2008 Barcelona - European Society of Human Genetics

Clinical genetics
MD2I or MDC1C show a variable reduction of α-DG glycosylation. We
report a 70 year-old man he was referred for muscle weakness of the
lower limbs starting at age 20 and mild but progressive hypotrophy of
girdle . After informed consent, mutations screening was performed on
genomic DNA in regard to of CAV3 and CAPN3 genes . The patient
found negative screening of these genes, has been investigated for
mutations of FKRP gene . The mutation analysis showed a missense
change (Ser115Leu), in heterozygous state, never described . To confirm
that the alteration found was mutation and not polymorphism, a
screening was carried out with 100 control Caucasian chromosomes .
In conclusion this mutation of the FKRP gene could even be responsible
for mild phenotype of the patient .
P01.205
mutation analysis of the cAPN3 gene in italian patients with
suspected LGmD type 2
A. La Russa 1 , P. Valentino 2 , V. Andreoli 1 , F. Trecroci 1 , I. Manna 1 , M. Liguori 1 , P.
Spadafora 1 , R. Cittadella 1 ;
1 Institute of Neurological Science, National Research Council, Cosenza, Cosenza,
Italy, 2 Institute of Neurology, University “Magna Graecia, Catanzaro,
Italy.
Autosomal recessive limb girdle muscular dystrophies (LGMD type 2)
are a clinically and genetically heterogeneous group of disorders, characterized
by progressive involvement of proximal limb girdle muscles .
LGMD2A (MIM# 253600), whose locus has been mapped to chromosome
15q15 .1, is considered to be the most frequent form of recessive
LGMD . LGMD2A is caused by single or small nucleotide changes
widespread along a 40-kb gene, named CAPN3 (MIM# 114240), which
encodes for the calpain-3 protein . Aims of this study were to assess
the frequency of mutations in 30 Calabrian patients suspected diagnosis
LGMD and identify possible genotype-phenotype correlation as
prognostic factors . At the screening of gene CAPN3 have been identified
already described mutation (R748X) in exon 21 and a new polymorphism
( CTCT) in intron 14, while all other samples had already
described polymorphisms . The subject bearer of R748X mutation in
heterozygosity had a mild phenotype, in fact related onset of disease
at 48 years and the muscle biopsy showed a slight myopathy associated
with a pain and weakness in the lower limbs . In particular, this
mutation was associated with another exchange in exon 5 Ala236Thr
described in the literature as polymorphism . However, the combination
of a polymorphism in one copy of the CAPN3 gene with an LGMD2A
mutation in the other copy could even be responsible for very mild phenotyphe
with low penetrance . Patients with LGMD2 phenotype in the
absence of mutations in CAPN3 should be investigated for the genes
responsible for other forms of LGMD2 .
P01.206
Myopathy - an early finding in several rare genetic syndromes
M. Bembea, C. Jurca, C. Skrypnyk, D. Bembea, C. Moldovan, C. Cladovan, K.
Kozma;
Clinical Municipal Hospital “dr. G. Curteanu”, ORADEA, Romania.
Introduction . Myopathies are part of the larger group of neuromuscular
disorders . The main clinical manifestation is muscular weakness . Myopathy
is associated with over 150 hereditary entities and may be the
first clinical manifestation in several rare genetic syndromes. Objective
. To present a case series of rare monogenic syndromes that were
initially diagnosed based on the finding of myopathic features. Results.
We are presenting a case of Schwartz-Jumpel syndrome with familial
distribution (consanguineous parents with three affected daughters),
a case of Dubowitz syndrome with familial distribution (consanguineous
parents with two affected sons) and a case of Camurati-Engelmann
syndrome. In all cases, the first manifestations of disease that
prompted medical care were myopathic in nature . Conclusion . Muscle
weakness in children, if no clear cause is found, should prompt further
investigation to rule out rare genetic disorders .
