14th Annual Meeting of the German Society of Neurogenetics

UNIVERSITÄTSKLINIKUM
Schleswig-Holstein
Campus Lübeck
Dept. of Neurology
Institute of Human Genetics
Dept. of Psychiatry and Psychotherapy
German
Society of
Neurogenetics
14 th Annual Meeting
of the German Society
of Neurogenetics
September 25 – 27, 2008, Lübeck
(c) DGNG e.V.

Wel c o m e
Dear Colleagues,
It is our pleasure to invite you to the 14 th Annual
Meeting of the German Society of Neurogenetics
held in Lübeck, September 25-27, 2008.
This year’s main topics include
▪ Genetics of Movement Disorders
▪ Genetics of Abnormal Brain Development
▪ Genetics of Psychiatric Diseases
In all three areas, new advances have emerged at
a rapid pace, impacting on our understanding of
disease mechanisms, genetic testing, and patient
care. While these fascinating developments have
provided important insights, they also sparked novel
questions, revealed further complexity of a genetic
contribution to neurological and psychiatric disease,
and challenged some of the previously held concepts.
Bringing together neurologists, human geneticists,
psychiatrists, neuropediatricians, and basic science
researchers with world-renowned experts, the
conference will combine formal lectures, workshops,
platform presentations, and poster sessions.
As Thomas Mann pointed out, „It is impossible for
ideas to compete in the marketplace if no forum for
their presentation is provided or available.“ We are
delighted to provide this forum in Lübeck, home of
the Mann Family, former Queen of the Hanseatic
League, and last but not least, a modern Baltic city
with a young, vibrant university.
We look forward to sharing ideas at an exciting
conference and to seeing you in Lübeck.
With kind regards
C. Klein C. Zühlke
G. Gillessen-Kaesbach R. Lencer
T. Gasser, President of the DGNG
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D i r e c t o r y
Page
Program ........................................................................................................................................................6
Workshop: Update on New Techniques .....................................................................................................8
Public Lecture ...........................................................................................................................................16
Key Note Lecture ......................................................................................................................................18
Genetics of Movement Disorders .............................................................................................................20
Genetics of Abnormal Brain Development ...............................................................................................26
Genetics of Psychiatric Diseases .............................................................................................................34
Free Communications ................................................................................................................................42
Poster Abstracts ........................................................................................................................................53
Sponsoring .................................................................................................................................................75
Local Organizers ........................................................................................................................................76
Contact .......................................................................................................................................................77

Fac u l t y
Volker Arolt, Münster, D
Michael Bonin, Tübingen, D
Cornelius Borck, Lübeck, D
Jürgen Deckert, Würzburg, D
Gabriele Gillessen-Kaesbach, Lübeck, D
Paola Giunti, London, UK
Ute Hehr, Regensburg, D
Fritz Hohagen, Lübeck, D
Christine Klein, Lübeck, D
Detlef Kömpf, Lübeck, D
Kerstin Kutsche, Hamburg, D
Rebecca Lencer, Lübeck, D
Susanne Lucae, München, D
Klaus-Armin Nave, Göttingen, D
Markus Nöthen, Bonn, D
Michael O’Donovan, Cardiff, UK
Daniela T. Pilz, Cardiff, UK
Stefan-M. Pulst, Salt Lake City, USA
Arndt Rolfs, Rostock, D
Anthony Schapira, London, UK
Constance Schrander-Stumpel, Maastricht,NL
Reiner Siebert, Kiel, D
Andreas Ziegler, Lübeck, D
Christine Zühlke, Lübeck D
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Pr o g r a m
Thursday, Sep 25, 2008
Workshop: Update on New Techniques
Chair: R. Siebert
16.30 Comparative genomic hybridization
R. Siebert
16.30 Array gene expression analysis
M. Bonin
17.00 Next generation sequencing
A. Rolfs
17.30 Association studies
A. Ziegler
Congress Opening
18.30 Welcome Address
Chairs: D. Kömpf / F. Hohagen
18.45 Public lecture
Metaphern und Modelle der Hirnforschung
C. Borck
19.15 Music
19.30 Key note lecture
Neuron-glia interactions and the genetics
of myelin diseases K.-A. Nave
20.00 Music
20.15 Get-together
Friday, Sep 26, 2008
Genetics of Movement Disorders
Chairs: C. Zühlke / A. Schapira
9.00 Ion channel dysfunction in the SCAs
S. Pulst
9.45 SCA11: Clinical and genetic features
P. Giunti
10.15 Coffee break
10.45 Mitochondrial involvement in the
cause of Parkinson’s disease
A. Schapira
11.15 Genetics of dystonia C. Klein
Free Communications
11.45 Regulation of astrocyte inflammatory
responses by the Parkinson’s
disease-associated DJ-1
J. Waak
12.00 Abnormal basal ganglia activity during
response selection in Parkin mutation
carriers J. v.d. Vegt
12.15 Pathogenic HSP gene duplications
and protection of female carriers
C. Beetz
12.30 Novel mutations in the senataxin gene
in six patients with AOA2
V. Bernard
12.45 Lunch break and poster viewing
13.00 DGNG Board Meeting

Pro g r a m
Friday, Sep 26, 2008
Genetics of Abnormal Brain Development
Chairs: G. Gillessen-Kaesbach / D. Pilz
14.15 The lissencephalies D. T. Pilz
15.00 Holoprosencephaly: Genetics and
what a face can tell about the brain
U. Hehr
15.30 Coffee break
16.00 Mutations of CASK cause a novel Xlinked
brain malformation phenotype
K. Kutsche
16.30 Congenital hydrocephalus: The
Maastricht experience and the concept
of ciliopathy
C. Schrander-Stumpel
Free Communications
17.00 Mutations in FOXG1 cause a broad
phenotypic spectrum ...
F. Kortüm
17.15 14-months old girl with holoprosencephaly,
microcephaly, microtia, short
stature and developmental delay. A
new syndrome? J. Stefanova
17.30 Chromosomal inversion combined
with interstitial deletions ...
H. Gabriel
17.45 Refining the phenotype of α-1a Tubulin
(TUBA1A) mutation ...
D. Morris-Rosendahl
20.00 Conference dinner
Saturday, Sep 27, 2008
Genetics of Psychiatric Diseases
Chairs: R. Lencer / V. Arolt
9.00 Schizophrenia genetics:
new insights from new approaches
M. O’ Donovan
9.45 Genetics of bipolar affective disorder
M. Nöthen
10.15 Coffee break
10.45 Genetics of the response to antidepressant
treatment S. Lucae
11.15 Genetics of anxiety disorders
J. Deckert
Free Communications
11.45 MAOA genotype: Impact on amygdala-prefrontal
connectivity in major
depression U. Dannlowski
12.00 Fine-mapping in multiplex families
with Attention-Deficit Hyperactivity
Disorder K. Lin
12.15 Psychiatric symptoms in genetic
forms of Parkinson disease
M. Kasten
12.30 DGNG awards and poster prices
12.45 Closing remarks
13.00 Lunch
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Wor k s h o P : uP D a t e on ne W te c h n i q u e s
Reiner Siebert is “Facharzt für Humangenetik”
and since 2006 full Professor and Chair of
Human Genetics at the Christian-Albrechts-
University of Kiel and Director of the Institute
of Human Genetics at the University Hospital
Schleswig-Holstein, Campus Kiel. After studying
Medicine at the University of Essen he started
his residency at the Institute of Human Genetic in
Kiel in 1996. He finished his habilitation in 2001
and received a call as Professor for Molecular
Oncology in Hamburg in 2002. He is Section
Editor of the journal “Leukemia” and reviewer for
various international journals and funding bodies.
His research interests among others cover
the development and application of molecular
cytogenetic techniques, genetic changes in
hematologic tumors and the role of epigenetic
changes in disease development.
Reiner Siebert, MD
Institute of Human Genetics
University of Kiel, Germany

Comparative genomic hybridization
Array CGH merges molecular diagnostics with
traditional conventional cytogenetics and opens
a rapidly growing field of genetic diagnostics. The
technique is based on the competitive hybridization
of a test and a reference genome onto a
microarray containing oligonucleotides or BAC
clones. Thus, it provides a high-resolution overview
of chromosomal imbalances across the genome
and can detect chromosomal microdeletions or
microduplications which are common aberrations
leading to mental retardation and malformation
syndromes.
We apply CGH to oligonucleotide arrays (105k
and 244k arrays) in the postnatal diagnostic and
research setting on a routine basis. In the postnatal
setting submicroscopic imbalances (

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Wor k s h o P : uP D a t e on ne W te c h n i q u e s
Dr. Michael Bonin graduated from the University
Kassel in 1998 with a first class degree in
Genetics. His PhD studies were conducted at
the Genetics Department at the same University,
where he worked on the biophysics of RNA-protein
interactions under the mentorship of Wolfgang
Nellen. In 2001 Dr. Bonin moved to the Medical
Faculty at the University of Tübingen where he
headed the Research Management Group for
one year. After this, he established the Microarray
Facility Tübingen, as a Core Facility for microarray
applications. The Facility is an integrated part of
the Institute of Human Genetics and he is now
head of the group for neurotranscriptomic studies.
Michael Bonin, PhD
Institute of Human Genetics
University of Tübingen, Germany

Array gene expression analysis
Neurological diseases (ND) are one of the greatest
challenges facing our population, from medical,
financial, and social perspectives. The application
of new research approaches to understand the
underlying pathogenesis of ND is critical. In
this workshop, we review the use of microarray
analysis in different Neurological diseases.
Microarray technology has become a common tool
for developing expression profiles. Microarrays
have tremendous power, simultaneously querying
the expression of tens of thousands of genes from
a given biological sample. Coupled with impressive
advances in statistical tools for analyzing large,
complex data sets, well-designed microarray
experiments are poised to make a big impact in the
field of ND.
The fact that microarray investigators do not
know which genes or pathways will be discovered
by their experiments is precisely the strength of
microarrays. The ability to examine the expression
profile of potentially the entire genome at once,
without preconceptions, offers the possibility of
completely novel and unexpected insights into
entities as complex as the nervous system. But
before these insights can be made, the practical
problems of experimental design, data analysis,
verification, and interpretation need to be
addressed.
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Wor k s h o P : uP D a t e on ne W te c h n i q u e s
Arndt Rolfs, M.D., studied Medicine at the
Universities of Mainz and Vienna and received
his degree in Medicine from both Universities
in 1985. After working at the Free University
of Berlin, he got a scholarship from the Max-
Planck-Society with employment at the Max-
Planck-Institute for Molecular Genetics in Berlin.
In 1993, he began working at the University of
Rostock as Senior Physician at the Department
of Neurology and Professor for Neurology and
Psychiatry. In parallel to this he was the head
of the Neurobiological Laboratory. Following
several years in clinical and research working, he
became the head of the Albrecht-Kossel-Institute
for Neuroregeneration in 2008.
Arndt Rolfs
Albrecht-Kossel-Institut für Neuroregeneration
University of Rostock, Germany

Next-generation sequencing
In 2004, the National Human Genome Research
Institute (NHGRI) proposed a way to achieve
affordable human genome sequencing by 2014,
in two increments. NHGRI program director Jeff
Schloss explains: “The way the [Requests for
Applications] were laid out, at the time we launched
the program, we were hoping the $100,000 genome
might come in five years. The goal for $1,000 was
to be five years after that.” In the quest for the
$1,000 genome, every imaginable approach is
being explored to develop sequencing technologies
with improvements in miniaturization, parallelism
and simplification. Next-generation sequencing is
already several orders of magnitude more efficient
than the Sanger capillary-array electrophoresis
(CAE) machines. About one year ago, Solexa, of
Hayward, California, announced the completion
of an early-access program evaluating its nextgeneration
Genome Analysis system with customers
and reiterated its intention to begin full commercial
sales this quarter. Curagen spin-off 454 Life
Sciences, of Branford, Connecticut, and Agencourt
Personal Genomics in Beverly, Massachusetts,
a part of Applied Biosystems Group, are already
on the market with systems that bring sequencing
costs down several orders of magnitude below
the millions of dollars per genome cost associated
with capillary-array electrophoresis (CAE)
sequencing—the technology that made possible
the Human Genome Project a mere seven years
ago. Helicos Biosciences, for its part, claims that its
single-molecule sequencing technology, expected
to debut in the second half of 2008, will enable the
sought-after ‘$1,000 genome’ price point, although
not immediately. One of the newest winners of
NHGRI’s $100,000 genome grant, Intelligent Bio-
Systems, of Waltham, Massachusetts, is developing
a four-color sequencing-by-synthesis method
using cleavable fluorescent nucleotide reversible
terminators—an approach similar to that of Solexa.
It is placing instruments in selected laboratories for
beta testing, with a technology that features faster
run cycles, less up-front expense and less costly
implementation. On the horizon are other singlemolecule
sequencing technologies from Visigen
Biotechnologies and Pacific Biosciences. These
companies are developing different approaches
based on real-time massively parallel imaging of
single-molecule base addition events catalyzed by
DNA polymerase. Data are generated at a rate of
10–50 bases per second per polymerase molecule,
as tens of thousands of polymerases read DNA
templates. Read lengths of 8,000 bases may be
within reach, making these technologies ideal for
the most challenging applications, like sequencing
of structurally rearranged cancer cell genomes.
Although shotgun-SBH may not be well suited to
tackling genome rearrangements, its potential for
extremely high parallelism through inexpensive
scaling of the imaging area could give it a cost
advantage in standard genome resequencing
applications. Nearly 20 years have elapsed since
sequencing by hybridization was first envisioned
and the sequencing of single molecules of DNA was
proposed. We are now on the cusp of a new era in
which widely available high-throughput platforms
will generate DNA sequence information from any
organism at a cost of pennies per megabase.
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Wor k s h o P : uP D a t e on ne W te c h n i q u e s
Andreas Ziegler received his Ph.D. in Statistics
(Dortmund) for his work on regression models
for correlated data after receiving his diploma in
Statistics (Munich) in 1992. In 1998, he completed
his habilitation in genetic epidemiology (Marburg)
on linkage analysis of quantitative traits for which
he received the Johann-Peter Süßmilch Medal
from the German Society for Medical Informatics,
Biometry and Epidemiology. Since 2001, Dr.
Ziegler has served as head of the Institute of
Medical Biometry and Statistics and full professor
at the University of Lübeck. He was President of
the German Region of the International Biometric
Society and currently is member of the Board of
Directors of the International Biometric Society and
the International Genetic Epidemiology Society.
After his move to Lübeck, his primary interest for
applications has shifted to infectious diseases.
Andreas Ziegler, PhD
Institute of Medical Biometry and Statistics,
University of Lübeck, Germany
Thus Dr. Ziegler is currently involved in genetic
studies of malaria, tuberculosis and sepsis and
serves as a delegate of an expert group off-label
infectious diseases with main area of concentration
in HIV/AIDS for the BfArM. Other major ongoing
studies relate to cardiovascular diseases. Over the
past five years, Dr. Ziegler has authored or coauthored
more than 100 peer-reviewed papers and
has authored a textbook on statistical approaches
in genetic epidemiology.

