Geneeskundige Stichting Koningin Elisabeth verslag - GSKE - FMRE

152
Of a total of 2400 senile plaque cores studied from various brain regions from three patients,
68% enclosed a vessel, whereas the remainder were associated with vascular walls. These
observations were confirmed by electron microscopy coupled with examination of serial semithin
plastic sections, as well as three-dimensional observations by confocal microscopy. Diffuse
plaques did not associate with vessels, or with neuritic or inflammatory pathology. Together
with earlier in vitro data on APP692, our analyses suggest that the altered biological properties
of the Flemish APP and Abeta facilitate progressive Abeta deposition in vascular walls that in
addition to causing strokes, initiates formation of dense-core senile plaques in the Flemish
variant of AD.
PERIPHERAL NEUROPATHIES
We aim to identify novel loci and genes in which mutations result in known or currently
unknown forms of inherited peripheral neuropathies (IPN). Genetic linkage studies and
positional cloning efforts have mapped more than 30 loci and identified 18 genes for distinct
inherited peripheral neuropathies. Correlation between genotypes and phenotypes are made
using clinical, neurophysiological and neuropathological data. The timely publication of large
data sets from the Human Genome Project provides new opportunities for molecular genetic
laboratories. It is our priority to make optimal use of these opportunities and to force
breakthroughs in all our research topics by mapping and identifying the genes involved. The
identification of these genes is the first step towards a better understanding of fundamental
biological processes operating in myelination, axon-glia interaction, structure of the axonal
cytoskeleton and axonal transport. Here we provide the most relevant data on our mutation
screening in known and novel genes for IPN. These mutations are updated in our mutation
database (Inherited Peripheral Neuropathies Mutation Database at http://molgenwww.uia.ac.be/CMTMutations/).
In 2002, we wrote a review paper on clinical and genetic aspects of hereditary neuropathy with
liability to pressure palsies (HNPP) caused by a 1.4 Mb deletion on chromosome 17p11.2 (Pou-
Serradell et al., 2002). In addition we characterised a smaller HNPP deletion patient (van de
Wetering et al., 2002). We focussed our mutation analysis on the known genes causing recessive
Charcot-Marie-Tooth (CMT) neuropathy. Mutations in periaxin (PRX) on chromosome 19q13 were
recently reported in autosomal recessive DSS and CMT4F. PRX is a novel cytoskelet-associated
protein with two PDZ-domains, and two alternative splice-variants, L- and S-periaxin. The PDZ
domains are involved in membrane-protein interactions that stabilise the myelin sheaths in the
peripheral nerve. We have screened DSS and CMT patients with a severe phenotype and found
a nonsense (C715X) and frameshift (R82fsX96) mutation in a Turkish and Belgian family
(Takashima et al., 2002). This finding was possible thanks to a collaboration with our colleagues
in Houston, USA. For another recessive type of CMT, we screened the myotubularin related
protein 2 (MTMR2) gene in a consanguineous Turkish CMT family compatible with linkage to
11q22, and now reported a homozygous missense mutation (R283W) associated with recessive
CMT4B1 with myelin outfoldings (Nelis et al., 2002a). Recently, mutations in the ganglioside
differentiation associated protein 1 (GDAP1) were shown to be responsible for autosomal