0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

TEL.13 – Clinical and laboratory criteria for FSHD diagnosis in view of a national registry…
smaller EcoRI/BlnI fragment should define the frequency of such deletions
in the FSHD population.
We expect the studies proposed in specific aim 1 to contribute to the definition
a general diagnostic protocol for FSHD.
FSHD molecular diagnosis and clinical phenotype
Facioscapulohumeral muscular dystrophy is a mendelian disorder with
a complex phenotype and unique molecular defects. It shows insidious
onset and unpredictable outcome. Clinical and molecular studies performed
in recent years have revealed that clinical ascertainment and molecular
diagnosis can encounter several difficulties. In view of these difficulties,
criteria established in 1991, before the advent of molecular diagnosis, and
in 1998, following the ENMC workshop on FSHD, need probably to be
revised.
First, FSHD patients carrying alleles of 38 kb and atypical FSHD phenotype
have been described [Vitelli et al. 1999; Felice et al. 2000; Felice, Moore
2001; Butz et al. 2003; Krasnianski et al. 2003] and D4Z4 repeat arrays of
38 kb were encountered in 3% of 200 control subjects in a Dutch study [van
Overveld et al. 2000]. This seems to indicate that penetrance may be close to
zero in a substantial proportion of 35 to 45 kb-sized repeat arrays, but in
some families 38-45 repeat arrays are associated with myopathy. Supplementary
larger studies will be needed to confirm this observation that further
complicates FSHD diagnosis.
Second, non-penetrance is estimated to be less than 2% after the age of 50
years and is more likely with fragment sizes larger than 30 kb [Tawil et al.
1996]. Notably, knowledge of value of non-penetrance at 20 years of age is
important in order to identify subjects who are at risk of transmitting a pathogenic
D4Z4 allele. Interestingly, asymptomatic gene carriers seem to be more
prominent in some families, and non-penetrance has even been found in carriers
of a 25 kb-EcoRI fragment in one of these families [Ricci et al. 1999]. In
his work, Ricci et al. described short fragments in several unaffected family
members (non-penetrant gene carriers) who are capable of transmitting the
disease to their offspring.
Third, reduced penetrance for FSHD-sized alleles was described in families
in which patients heterozygous for FSHD alleles on both 4q chromosomes
were present [Wohlgemuth et al. 2003; Tonini et al. 2004].
Collectively, all these observations indicate the necessity to establish
a standard clinical approach to examine a patient affected by FSHD and
to study his/her family. In addition, an inverse relationship has been
established between the D4Z4 repeat size and the severity and progression
of the disease [Lunt et al. 1995; Tawil et al. 1996; Zatz et al. 1998; Ricci et
al.1999] and great variability of clinical expression has been described
among FSHD patients even within the same family. At present, penetrance
of FSHD correlated with the length of the repeat array is unknown. Thus,
the risk of developing the disease in correlation with D4Z4 allele sizes cannot
be estimated.
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