European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Clinical genetics
A 29 years old man with problem in walking and diagnosis of ataxia
which was began from 5 years before with alternating dizziness, ataxia,
tremor, vision disturbance and chocking.
Normal mental state, cranial nerve, autonomic function, motor exam
in inspection with mild hypotonia and normal sensory were seen in
examination.
In ophthalmologic exam all was normal but nystagmous with low speed
and range.
All cerebellar exam was disturbed including, ataxic gait, scanning
speech, intention tremor, hyperreflexia, dysphagia, dysmetria and dysdiadokinesis.
Brain MRI was normal.
There was history of such a problem in his mother, his mother’s 3
sibling and also grandfather which was presented in higher age and in
their children in lower age.
Case 2:
A 36 years old man with progressive ataxia and tremor which was began
from 6 years before with one apparently normal child, normal mental
state, disturbed cerebellar exam including progressive ataxic gait,
dysartheria, intention and postural tremor, dysmetria, dysdiadokinesis
was seen in exam. Brain MRI showed cerebellar atrophy.
There was some history of such a problem in his father, sib line and
also in pedigree
Diagnosis:
Extracted DNA was investigated for the GAA expansion repeat in the
FRDA gene and SCA types including 1,2,3,6,7.
The two probands showed abnormal pattern for SCA 7 and SCA 2
respectively.
P0236. Juvenile and young adults SCA1 patients in Poland -
genetic and clinical features.
E. Zdzienicka, M. Rakowicz, R. Rola, A. Sulek-Piatkowska, T. Jakubowska, W.
Szirkowiec, R. Poniatowska, U. Zalewska, J. Zaremba, E. Bertrand;
Institute of Psychiatry and Neurology, Warsaw, Poland.
Spinocerebellar ataxia type 1 (SCA1) is the most common form of
ADCA in Poland. The phenotype and age at disease onset are highly
variable. The aim of the study was to investigate the influence of the
transmission pattern on genetic and clinical features of juvenile SCA1
patients.
Methods: 125 SCA1 patients from 101 families were analysed retrospectively.
The mean age at onset was 35.6 +/- 9.6 and the average
CAG repeats in affected family members was 50.7 +/- 5.5, ranging
from 42 to 72. Paternal and maternal transmission was equal. In 21
SCA1 families with 25 juvenile patients, the relation of clinical severity,
sex, CAG repeats number and age at disease onset of transmitting
parents was analysed. The International Cooperative Ataxia Rating
Scale (ICARS), electrophysiological and psychological examinations
were compared in regard to transmission pattern.
Results: In 14 cases with paternal and in 11 patients with maternal
transmission the mean age at onset 20.5 +/-3.6 y. (range 12 - 25 y.),
disease duration 6.3 +/-3.7 y. and the CAG repeats number, mean
58.0 +/- 5.7 were not different. However, mean age at onset of fathers
was 33.0 y. and of mothers 29.1y. Severity of non-cerebellar signs and
ataxia were more pronounced in patients with paternal than with maternal
transmission: ICARS 34.8 and 32.8, Intelligence Quotient 92.9
and 107, respectively.
Conclusions: In our SCA1 patients the anticipation was more prominent
in subjects with paternal than with maternal transmission.
Supported by Polish Ministry of Science grant 3PO5B 019 24, partly by
EUROSCA/LSHM-CT-2004-503304.
P0237. A case of spinocerebellar ataxia type 17 (SCA17)
associated with homozygous 46/47 repeats of the TBP gene
P. Tarantino1 , E. V. De Marco1 , E. Pisano2 , F. Annesi1 , F. E. Rocca1 , D. Civitelli1 ,
I. C. Cirò Candiano1 , S. Carrideo1 , G. Provenzano1 , V. Greco1 , G. Squillace1 , M.
Caracciolo1 , G. Annesi1 ;
1 2 Institute of Neurological Sciences, Mangone (Cosenza), Italy, Department of
Neurology Hospital Cosenza, Cosenza, Italy.
Spinocerebellar ataxia type 17 (SCA17) is a dominant progressive
neurodegenerative disorder, caused by a triplet repeat expansion
within the TATA-binding protein gene (TBP); normal expansions range
from 29 to 42 repeats, whereas abnormal expansions range from 43
to 63 repeats. A reduced penetrance is associated to 43-48 repeats.
