0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

TEL.13 – Clinical and laboratory criteria for FSHD diagnosis in view of a national registry…
the clinical expression of the disease. In addition, genotype-phenotype correlation
studies can provide useful information to define FSHD factors that can
influence FSHD outcome. Collectively, the proposed studies will allow outlining
a complete diagnostic approach and provide prognostic tools that will
benefit myopathic patients, one of Telethon’s major goals.
Moreover, the validation of the FSHD clinical score will provide an essential
instrument to gauge the efficacy of therapeutic approaches.
THERAPEUTIC POTENTIAL
This study aims at validating a diagnostic protocol for FSHD through the
clinical evaluation and molecular analysis of more than 1000 FSHD families
and sporadic cases and the re-evaluation of FSHD-like subjects that do not
carry the molecular mutation associated with FSHD.
The use of the FSHD clinical score will allow the quantification of the
severity of the clinical expression of the disease in six different muscle groups.
Through genotype-phenotype correlation studies, factors that can influence
FSHD outcome can be identified. In addition, the validation of the FSHD clinical
score will provide an essential instrument to gauge the efficacy of therapeutic
approaches.
The results of this study will lay the basis for the constitution of the
National Registry of the disease. It will provide a large cohort of FSHD subjects
for a rational approach to FSHD clinical and therapeutic studies.
BACKGROUND
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal
dominant myopathy characterized by a progressive and variable atrophy
and weakness of the facial, shoulder, and upper-arm muscles [Padberg
1982]. There is a wide variability in clinical spectrum among patients with
the disease, ranging from subjects with slight muscle weakness to patients
who are wheelchair dependent [Lunt 1998; Tupler et al. 1998]. Before the
advent of molecular diagnosis, penetrance for FSHD was evaluated on clinical
examination of patients at risk and estimated between 83% and 95% by
age of 20 years [Padberg 1991]. Notably a significantly higher penetrance of
the disease has been observed in men than in women [Lunt et al. 1995; Zatz
et al. 1998; Ricci et al. 1999]. FSHD1, which defines the major form of
FSHD, genetically maps to chromosome 4q35 [Sarfarazi et al. 1992]. It has
been estimated that 5% of FSHD families are not linked to the genetic locus
on chromosome 4 suggesting that at least one additional genetic locus associated
with FSHD is present in the genome [Wijmenga et al. 1991; Iqbal et
al. 1992; Gilbert et al. 1993], although to date a second putative genetic
locus has not yet been defined for non-4q linked form(s) of FSHD [Bastress
et al. 2005; Deak et al. 2007].
FSHD1 has been associated with DNA rearrangements characterized by
an allele with a shorter EcoRI fragment as detected by Southern analysis
with the probe p13E-11 [Wijmenga et al. 1992]. The polymorphic genomic
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