2009 Vienna - European Society of Human Genetics

Genetic analysis, linkage ans association
40-50 fold reduction in Na + affinity. The structural basis for this impairment
in Na + binding are provided by molecular modelling of ATP1A3 in
the E1 (Na + bound) conformation. Both the clinical presentation and the
biochemical findings associated with the p.1013Ydup mutation provide
in vivo and in vitro evidence for a crucial role of Na + affinity in the
pathophysiology of DYT12.
P17.63
A novel SCN A mutation in a family with GEFs+ and sudden
unexpected death in epilepsy (sUDEP)
R. Sanz1 , R. Guerrero1 , C. Almaraz1 , A. Marinas1 , B. Gonzalez-Giraldez1 , J.
Macarron2 , J. Serratosa1 ;
1 2 Fundacion Jimenez Diaz, Madrid, Spain, Hospital General Yagüe, Burgos,
Spain.
Sudden unexpected death in epilepsy (SUDEP) is a rare and unexplained
cause of death in patients with epilepsy. Different risk factors
and mechanisms may lead to a final common pathway of cardio-respiratory
compromise. Mutations in the gene coding for the alfa-1 subunit
of the neuronal voltage-gated sodium channel (SCN1A) gene, have
been described in families with generalized epilepsy with febrile seizures
plus (GEFS+). Mutations in genes coding for ion channels have
also been associated to cardiac channelopathies. SUDEP is the most
important direct epilepsy-related cause of death, and it has been suggested
that some of these deaths may be due to cardiac arrhythmias.
The neuronal voltage-gated sodium channel may have a role in pacemaker
function of the sino-atrial node and blocking this channel slows
the heart and increases heart rate variability.
The SCN1A gene was analyzed in a three generation GEFS+ family
with two SUDEP cases. In this family, different epileptic phenotypes
were present: Dravet syndrome, Doose syndrome and febrile seizures
plus. Bi-directional sequencing of SCN1A revealed a new mutation
(M1427T) in the patient with Dravet syndrome. This mutation is located
in domain III, between transmembrane segments S5 and S6. Segregation
analysis in the family revealed that all living members affected with
epilepsy carried the mutation.
Our findings suggest that SCN1A mutations may play a role, either
directly or indirectly, in SUDEP.
P17.64
Phenotypic variability of neuropsychiatric symptoms in EPm1-
Unverricht-Lundborg disease (ULD)
D. R. Amrom 1,2 , M. Talani 1,2 , F. Andermann 1,3 , A. Lehesjoki 4 , E. Andermann 1,5 ;
1 Montreal Neurological Hospital, Montreal, QC, Canada, 2 Department of Neurology
and Neurosurgery, and Neurogenetics Unit, Montreal, QC, Canada,
3 Department of Neurology and Neurosurgery, Epilepsy Service, Department of
Pediatrics, McGill University, Montreal, QC, Canada, 4 Folkhalsan Institute of
Genetics and Neuroscience Center, Biomedicum Helsinki, University of Helsinki,
Helsinki, Finland, 5 Department of Neurology and Neurosurgery, and Neurogenetics
Unit, Department of Human Genetics, McGill University, Montreal,
QC, Canada.
Purpose: To present the differences in neuropsychiatric symptoms in
two unrelated individuals and two siblings, all with molecularly confirmed
ULD.
Method: Review of medical records and investigations.
Results: Our four Caucasian patients had disease onset at the age of
8-10 years. They received valproic acid and various add-on medications.
Patient 4 had a vagal nerve stimulator implanted.
Patient 1, a 30-year-old woman, has mild motor disability and mild
mental retardation, adjustment disorder, drug abuse, and has had several
suicide attempts.
Patient 2, her 31-year-old brother, walks independently, drinks alcohol
since it has an antimyoclonic effect, has a history of drug abuse, and
mood disorder.
Patient 3, a 25-year-old man, is able to walk and perform some activities
of daily living, but presents frequent drop attacks. He has a positive
mood, no psychiatric symptoms.
Patient 4, a 43-year-old man, is wheelchair bound. He is irritable and
presents suicidal ideas, although these probably represent “acting-out”
behaviour.