Comparative genomic hybridization
Association studies
To search the entire human genome for
association is a promising approach to unravelling
the genetic basis of complex genetic diseases.
The last year has seen a tremendous number of
publications on these genome-wide association
studies (GWAs), and many novel loci have
been identified. Because several hundreds of
thousands of single nucleotide polymorphisms
(SNPs) are analyzed at the same time, substantial
biostatistical and computational challenges are
posed. In this presentation, we give an overview
of approaches to GWAs. We specifically discuss
quality control aspects, adjustments for population
stratification and imputation of SNP markers by
using HapMap data.
Finally, we briefly consider multistage approaches
to GWAs and meta-analyses.
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Pu b l i c le c t u r e
Studium der Medizin, Philosophie,
Religionswissenschaften und Medizingeschichte
in Hamburg, Heidelberg und Berlin. 1994 MA
phil. (Berlin), 1995 Promotion zum Dr. med. in der
Aidsforschung (Berlin), 1996 Promotion zum PhD
in Neurosciences (London). 2003 Habilitation für
Medizin- und Wissenschaftsgeschichte (Berlin).
Seit 2007 Professor für Geschichte, Theorie
und Ethik der Medizin und Naturwissenschaften
an der Universität zu Lübeck und Direktor des
dortigen Instituts für Medizingeschichte und
Wissenschaftsforschung. Frühere Stationen seines
Werdeganges waren das Max-Planck-Institut für
Wissenschaftsgeschichte in Berlin (1998-2002),
die Bauhaus Universität Weimar (2002-2004) und
die McGill University in Montreal (2004-2007), wo
er einen Canada Research Chair in Philosophy
and Language of Medicine innehatte.
Cornelius Borck, MD, PhD
Ethik der Medizin
University of Lübeck, Germany

Modelle und Metaphern der Hirnforschung
Die Hirnforschung profitiert ohne Zweifel enorm
von technischen Innovationen. Ganze Zweige
der Neurowissenschaften hängen von wichtigen
Entwicklungen wie z.B. neuen Registrier- und
Visualisierungsverfahren ab. Technische
Erfindungen und Apparate haben aber auch noch
andere Funktionen in der Hirnforschung. Immer
wieder dienten sie z.B. als zentrale Modelle für
die Leistungen des Gehirns. Vor gut hundert
Jahren galt so das Gehirn gemeinhin als eine Art
Telefonzentrale, und gerade erst sind wir dabei,
uns von der Vorstellung zu verabschieden, unser
Gehirn sei ein Supercomputer. In ihrem neuen
Paradgima der Neuroplastizität scheint sich die
Hirnforschung immer weniger für programmierte
Schaltpläne und feste Verdrahtungen, aber umso
mehr für Organismus-Umwelt-Interaktionen zu
interessieren. Der Vortrag hinterfragt Genese,
Strukturen und Folgen solcher Leitvorstellungen.
Schon heute liegt dabei die besondere ethische
oder politische Brisanz neuer Erkenntnisse und
Einsichten der Hirnforschung vielleicht weniger
in dem, was die Neurowissenschaft feststellen,
sondern eher darin, wie sie dazu beitragen,
Gehirne zu neuen, bislang unbekannten
Leistungen freizustellen.
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key no t e le c t u r e
Prof. Klaus-Armin Nave graduated in Biology
at the University of Heidelberg in 1983. As a
DAAD Scholar he obtained his PhD degree in
Neurosciences at the University of California in
San Diego. Following a postdoctoral fellowship at
the Salk Institue for Biological Studies in La Jolla,
he established an independent research group
at the Center of Molecular Biology Heidelberg
(ZMBH) in 1991 and completed his ‚Habilitation’ in
Molecular Biology and Genetics in 1996. He was
appointed a Full Professor of Molecular Biology at
the University of Heidelberg in 1997 and remains
a faculty member on equal terms. Since 1999 he
has been Director of the Max-Planck Institute for
Experimental Medicine in Göttingen.
Klaus-Armin Nave, MD
Department of Neurogenetics Max Planck Institute of Experimental Medicine
Göttingen, Germany

Neuron-Glia interactions
and the genetics of myelin diseases
It is thought that oligodendrocytes myelinate
axons for rapid impulse conduction, but other
important functions of myelinating glial cells have
remained obscure. We have identified genes
expressed exclusively in mature oligodendrocytes
that are not required for myelination, but essential
for maintaining long-term axonal integrity. Also
the absence of functional peroxisomes selectively
from oligodendrocytes in conditional mouse
mutants causes widespread axonal degeneration
and progressive subcortical demyelination,
without interfering with oligodendrocyte survival.
Surprisingly, glial peroxisomal dysfunction
causes a strong proinflammatory milieu in the
white matter leading to the infiltration of B and
activated CD8(+) T cells into brain lesions.
Thus, oligodendrocytes themselves provide
a neuroprotective function against axonal
degeneration and neuroinflammation, a finding
relevant for myelin disease, incl. MS or X-linked
adrenoleukodystrophy. We propose the model
that myelination per se causes a risk for axonal
functions unless glial cells are able to support the
axons that they ensheath.
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ge n e t i c s oF mo v e m e n t Di s o r D e r s
Stefan Pulst is Professor and Chair of Neurology
and member of the Brain Institute at the
University of Utah in Salt Lake City. His research
focuses on inherited diseases of the nervous
system with an emphasis on spinocerebellar
ataxias and Parkinson disease. Another interest
relates to tumor suppressor genes controlling
proliferation of Schwann cells. Recently, his work
has also branched out into understanding the
genetic structure of human visual attention.
Dr. Pulst was the founding chair of the Section
on Neurogenetics and of the Basic Science
Subcommittee of the American Academy of
Neurology and currently serves as chair of the
AAN Science Committee. From 1999 to 2006,
he was Scientific Director of the National Ataxia
Foundation of the US.
Stefan Pulst, MD
Department of Neurology
University of Utah, Salt Lake City, USA

Ion channel dysfunction in the SCAs
Spinocerebellar ataxia type 2 (SCA2) is caused
by CAG repeat expansion in the ATXN2 gene.
In SCA2 as in other polyQ diseases, length of
the CAG repeat inversely correlates with age of
disease onset (AO), but significant variation is
observed within each repeat class. We used the
Cuban SCA2 founder population to examine ageof-onset
variance. No evidence of gender effects
or imprinting was observed.
We found that polyQ expansion only accounted
for about 60% of the overall variance, but only
for 30% in patients with repeats from 32 to 40
CAG. Of the remainder, 50% was heritable.
Heritability was higher in sib-sib than in parentchild
pairs suggesting presence of recessive
modifier alleles. As had been described in
Huntington disease, we observed a higher
heritability in female sibpairs, a phenomenon that
has remained unexplained. We have begun a
candidate gene-based search for modifier alleles
focusing on normal repeat variation in other
polyQ disease genes. The CACNA1A (SCA6)
repeat modified AO suggesting that either polyQ
domain interaction or modified calcium flux may
influence Purkinje cell dysfunction in SCA2. The
SCA1 repeat showed a tendency to influence
SCA2 AO, an observation that was recently
replicated in the fly.
Although polyQ ataxias comprise the majority
of SCAs, recent investigations have identified a
number of non-CAG repeat mutations in ataxia
families. We studied a Filipino family with a
late onset pure cerebellar ataxia and identified
a mutation in KCNC3 (Kv3.3), as well as in a
second family that had early-onset ataxia with
mental retardation and seizures. We will report
on a mutation screen of more than 400 ataxia
patients that identified a number of DNA variants
in KCNC3 with two recurrent mutations. Studies
in Xenopus oocytes confirmed that these variants
change channel function, although genotype-in
vitro phenotype-clinical phenotype correlations
are not straight forward. Some variants change in
vitro function, although genetically they may not
fulfill all genetic criteria to qualify as a mutation.
The identification of causative and modifier
alleles in CACNA1A and KCNC3 point to the
importance of ion channels as drug targets both
for symptomatic and disease-modifying therapies.
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ge n e t i c s oF mo v e m e n t Di s o r D e r s
Professor Anthony Schapira MD DSc FRCP
FMedSci was appointed in 1990 as Chairman
of the University Department of Clinical
Neurosciences, at the Institute of Neurology,
Queen Square and Professor of Neurology at the
National Hospital and the Royal Free Hospital.
He is Director of Research and Development,
and Clinical Head of Service for Neurosciences at
the Royal Free Hospital.
Professor Schapira’s research interests
include the molecular and clinical aspects
of neurodegenerative diseases, with special
emphasis on Parkinson’s disease and other
movement disorders. He has over 500
publications. Professor Schapira is the recipient
of the Harveian Medal, the Royal College of
Physicians Clinical Science Prize, the 1998
Anthony Schapira, MD DSc FRCP FMedSci
University Department of Clinical Neurosciences
Institute of Neurology, Queen Square, UCL, London
European Prize for Clinical Science and the 1999
Opprecht Foundation Award. He was elected a
Fellow of the Academy of Medical Sciences in
1999. He was awarded the Duchenne Prize in
2005.

Mitochondrial involvement in the cause
of Parkinson’s disease
Several biochemical abnormalities have been
described in Parkinson’s disease (PD) brain
including oxidative stress and mitochondrial
dysfunction and the more recent identification of
specific gene mutations that cause PD has reenforced
the relevance of both in the causation
of familial as well as the sporadic forms of the
disease. Importantly, of the proteins that are
associated with familial PD, two (PINK1 and DJ1)
and possibly a third (parkin) are mitochondrial
proteins, and both alpha-synuclein and LRRK2
appear to be associated with mitochondria.
All these proteins also interface with the
pathways of oxidative stress and free radical
damage. These recent insights into the aetiology
and pathogenesis of PD provide hope that from
converging rather than diverging pathways to
cell dysfunction and death, can come drugs or
combinations of drugs, that may successfully
intervene in pathogenesis and slow disease
progression.
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ge n e t i c s oF mo v e m e n t Di s o r D e r s
Dr. Christine Klein is a native of Hamburg,
Germany. She attended the Medical Schools of
Hamburg, Heidelberg, and Lübeck, Germany,
and took her final year studies in England,
including one trimester at The National Hospital
for Neurology and Neurosurgery, Queen Square,
London with Dr. Niall P. Quinn. She moved
to Boston from 1997-1999 for a fellowship in
Molecular Neurogenetics under the mentorship of
Dr. X. O. Breakefield.
Dr. Klein completed her neurology training at
Lübeck University with Dr. D. Kömpf in 2004,
followed by a research and clinical fellowship and
two short sabbaticals in movement disorders with
Dr. A. E. Lang in Toronto, Canada in 2004 - 2007.
She was appointed a Lichtenberg Professor
of Clinical and Molecular Neurogenetics at the
Christine Klein, MD
Department of Neurology
University of Lübeck, Germany
Department of Neurology of Lübeck University
in 2005, where her research has focused on the
clinical and molecular genetics of movement
disorders.
Dr. Klein is a past member of the Editorial Board
of the Movement Disorders Journal and a present
member of the Editorial Board of ‘Neurology’. She
has published over 150 scientific papers.

Genetics of dystonia
The dystonias are a heterogeneous group of
movement disorders, characterized clinically by
involuntary twisting and repetitive movements and
abnormal postures.
Familial, early-onset, generalized torsion dystonia
(DYT1) is the most common and severe form of
primary dystonia. It usually begins in childhood,
first starts in a limb and tends to generalize to
other body parts as the disease progresses. The
mode of inheritance is autosomal dominant with
reduced penetrance of about 30-40%, including
both mild and severe cases. Most cases are
caused by a 3-bp deletion (904_906delGAG) in the
coding region of the DYT1 gene, which is widely
expressed in human brain and encodes the protein
torsinA.
Dopa-responsive dystonia is characterized by
childhood-onset of dystonia, diurnal fluctuation of
symptoms, and a dramatic response to L-dopa
therapy. Later in the course of the disease,
parkinsonian features may occur. While the
rare autosomal recessive form of DRD (DYT5b)
is associated with mutations in the tyrosine
hydroxylase (TH) gene, the more frequent
dominantly inherited DRD is often caused by
mutations in the GTP cyclohydrolase I (GCHI)
gene (DYT5a).
In myoclonus-dystonia (DYT 11), a predominantly
myoclonic syndrome is combined with
dystonic features which may rarely be the only
manifestation of the disorder. Symptoms frequently
respond to alcohol. Age of onset is usually in the
first or second decade of life. The inheritance
pattern is autosomal dominant with variable
expressivity and incomplete penetrance due to
maternal imprinting of the epsilon-sarcoglycan
(SGCE) gene.
Other rare forms of dystonia-parkinsonism or
dystonia/dyskinesias with known genes include
DYT3 dystonia (X-linked dystonia-parkinsonism;
”lubag”), DYT8 dystonia (paroxysmal
nonkinesigenic dyskinesia), and DYT12 dystonia
(rapid-onset dystonia-parkinsonism), and DYT16
dystonia (recessively inherited juvenile-onset,
generalized dystonia).
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ge n e t i c s oF ab n o r m a l br a i n De v e l o P m e n t
Daniela Pilz is a Consultant in Medical Genetics
at the Institute of Medical Genetics, University
Hospital of Wales, Cardiff. She graduated
from Medical School in Hannover, Germany,
and trained in paediatrics and clinical genetics
in the UK. The topic of her MD thesis was
“Lissencephaly”. She spent 2 years as a
research associate in a molecular laboratory
at the University of Chicago in the Department
of Human Genetics working on cortical
malformations, specifically the molecular causes
of the classical lissencephaly spectrum. Her
clinical expertise lies in dysmorphology and
paediatric neurogenetics, and she continues her
research interest in cortical malformations.
Daniela T. Pilz, MD
Institute of Medical Genetics,
University Hospital of Wales, Cardiff, UK

The lissencephalies
Cortical malformations are an important cause for
epilepsy and intellectual disability. A significant
subgroup is the “lissencephalies”, classified
into Type 1 (classical lissencephaly) and Type
II (cobblestone lissencephaly). The latter is
less common and typically associated with eye
abnormalities and muscular dystrophy (muscleeye-brain
disease spectrum). The molecular
abnormalities identified in these conditions
are associated with abnormal dystroglycan
glycosylation, and they are now often known as
the “dystroglycanopathies”.
In this talk I want to focus on the more common
classical (Type 1) lissencephalies (LIS) and
related disorders, lissencephaly with cerebellar
hypoplasia (LCH), and X-linked lissencephaly
with abnormal genitalia (XLAG). Mutations
in LIS1 and DCX are found in about 85% of
patients with LIS, the former associated with
a posterior predominant and the latter with an
anterior predominant severity gradient of cortical
malformation. Anomalies in the recently identified
TUBA1A gene appear to account for some of the
remaining 15%. Their lissencephaly phenotype
seems to show a posterior predominant
severity gradient as seen in association with
LIS1 mutations. However additional structural
anomalies, including callosal and cerebellar
anomalies, appear more prevalent. All 3 genes
either interact with or are part of the cytoskeleton,
which determines cell shape/structure and plays
important roles in mitosis, cell movement and
intracellular transport. Some patients with LCH
have been found to have a RELN mutation,
an extracellular matrix protein required for
normal neuronal migration to the appropriate
cortical layers. XLAG is caused by mutations
in the transcription factor ARX, thought to be
involved tangential migration of neurons during
development.
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28
ge n e t i c s oF ab n o r m a l br a i n De v e l o P m e n t
Dr. Ute Hehr was born in Dresden, Germany,
and obtained her formal medical training at the
University Halle-Wittenberg, where she also
performed mouse studies as part of her diploma
thesis at the Department of Biochemistry. Her
laboratory training in molecular cytogenetics was
broadened during a stay at the State University of
Leiden, Netherlands.
She then received a research grant of the German
Academic Exchange Service and in 1993 moved to
Philadelphia to work for 2 years in the lab of Dr. M.
Münke (Division of Human Genetics and Molecular
Biology of the Children´s Hospital of Philadelphia,
University of Pennsylvania) on craniosynostosis
and holoprosencephaly. In addition, she pursued
there her training in clinical genetics with Dr. E.H.
Zackai. Dr. Hehr completed her clinical training at
Ute Hehr, MD
Department of Human Genetics
University of Regensburg, Germany
the University Halle-Wittenberg and in 2000 moved
to Regensburg. Together with Dr. B.H.F. Weber she
currently leads the Diagnostic Center of Human
Genetics at the University of Regensburg, where
her major research interests include the clinical
and molecular genetics of craniofacial and brain
malformations in collaboration with Dr. G. Uyanik
and Dr. J. Winkler, Department of Neurology.
In 2000 she received the award of the Novartis
foundation for therapeutic research. She currently
is president of the consortium for Reproductive
Genetics of the German Society of Reproductive
Medicine and in 2004 was appointed as expert of
the National Ethics Council on polar body diagnosis.

