Article

In recent years, the advances of knowledge in clinical, genetic and
epigenetic features of facioscapulohumeral muscular dystrophy (FSHD) allowed the
identification of two forms of FSHD, the classical autosomal dominant FSHD type
1, and FSHD type 2 characterized by an identical clinical phenotype but
associated with a different (epi)genetic defect. STATE OF THE ART: In the large
majority of FSHD1 patients, the identification of D4Z4 pathogenic contraction on
a permissive chromosome 4 is sufficient for diagnosis, while FSHD2 diagnosis is
complicated by the fact that the genetic defect associated with this disease is
not known yet and a complete D4Z4 genotype and a D4Z4 specific methylation test
are required. Indeed, FSHD2 patients display a non-contracted D4Z4 allele on
chromosomes 4, at least one permissive chromosome 4QA and a profound
hypomethylation of both chromosomes 4 and 10. A common pathophysiological pathway
has been hypothesized for FSHD1 and FSHD2 in order to explain the identical
clinical phenotype and the highly similar epigenetic changes found in patients
affected by these diseases. According to this hypothesis, chromatin relaxation -
due to pathogenic D4Z4 contraction in FSHD1 patients, and to important
hypomethylation of this locus in FSHD2 patients - would allow the last D4Z4 unit
to encode for a toxic DUX4 transcript. This transcript would be stable only when
encoded from a permissive chromosome 4 carrying a polyadenylation signal
immediately distal to the last D4Z4 unit on chromosome 4. PERSPECTIVES: Since, to
express clinical phenotype, FSHD2 patients have to carry both 4QA chromosome and
hypomethylated D4Z4 on chromosomes 4 and 10, digenic transmission has been
hypothesized for this disease. The identification of the gene(s) and the exact
epigenetic pathway underlining this disease will be mandatory to increase the
rate of diagnosis for FSHD2 patients and to confirm the hypothesis of a common
FSHD1 and FSHD2 pathophysiological pathway involving DUX4 gene. CONCLUSIONS: The
identification, among patients carrying a FSHD phenotype, of FSHD2, a new disease
with distinct (epi)genetic features but having a common pathophysiological
pathway with FSHD1, suggests the possibility of developping new therapeutic
strategies suitable for both diseases.
CI - Copyright (c) 2013 Elsevier Masson SAS. All rights reserved.

Langue : FRANCAIS