0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
All these information will be used for genetic counseling, clinical prognosis
and to identify factors of risk and/or protection. Collected data will contribute
to the National Registry of FSHD and made available to design and
evaluate the efficacy of therapeutic interventions.
SPECIFIC AIMS
The incomplete knowledge of the pathogenesis of FSHD hampered the
possibility of designing therapeutic tools. At present there is no effective treatment
for FSHD. The major goal of this proposal is the acquisition of information
shedding light on the development of FSHD through an accurate genotype-phenotype
correlation. The development of a methodology to quantify
the clinical severity of the disease will gauge the efficacy of therapeutic interventions.
To achieve this goal we set up a multicenter study that will evaluate the
familial and sporadic cases collected by the partner neuromuscular centers or
referred to the diagnostic laboratories for molecular diagnosis of FSHD.
Our specific aims are:
1. To define the clinical and molecular features of a large Italian population
of subjects affected by FSHD and to investigate the genotype−phenotype
correlation in FSHD.
Since 1992, patients presenting FSHD clinical features have been
searched for deletion of D4Z4 repeat in the diagnostic laboratories directed
by Galluzzi and Tupler. Presently, a total of 1752 subjects carrying the D4Z4
deleted allele have been identified. Here we propose in−depth analysis of
such large population of FSHD patients to define their clinical features and
obtain useful information to dissect the pathogenic mechanism of this disease.
To perform the proposed genotype-phenotype correlation, patients and
their relatives will be evaluated through a specific clinical data questionnaire.
This questionnaire will investigate the clinical, familial and pharmacologic
history of each subject. In addition, all patients and their relatives
will be evaluated using a clinical evaluation protocol to obtain a functional
score (FSHD clinical score) to define the grade of severity of the disease at a
specific time. The evaluation score will be used to identify, if any, clinical
categories that can correlate with the detected genetic alterations. Moreover,
clinical and molecular investigation of FSHD families can provide
information about the disease penetrance and factors that can influence its
outcome. We expect the evaluation score to become a useful tool to monitor
the progression of the disease.
2. To examine and characterize FSHD-like myopathic patients not carrying
the D4Z4 pathognomonic mutation.
Previous studies suggested that FSHD is a genetically heterogeneous disorder.
Three-hundred-thirty-two myopathic patients analyzed by the diagnostic
laboratories did not show the pathogenic deletion of D4Z4 repeat. It is thus
possible that some of those myopathic patients carry a different molecular
defect leading to FSHD phenotype. Our aim is to re-evaluate those patients to
766 2009