Genetics and what a face can tell about the brain
Holoprosencephaly (HPE) is a complex brain
malformation, resulting from incomplete cleavage
of the anterior part of the forebrain into the two
hemispheres and ventricles between days 18 and
28 of gestation. A current prevalence of about
1.3 : 10 000 live births when compared to 1 : 250
early embryos reflects both, a high intrauterine
lethality as well as a high detection rate during
routine prenatal sonography. The etiology of HPE
is very heterogeneous and includes chromosomal
abnormalities, teratogenic effects, monogenic
syndromes as well as familial and sporadic isolated
HPE. Currently, a causal mutation resulting in
monogenic, autosomal dominant inherited HPE
can be identified in about 15-25% of HPE patients
with normal chromosomes. For these families
an incomplete penetrance and extremely wide
intrafamilial clinical variability has been observed.
Clinical evaluation of these families significantly
expanded the spectrum of HPE-associated
brain malformations. In particular, the additional
distinct heterogeneous entities of arrhinencephaly,
syntelencephaly, agenesis of the corpus callosum,
pituitary anomalies as well as septo-optic dysplasia
are discussed as possible variants of the HPE
spectrum. In about 70-80 % of the HPE patients
characteristic craniofacial features allow to predict
the severity of the brain malformation („The face
predicts the brain“, De Myers et al., 1963). The
spectrum of observed facial features includes
cyclopia, proboscis, microphthalmia and median
cleft lip and palate as well as milder manifestations
like hypotelorism or singular median maxillary
incisor. Obligate mutation carriers may present with
such craniofacial minor signs and/or microcephaly,
retarded language acquisition or learning problems
as the only clinical manifestation. Genetic workup of
each prenatal and postnatal HPE case should not
only include a chromosome analysis, but also good
cerebral MR imaging as well as a careful search
for associated anomalies in the setting of a genetic
counseling session. Further molecular genetic
testing should be individually assigned based on the
obtained clinical and anamnestic data. Furthermore,
genetic workup of HPE patients is also providing
important insights into early forebrain development.
Together with animal models two current concepts
emerge: most of classic HPE appears to result
from direct or indirect disruption of the ventralizing
effect of sonic hedgehog signaling and usually
is accompanied by the characteristic HPE facial
gestalt. In contrast, disruption of the dorsalizing
effect of bone morphogenic protein signaling may
account for the middle interhemispheric variants.
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ge n e t i c s oF ab n o r m a l br a i n De v e l o P m e n t
Professor Dr. Kerstin Kutsche is a native of
Hannover, Germany. She attended the Universities
of Hannover and Bielefeld, Germany, to study
Biology and performed her PhD in genetics of
prokaryotes under the supervision of Professor
Dr. Werner Klipp. She moved to Freiburg and
Heidelberg, Germany, from 1994-1996 for a Post
Doc under the mentorship of Professor Dr. Thomas
Boehm to study the winged-helix transcription
factor Foxn1.
In 1996, Dr. Kutsche joined the Department of
Human Genetics at the University Medical Center
Hamburg-Eppendorf, Hamburg, Germany, with
Andreas Gal as Chairman. Since then she has
been working on the identification of novel disease
genes with the help of balanced chromosomal
rearrangements. She also performs functional
Kerstin Kutsche, PhD
Institute of Human Genetics
University of Hamburg, Germany
studies on selected proteins encoded by disease
genes. She was appointed a C3 Professor of
Molecular Human Genetics at the Department of
Human Genetics of Hamburg University in 2004.
Dr. Kutsche did her “Habilitation” in 2005.
She completed her training in Human Genetics in
2006 with the degree “Fachhumangenetikerin”.
She has published about 40 scientific papers.

Mutations of CASK cause a novel X-linked brain
malformation phenotype with microcephaly and hypoplasia
of the brainstem and cerebellum
Microcephaly occurs as an isolated malformation
or with associated brain anomalies such as a
simplified gyral pattern or cerebellar hypoplasia.
Recently, homozygous silencing of EOMES
(TBR2), encoding a transcription factor of the
brain-specific T-box family, was associated with
microcephaly and additional brain malformations.
TBR2 has a putative function in regulating
cortical neurogenesis and neural identity, and
plays a role in a signalling cascade upstream
of TBR1, which is highly related to TBR2. We
describe a novel X-linked brain malformation
phenotype with postnatal microcephaly, hypoplasia
of the cerebellum and brainstem, and severe
developmental delay that is caused by mutations
of CASK in Xp11.4. We mapped one breakpoint
of a paracentric Xp inversion within the CASK
gene in an affected female. By array comparative
genomic hybridization we identified a heterozygous
deletion of ~740 kb encompassing CASK, GPR34
and GPR82 in female patient 2 and two separated
regions of copy number loss in female patient 3,
including ~170 kb covering the 3’ and ~150 kb
encompassing the 5’ region of CASK. Mutation
analysis of CASK in 13 females and 33 males with
a phenotype similar to patients 1-3 identified a
heterozygous nonsense mutation (c.1915C>T/p.
R639X) in a female and the hemizygous c.915G>A
(p.K305) mutation altering splicing in a severely
affected male who died at age 2 weeks. CASK
encodes a multi-domain scaffolding protein that
interacts with the transcription factor TBR1 and
regulates expression of genes involved in cortical
development, such as RELN. The potential
importance of the CASK-TBR1-RELN signaling
cascade in brain development is highlighted by our
neuropathological findings in the deceased boy,
which show changes nearly identical to the Reln
mouse mutant in the cerebellum, and overlap with
the Tbr1�/� mouse in the cerebral cortex.
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ge n e t i c s oF ab n o r m a l br a i n De v e l o P m e n t
Connie Schrander-Stumpel became a
paediatrician in 1984 in Amsterdam. In 1985
she started her carrier in clinical genetics at the
Maastricht University. Since 1989 she is a clinical
geneticist. From 1985 on she is head of the
outclinic Clinical Genetics and since 1992 head of
the training program for clinical genetics with, in
2008, 7 residents.
X-linked hydrocephalus was the topic of her
thesis in 1994, and research in this area
continues.
In 2002 she became Professor of Clinical
Genetics, especially for Dysmorphology and
Mental Retardation. The research mainly focuses
on Prader-Willi -, Rett -, and Kabuki syndrome.
Constance T.R.M. Schrander-Stumpel, MD
Department of Clinical Genetics
Research Institute Growth and Development (GROW)
Maastricht University, The Netherlands

Congenital hydrocephalus:
The Maastricht experience and the concept of ciliopathy
Retrospectively, data of 66 individuals with
congenital hydrocephalus were reviewed. Nonsyndromic
hydrocephalus (NSH) was identified
in 25/66 and hydrocephalus “plus” (H+) in
41/66 patients. In 55/66 patients the cause of
hydrocephalus was unknown. The male/female
ratio was 7.8:1, strongly indicating an X-factor.
In the group of 41 H+ patients, 11 had a known
cause of hydrocephalus. Three out of 4 familial
cases with an unknown cause were possibly
X-linked. Within the group of patients with an
unknown cause of H+ (30/41), 5/30 patients
had renal abnormalities, 3/30 had congenital
diaphragmatic hernia. 5/30 patients had clinical
features overlapping with those present in
chromosome breakage disorders, e.g. radial
ray defects or VACTERL-H as seen in FANCB
gene defect. Especially in the groups with renal
malformations and VACTERL-H with radial
ray defects a ciliopathy may be involved in its
pathogenesis. Congenital hydrocephalus is
reported in about 20% of the patients with cilia
disorders.
We characterized a spontaneous mouse mutant
with a (new) autosomal recessive form of
congenital hydrocephalus, cerebellar hypoplasia,
growth retardation, and situs inversus/
heterotaxia in about 20% of the affected mice.
Electron microscopic studies of ependymal cilia
demonstrate an axonemal outer dynein arm
(ODA) defect.
We developed a new fast one-day functional
motile cilia assay to identify immotile ependymal
cilia in these mice. Real time (semi)quantitative
mRNA studies of ependymal cilia enriched brain
cDNA excluded 6 of the known ODA genes:
Dnahc5, Dnahc9, Dnahc11/lrd, Dnaic1, Dnalc1
and Dnalc4 in the affected mice.
Mapping procedures combined with
immunocytochemistry/-electronmicroscopy
and further candidate gene analysis is ongoing
to identify a possibly new candidate gene for
autosomal recessive congenital hydrocephalus.
33

34
ge n e t i c s oF Ps y c h i a t r i c Di s e a s e s
I began my research career in 1989 as an
MRC Training Fellow, where I developed novel
methods for quantitating mRNA and used these
to show relative expression of genes encoding
subunits of GABAA receptors was a mechanism
that contributes the biology of benzodiazepine
tolerance. From 1992-1993, I was an MRC
Travelling Fellow at MIT where I was a member
of The Huntington‘s Disease Collaborative
Research Group, a team of scientists from leading
genetics institutions in Europe and the USA. The
group successfully identified the gene causing
Huntington‘s disease in 1993. In 1993, I was
appointed Senior Lecturer in the Department
of Psychological Medicine, University of Wales
College of Medicine, and was awarded a chair
in Psychiatric Genetics in 1999. I have a broad
interest in the molecular genetics of mental
Michael O’Donovan, MD
Department of Psychological Medicine
Cardiff University, UK
disorders and hold grants from major funding
bodies (MRC, Wellcome Trust, National Institutes
of Health (USA) for molecular genetic studies of
schizophrenia, bipolar disorder, dyslexia, ADHD,
and Alzheimer’s disease.

Schizophrenia genetics: new insights from new approaches
It has long been known that there is a strong
genetic contribution to schizophrenia, but
identifying the specific genes responsible for this
disorder has proven to be a major challenge.
Over the past 10 years or so, molecular genetic
approaches to complex diseases in general have
progressed from being small sample studies
based upon at best a handful of genetic markers
into large sample studies of several hundred
thousand markers with the power to extract a high
proportion of all common genetic variation in the
genome. While few studies on this scale have
yet been performed in schizophrenia, the early
signs are striking. In the first few large studies of
common variation, the new genome-wide approach
at last has provided robust replicable evidence
for the involvement of specific common genetic
variants in the disorder. As a bonus, the same
technologies have now for the first time provided
the capacity to systematically scan the genome
for certain types of rare variant known as CNVs or
copy number variants representing chromosome
deletions and duplications. Again, the results are a
dramatic break with the past, with clear replicable
evidence for the involvement of specific copy
number variants emerging from the first two large
studies performed. In this presentation, I will review
what is currently known about the genetics of
schizophrenia with an emphasis on the novel but
robust findings.
35

36
ge n e t i c s oF Ps y c h i a t r i c Di s e a s e s
Markus Nöthen received his MD degree from
the University of Würzburg. He was trained as a
human geneticist at the University of Bonn and
worked there till 2001 as a clinical geneticist
and scientist. From 2001 to 2004 he has been
Professor of Medical Genetics and Director of
the Center of Medical Genetics at the University
of Antwerp, Belgium. In 2004 Markus Nöthen
became the Alfried Krupp von Bohlen und
Halbach Professor of Genetic Medicine at the
University of Bonn. Since 2001 he is founding
head of the Department of Genomics at the
Life & Brain Research Center and since 2004
Director of the Institute of Human Genetics at the
University of Bonn.
His research interest lies in the genetic analysis
of complex diseases. He is coordinator of
Markus M. Nöthen, MD
Institute of Human Genetics
University of Bonn, Germany
the NGFNplus Integrated Genome Research
Network “Systematic Investigation of the
Molecular Causes of Major Mood Disorders and
Schizophrenia (MooDS)”.

The Genetics of Bipolar Affective Disorder
Bipolar affective disorder (BPD), also known as
manic depressive illness, is a common psychiatric
disorder which imposes a severe burden on the
individual and society. Family, twin, and adoption
studies provide consistent evidence for a major
genetic contribution to the etiology of BPD, with
heritability estimates of around 85 %.
The first susceptibility genes were proposed
based on candidate gene and linkage-based
positional cloning attempts. At best, these genes
explain only a small fraction of the genetic risk
of the disorders, however. Recently, the first
genome wide association studies have been
performed for BPD, revealing some points of
agreement between studies. In contrast to
common diseases, for which genes with larger
affects exist, BPD seems to be truly polygenic,
and these first studies are currently followed by
large collaborative studies to attribute a causal
relationship of specific genes with BPD robustly.
The talk will give an update on the latest findings
in BPD.
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38
ge n e t i c s oF Ps y c h i a t r i c Di s e a s e s
Dr. Susanne Lucae was born in Dornbirn, Austria.
She studied biology and medicine at the University
of Vienna, Austria and completed her PhD thesis
at the Institute of Pathophysiology, University of
Vienna, where she also spent her postdoctural.
In 2003 she moved to the Max-Planck-Institute
of Psychiatry in Munich, Germany, where she
presently works as staff member of the outpatient
clinic of psychiatry. Dr. Lucae has been head of the
research group “Psychiatric Pharmacogenetics” at
the MPI in Munich since 2007.
Susanne Lucae, MD
Max-Planck-Institute of Psychiatry
Munich, Germany

Genetics of the response to antidepressant treatment
Major depression is by far the most prevalent
mental disorder frequently characterized by
recurrent episodes or chronicity. Despite a variety
of available treatments only 60% of severely
depressed patients achieve full remission of
depressive symptoms, even after several treatment
trials. Both, clinical characteristics and genetic
factors influence the likelihood of a favourable
treatment outcome.
Genome-wide pharmacogenetic association
studies in 339 depressed inpatients from the
Munich Antidepressant Response Signature
(MARS) project and in a second independent
sample of 361 depressed inpatients were
performed. All patients were of Caucasian
descent. 328 SNPs with the highest association
with treatment outcome were then genotyped in
a Caucasian depressed outpatients subsample
(n=832) from the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) study
selected based on clinical criteria from the initial
samples.
46 SNPs could be replicated at a nominal level of
significance, which did not withstand correction for
multiple testing. However, a multi-locus analysis
that assumed additivity of the investigated SNPs
revealed a significant contribution of the number
of responses alleles combined with clinical
characteristics to predict treatment outcome
in both MARS and STAR*D samples. These
findings constitute the first empirical evidence
that many genetic variants contribute to treatment
outcome in major depression in a cumulative
way corroborating the multifactorial nature of this
complex clinical trait.
39