DNA analysis of the cystatin B gene showed: in patients 1 and 2, a
dodecamer repeat expansion on one allele and a c.67-1G>C mutation
on the other allele; in patient 3, a dodecamer repeat expansion on
one allele and an IVS1-1G→C mutation on the other allele; in patient
4 (non-consanguineous parents), a dodecamer repeat expansion on
both alleles.
Conclusion: In these patients, the differences in symptomatology and
disability were striking and unexplained. Although the severity and rate
of progression of ULD are known to be variable, the relationship to the
type of mutation requires further study.
P17.65
Influence of polymorphism IVS5-91G>A in SCN1A gene in
patients with partial epilepsia treated by carbamazepine
monotherapy
C. Rooryck Thambo 1,2 , A. Pariente 3 , K. Forest 3 , C. Marchal 4 , V. Michel 4 , T.
Barnetche 1 , B. Arveiler 1,2 ;
1 Laboratoire de Génétique Humaine, Bordeaux, France, 2 Service de Génétique
Médicale CHU Pellegrin, Bordeaux, France, 3 Department of Pharmacology
CHU Bordeaux, Bordeaux, France, 4 Department of Neurology CHU Pellegrin,
Bordeaux, France.
Introduction: Carbamazepine is still widely used as a first-line drug to
treat partial epilepsy. It acts by binding to the α-subunit of voltagesensitive
sodium channels in neurons. Despite its efficacy has been
clearly proven, some discrepancies were observed in the treatment
response with 30% of non-responders patients. The aim of this study is
to determine whether nine functional single-nucleotide polymorphisms
in the SCN1A, SCN2A and SCN1B genes, coding for ion sodium channels,
correlate with epilepsy susceptibility and with response to carbamazepine.
Patients and methods: The population study included a French cohort
of 47 patients with partial epilepsy treated by carbamazepine monotherapy
and 95 healthy controls. Allele and genotype frequencies were
compared between patients and controls, according to their response
to carbamazepine therapy. The patients were considered to be drug
responsive if they had not experienced any seizure for one year after
receiving carbamazepine monotherapy. We also observed clinical
correlation with carbamazepine maximum doses. Genotypes were determined
on genomic DNA extracted from whole blood, using primer
extension method (SnapShot, ABI).
Results: No association was found between these nine SNPs and epilepsy
susceptibility. A significant correlation was found between one
SNP (IVS5-91G/A) and response to treatment. A allele carriers get
a better response to carbamazepine therapy. These results show a
trend opposite to that described in previous studies. Larger studies are
needed to confirm the relevance of this association.
P17.66
study of the possible role of DRD2 and DAt1 gene
polymorphisms on behavioral characteristics in animal model of
epilepsy
A. Hannanova 1 , A. Kazantseva 2 , N. Leushkina 1 , L. Kalimullina 1 ;
1 Bashkir State University, Ufa, Russian Federation, 2 Institute of Biochemistry
and Genetics Ufa Scientific Centre Russian Academy of Sciences, Ufa, Russian
Federation.
Despite of the increasing interest in the study of epilepsy known to be
one of the severe psychoneurological disorders, mechanisms of its
forming remain unclear. WAG/Rij strain rats belong to inbred line with
genetically determined absens epilepsy and thus might be considered
as model of epilepsy manifesting as result of sound sensitivity in particular.
It has been reported earlier that dopaminergic system functioning
is associated with epilepsy.
We aimed to define a single genotype effect of polymorphisms in
dopaminergic system genes: DRD2 rs8154872 in exon 7 and DAT1
rs13448119 in exon 2 - on audiogenic sensitivity and on behavioral
characteristics in WAG/Rij strain rats.
The present study sample was comprised of 55 WAG/Rij rats genotyped
previously for DRD2 Taq1A polymorphism in order to reveal
inbred lines in direction to A1-allele and A2-allele. Audiogenic sensitivity
was assessed by the presence / absence of epileptic seizure as
response to stimuli, while exploratory and locomotor activities were
detected by means of open-field test and elevated plus maze. Genotyping
of two polymorphisms was performed using PCR, PCR-RFLP
technique.
According to genotyping of DAT1 rs13448119 polymorphism only
samples with T/T genotype were detected, while analyzing DRD2
rs8154872 polymorphism one C/T genotype was observed. Unfortu-