0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

TEL.13 – Clinical and laboratory criteria for FSHD diagnosis in view of a national registry…
verify in how many the clinical phenotype matches with the criteria of FSHD
diagnosis.
In particular we will consider the following inclusion criteria:
– facial weakness with involvement of the orbicularis oculi and/or oris
muscle(s);
– weakness of the upper girdle with anterior rotation of the scapula;
– upward and forward riding with sloping of the shoulders.
Criteria of exclusion will be impairment of ocular movements, pharyngeal
and tongue muscles. Electrophysiological study, including electromyography,
repetitive nerve stimulation, and nerve conduction testing will be performed
to exclude non-myopathic conditions Muscle biopsies will be analyzed to
exclude alterations suggesting other muscle disorders (mitochondrial abnormalities,
lipid or glycogen storage, structural changes specific of other
pathologies). To exclude other muscular dystrophies, structural proteins (dystrophin,
sarcoglycans, caveolin, merosin, emerin, a-dystroglycan, calpain, dysferlin)
will be tested by immunohistochemistry or immunoblotting and
fukutin-related protein (FKRP) will be investigated by genetic analysis. Only
patients with a clinical picture compatible with FSHD and in whom electrophysiological
studies and muscle biopsy ruled out other neuromuscular diseases
will be included in the study as FSHD-like and further investigated. We
expect this analysis to provide molecular markers for the identification of
non-4q deleted FSHD patients.
In summary, this study will bring knowledge to the comprehension of the
complex pathophysiology of FSHD and improve the diagnostic approach to
myopathic patients.
The proposed study will lay the basis for the definition of the criteria for
the National Registry for Facioscapulohumeral Muscular Dystrophy.
RATIONALE
Facioscapulohumeral muscular dystrophy is a complex disorder both
clinically and genetically and its outcome is difficult to predict. At present,
molecular diagnosis of FSHD is based on the analysis of the D4Z4 polymorphic
alleles detected by PFGE and Southern analysis using the probe p13E-
11 [Wijmenga et al. 1992]. Normal subjects carry p13E-11EcoRI alleles
larger than 50 kb originating from chromosome 4, whereas alleles shorter
than 35 kb are present in the majority of either de novo or familial FSHD
patients [Lunt 1998]. Consistently, de novo deletions transmitted by an
affected parent to the offspring co-segregate with the disorder [Griggs et al.
1993]. New mutations account for a surprisingly high percentage of FSHD
patients (10%-33%) [Padberg et al. 1995; Zatz et al. 1995]. This high incidence
can be partly explained by the presence of parental mosaicism for 4q
short alleles that has been reported in 40% of de novo cases [Griggs et al.
1993; Weiffenbach et al. 1993; Upadhyaya et al. 1995; Bakker et al. 1996;
van der Maarel et al. 2000]. The presence of somatic mosaicism for a
rearrangement of D4Z4 was found in as much as 3% of the general popula-
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