40
ge n e t i c s oF Ps y c h i a t r i c Di s e a s e s
Jürgen Deckert graduated from Würzburg
medical school in 1984. He worked in the Unit
on Neurochemistry, Biological Psychiatry Branch,
NIMH from 1985-1988 and in the Department
of Human Genetics, University of Bonn from
1994-1996.
In 1992 he obtained his board license as a
psychiatrist and in 1997 his habilitation in
psychiatry at the Department of Psychiatry,
University of Würzburg. From 1999-2006 he was
vice director and finally professor for molecular
psychiatry at the Department of Psychiatry,
University of Münster. In 2006 he moved back
to Würzburg to become department director and
professor for psychiatry.
Jürgen Deckert, MD
Department of Psychiatry, Psychosomatics and Psychotherapy
University of Würzburg, Germany

Genetics of anxiety disorders
Panic disorder with a life-time prevalence of 2-3%
is not the most common, but the most severe
anxiety disorder and according to the WHO ranks
among the 10 most disabling neuropsychiatric
disorders among middle-aged Europeans and
North Americans.
Its heritability based on twin and family studies
is estimated at about 50%. Segregation studies
though failed to demonstrate Mendelian
inheritance. Accordingly, only a few linkage
studies have been published and proposed
loci on chromosome 1, 4, 9, 13, 18 and 22 are
in need of replication. In contrast, numerous
association studies with candidate genes have
been published. Candidates were chosen on
the basis of the known molecular mechanisms
of therapeutic drugs or anxiety provoking
agents, on the basis of our knowledge on the
pathophysiology of anxiety and more recently, on
the basis of animal models. As to be expected
numerous modest associations were reported,
of which, however only few (e.g. COMT, MAO-A,
A2A, CCKRB) could be confirmed in independent
replication studies.
Functional relevance of some of the associated
polymorphisms were confirmed by means of
cellular, pharmacological or imaging studies
providing in addition hints as to potential geneenvironment
interactions. At present, the first
genome-wide association studies are being
performed with preliminary results pointing to a
role for genes hitherto unknown to be involved in
the pathophysiology of anxiety.
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42
Fre e co m m u n i c a t i o n
Regulation of Astrocyte Inflammatory Responses by the
Parkinson’s Disease-Associated DJ-1
Jens Waak, 1 Stephanie S. Weber, 1 Daniela Vogt-Weisenhorn, 2 Thu-Trang Pham, 2
Karin Görner, 3 Marianna Alunni-Fabbroni, 3 Wolfgang Wurst, 2 and Philipp J. Kahle1 1 Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie
Institute for Clinical Brain Research, University Clinics, 72076 Tübingen, Germany
2 Institute of Developmental Genetics, Helmholtz Center Munich, German Research
Center for Environmental Health, 85764 Neuherberg, Germany
3 Olympus Life Science Research Europe, BBD, Advalytix Products, 81377 Munich,
Germany
Mutations of DJ-1 cause autosomal-recessive
Parkinson’s disease (PD). In addition to neuronintrinsic
protective functions, its up-regulation
in reactive astrocytes also suggests a glial
contribution of DJ-1. Here we show in astrocyterich
primary cultures derived from DJ-1 deficient
mice that DJ-1 regulates pro-inflammatory
responses. When treated with lipopolysaccharide
as well as α-synuclein protein, DJ-1 mutant
astrocytes generated ≈10 times more nitric oxide
(NO) than littermate controls. This effect was
mediated by hyper-stimulation of type II NO
synthase (iNOS) via the p38MAPK pathway.
Inhibition of this pathway with SB203580
suppressed NO production and iNOS induction.
Stimulation of p38MAPK in astrocytes was also
detected in DJ-1-/- mice treated systemically
with LPS. DJ-1 most likely regulates the p38
pathway by modulating the activity of Apoptosis
Signal Regulating Kinase (ASK-1) activity. We
identified ASK-1 as the main target of regulation
of the ASK/JNK/p38 MAPK pathway by DJ-1.
DJ-1 directly interacts with ASK-1 and suppresses
its ROS-mediated activation. In addition to
iNOS, DJ-1 mutant astrocytes hyper-induced
cyclooxygenase-2 and interleukin-6. These
findings identify DJ-1 is a major regulator of proinflammatory
responses in astrocytes and suggest
that loss of DJ-1 contributes to PD pathogenesis
by deregulation of neuroinflammatory damage.

Abnormal basal ganglia activity during response selection in
Parkin mutation carriers
J.P.M. van der Vegt 1,3 , M. M. Weiss 1 , B.R. Bloem 3 , F. Binkofski 2 , C Klein 2 , H. R.
Siebner 1
1 Dept. of Neurology, Christian-Albrechts-University Kiel, Germany
2 Dept. of Neurology, University Lübeck, Germany
3 Radboud University Medical Centre, Nijmegen, The Netherlands
Objective: Asymptomatic carriers of a single mutant
Parkin allele show a latent nigrostriatal dopaminergic
dysfunction. We examined how the presence of a
mutant Parkin allele influences task related acvtivity
in the basal ganglia when subjects have to select
a movement in the context of competing response
tendencies.
Methods: Asymptomatic individuals carrying a
single mutant Parkin allele (n=6) and healthy agematched
controls (n=10) performed a Simon task
during fMRI at 3T. Responses are coded by two
symbolic cues in this two-choice reaction time
task. The position of these cues is either spatially
compatible or incompatible with the response
instructed by the symbolic cue. We chose the Simon
task because patients with Parkinson´s disease are
impaired at resolving the conflict induced by spatial
incompatibility (Praamstra & Plat, 2001). Mean
reaction times (RT) and error rates (ER) during fMRI
were analyzed using ANOVA. Task-related BOLD
signal changes were analysed using SPM2 software.
Only correct responses were included in these
analyses.
Results: Participants respond faster when relative
spatial positions of stimulus and response match.
Incompatible trials were associated with higher
ER in both groups. Parkin mutation carriers made
significantly more errors than healthy non-carriers
in compatible and incompatible trials. No significant
differences in RT were found between groups.
Analysis of the fMRI data revealed an increased
activation of the left anterior putamen during spatially
incompatible trials in Parkin mutation carriers relative
to non-mutation carriers. This hyperactivity was only
present in right hand responses. No differences
between groups were found during spatially
compatible trials.
Conclusions: The fMRI results indicate that a
mutant Parkin allele is associated with overactivity
of the basal ganglia when a correct action has to
be selected in the context of conflicting response
tendencies, due to a latent dopaminergic dysfunction.
Given the overall increase in error rate, this may
indicate basal ganglia dysfunction associated with
latent nigrostriatal dopaminergic degeneration.
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44
Fre e co m m u n i c a t i o n s
Pathogenic HSP gene duplications and protection of female
carriers
Christian Beetz 1 , Anders O.H. Nygren 2 , Rebecca Schüle 3 , Ludger Schöls 3 ,
Thomas Deufel 1
1 Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum,
Jena, Germany
2 MRC-Holland, Amsterdam, The Netherlands
3 Hertie Institut für Klinische Hirnforschung, Tübingen, Germany
Background: Hereditary spastic paraplegias
(HSP) are neurodegenerative disorders primarily
affecting lower limb movement. The two major
disease genes SPG3A and SPG4 are associated
with autosomal dominant (AD) inheritance.
Mutational class in these genes does not predict
age at onset (aao).
Objective: To screen AD-HSP patients for copy
number aberrations in SPG3A and SPG4.
Methods: A multiplex ligation-dependent probe
amplification assay simultaneously targeting both
genes was applied to index patients for which
“small” mutations had been excluded.
Results: Large deletions affecting SPG4 were
frequently identified; aao in these patients
was as in other cases of SPG4 HSP. A single
SPG3A whole gene deletion was apparently non-
pathogenic. The only instance of a (partial) SPG4
duplication was found in a large Brazilian pedigree
where male carriers (n=14) showed aao typical for
SPG4 HSP (median 30 years) whereas females
carriers (n=13) were significantly protected from
developing the disease (median aao >67 years)
(p=0.017). An SPG3A whole gene triplication
was found in an early onset male index patient,
in his similarly affected male cousin, and in their
unaffected mothers (both > 50 years of age). Of
three related patients, which have not yet been
genotyped, two males show early onset whereas
one female started to develop mild symptoms
in her fifties. In addition, there is another seven
females representing potential carriers but not
being affected.
Conclusions: It appears that female carriers of
SPG3A and SPG4 amplifications are less likely
to develop the typical phenotype associated with
mutations in these HSP genes. The underlying
mechanisms are unclear at present and can only
be speculated about.

Novel Mutations in the Senataxin Gene in Six Patients
Affected by Ataxia-oculomotor Apraxia 2
Veronica Bernard 1 , Ulf Edener 1 , Friedmar Kreuz 2 , Martina Minnerop 3 , Gabriele
Gillessen-Kaesbach 1 , Christine Zühlke 1
1 Institut für Humangenetik, Universität Lübeck
2 Praxis für Humangenetik, Berlin
3 Klinik für Neurologie, Universität Bonn
Background: The recessively inherited
ataxia-oculomotor apraxia 2 (AOA2) is a
neurodegenerative disorder characterised by
adolescent age at onset, gait ataxia, cerebellar
atrophy, axonal sensorimotor neuropathy,
oculomotor apraxia, and elevated serum AFP level.
AOA2 is caused by mutations within the senataxin
gene (SETX) that is localised on chromosome
9q34. The SETX gene encodes a large 2677
amino acid protein, named senataxin. The protein
senataxin is the ortholog of the yeast RNA helicase
Sen1p and contains a DNA/RNA helicase domain
at its C terminus and a putative protein interaction
domain at its N terminus.
Objective and Methods: We screened six patients
showing a clinical phenotype consistent with
AOA2 and for mutations in the SETX gene. We
sequenced all 24 coding exons flanking intronic
sequences of the SETX gene, to confirm the
molecular genetic diagnosis in these patients.
Results: Sequence analysis revealed 12 novel
DNA variations: patient 1 was homo-zygous for
the missense mutation R2414Q, patient 2 showed
homozygosity for the amino acid exchange K992R
and the missense mutation R2444H. The other
four patients were compound heterozygous for
different mutations in the SETX gene. Patients 3
and 4 carried the missense mutations L2155W and
K2382E, and D2207V and T2373P, respectively.
The missense mutation R2444C and a 2 bpdeletion
(c.4095_4096delTT) were found in
patient 5, as well as the unknown polymorphism
R20H. Patient 6 was heterozygous for the
missense mutation P311L and a four-nucleotide
deletion affecting the 5’ splice site of exon 22
(c.6847_6850delACAG).
Conclusion: Remarkably, most of these mutations
are located in the DNA/RNA helicase domain,
which is reported to span amino acid residue 1931
to 2456. Although the function of the human protein
is still unknown, the correct function of the helicase
domain seems to be important, to prevent the
AOA2 phenotype.
45

46
Fre e co m m u n i c a t i o n s
Mutations in FOXG1 cause a broad phenotypic spectrum incl.
microcephaly, frontal pachygyria + agenesis of the corpus callosum
Fanny Kortüm 1 , William B. Dobyns 2 , Ute Hehr 3 , Gökhan Uyanik 1,4 , and Kerstin
Kutsche 1
1 Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg,
Germany
2 Departments of Human Genetics, Neurology and Pediatrics, University of Chicago,
Chicago, Illinois, USA
3 Zentrum für Humangenetik und Institut für Humangenetik, Universität Regensburg,
Regensburg, Germany
4 Klinik und Poliklinik für Neurologie, Universität Regensburg, Regensburg, Germany
Background: Heterozygous loss-of-function
mutations in FOXG1, located in 14q12, have been
reported in two patients showing neurological
symptoms consistent with the diagnosis of a
congenital variant of Rett syndrome. They also had
microcephaly and their MRI scans revealed corpus
callosum hypoplasia. FOXG1 encodes a winged
helix transcriptional factor of the forkhead protein
family which is mainly expressed in brain and
regulates early steps in cortical development.
Objective: We wanted to explore the phenotypic
spectrum associated with a FOXG1 mutation.
Therefore, we investigated a female patient
with a balanced de novo 2;14 translocation
[46,XX,t(2;14)(q11.2;q12)]. She had postnatal
microcephaly, seizures, mental retardation, and
a gastroesophageal reflux. Selected MRI images
showed subtle to mild pachygyria over the anterior
frontal lobe, a mildly thickened cortex in the affected
area, and a thin and poorly formed corpus callosum.
We also performed FOXG1 mutation analysis in a
patient cohort with mental retardation, microcephaly
and pachygyria.
Methods: We mapped the breakpoints of the 2;14
translocation by fluorescence in situ hybridization
and sequenced the FOXG1 gene in 36 patients.
Results: The translocation breakpoint in 14q12 was
located ~265 kb downstream of FOXG1, suggesting
that a position effect causes transcriptional
misregulation of FOXG1. We detected the
heterozygous de novo missense mutation
c.757A>G (p.N253D) in FOXG1 in a female patient.
Asparagine at position 253 is an invariant residue
located in the DNA-binding domain of FOXG1. MRI
images of the affected girl showed mild pachygyria
of the anterior-middle frontal lobe, moderately
thickened cortex in abnormal areas frontally and
a normal corpus callosum. She is mildly mentally
retarded and did not develop seizures although her
EEG was abnormal.
Conclusions: We conclude that de novo mutations
in FOXG1 are a cause of autosomal dominant
mental retardation in patients with microcephaly
and various brain malformations that could include
frontal pachygyria and abnormal corpus callosum.