P01.207
Prenatal diagnosis of Duchenne/Becker muscular dystrophy in
serbia-twelve years experience
T. Lalic, D. Radivojevic, M. Djurisic, M. Guc-Scekic, V. Ivanovski;
Mother and Child Health Institute of Serbia, Belgrade, Serbia.
In Serbia, prenatal testing for Duchenne/Becker muscular dystrophy
(D/BMD) is an option for women at risk of having an affected son,
since 1996 .
During period 1996-2007 in total 54 prenatal tests were performed in
43 families . From these, 34 pregnancies were male pregnancies at risk
of D/BMD and 8 of them (23 .5%) showed an increased risk .
DNA extraction was done from chorionic villuses samples in 41 (76%)
cases, amniotic fluid cells in 11 (20.3%) cases and in 2 cases (3.7%)
from fetal blood samples . Prenatal diagnosis was based on direct detection
of the mutation in 51 cases . In 49 of them, we used standard
multiplex PCR for simultaneous amplification of 18 DMD exons. In two
cases MLPA was applied for determining carrier status of mothers and
the detection of the duplications in DMD gene of fetuses . In 3 cases
(5 .55%), with unknown mutation in proband, prenatal diagnosis was
done by indirect DNA analysis . Maternal contamination has been excluded
in all cases using polymorphic CA markers .
Since no clinically applicable and effective therapy for DMD patients
has yet been developed, a molecular diagnosis should be proposed
to the families in order to detect the carrier women and to suggest an
antenatal diagnosis .
P01.208
Genetic testing, carrier detection and prenatal diagnosis of 300
Egyptian families with Duchenne muscular dystrophy: a 10
years experience
K. S. Amr, A. Elharouni, L. K. Effat;
National Research Centre, Cairo, Egypt.
Duchenne Muscular Dystrophy (DMD) is the most common lethal Xlinked
recessive muscle disorder that is caused by mutations in the
dystrophin gene. Due to lack of efficient rehabilitation and treatment,
prenatal diagnosis and counseling of families with DMD are of great
importance . Here we report a 10 years Egyptian experience on the
molecular diagnosis and genetic counseling of 300 families with DMD
at the National Research Centre, Cairo .
300 probands with DMD were screened for dystrophin gene deletion
mutations by multiplex PCR . Four CA dinucleotide repeats and three
restriction fragment length polymorphisms (RFLPs) were used to detect
the carrier status in 35 families . Prenatal molecular diagnosis was
pursued for 32 pregnant mothers at risk of having a child with DMD by
multiplex PCR when there is a deletion mutation in the affected sib or
by intragenic markers in families with no deletion mutations .
55% of probands had deletion mutations . 60% of detected deletions involved
multiple exons spanning the major and/or minor hotspots of the
gene while 40% involved single exon deletions . The combined use of
CA repeats and RFLPs detected the carrier status in all families identifying
20 female carriers . Molecular diagnosis of the fetal DNA showed
that 15 fetuses inherited the same deletion mutations present in the
index cases . A high acceptability of seeking prenatal diagnosis and a
change in attitude towards the decision of abortion was noticed .
Molecular diagnosis, carrier detection and prenatal diagnosis are effective
tools for definitive diagnosis and genetic counseling in families
affected with DMD .
P01.209
Prenatal diagnosis in a DmD family at risk
D. F. Albu, C. Albu, E. Severin;
“Carol Davila” Univ Med Pharm, Bucharest, Romania.
A 23-year-old pregnant woman is the sister of a patient who is affected
by Duchenne muscular dystrophy (DMD) . Her brother, an 18-year-old
male, was detected to have a novel mutation in exon 6 of the DMD
gene (c .587delAT) . She asked for prenatal diagnosis to detect whether
her unborn child has DMD or not . A prenatal diagnosis by chorionic villi
sampling (CVS) was performed at 10 weeks of pregnancy . Analysis
consisted of PCR amplification followed by direct sequencing of the
entire coding region of the DMD gene . The fetus showed a normal
male karyotype (46,XY) and no abnormality of the dystrophin gene . In
this case, prenatal diagnosis by CVS was able to exclude DMD in the
unborn child .