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.
Address correspondence to Dr Rabi Tawil, University of Rochester Medical Center, Box 673, 601 Elmwood Ave, Rochester, NY 14642, firstname.lastname@example.org.
Relationship Disclosure: Dr Statland received personal compensation for serving on the advisory boards of Bristol-Myers Squibb and Sarepta Therapeutics and for serving as a consultant for Acceleron Pharma, Clinical Leader, and Novartis AG. Dr Statland has received research/grant support from the FSH Society and the National Center for Advancing Translational Sciences through the Clinical and Translational Science Award (KL2TR000119) and the Multi-institution Clinical and Translational Science Award. Dr Tawil has received personal compensation as a consultant for Acceleron Pharma; aTyr Pharma; Novartis AG; and Third Rock Ventures, LLC and has received research/grant support as co-investigator of studies for the National Institutes of Health (U01 NS061795-04, 1U54AR065139, 1P01 NS069539) and as investigator of studies for the FSH Society and Northwest Friends of FSH Research. Dr Tawil receives publishing royalties from Wiley-Blackwell.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Statland and Tawil report no disclosures.
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