14-months old girl with microtia, short stature and
developmental delay. A new syndrome?
Irina Stefanova 1 , Almuth Caliebe 2 , Reiner Siebert 2 , Jürgen Sperner 3 , Holger
Tönnies 2 , Gabriele Gillessen-Kaesbach 1
1 Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
2 Institut für Humangenetik, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
3 Klinik für Kinder- und Jugendmedizin, Universität zu Lübeck, Lübeck, Germany
Background: Holoprosencephaly is a complex
brain malformation resulting from incomplete
cleavage of the prosencephalon, occuring between
the 18th and 28th day of gestation. In most cases
facial abnormalities are observed in association
with holoprosencephaly, like hypotelorism,
cyclopia, cleft lip or palate. Holoprosencephaly is
a genetically heterogenous anomaly and is known
to be part of different syndromes and chromosomal
abnormalities. Several genes, such as SHH, ZIC2,
SIX3, TGIF, PTCH, GLI2 and TDGF1 have been
positively implicated in holoprosencephaly.
Clinical report: Here we report a 14-months
old girl with a semilobar holoprosenencephaly,
microcephaly, bilateral microtia with absent auditory
canals, short stature and developmental delay.
Semilobar holoprosencephaly and an arachnoidal
cyst were noted at 33 weeks of gestation by fetal
MRI. After spontaneous delivery at 40 weeks of
gestation body measurements at birth were: length
48 cm (-1,7 SD), weight 2490 g (-2,3 SD), head
circumference 31,5 (-2,6 SD). Microtia with absent
auditory canals was diagnosed after birth. Later on
the child developed feeding difficulties and diabetes
insipidus. At the age of 14 months she showed
pronounced developmental delay. Both parents are
healthy and further family history is unremarkable.
Methods: Cytogenetic analysis on blood
lymphocytes, CGH to oligonucleotide arrays (105 K,
Agilent) of peripheral blood DNA of the patient and
both parents.
Results: Cytogenetic analysis revealed a normal
karyotype 46,XX in the patient. Array-CGH analysis
detected an approximately 0,3Mb-sized duplication
at 2q37.2 of paternal origin.
Discussion and conclusions: We report a patient
with semilobar holoprosencephaly, microcephaly,
bilateral microtia with missing auditory canals.
The combination of these features has not been
described in the literature until now. We suggest that
our patient might have a new previously unknown
syndrome.
47

48
Fre e co m m u n i c a t i o n s
Chromosomal inversion combined with interstitial deletions
on chromosomes 4q and 14q revealed by oligo-arrayCGH in
a patient with autism
Lott, A. 1 ; Kukuckova, M. 2 ; Čmelova, E. 3 ; Gencik, M. 1,2
1 Zentrum für Medizinische Genetik, Osnabrück, Germany
2 Medgene, Bratislava, Slovakia
3 Oddelenie klinickej genetiky, Bratislava, Slovakia
Background: Autism is a behaviorally defined
syndrome with a variety of causes, mostly on a
complex genetic basis with many genes involved.
Especially genes that are expressed during brain
development are candidate genes for autism.
Objective:In this case study we present an 8 year
old male patient with psychomotoric retardation,
autistic features and cytogenetically visible
paracentric inversion of chromosome 14. To reveal
cryptic chromosomal imbalances, high resolution
arrayCGH was performed.
Methods: Array CGH was performed using a
44k 60mer oligonucleotide array (Agilent) with a
theoretical resolution of about 100kb.
Results: A deletion of 3,2 Mb was found at
one inversion breakpoint at 14q12q13.1. The
deleted region contains 5 known genes, one of
them NPAS3. This gene codes for a neuronal
transcription factor that is especially expressed in
the developing human fetal brain and defects of
this gene are implicated in psychiatric disorders.
Additionally, a deletion of 5,0 Mb was found at
4q31.3q32.1. The deleted region comprises
22 known genes, including AMPA2 and TDO2.
The AMPA2 gene product is a neurotransmitter
receptor and plays a key role in several
aspects of developmental and adult synaptic
plasticity. The TDO2 gene product is involved in
serotonin production. Serotonin is pivotal during
development and disturbed levels may contribute
to structural brain abnormalities and autistic
features.
Conclusions: Cases of autism in which
chromosomal inbalances occur are very important
to highlight chromosome regions that are the sites
of autism candidate genes. Oligo-arrayCGH is a
powerful tool to search for such imbalances with
high resolution. This case reveals the possible
involvement of some genes in autism.

Refining the phenotype of α-1a Tubulin (TUBA1A) mutation in
patients with classical lissencephaly
Morris-Rosendahl DJ 1 *, Najm J2, Lachmeijer AMA 3 , Sztriha L 4 , Kuechler A 5 , Haug
V 6 , Zeschnigk C 1 , Martin P 7 , Santos M8, Omran H 6 , Kraus U 7 , Van der Knaap MS 9 ,
Schuierer G 10 , Kutsche K 2 , Uyanik G 11
1 Inst. for Human Genetics and Anthropology, Albert-Ludwigs University of Freiburg, D
2 Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, D
3 Dept. of Clinical Genetics, VU University Medical Center, Amsterdam, NL
4 Dept. of Paediatrics, University of Szeged, Szeged, Hungary
5 Institute for Human Genetics, University of Essen, Essen, Germany
6 Centre for Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, D
7 Epilepsy Center Kork, Kehl-Kork, Germany
8 Neuropediatrics Service, Hospital Maria Pia, Porto, Portugal
9 Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
10 Institute of Neuroradiology, Bezirksklinikum Regensburg, Regensburg, Germany
11 Department of Neurology, University of Regensburg, Regensburg, Germany
Background: Classical or Type 1 lissencephaly
is an autosomal dominantly inherited disorder
of neuronal migration which results in agyria
or pachygria, a thickened cortex and may be
accompanied by various other structural brain malformations.
Patients with classical lissencephaly
have severe psychomotor retardation and epilepsy.
Mutations in the α-1a Tubulin (TUBA1A) gene have
recently been found to cause cortical malformations
resemblant of classical lissencephaly, but with a
specific combination of features. To date, TUBA1A
mutations have been described in five patients and
three foetuses.
Objective: Our aim was to establish how common
TUBA1A mutations are in patients with lissencephaly
and to contribute to defining the phenotype
associated with TUBA1A mutation.
Methods: We performed mutation analysis in
the TUBA1A gene in 46 patients with classical
lissencephaly. In 44 of the patients, mutations in
the LIS1 and/or DCX genes had previously been
excluded; in two patients mutation analysis was only
performed in TUBA1A, based on MRI findings.
Results: We identified three new mutations and
one recurrent mutation in five patients with variable
patterns of lissencephaly on brain MRI. Four of the
five patients had congenital microcephaly, all had
dysgenesis of the corpus callosum and cerebellar
hypoplasia, and variable cortical malformations,
including subtle subcortical band heterotopia, and
absence or hypoplasia of the anterior limb of the
internal capsule.
Conclusions: The new findings that mutations
in TUBA1A also cause a disorder of neuronal
migration, adds a fifth gene to the molecular genetic
diagnosis for patients with classical lissencephaly.
We estimate the frequency of mutation in
TUBA1A in patients with classical lissencephaly
to be approximately 4%, and although not as
common as mutations in the LIS1 or DCX genes,
mutation analysis in TUBA1A should be included
in the molecular genetic diagnosis of classical
lissencephaly, particularly in patients with the
combination of features highlighted in this paper.
49

50
Fre e co m m u n i c a t i o n s
MAOA genotype: Impact on amygdala-prefrontal connectivity
in major depression
Udo Dannlowski 1,2,5 , Patricia Ohrmann 1 , Carsten Konrad 1,2 , Katharina Domschke 1 ,
Jochen Bauer 1 , Harald Kugel 3 , Christa Hohoff 1 , Sonja Schöning 1,2 , Anette
Kersting 1 , Bernhard T. Baune 1,4 , Lena S. Mortensen 1 , Volker Arolt 1 , Pienie
Zwitserlood 5 , Jürgen Deckert 1,6 , Walter Heindel 3 , Thomas Suslow 1 ,*
1 Department of Psychiatry, University of Münster, Germany
2 IZKF-Research Group 4, IZKF Münster, University of Münster, Germany
3 Department of Clinical Radiology, University of Münster, Germany
4 Department of Psychiatry, James Cook University, Townsville, Australia
5 Department of Psychology, University of Münster, Germany
6 Department of Psychiatry, University of Würzburg, Germany
Background: The amygdala plays a pivotal role in
a prefrontal-limbic circuitry implicated in emotion
processing and regulation. Major depression has
been associated with a common functional variable
number tandem repeat (VNTR) polymorphism in the
promoter region of the monoamine oxidase A gene
(MAOA u-VNTR) as well as reduced amygdalaprefrontal
functional connectivity, which could be a
useful intermediate phenotype for depression.
Objective: In the present study, we sought to
investigate the impact of MAO-A genotype on
the functional connectivity of amygdala-prefrontal
emotion regulation circuitries in depressed
patients.
Methods: Functional connectivity of the amygdala
with prefrontal areas involved in emotion
regulation was investigated during a facial
expression processing task in a sample of 34
depressed inpatients and 31 healthy controls. All
patients were genotyped for the MAOA u-VNTR
polymorphism.
Results: We observed strong coupling of the
amygdala and dorsal prefrontal areas comprising
the dorsolateral prefrontal cortex (DLPFC), dorsal
parts of the anterior cingulate cortex (dACC), and
lateral orbitofrontal cortex in healthy subjects.
Amygdala-prefrontal connectivity was significantly
reduced in depressed patients compared with
controls. Among both samples, carriers of the
higher active MAOA risk alleles (MAOA-H)
showed weaker amygdala-prefrontal coupling.
Furthermore, reduced coupling of this circuitry
predicted more than 40% variance of clinical
variables characterizing a longer and severer
course of disease.
Conclusions: We conclude that genetic variation
in the MAOA gene may affect the course of major
depression by disrupting cortico-limbic connectivity,
a potential neural substrate for emotion regulation.

Fine-mapping in multiplex families with Attention-Deficit
Hyperactivity Disorder
Michelle K. Lin 1 , Haukur Palmason 1 , Christine Freitag 4 , Christiane Seitz 4 , Tobias
J. Renner 2 , Marcel Romanos 2 , Susanne Walitza 2 , Christian Jacob 3 , Klaus P.
Lesch 3 , Jobst Meyer 1
1 Department of Neurobehavioral Genetics, University of Trier, Germany
2 Department of Child and Adolescent Psychiatry and Psychotherapy, University of
Wuerzburg, Germany
3 Department of Psychiatry and Psychotherapy, University of Wuerzburg, Germany
4 Institution:Department of Child and Adolescent Psychiatry, Saarland University
Hospital, Homburg, Germany
Attention-deficit hyperactivity disorder (ADHD)
is a neuropsychiatric disorder characterized
by symptoms of inattention, hyperactivity and
increased impulsiveness. Despite many studies
over the last decades, the etiology of ADHD
remains unknown.
Eight large ADHD-affected families were recruited
for this study. Using genetic data derived from
related individuals within each of the large families,
an attempt is made to identify predisposing
chromosomal regions in these families. Finemapping
of the significant loci reported in a recent
paper (Romanos et al, 2008) of a genome-wide
linkage study of the eight large familes was carried
out. These families were recruited in a multicenter
collaboration study conducted by three clinical
units of child and adult psychiatry (University of
Trier, Homburg/Saar, and Wuerzburg). These
families comprised of 191 individuals, of which 95
were affected with ADHD.
From the preliminary results, in one of the large
families, a 20 cM interval on chromosome 18
was narrowed down to 18q11-18q2. All affected
individuals in this family share the same haplotype.
ADHD is believed to be a complex, polygenic
disease in which many genes of small effect
contribute to disease susceptibility. However,
there may be monogeneous Mendelian
inheritance in large families. Currently, interesting
candidate genes in the narrowed down region
of chromosome 18 are being selected for further
functional studies.
51

52
Fre e co m m u n i c a t i o n s
Psychiatric symptoms in genetic forms of Parkinson disease
M. Kasten 1 , L. Kertelge 1,2 , C. Klein 2
1 Dept. of Psychiatry and Psychotherapy, University of Lübeck, Germany
2 Dept. of Neurology, University of Lübeck, Germany
Background: Psychiatric symptoms are recognized
as important features in monogenic forms of
parkinsonism.
Objective: To review current knowledge on non
motor symptoms, particularly psychiatric features in
monogenic forms of parkinsonism in the literature.
Methods: A Medline search was performed using
the search terms “parkinson” and the name of known
PD genes including all publications from January
1966 to January 2008. This resulted in 1,855
citations, 305 of those included genetic information
on PD patients. While avoiding double counts 119
articles containing any information on any type of
non motor symptom (990 cases) could be included.
We focused on presence of depression, anxiety,
hallucinations, and dementia for each of the genes
with available information.
Results: The number of cases with available
information was variable, ranging from 12 cases for
DYT1 to 314 cases for LRRK2. Likewise methods
differed widely across studies. Furthermore,
cases differed regarding ages at onset, disease
durations, ethnicities, treatments, and comorbidities.
Overall, hallucinations and dementia were most
frequently commented on, followed by depression
and anxiety. Detailed information on psychiatric
symptom frequencies linked to SNCA, Parkin,
PINK1, and LRRK2 mutations include hallucinations:
SNCA: 10/43(23%); Parkin: 7/206(3%); PINK1:
9/60(15%); LRRK2: 37/216(17%); dementia:
SNCA: 11/43(26%); Parkin: 3/62(5%); PINK1:
6/54(11%); LRRK2: 35/314(11%); depression:
SNCA: 16/43(37%); Parkin: 22/207(8%); PINK1:
25/64(30%); LRRK2: 58/204(28%); anxiety: SNCA:
3/24(13%); Parkin: 14/192(7%); PINK1: 15/41(37%);
LRRK2: 28/140(20%).
Conclusions: There is currently only very limited
data on psychiatric features in genetic forms of
parkinsonism. Overall, the frequency of psychiatric
features in patients with genetic parkinsonism does
not appear to be higher and may even be lower
than in idiopathic PD. Possible exceptions include
the occurrence of specific psychiatric disorders
in PINK1-linked disease or of dementia in SNCAassociated
parkinsonism. Psychiatric symptoms
have a high impact on the patients’ quality of life
and caregiver burden and should be considered as
important and often treatable concomitant features
of genetic parkinsonism.

Pos t e r ab s t r a c t P1
Enhanced stress reactivity in NOS2 mutant mice: findings in
support of astrocytic nitrosative modulation of behavior.
Abu-Ghanem Yasmin 1,2 , Cohen Hagit 3 , Buskila Yossi 1,2 , Grauer Ettie 4 , Amitai
Yael 1,2
1 Dept of Physiology
2 Zlotowski Center for Neuroscience
3 Mental Health Center, Ben-Gurion University Beer-Sheva
4 Israel Institute for Biological Research, Ness-Ziona
Alterations of nitric oxide (NO) metabolism in the
brain have been associated with modifications of
stress-related behavior in animal models. It has
been generally assumed that these behavioral
changes are due to the neuronal nitrosative
activity. On the other hand, glial NO production
has been demonstrated mainly as a slow reaction
to brain insults through the activity of an inducible
NOS isoform (NOS2). Recently we uncovered
increased NOS activity in astrocytes of mice with a
NOS2 mutation. Interestingly, these mice revealed
a behavioral phenotype suggestive of increased
susceptibility to stress.
In the present study we investigated the responses
of these mutants to stress by exposing them
to predator scent. Seven days later, mutant
mice exhibited significantly higher anxiety like
behavior in the elevated-plus maze, increased
acoustic startle responses, and higher plasma
corticosterone levels compared to their controls.
Systemic administration of a NOS inhibitor prior to
the stress exposure reversed these stress-related
effects without affecting controls’ behavior. These
findings are in agreement with previous studies
showing an association between increased NO
levels and enhanced anxiety-like responses. In
addition, mutant mice performed better in the
Morris water maze prior to stress exposure, but the
two animal groups performed alike in an objectrecognition
test.
Taken together, our results suggest the
involvement of astrocytic-derived NO in modulating
behavior.
53

54
Pos t e r ab s t r a c t P2
Mapping of a novel syndrome involving spastic paraplegia,
ataxia, and mental retardation
Christian Beetz 1 , Nihal O. Dündar 2 , Rebecca Schüle 3 , Senay Haspolat 2 , Peter
Nürnberg 4 , Ozgur Duman 2 , Ludger Schöls 3 , Thomas Deufel 1 , Christian Hübner 1
1 Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum, Jena,
Germany
2 Department of Child Neurology, Faculty of Medicine, Akdeniz University Antalya, Turkey
3 Hertie Institut für Klinische Hirnforschung, Tübingen, Germany
4 Cologne Center of Genomics, Universität Köln, Germany
Background: Hereditary spastic paraplegias
(HSP) and cerebellar ataxias (CA) are
neurodegenerative conditions with highly
heterogeneous genetic backgrounds. Spastic
ataxias (SA) are increasingly recognized as a
separate group of disorders showing phenotypic
features of both HSP and CA.
Objective: To characterise a large Turkish
pedigree for which the index patient had been
diagnosed with spastic paraplegia.
Methods: Available family members were clinically
examined. The disease status of unavailable
or deceased family members was inferred from
reports provided by relatives. Genomic DNA of six
individuals was analysed on 10K SNP arrays.
Results: The index case, whose parents are
first cousins, shows pure spastic paraplegia that
started at age 5. His paternal aunt and uncle
have also suffered from spastic paraplegia since
their first decade of life. Later on, they developed
ataxia, dysarthria, and mental retardation. Their
parents, i.e. the index patient’s grandparents,
are first cousins too. Four additional individuals
representing offspring from yet another but more
distant consanguineous marriage are reported to
have had similar symptoms; they died at relatively
young age. SNP genotyping using DNA from the
three patients available and from three unaffected
relatives revealed linkage to a single region on
chromosome 1p. This region, being homozygous
in the patients, spans 54MB and contains
approximately 500 genes. It does not overlap with
any known locus for recessive HSP, CA, and SA.
Conclusions: Our data suggest the identification
of a novel form of recessive SA that is complicated
by mental retardation and, possibly, short lifespan.

