Jean K. Mah, Yi-Wen Chen.
A Pediatric Review of Facioscapulohumeral Muscular Dystrophy. J Pediatr Neurol 2018; 16(04): 222-231.
Abstract
Facioscapulohumeral dystrophy is one of the most common
forms of muscular dystrophies worldwide. It is a complex and heterogeneous
disease secondary to insufficient epigenetic repression of D4Z4 repeats and
aberrant expression of DUX4 in skeletal muscles. Type 1 facioscapulohumeral
muscular dystrophy (FSHD) is caused by contraction of D4Z4 repeats on 4q35,
whereas type 2 FSHD is associated with mutations of the SMCHD1 or DNMT3B gene
in the presence of a disease-permissive 4qA haplotype. Classical FSHD is a
slowly progressive disorder with gradual-onset of muscle atrophy and a
descending pattern of muscle weakness. In contrast, early-onset FSHD is
associated with a large deletion of D4Z4 repeats and a more severe disease
phenotype, including early loss of independent ambulation as well as
extramuscular manifestations, such as retinal vasculopathy, hearing loss, and
central nervous system (CNS) involvement. However, the correlation between D4Z4
repeats and disease severity remains imprecise. The current standard of care
guidelines offers comprehensive assessment and symptomatic management of
secondary complications. Several clinical trials are currently underway for
FSHD. New and emerging treatments focus on correcting the transcriptional
misregulation of D4Z4 and reversing the cytotoxic effects of DUX4. Other
potential therapeutic targets include reduction of inflammation, improving
muscle mass, and activating compensatory molecular pathways. The utility of
disease-modifying treatments will depend on selection of sensitive clinical
endpoints as well as validation of muscle magnetic resonance imaging (MRI) and
other biomarkers to detect meaningful changes in disease progression.
Correction of the epigenetic defects using new gene editing as well as other
DUX4 silencing technologies offers potential treatment options for many
individuals with FSHD.
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