The disease is characterized by progressive limb and gait ataxia, dys-
arthria, motor, cognitive and psychiatric abnormalities.
In this study, we describe a SCA patient from Southern Italy with ataxia,
pyramidal and extrapyramidal signs and peripheral neuropathy.
We investigated this patient for CAG repeat expansions in the genes of
the spinocerebellar ataxias SCA1, SCA2, SCA3 SCA6, SCA7, SCA8,
SCA12, SCA17 and DRPLA.
Genomic DNA was amplified with fluorescent primers spanning the
SCA expansions. PCR products were separated onto a capillary sequencer
(3130XL genetic analyzer-Applied Biosystems) and the length
of specific SCA fragments was calculated referring to a size standard
and to related SCA controls. We identified an abnormal CAG/CAA repeat
expansion of 46/47 size, within the TBP gene, confirmed by direct
sequencing of the expanded SCA17 alleles showing the following structure:
(CAG)3 (CAA)3(CAG)9CAACAGCAA(CAG)26/27CAACAG.
This is the second case of homozygous expansion reported in a patient
with SCA17. Currently, genetic and clinical analysis of other family
members are ongoing to evaluate the genotype-phenotype correlation
in this family.
P0238. Identification of genomic dosage variation of CNTNAP2
in patients with schizophrenia and epilepsy
T. Vrijenhoek;
Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
Contactin-associated protein-like 2 (Caspr2) clusters voltage-gated
potassium channels (K v1.1) at the nodes of Ranvier and is encoded
by CNTNAP2 - the largest gene in the human genome. Homozygous
stop mutations in exon 22 of this gene were recently identified in Old
Order Amish children with cortical dysplasia, focal epilepsy, relative
macrocephaly, and diminished deep-tendon reflexes. We identified
deletions affecting (part of) CNTNAP2 in three patients by routine
chromosome analysis and microarray-based genomic copy number
analysis methods.
A deletion covering the chromosomal region 7q34-7q36.1 was revealed
in one severely mentally retarded epilepsy patient by routine
chromosome analysis, and shown to be de novo by Fluorescent In-
Situ Hybridisation (FISH) analysis. The deletion was 10.7 Mb in size,
affecting 58 genes including CNTNAP2. A second deletion was identified
by array-based Comparative Genomic Hybridisation (arrayCGH)
in a patient suffering from both epilepsy and schizophrenia. This deletion
of 1.5 Mb was confirmed by Multiplex Logation-dependent Probe
Amplification (MLPA), and also affected CNTNAP2. To study the link
between schizophrenia and CNTNAP2 further, we developed a targeted
Single Nucleotide Polymorphism (SNP) array for this gene and its
surrounding genomic region. Out of 315 patients and an equal number
of controls, we identified a deletion in intron 3 of CNTNAP2 in a third
schizophrenic patient, which also has a history of epilepsy.
Together these results confirm that CNTNAP2 is associated with epilepsy,
but they also show that genomic rearrangements resulting in
haploinsufficiency of CNTNAP2 may lead to a more complex phenotype
that also includes schizophrenia.
P0239. A Case of Seckel Syndrome conceived by Assisted
Reproductive Technology
N. Andıran1 , E. Tuncbilek2 , E. Odemıs1 , D. Aktas2 ;
1 2 Fatih University, Department of Pediatrics, Ankara, Turkey, Hacettepe University
School of Medicine, Department of Genetics, Ankara, Turkey.
Seckel syndrome is a rare autosomal recessive disorder characterized
by severe pre- and postnatal growth retardation, microcephaly, mental
retardation and typical facial appearance. It has also been called “birdheaded
dwarfism”. Related with Seckel syndrome, three loci have been
mapped and to date the only causative mutation has been observed
as a hypomorphic mutation in Ataxia telengiectasia and Rad3-related
(ATR) gene. Although assisted reproductive technologies (ART) including
in vitro fertilization (IVF) and intracytoplasmic sperm injection
(ICSI) are generally considered safe, some studies have suggested an
excess occurrence of birth defects and low birth-weight. Recently, various
syndromes involving epigenetic alterations have been reported to
occur in individuals following ART. Here we report a patient with Seckel
Syndrome conceived by ICSI. To the best of our knowledge, Seckel
syndrome has not been reported in patients conceived by ART and we
think that epigenetic mechanisms may be related with this syndrome
in our patient.