Pos t e r ab s t r a c t P3
Heterozygous ATP13A2 mutations in Parkinson´s disease
Butz, E. 1 , Djarmati, A. 1 , Hagenah, J. 1 , Winkler, S. 1 , Lohmann, K. 1 , Berg, D. 3 , Kostić,
V.S. 2 , Volkmann, J. 4 , Gasser, T. 3 , Klein, C. 1
1 Depart. of Neurology, University of Lübeck, Lübeck, Germany;
2 Institute of Neurology CCS, Belgrade, Serbia;
3 Department of Neurodegenerative Diseases, Hertie-Institut for Clinical Brain
Research, University of Tübingen, Germany;
4 Department of Neurology, Christian-Albrechts University, Kiel, Germany
Background: Juvenile parkinsonism and
young-onset Parkinson´s disease (YOPD) are
neurodegenerative disorders with an early disease
onset (< 21 years and 21-40 years, respectively). To
date, four genes linked to the recessively inherited
form of parkinsonism have been identified. Since
the year 2006, when the ATP13A2 gene was first
associated with parkinsonism, seven different
homozygous, compound and single heterozygous
mutations have been reported in patients with
an autosomal recessive form of early-onset
parkinsonism with dementia (Kufor-Rakeb syndrome)
and parkinsonism of juvenile or young onset.
Objective: To further investigate the role of the
ATP13A2 gene in the etiology of parkinsonism in a
large cohort of patients with juvenile parkinsonism
and YOPD.
Methods: We performed a mutational screen of
all 29 exons of ATP13A2 in 112 patients and 55
neurologically healthy individuals. Our patients were
mainly of European ethnic origin and were affected
with juvenile parkinsonism (n=16; 66.7% men; mean
age of onset±SD: 15.1±4.5 years; range: 8-20 years)
and YOPD (n=96; 55.4% men; mean age of onset ±
SD: 31.8±3.9 years; range: 21-40 years). A subset
of patients (n=22; 19.6%) had mutations in other PD
genes.
Results: We identified four different novel single
heterozygous mutations in 3 patients with YOPD
and one with juvenile parkinsonism (3.6%). None of
these were found in healthy, neurologically examined
control individuals. All of these mutations affected
amino acids highly conserved among mammalian
species. Interestingly, the carrier of one of these
changes also harbored a heterozygous deletion and
duplication in the Parkin gene, thus representing
a possible case of digenic parkinsonism. A further
mutation was present in one YOPD patient and in
one control individual.
Conclusion: Although this work represents the
most comprehensive mutational analysis for
mutations in ATP13A2 published to date, no
definitive conclusions can be drawn on the potential
significance of this gene in the etiology of earlyonset
parkinsonism. The presence of single,
possibly pathogenic missense mutations might
suggest that even single heterozygous mutations
in ATP13A2 may have a role as a susceptibility
factor for parkinsonism.
55

56
Pos t e r ab s t r a c t P4
Identification of SOD1 Ala4Val mutation in a Mexican family
with lateral amyotrophic sclerosis
Castañeda-Cisneros G 1,2 , García-Cruz D 3 , Moran-Moguel MC 1 , Rosales-Gómez
R1,5, Gutiérrez-Rubio SA 1 , Dávalos-Rodríguez IP 4 , Nuñez-Revélez N 1,5 , Sánchez-
Corona J 1 .
1 División de Medicina Molecular, Centro de Investigación Biomédica de Occidente
(CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, México.
2 Departamento de Neurocirugía, Hospital de Especialidades, IMSS, Guadalajara,
México.
3 Instituto de Genética Humana, Universidad de Guadalajara, Guadalajara, México.
4 División de Genética, CIBO, IMSS, Guadalajara, México.
5 Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud
(CUCS), Universidad de Guadalajara, Guadalajara, México.
Background: The amyotrophic lateral sclerosis
(ALS) is included within the group of neurogenetic
and neurodegenerative diseases. It is a condition
that involves upper and lower motor neurons,
typically presents asymmetrical focal weakness
of the limbs, and/or findings at bulbar level like
dysarthria/dysphagia, and lacking of sensory
disturbances. ALS familial cases correspond to the
10 %, and 20 % of them are related to mutations
in the SOD1 gene. The mutation Ala4Val covers
50 % of affected individuals in familial ALS and is
characterized by rapid progression and severe
clinical signs.
Objective: To describe a Mexican family
that corresponds to the clinical diagnosis of
amyotrophic lateral sclerosis according to the
established clinical criteria and their correlation
with SOD1 Ala4Val mutation.
Methods: Clinical, electromyography and
neuroimaging studies for diagnosis of ALS; and
polymerase chain reaction (PCR) with HaeIII
digestion to identification of SOD1 Ala4Val mutation.
Results: The pattern of inheritance is autosomal
dominant, with variable expressivity and a probable
phenomenon of anticipation. The number of
affected individuals in the present family is eight
in three generations and average age of onset
35.7 years, with a male/female ratio of 0.6/1. The
molecular studies showed the presence of the
mutation SOD1 Ala4Val in two affected individuals
and six unaffected individuals (generation IV: 43-50
years; generation V: 6 -20 years), corresponding to
100 % and 43.75 % respectively.
Conclusions: In Mexico, there are not familial
reports with ALS related to SOD1 Ala4Val mutation,
therefore is unknown if this is the most frequent
one and presents severe symptoms in individuals
affected by this disease.

Pos t e r ab s t r a c t P5
Spinocerebellar Ataxia Type 11: Novel variations in the
TTBK2 gene
Ulf Edener 1 , Veronica Bernard 1 , Katrin Bürk 2 , Gabriele Gillessen-Kaesbach 1 ,
Christine Zühlke 1
1 Institut für Humangenetik, Universität Lübeck
2 Klinik für Neurologie, Universität Marburg
Background: The autosomal dominant
spinocerebellar ataxias (SCAs) are a heterogeneous
group of neurodegenerative disorders characterised
by poor coordination, impairment of speech
and swallowing, abnormal eye movements and
pyramidal signs. To date 30 SCA loci have been
discovered and for at least 16 the respective gene
or mutation has been determined. In 2007 Houlden
and colleagues described mutations in the TTBK2
gene to be associated with SCA11. This gene
localised on chromosome 15q15.2 encodes tau
tubulin kinase 2 which is highly expressed in the
cerebellum Purkinje cells and seems to play an
important role in the tau cascade. They identified a
one-base insertion (c.1328_1329insA) at codon 444
in a British family and a deletion of a dinucleotide
(c.1284_1285delGA) at codons 428 and 429 in
a family of Pakistani ancestry. Both frameshift
mutations occured in exon 13 of the 15-exontranscript
and created premature stop sites at
codons 450 and 449 respectively.
Objective and Methods: To determine the
frequency and to search for further mutations
concerning TBK2 we sequenced the 18 translated
exons and flanking intronic sequences of the
currently longest 19-exon-transcript for 48 unrelated
patients with dominant ataxia.
Results: We found six variations at DNA level.
A 157-bp-frameshift-deletion in exon 11 was
detected in 8,5 % of ataxia patients and in 12,5 %
of 95 unrelated control individuals. Remarkably,
the 19-exon-transcript being the only transcript
harbouring exon 11 could not be detected in
lymphoblasts of patients and control individuals by
RT-PCR. Furthermore three novel DNA variations
were found in the TTBK2 coding region: a missense
exchange E1247G in one ataxia patient of Arabian
ancestry and the two silent mutations S758S and
E1269E in one and four patients respectively. Beside
these novel variations two known 1-bp-substitutions
in the 5’-UTR at mRNA positions -37 and -67 were
detected in more than 30 % of the ataxia patients.
Conclusion: In conclusion SCA11 is not a frequent
cause for dominantly inherited ataxias. The presence
of the 157-bp-deletion in samples from patients and
unaffected individuals argues against a disease
causing potential. The E1247G missense exchange
should be further investigated to determine whether
it is a mutation or a polymorphism.
57

58
Pos t e r ab s t r a c t P6
Differential effect of PINK1 nonsense and missense
mutations on mitochondrial function and morphology
A. Grünewald, MS 1,2 , M. Gegg, PhD 3 , J-W. Taanman, PhD 3 , C. Klein, MD 1,2 , A.H.V.
Schapira, MD 3
1 2 Departments of Neurology and Human Genetics, Lübeck University, Lübeck,
Germany
3 University Department of Clinical Neurosciences, Royal Free and University College
Medical School, University College London, London, UK
Background: Recessive mutations in PTEN-induced
putative kinase 1 (PINK1) are responsible for a
familial form of early-onset parkinsonism. PINK1
localizes to the inner mitochondrial membrane.
Objective: The aim of the present study was to
investigate fibroblasts of patients with parkinsonism
for functional and morphological effects of nonsense
and missense mutations in PINK1.
Methods: We examined 4 members of Family
W with the homozygous p.Q456X nonsense
mutation and one patient with the homozygous
p.V170G missense mutation. Additionally, 3
healthy members of Family W and 5 independent
age-matched individuals were included.
Fibroblasts were cultured under standard
conditions and treated with paraquat (PQ).
The activities of complexes I-IV (CI-IV) were
measured spectrophotometrically in mitochondrial
preparations. For determination of the cellular
ATP levels [ATP] a luminometric kit was used.
The mitochondrial membrane potential (mMP)
was detected by means of 5,5’,6,6’-tetrachloro-
1,1’,3,3’-tetraethylbenzimidazolocarbocyanine
iodide. The cellular gluthatione concentration
[GSH] was quantified by reverse-phase HPLC. The
mitochondrial DNA level [mtDNA] was assessed by
real-time PCR. The mitochondrial morphology was
studied by electron microscopy.
Results: In the nonsense samples no significant
differences were detected when the activities of
CI-IV were compared with controls. However,
relative to the mean control values, the missense
mutant revealed a 112% increased CII+III activity
and a 43% decreased CIV activity. The average
[ATP] in the nonsense cases amounted to 75%
of the control group (p

Pos t e r ab s t r a c t P7
Blood expression profiles of symptomatic DYT1 dystonia
patients differ from asymptomatic mutation carriers – a
signature for penetrance in DYT1 dystonia
K. Grundmann 1 , M. Walter 1 , E. Valente 2 , M. Gambarin 3 , M. Tinazzi 3 , C. Kamm 4 , M.
Bonin 1 , C. Klein5, O. Riess 1
1 Dept of Medical Genetics, University of Tübingen, Germany
2 Neurogenetics Unit, IRCCS CSS-Mendel, Rome, Italy,
3 Unità operativa di Neurologia, Ospedale Civile Maggiore Borgo Trento Verona, Italy
4 Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain
Research University of Tübingen, Germany
5 Clinical and Molecular Neurogenetics, Department of Neurology, University of
Lübeck, Germany,
DYT1 dystonia is a neurodevelopmental
movement disorder which is inherited in an
autosomal dominant pattern. Most cases of this
early-onset form of primary dystonia are due to
a GAG deletion in the torsinA gene. Although the
underlying genetic defect has been identified, the
determination of the GAG deletion in a subject is
of limited use with regard to factual manifestation
of the disease, as the penetrance of the mutation
is reduced to ~30-40%. Thus it is of extreme
importance to develop new diagnostic tools.
In the present study, we tried to implement a
novel genetic paradigm: Affymetrix oligonucleotide
microarrays were used to analyze global gene
expression in blood samples of 24 DYT1 patients,
22 nonmanifesting mutation carriers and controls.
We identified 269 mRNAs that showed a
significantly altered expression in DYT1 patients
compared to nonmanifesting mutation carriers
(P

60
Pos t e r ab s t r a c t P8
Functional characterization of the murine Mlc1 promoter with
respect to stress-related behavior and psychoses
Darja Henseler, Thorsten Kranz, Jobst Meyer
Department of Neurobehavioural Genetics, University of Trier
Background: Mutations in the MLC1 cause a
severe neurological disorder, megalencephalic
leukoencephalopathy with subcortical cysts, that is
clinically characterized by macrocephaly and the
deterioration in motor functions, ataxia, spasticity
and mental decline.
Furthermore, a L309M mutation was found to cosegregate
with catatonic schizophrenia in a large
family. Aside from genes, other environmental
factors, like stress, have been suggested to
play a role in the susceptibility to psychoses like
schizophrenia.Like the human MLC1, the murine
Mlc1 is mainly expressed in astrocytes. The
genomic organization of the murine Mlc1 was
described by Steinke and coworkers (2003) which
revealed 12 exons encoding a membrane protein
consisting of 382 amino acids.
Objective: The aim of the current work is to study
the effect of stress on Mlc1 expression in mice.
Furthermore, the function of the MLC1 protein,
which still remains unclear, will be investigated.
Methods: We assayed the murine Mlc1 promoter
region using reporter gene constructs. We focus
on changes in the regulation of gene expression,
especially with respect to glucocorticoids.
Results: We found a predicted promoter 3.9
kb upstream of the Mlc1 gene, followed by a
transcribed region including a pseudogene of
Pomp. NFкB binding sites in the regulatory region
suggest a potential effect of stress on Mlc1
expression.
Conclusions: According to the literature and our
findings, the murine Mlc1 seems to be differentially
regulated compared to the human orthologue. This
implies the need for a knock-out mouse model for
both schizophrenia and MLC1. Currently, we are
creating Mlc1 knock-out mouse to elucidate the
role of Mlc1 in brain development and behaviour.

