 will show bursts of DUX4 expression. Reprinted with permission from Cell. Photograph by Linda Geng. © 2012 Elsevier, Inc. www.cell.com/cell/fulltext/S0092-8674(12)00160-2.
FIGURE 8-4
FIGURE 8-4
Unified genetic model of facioscapulohumeral muscular dystrophy (FSHD). In FSHD, loss of methylation in the D4Z4 region on the long arm of chromosome 4q (due to loss of D4Z4 repeats in FSHD1 and due to mutations in other genes involved in methylation in FSHD2) causes epigenetic derepression, opening of the chromosome structure, and certain permissive polymorphisms that provide a polyadenylation sequence (poly A), resulting in the expression of DUX4.
FIGURE 8-5
FIGURE 8-5
DUX4 is a transcription factor that activates a number of genetic cascades not normally expressed in adult tissue. FSHD = facioscapulohumeral muscular dystrophy. Reprinted with permission from Geng LN, et al, Dev Cell. © 2012 Elsevier, Inc. www.cell.com/developmental-cell/fulltext/S1534-5807(11)00523-5.
FIGURE 8-6
FIGURE 8-6
The relationship of the number of residual D4Z4 units to age-adjusted clinical severity and methylation. The relationship of age-adjusted clinical severity to D4Z4 repeat size is not linear (left y axis, n = 74). While the relationship of severity to repeat size is linear from 1 to 6 repeats, some other factor aside from repeat size appears to determine severity for 7 to 10 repeats. The bottom of the graph shows box plots of the difference between observed methylation values and expected methylation values (right y axis) for 1 to 6 repeats (left) and 7 to 10 repeats (right). Note the negative difference in methylation values for 7 to 10 repeats, suggesting that some other factor, other than he number of D4Z4 units, is affecting disease severity for this group. Reprintedwith permission fromStatland JM, et al, Neurology. © 2015 American Academy of Neurology. www.neurology.org/content/85/24/2147.short.
FIGURE 8-7
FIGURE 8-7
Manual fixation of scapula in the clinic. A, In this patient with facioscapulohumeral muscular dystrophy, abduction of shoulder is only to approximately 90 degrees. B, The physician manually pulls the shoulder back while pushing against the scapula with the other hand, fixing the scapula to the chest wall, and abduction increases beyond 90 degrees. This would be a positive test and may support the notion that scapular fixation surgery could improve function for this patient. Reprinted with permission from Tawil R, Van DerMaarel SM, Muscle Nerve. © 2006 John Wiley & Sons, Inc. onlinelibrary.wiley.com/doi/10.1002/mus.20522/full.

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