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354
Abstracts
phin pre-mRNA splicing. In myotube cultures from a DMD
patient carrying an exon 20 deletion, the induced skipping of
exon 19 in mRNA led to the production of in-frame dystrophin
mRNA and internally deleted dystrophin in myotubes.
Our results provide evidence of restoration of dystrophin
expression from the endogenous gene in DMD patientderived
muscle cells. In addition, current proposals of other
molecular therapies for DMD are discussed.
SY-03-4
Signal transduction defects: an emerging family of
genetic encephalopathies
J. Jaeken a , K. Freson b , N. Goemans a , P. De Cock a , C. Van
Geet a,b
a Department of Pediatrics and b Center for Molecular and
Vascular Biology, University Hospital Gasthuisberg,
University of Leuven, Leuven, Belgium
Mutations in the alpha subunit of the Gs proteins
(encoded by GNAS1 located in an imprinted region on
chromosome 20q13.12–13) cause rare endocrine disorders.
The GNAS1 gene also encodes XL-GNAS1, which is
paternally expressed and maternally methylated. Using a
modified platelet aggregation test (Freson et al., Thromb
Haemost 2001;86:733–738) to evaluate Gs function we
identified six patients (from four families) with an internal
repeat extension of the XL-GNAS1 exon 1 on the paternal
allele. These patients had mainly a neurological syndrome
(psychomotor retardation, hypotonia, behaviour disturbances,
movement disorders) as well as variable dysmorphy
(mainly of face and hands) and, in only one, a
clinically important bleeding tendency. This defect was
associated with over expression of GNAS1 and increased
cAMP levels in platelets and fibroblasts upon stimulation.
In four patients this defect was combined with a polymorphism
in G-b 3 . (Jaeken et al., J Inherit Metab Dis
2000;23(Suppl. 1):205). In two other patients (sisters)
with severe psychomotor retardation, axial hypotonia,
hyporeflexia, overgrowth, thrombocytosis and hypercholesterolemia
a maternally inherited G-b 3 null-allele associated
with the same G-b 3 polymorphism on the paternal allele,
was identified. One of them died at the age of 4 years.
Conclusion: G protein defects can be associated with
neurological syndromes. Platelet function analysis is a
valuable tool in the identification of these (and other)
signal transduction defects.
SY-03-5
Gene therapy/cell therapy for genetic neurological
disorders
Y. Eto, T. Ohashi
Department of Pediatrics/Department of Gene Therapy,
Institute of DNA Medicine, Tokyo Jikei University School
of Medicine, Tokyo, Japan
Among various genetic diseases, we focused to lysosomal
storage diseases (LSD) which are caused by a genetic
deficiency of lysosomal enzyme and accumulates various
compounds in lysosomes. Recently, LSD patients can be
treated by: (1) enzyme replacement therapy for Gaucher
disease, Fabry disease, Hunter syndrome, Pompe disease
and Hurler syndrome. The enzyme replacement therapy is
limited to treat in non-neurological form of LSD. (2) Bone
marrow transplantation (BMT) is also potentially important
therapy to treat LSD since BMT may treat neurological
involvement of LSD, if treated in early period. (3) Cell
therapy/gene therapy are most promising treatment in
future. We are trying to treat LSD using mucopolysaccharidoses
(MPS) VII model mice and twitcher mice (model
for human Krabbe disease). Using these model mice, we
tried to treat these mice with adenovirus vector by intravenous
administration or intraventricular administration.
Visceral involvement in MPS VII mice was successfully
treated by adenovirus administration at least for 1 month.
In twitcher mice, intraventricular administration of adenovirus
showed reduced number of globoid cells in CNS,
which indicated that the CNS involvement could be treated
with gene therapy. Many LSD patients show neurological
disorders, since these cells can be converted into neuronal
cells in a certain condition. These results suggest that
mesenchymal cells can be used fro the treatment of CNS
involvement in LSD.
SY-4
Epilepsies and Related Disorders in Infancy, Childhood
and Adolescence
SY-04-1
Epileptogenic malformations of the cerebral cortex:
classification and genetic mechanisms
R. Guerinni
Department of Child Neuropsychiatry, University of Pisa,
Italy
Abstract not submitted
SY-04-2
Seizure induced brain injury in immature rat: short
term and long term
Y.-W. Jiang, G.-J. Zhang, H.-Y. Cao, X.-R. Wu
Department of Pediatrics, Peking University First Hospital,
Beijing, China
Objective: To study seizure induced brain injury and its
mechanism in immature rats. Method: We established two
seizure models: flurothyl inhalation induced seizure (Postnatal
day 15) (in vivo model) and magnesium-free culture
induced epileptiform discharge in cultured rats embryo
cortical neurons (in vitro model). The apoptosis and cellu-