Pos t e r ab s t r a c t P9
Late-onset PEO and proximal myopathy in a patient carrying
mutations in the POLG2 gene
Rita Horvath. 1,2,4 , Maggie Walter 1 , Birgit Czermin 2 , Joanna Stewart 4 , Gavin
Hudson 4 , Stefanie Bulst1, Peter Schneiderat1, Angela Abicht 1,2 , Hanns
Lochmüller 3 , Patrick F. Chinnery 4 , Thomas Klopstock 1
1 Friedrich-Baur-Institute and 2 Medical Genetic Centre, Munich, Germany
3 Institute of Human Genetics and 4 Mitochondrial Research Group, University of
Newcastle upon Tyne, UK
Aims: Polymerase gamma 1 (POLG1) mutations
are a frequent cause of both autosomal dominant
and recessive complex neurological phenotypes.
In contrast, a pathogenic mutation in POLG2 was
detected in one patient only world-wide.
Here we describe a 62 year-old woman carrying
two novel heterozygous sequence variants in the
POLG2 gene.
Patient and Methods: The first symptoms started
at age 30 years with bilateral ptosis, followed by
exercise intolerance and proximal weakness in the
late forties. CK was occassionally elevated up to
500 U/L. Her 22 year old daughter and one of her
three brothers also show ptosis.
Results: Histological examination of skeletal
muscle and biochemical measurement of the
respiratory enzymes showed normal results. Long
range PCR analysis detected multiple mtDNA
deletions in muscle DNA of the patient. The
molecular genetic analysis of POLG1, Twinkle and
ANT1 did not reveal any abnormalities. Two novel
heterozygous mutations were detected in POLG2,
an intronic variant c.1192-16_1192-15hetinsT and
a complex mutation predicted to insert 8 additional
amino acids into the protein. The analysis of further
family members and cDNA studies are underway.
Conclusions: POLG2 mutations are a rare
cause of autosomal dominant PEO. The clinical
presentation of our patient is in keeping with the
previously described clinical phenotype.
61

62
Pos t e r ab s t r a c t P10
Analysis of the SCN1A gene for idiopathic epilepsy
Kuhn, M. 1 , Gabriel, H. 1 , Jagiello, P. 1 and Gencik, M. 1,2
1 Zentrum für Medizinische Genetik, Osnabrück, Germany
2 Medgene, Bratislava, Slovakia
Background: Idiopathic epilepsies represent
~40% of the epilepsy spectrum. So far, about
~12 genes for ‘single gene’ epilepsies have been
identified, mostly encoding ion channels joining the
epilepsy phenotype to the channelopathies. Ion
channels are critical for neuronal excitability and,
therefore for the delicate balances that maintain
electric stability in the CNS.
Objective: Here, we present the diagnostic of the
SCN1A gene in 35 children suffering from GEFS+
type 2 (n=15) and SMEI (n=20). Both phenotypes
belong to the spectrum of GEFS+. GEFS+2 is a
relatively mild form of the GEFS+ spectrum and
therapeutic strategies work well, SMEI (Dravet
syndrome) is the most severe phenotype with
a poor outcome. In 33-100% (different studies)
mutations in the SCNA1 gene in SMEI are de novo.
Methods: We perform this test by the DGGE
method in addition to direct sequencing of selected
exons of the SCN1A gene including the splicing
sites. Additionally, we have screened for deletions
or duplications of single exons by MLPA technique.
Results: We detected missense-mutations in
two of our GEFS+2 patients. In 6/20 SMEI cases
(all de novo) including small deletions/insertions,
truncating and missense mutations, mostly located
in the pore and voltage sensitive region of the
SCN1A protein. In one patient a novel homozygous
sequence variation was found. Both parents were
heterozygous carriers of this variation. It is unlikely
that this variant is a causative mutation. Although
unknown for SCN1A mutations a recessive trait
can not be excluded.
Conclusion: The molecular genetic diagnostic of
epilepsies particularly in children is challenging,
but will facilitate the early diagnosis, prognosis and
also therapeutic strategy.

Pos t e r ab s t r a c t P11
Huntingtin-associated protein-1 is a modifier of the
age-at-onset of Huntington’s disease
Silke Metzger 1 , Juan Rong 2 , Huu-Phuc Nguyen 1 , Jürgen Tomiuk 1 , Anne Söhn 1 ,
Peter Propping 3 , Yun Freudenberg-Hua 3 , Jan Freudenberg 4 , Liang Tong 5 , Shi-Hua
Li 2 , Xiao-Jiang Li 2 , Olaf Riess 1
1 Medical Genetics, Tübingen, Germany
2 Human Genetics, Atlanta, US
3 Human Genetics, Bonn, Germany
4 Neurology, UCSF, US
5 Biological Sciences, Columbia University, US
Background: Huntington’s disease (HD) is caused
by an unstable CAG repeat expansion in the HD
gene that is inversely correlated with the age-atonset
of the disease. Since the size of the CAG
repeat only explains about 42-73% of the variance
of the age-at-onset, other factors might modify the
course of the disease.
Objective: We aimed to identify and characterize
a genetic modifier in Huntingtin-associated
protein-1 (HAP1), which participates in intracellular
trafficking, colocalizes and interacts with huntingtin,
thus representing a good candidate for a genetic
modifier.
Methods: We analyzed HAP1 polymorphisms
by association studies in 980 European HD
patients. As one of these turned out to modify the
disease, the functional analyzes of HAP1 and this
polymorphism concentrated on the examination
of protein-protein interactions by yeast two-hybrid
assays and coimmunoprecipitation, aggregate
formation, cellular localization and apoptotic
properties in cell culture.
Results: We identified one HAP1 polymorphism
as a genetic modifier for HD age-at-onset. Patients
homozygous for this polymorphism develop the
first symptoms about 8 years later than patients
with other genotypes. Functional analyses
showed that polymorphic HAP1 binds more
mutant huntingtin and reduces its degradation.
Additionally, it increases the number of large
aggregates, prevents the localization of huntingtin
in the nucleus and protects against huntingtinmediated
toxicity in transfected cells.
Conclusion: We identified the first genetic modifier
for HD that acts protective and has a functional
importance to huntingtin-mediated toxicity and thus
to HD pathogenesis.
63

64
Pos t e r ab s t r a c t P12
PolyQ-expanded TBP leads to aggregation and neuronal
death in primary neurons and transgenic mice
Nguyen HP 1 , Then F 2 , Osmand A 3 , Wolburg H 4 , Golub Y 1 , Ott T 1 , Bauer C 1 ,
Teismann P 5 , Hennek T 1 , Krainc D 2 , Riess O 1 , Bauer P 1
1 Department of Medical Genetics, Tübingen, Germany
2 Department of Neurology, Charlestown, US
3 Department of Medicine, Knoxville, US
4 Department of Pathology, Tübingen, Germany
5 Institute of Medical Sciences, Aberdeen, UK
Background and objective: SCA17 is a
progressive neurodegenerative disease leading
to cerebellar ataxia and dementia. Genetically, a
CAG/CAA expansion in the TATA binding protein
(TBP) is found in SCA17 patients. To further study
the pathogenesis of this disorder, we aimed to
develop a transgenic mouse model for SCA17.
Methods and results: Overexpression of
polyQ-expanded TBP in primary neurons lead to
aggregate formation and neuronal death. This
prompted us to generate transgenic mice which
express 64 CAG/CAA repeats containing human
TBP gene under the control of the truncated
human prion protein promoter. Transgenic
protein expression throughout different brain
regions was clearly demonstrable. Onset of
motor dysfunction started by 7 months and
progressed with age. By electron microscopy and
immunohistochemical methods we were able
to detect neurodegeneration and aggregation
selectively in the cerebellum, but not in striatum
and cortex. This could be confirmed using filter trap
assay with mouse brain lysates. SDS-insoluble
aggregates in the membrane were seen in lysates
from transgenic mice, whereas wild-type brain
lysates did not reveal significant retention of
aggregated material in cellulose acetate.
Conclusion: We present detailed morphological
and phenotypical data for this rodent model of
SCA17, which will be a valuable tool to conduct
preclinical therapeutic studies and to further study
the pathogenesis of this so far incurable disease.

Pos t e r ab s t r a c t P13
Late onset hereditary sensory neuropathie type 1 (HSN1)
caused by a novel p.C133R missense mutation in SPTLC1
Bernd Rautenstrauss 1,2 , Birgit Neitzel 1 , Christoph Muench 3 , Judith Haas 3 , Elke
Holinski-Feder 1,4 , Angela Abicht 1,2
1 Medical Genetics Center Munich, Germany
2 Friedrich-Baur-Institute, Ludwig-Maximilian-University Munich, Germany
3 Jewish Hospital Berlin, Germany
4 Ludwig-Maximilian-University Munich, Germany
The hereditary sensory and autonomic
neuropathies (HSAN), which are also referred to
as hereditary sensory neuropathies (HSN) in the
absence of significant autonomic features, are a
genetically and clinically heterogeneous group of
disorders associated with sensory dysfunction.
HSN1 is a dominantly inherited sensorimotor
axonal neuropathy usually with onset in the first
or second decades of life. We investigated a
female patient with age-of-onset at 50 years.
Her mother was also affected but died. Her
brother was diagnosed as chronic inflammatory
demyelinating neuropathy (CIDP) but - typical
for an inherited peripheral neuropathy - steroid
treatment failed. Neurological examination of the
index patient revealed a normal nerve conduction
velocity (NCV) of N. fibularis at 46 m/s. No motor
impairment was found in EMG and NCV studies,
also no atrophies were present. Major symptom
is a distal, symmetric hypesthesia. Sequence
analysis of all coding exons of the gene for the
Serine Palmitoyltransferase, Long-Chain subunit
1 (SPTLC1) revealed a heterozygous variation
c.397T>C resulting in a missense mutation
p.C133R. Serine palmitoyltransferase (SPT;
EC 2.3.1.50) is the key enzyme in sphingolipid
biosynthesis. It catalyzes the pyridoxal-5-primephosphate-dependent
condensation of L-serine
and palmitoyl-CoA to 3-oxosphinganine. The
p.C133Y and p.C133W mutations were earlier
described as cause of severe HSN1 accompanied
by deafness and ulcerations. Bejaoui et al. (2002)
found that the p.C133Y and p.C133W mutations
do not alter the steady state levels of the SPTLC1
or the SPTLC2 subunit but result in reduced
SPT activity and sphingolipid synthesis. These
functional results indicated that both of these
mutations have a dominant-negative effect on the
SPT enzyme. The here reported p.C133R mutation
may follow the same loss-of-function mechanism,
but the resulting phenotype is relatively mild
indicating a reduced but not completely missing
SPT activity.
65

66
Pos t e r ab s t r a c t P14
Clinical and genetic investigation of a multigenerational
Parkinson disease family
K. Rondorf 1 , W. Külper 1 , N. Brüggemann 1 , P. Vieregge 2 , J. Hagenah 1 , C. Klein 1 , K.
Lohmann 1
1 Department of Neurology, University of Lübeck, Lübeck, Germany
2 Department of Neurology, Klinikum Lippe-Lemgo, Lemgo, Germany
Background: Parkinson disease (PD) is a
common neurodegenerative disorder. In the past
10 years at least six genes have been identified
to be associated with PD. We performed a clinical
and genetic investigation of a multigenerational PD
family for whom known genetic factors had been
excluded through linkage or mutational analysis.
Objective: To clinically and genetically
characterize a family with PD.
Patients/Methods: Twenty-six family members
underwent a detailed neurological examination
by a movement disorder specialist. A consensus
diagnosis was obtained based on the findings of
the onsite examiner and the results of a videotape
review by two additional experts in movement
disorders. A genome-wide linkage analysis was
performed on 13 family members with a set of
450 microsatellite markers. LOD scores were
calculated using the ALLEGRO software. Regions
with a multipoint LOD score of >1.0 or a single
point LOD score of >1.5 were analyzed in all family
members by fine-mapping. Selected genes from
regions with potentially shared haplotypes were
sequenced.
Results: Four family members were definitely
affected with PD, two were considered to be
probably, and two possibly affected. The age of
onset was between 45 and 70 years. The pattern
of disease transmission was compatible with
autosomal dominant inheritance.Twelve regions
were investigated by fine-mapping and linkage
to all but one of these regions was excluded.
Thus, we identified a likely new PD gene locus
with a maximum lod score of 2.45. A haplotype
in a 10.7Mb region was shared by all 8 affected
patients. Sequencing of the first five candidate
genes in this region did not yet result in the
identification of a disease-associated mutation.
Conclusions: Linkage studies localized a new
gene locus for clinically typical, late-onset,
dominantly inherited PD in this family. Further
mutational analyses are underway to identify the
causative gene.

Pos t e r ab s t r a c t P15
Parkin protects the mitochondrial genome against
oxidative stress
Rothfuss, O. 1 , Hasegawa, T. 1 , Fischer, H. 1 , Sharma, M. 1 , Leitner, P. 1 ,
Bornemann, A. 2 , Berg, D. 1 , Gasser, T. 1 , and Patenge, N. 1
1 Hertie Institute for Clincical Brain Research (HIH), Center for Neurology, University
Hospital Tübingen
2 Institute for Brain Research, University Hospital Tübingen
Background: Parkinson’s disease (PD) is a
neurodegenerative disorder, characterized by
the progressive loss of dopaminergic neurons
in the substantia nigra pars compacta. Both
environmental and genetic factors have been
implicated in the development of PD. Mutations
in the parkin gene (prkn) are the most common
cause of recessive familial PD. Recently,
evidence accumulated that parkin is involved in
the maintenance of mitochondrial function and
biogenesis.
Objectives: The objective of this study was to
investigate the influence of parkin on mitochondrial
function.
Methods: We have employed Chromatin
Immunoprecipitation to identify parkin specific
binding sites in SH-SY5Y cells as well as in brain
tissue. In SH-SY5Y cell lines stably expressing
wildtype parkin and six pathogenic point
mutants, we evaluated the influence of parkin on
mitochondrial DNA (mtDNA) using LightCycler
approaches.
Results: Parkin is associated physically with
mtDNA in proliferating as well as in differentiated
SH-SY5Y cells. This phenomenon was not limited
to the regulatory sequences of the D-loop region,
but was detected all over the mitochondrial
genome. In vivo, the association of parkin with
mtDNA could be confirmed in brain tissue of mouse
and human origin. Replication and Transcription
of mtDNA were enhanced in SH-SY5Y cells overexpressing
the parkin gene. The ability of parkin
to support mtDNA-metabolism was impaired by
pathogenic parkin point mutations. Moreover, we
show that parkin protects mtDNA from oxidative
damage and stimulates mtDNA repair.
Conclusions: Our data suggest a novel
neuroprotective pathway of parkin by supporting
mitochondrial function and protecting mitochondrial
genetic integrity from oxidative stress.
67

68
Pos t e r ab s t r a c t P16
Analysis of CYP7B1 in non-consanguineous cases of
hereditary spastic paraplegia
Rebecca Schüle 1 , Elisabeth Brandt 2 , Kathrin N. Karle 1 , Maria Tsaousidou 3 ,
Stephan Klebe 4 , Sven Klimpe 5 , Michaela Auer-Grumbach 6 , Andrew H. Crosby 3 ,
Christian A. Hübner 2 , Ludger Schöls 1 , Thomas Deufel 2 , Christian Beetz 2
1 Research Division Clinical Neurogenetics, Hertie-Institute for Clinical Brain Research
and Department of Neurodegenerative Diseases, Center of Neurology, Tübingen,
Germany
2 Institute for Clinical Chemistry and Laboratory Diagnostics, University of Jena,
Germany
3 Department of Medical Genetics, St George’s University, London, UK
4 Department of Neurology, Christian-Albrechts-University, Kiel, Germany
5 Department of Neurology, Johannes-Gutenberg-University Mainz, Germany
6 Center for Medical Research, Medical University, Graz, Austria
Background: Hereditary spastic paraplegia (HSP)
is a neurodegenerative condition characterised by
lower limb spasticity and weakness. Homozygous
mutations in CYP7B1 have been identified in
several consanguineous families that represented
HSP type 5 (SPG5), one of the many genetic forms
of the disease.
Objective: To determine frequency and phenotypic
spectrum of SPG5.
Methods: We used direct sequencing and
multiplex ligation-dependent probe amplification to
screen apparently sporadic HSP patients (n=12) as
well as index patients from non-consanguineous
recessive (n=8) and from dominant families (n=8)
for alterations in CYP7B1.
Results: One sporadic patient showing HSP
as well as optic atrophy carried a homozygous
nonsense mutation. Compound heterozygosity
was observed in a recessive family with a clinically
pure phenotype. A heterozygous missense
change segregated in a small dominant family. We
also found a significant association of a known
coding polymorphism with cerebellar signs as
complicating a primary HSP phenotype.
Conclusions: Our findings suggest CYP7B1
alterations to represent a rather frequent cause
of HSP that should be considered in patients with
various clinical presentations.

Pos t e r ab s t r a c t P17
Genome-Wide Association Study in Parkinson’s Disease:
First stage analysis
C. Schulte 1 *, M. Sharma 1 *, M. Bonin 2 , P. Lichtner 3 , D. Berg 1 , C. Gieger 4 , R. Krüger 1 ,
C. Klein5, G. Deuschl 6 , O. Riess 2 , T. Gasser 1
1 Hertie Institute of Clinical Brain Research, Tübingen, Germany;
2 Department of Medical Genetics, University of Tübingen, Germany;
3 Institute of Human Genetics, GSF National Research Institute, Neuherberg, Germany
4 Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for
Environmental Health, Neuherberg, Germany;
5 Department of Neurology, University of Lübeck, Germany.
6 Dept. of Neurology, Christian-Albrechts-University Kiel, Kiel, Germany
Background: Parkinson’s disease (PD) is
the second most common neurodegenerative
disorder. The etiology of PD is largely unknown.
Epidemiological findings along with genetic
association studies highlight a significant genetic
contribution to disease risk. However, the genetics
of PD have only been partially explained by genes
which were identified in large multigenerational
families. Genome wide association scans offer
a powerful approach to identify common genetic
factors that influence the common form of PD.
Objective: To identify variants influencing the
susceptibility to sporadic PD.
Methods: We performed a genome-wide
association study in PD in 757 cases and 976
neurologically healthy controls. Each individual was
genotyped on Illumina genotyping chips (Illumina
humanhap550) yielding 561 466 genotypes/
individual. SNPs with minor allele frequencies
(MAF) > 5 %, Hardy-Weinberg Equilibrium p >
0.01 and genotype call rates > 95 % were included
in the analysis (498 560 SNPs). We performed
association tests using the trend test in PLINK
software.
Results: We identified a number of different
chromosomal regions across the genome which
may potentially harbour susceptibility genes for PD.
Conclusions: Our data suggest that there are
genetic variants contributing to the pathogenesis
of sporadic PD. The associated SNPs are currently
in the genotyping phase in an independent cohort
consisting of 1100 cases and 2200 controls.
69

70
Pos t e r ab s t r a c t P18
Frequency of SPG15 in complicated hereditary spastic
paraplegia (cHSP)
A. Seibel 1 , N. Schlipf 2 , D. Möcke 1 l, U. Hehr 3 , S. Klebe 4 , S. Klimpe 5 , M. Synofzik 6 ,
J. Winkler 7,8 , B. Winner 7 , L. Schöls 1,6 , P. Bauer 2 , R. Schüle 1,6
1 Research Division for Clinical Neurogenetics, Hertie-Institute for Clinical Brain
Research, Tübingen
2 Department of Medical Genetics, University of Tübingen
3 Department of Human Genetics, University of Regensburg
4 Department of Neurology, University of Schleswig-Holstein, Kiel
5 Department of Neurology, University of Mainz
6 Department of Neurodegenerative Diseases, Center for Neurology, Tübingen
7 Department of Neurology, University of Regensburg
8 Department of Neurology, Clinical Center Landshut
MutatioBackground: Hereditary spastic
paraplegias (HSP) are genetically exceedingly
heterogenous. Since 2007, two genes for
complicated HSP were identified: spatacsin
(SPG11) and spastizin (SPG15). Both forms of
HSP share a similar clinical phenotype including
thin corpus callosum, cognitive impairment,
peripheral neuropathy mild cerebellar signs as
main complicating features.
Objective: To determine the frequency of SPG15
in complicated early-onset HSP.
Methods: All 42 exons and exon-intron boundaries
of the SPG15 gene spastizin were sequenced in a
cohort of 35 index patients. Patients were selected
based on the following criteria: early-onset HSP
(C) were identified in a boy with
sporadic complicated spastic paraplegia. The first
presenting symptom was slurring of speech at the
age of three, whereas spastic gait disturbances
started at age 16. Predominantly posterior thinning
of the corpus callosum and mild periventricular
white matter changes were noted on MRI. A
heterozygous sequence change of unknown
significance (c.1925C>T, p.A642V) was found in a
child with early onset spastic paraplegia that was
absent in ~400 control chromosomes. No second
mutation however was identified in this child.
Additionally, two unpublished SNPs were identified
in the sample as well as in controll samples:
c.282G>A, p.M942I and c.1844C>T, p.S615F.
Conclusions: SPG15 is rare (1/35) in complicated
HSP. As its phenotype is virtually indistinguishable
from SPG11 it is certainly advisable to screen the
SPG11 gene prior to SPG15 testing.

Pos t e r ab s t r a c t P19
Cellular model for monogenic parkinsonism
Philip Seibler, Norman Kock, Slobodanka Orolicki, Christine Klein
Department of Neurology, University of Lübeck, Lübeck, Germany
Background: Despite intensive, international
research efforts, the cause of degeneration of
dopaminergic neurons in the substantia nigra
observed in Parkinson’s disease (PD) is still
unknown. To date, several genes have been
identified, mutations in which are clearly linked
to PD-specific cell loss. The availability of human
neuronal cells is limited, thus requiring a model
system that reflects in vivo conditions. One of the
disadvantages of current animal and cell culture
models for monogenic PD is overexpression of
mutated sequences.
Objective: To generate a model of “dopaminergic”
fibroblasts to study the influence of Parkin
mutations on dopamine-producing human skin
fibroblasts.
Methods: Human skin fibroblast cultures were
obtained from 12 patients with Parkin mutations
(two homozygous, one compound heterozygous
and nine heterozygous) and 3 control individuals
and grown. In order to establish dopaminergic
metabolism in these cells, the following genes were
cloned and transfected via Nucleofection (Amaxa
Biosystems, Köln, Germany) into fibroblasts:
Tyrosine hydroxylase 2 (TH2), GTP cyclohydrolase
1 (GCH1) and L-DOPA decarboxylase (DDC).
Results: First, expression of the Parkin protein in
fibroblasts was confirmed in the control individuals
and the heterozygous mutation carriers. Thirtysix
hours after transfection with TH2, GCH1 and
DDC, the cells were analyzed. Overexpression
of the three genes was shown by Western blot
and production of dopamine was revealed highperformance
liquid chromatography.
Conclusions: Here we report, for the first time, a
model of human skin fibroblasts, originating from
PD patients, with a fully expressed dopamine
metabolism. Future investigations of this cellular
model regarding levels of dopamine production,
cytotoxicity levels or activities of Parkin
substrates, will yield new insights into disease
mechanisms of PD.
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Pos t e r ab s t r a c t P20
Dopamine Receptor D3 Gene and Essential tremor in Large
Series of German, Danish and French Patients
Thier, S 1 , Klebe S 1 , Lorenz D 1 , Stevanin G 2,3,4 , Nebel A 5 , Feingold J 2,6 , Frederiksen
H 7 , Denis E 2 , Christensen K 7 , Schreiber S 2 , Brice A 2,3,4,8 , Deuschl G 1 , Dürr A 2,3,4
1 Department of Neurology, UK S-H, Campus Kiel, Kiel, Germany
2 AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris,
France
3 INSERM, UMR_S679, Paris, France
4 Université Pierre et Marie Curie-Paris, Pitié-Salpêtrière Hospital, Paris, France
5 Institute of Clinical Molecular Biology, UK S-H, Campus Kiel, Kiel, Germany
6 Université Pierre et Marie Curie-Paris, Modelling in Clinical Research, Paris, France
7 Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern
Denmark, Denmark
8 AP-HP, Pitié-Salpêtrière Hospital, Federation of Neurology, Paris, France.
Aim of this study: To examine the DRD3 variant
in three different populations from Germany,
Denmark and France Background: The genetic
causes of ET seem to be heterogeneous. Recently,
ET has been found associated with a functional
variant (Ser9Gly) of the dopamine D3-receptor,
located close to the 1997-first-time described
ETM1 locus on chromosome 3q13.3.Methods: We
undertook an association study of the Ser9Gly
variant in 299 ET patients and 528 healthy
controls from three different European populations
(Germany, France, Denmark). ET patients contain
97 sporadic cases and 202 familial cases. In
addition, linkage analysis was carried out in 22
informative ET families.
Results: Comparing the whole study sample
(n=299) with healthy controls (n=528) of the
same origins no difference of genotypes or allele
frequency was shown between ET patients and
controls. Regarding ET patients with a positive
(n=202) or no family history (n=97) no difference
between ET patients and healthy controls could
be found. Age of onset of tremor, tremor duration
and tremor severity did not show an association
with the DRD3 variant. In addition, the G allele of
the variant was not found linked to the disease in
a subset of informative ET families.Conclusion:
We did not find a significant association nor
linkage of the DRD3 variant to ET for the so far
largest sample of European ET patients from three
different national cohorts, suggesting that it is
unlikely a common risk factor for ET in Caucasians.

Pos t e r ab s t r a c t P21
Generation and expression characterization of BAC-HD
transgenic rats with full-length mutant huntingtin
Libo Yu 1 , Silke Metzger 1 , Alexandra Schwienbache r1 , Thomas Ott1, Xiaofeng Gu 2 ,
Michelle Gray 2 , William Yang 2 , Olaf Riess 1 and Huu Phuc Nguyen 1
1 Department of Medical Genetics, Tübingen, Germany
2 Department of Psychiatry & Biobehavioral Sciences, Los Angeles, USA
Background and objective: Our group has
previously generated and characterized transgenic
rats, which express a fragment of mutant
huntingtin. This rat model mirrors many aspects
of Huntington’s disease, but it lacks the full-length
mutant protein and therefore some aspects of the
human condition might be imperfectly replicated.
To overcome this potential disadvantage, we
aimed to generate transgenic rats, which express
full-length mutant human huntingtin in the same
developmental and tissue- and cell-specific
manner seen in patients.
Methods: Bacterial artificial chromosomes (BACs)
containing human genomic DNA spanning the fulllength
gene with 97 CAGs including all regulatory
elements, were microinjected into oocytes of
Sprague–Dawley rats. Founders and F1 transgenic
rats were screened for copy number of BAC
insertion, number of integration sites, integrity of
the BAC insertion and level of mutant huntingtin
RNA by QPCR. Protein expression in brain was
measured by Western Blot.
Results: Initially we established one line, in
which the full-length huntingtin expression was
detected in all the brain regions at low level. 24
new founders were therefore generated, which all
showed germline transmission of the transgene.
Many potential founders had multiple copies of
the transgene integrated into their genome, in
some cases more than 5-fold in comparison to the
low-expressing line. Also 22 potential founders
expressed the full-length mutant huntingtin gene.
Expression of the full-length protein was confirmed
in the brains of F1 transgenic rats, in several lines
at high levels.
Conclusion: We have established several lines of
transgenic rats, which express full-length mutant
huntingtin at high levels.
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Pos t e r ab s t r a c t P22
Abnormal interhemispheric interactions and sensorimotor
integration in ATP13A2 mutation carriers: a TMS study
S Zittel 1 , J Kröger 1 , T Bäumer 1 , C Gerloff 1 , HR Siebner 2 , N Brüggemann 3 ,
A Schmidt 3 , J Hagenah 3 , ME Behrens 4 , A Ramirez 5 , C Klein 3 , A Münchau 1
1 Department of Neurology, University Medical Center Eppendorf, Hamburg
2 Department of Neurology, University of Kiel, Kiel, Germany
3 Department of Neurology, University of Lübeck, Lübeck, Germany
4 University of Santiago de Chile, Chile
5 Institute of Human Genetics, University of Cologne, Cologne, Germany
Background: Kufor Rakeb syndrome (PARK 9) is an
autosomal recessive nigro-striatal-pallidal-pyramidal
neurodegeneration characterized by juvenile-onset
parkinsonism, pyramidal signs, dementia and
supranuclear gaze palsy. Sensorimotor integration
and interhemispheric interactions investigated by
transcranial magnetic stimulation (TMS) are altered
in idiopathic Parkinson’s disease (IPD) with a
reduced inhibitory tone. As yet it is unclear whether
these alterations are due to neurodegeneration
per se or represent compensatory adaptive
mechanisms. Here we investigated a Chilean PARK
9 family using a number of TMS paradigms.
Methods: Five heterozygous asymptomatic carriers
of an ATP13A2 mutation, one affected homozygous
carrier, two unaffected family members, and nine
healthy subjects were investigated. All mutation
carriers were members of one Chilean family. We
studied short latency afferent inhibition (SAI) after
digital nerve stimulation, interhemispheric inhibition
(IHI) with a paired pulses paradigm and the ipsilateral
silent period (iSP) and postinhibitory excitability to
probe sensorimotor integration and interhemispheric
interaction in mutation carriers. ISP and corticospinal
excitability following iSP for an interval of 100 msec
were measured using TMS applied over the
left and right primary motor cortex (M1) with an
intensity of 175% resting motor threshold (RMT)
during ipsilateral pinch grips of maximal voluntary
contraction. IHI was investigated by a subthreshold
conditioning stimulus (intensity 120% RMT) applied
over left and consecutively right M1 followed by a test
stimulus (intensity 120% RMT) over the contralateral
motor cortex at interstimulus intervals (ISI) of 6 – 10
msec. SAI was tested by electrical stimulation of the
right index finger followed by magnetic stimuli over
the left M1 at ISIs of 25, 30 and 40 msec.
Results: Postinbitory facilitation following iSP was
enhanced in the group of mutation carriers at an
ISI of 40 msec. SAI was stronger at an ISI of 40
msec in mutation carriers as compared to healthy
controls but this was not significant. IHI was normal
in mutation carriers.
Conclusion: Interhemispheric interactions are
altered in carriers of the ATP13A2 mutation. In
contrast to reduced SAI in IDP and heterozygous
Parkin mutation carriers SAI was increased in
ATP13A2 mutation carriers. These alterations might
be a direct consequence of the PARK 9 mutation or
represent compensatory adaptive changes.

sPo n s o r i n g
Wir danken der Deutschen Forschungsgemeinschaft
und folgenden Firmen für Ihre
freundliche Unterstützung:
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loc a l or g a n i z e r s
Department of Neurology
Prof. Dr. Detlef Kömpf
Prof. Dr. Christine Klein
Dr. Katja Lohmann
Institute of Human Genetics
Prof. Dr. Gabriele Gillessen-Kaesbach
Prof. Dr. Christine Zühlke
Department of Psychiatry
and Psychotherapy
Prof. Dr. Fritz Hohagen
PD Dr. Rebekka Lencer
Dr. Meike Kasten
The congress has been CME-certified.

con t a c t
Congress Secretariat
UNIVERSITÄTSKLINIKUM Schleswig-Holstein
Institut für Humangenetik
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23538 Lübeck, Germany
Phone: +49 451 500-26 21, Fax -41 87
E-Mail: Marianne.Schirr@uk-sh.de
www.neuro.uni-luebeck.de/dgng2008
Congress Venue
Audimax, AM3, University of Lübeck
77

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UNIVERSITÄTSKLINIKUM
Schleswig-Holstein
Stabsstelle UEM, G. Weinberger; Stand September 2008