Publications by authors named "Ulvi Vaher"

12 Publications

  • Page 1 of 1

Epilepsy after perinatal stroke with different vascular subtypes.

Epilepsia Open 2018 Jun 2;3(2):193-202. Epub 2018 Mar 2.

Radiology Clinic of Tartu University Hospital Tartu Estonia.

Objective: With an incidence up to 63 per 100,000 live births, perinatal stroke is an important cause of childhood epilepsy. The aim of the study was to find the prevalence of and predictive factors for epilepsy, and to describe the course of epilepsy in children with perinatal stroke with different vascular subtypes.

Methods: Patients were retrieved from the Estonian Paediatric Stroke Database with follow-up time at least 24 months. Patients were divided into 5 perinatal stroke syndromes: neonatal arterial ischemic stroke (AIS), neonatal hemorrhagic stroke, neonatal cerebral sinovenous thrombosis, presumed AIS, and presumed periventricular venous infarction.

Results: The final study group included 73 children with perinatal stroke (39 boys). With a median follow-up time of 8.6 years, epilepsy was diagnosed in 21/73 (29%) children, most of whom had AIS (17/21, 81%). The 18-year cumulative poststroke epilepsy risk according to the Kaplan-Meier estimator was 40.8% (95% confidence interval [CI] 20.7-55.9%). The median age at epilepsy diagnosis was 50 months (range 1 month to 18.4 years). Children with neonatal AIS had the highest risk of epilepsy, but children with presumed AIS more often had severe epilepsy syndromes. Cortical lesions (odds ratio [OR] 19.7, 95% CI 2.9-133), and involvement of thalamus (OR 9.8, 95% CI 1.8-53.5) and temporal lobe (OR 8.3, 95% CI 1.8-39.6) were independently associated with poststroke epilepsy.

Significance: The risk for poststroke epilepsy after perinatal stroke depends on the vascular subtype. Patients with perinatal AIS need close follow-up to detect epilepsy and start with antiepileptic treatment on time.
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http://dx.doi.org/10.1002/epi4.12104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983200PMC
June 2018

Incidence of Childhood Epilepsy in Estonia.

J Child Neurol 2018 08 4;33(9):587-592. Epub 2018 Jun 4.

1 Department of Pediatrics, University of Tartu, Tartu, Estonia.

The aim of this prospective epidemiological study was to establish the incidence rate of childhood epilepsy in Estonia, to describe the clinical spectrum and to identify etiology of childhood epilepsy. The overall incidence rate was 86.3/100 000. The incidence rate was the highest (141.9/100 000) in the age group from 5 to 9 years. Specific electroclinical syndromes were identified in 22.8% of cases. Structural or metabolic etiology was identified in 20.0% of cases, presumed genetic origin was identified in 33.9% of cases, and in 46.1% of cases the cause of epilepsy remained unknown. The incidence rate of childhood epilepsy in Estonia (86.3/100 000) is similar to the other European countries. In comparison with the results of the first epidemiological study of childhood epilepsy in Estonia (incidence rate 45/100 000; Beilmann et al), the incidence rate in this study is almost 2 times higher, what can be explained with better case collection and improved diagnostic modalities in Estonia.
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http://dx.doi.org/10.1177/0883073818776760DOI Listing
August 2018

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies.

Neurology 2017 01 4;88(5):483-492. Epub 2017 Jan 4.

From the Danish Epilepsy Centre (R.S.M., K.M.J., M.N.), Dianalund; Institute for Regional Health Services (R.S.M., K.M.J., M.N.), University of Southern Denmark, Odense; Department of Neurology and Epileptology (T.V.W., S.V., H.L., S.M.), Hertie Institute for Clinical Brain Research, and Department of Neurosurgery (T.V.W.), University of Tübingen; Department of Neuropediatrics (I.H., M.P., S.v.S., H.M.), University Medical Center Schleswig-Holstein, Kiel, Germany; Division of Neurology (I.H., S.H., H.D.), The Children's Hospital of Philadelphia, PA; Neuroscience Department (C.M., R.G.), Children's Hospital Anna Meyer-University of Florence, Italy; Department of Genetics (E.H.B., M.S., K.L.v.G.), University Medical Center Utrecht, the Netherlands; Department of Neurology and Neurorehabilitation (U.V., I.T., T.T.), Children's Clinic of Tartu University Hospital, Estonia; Department of Pediatric Neurology and Epilepsy Center (I.B.), LMU Munich, Germany; Department of Pediatrics (I.T., T.T.), University of Tartu; Tallinn Children's Hospital (I.T.), Tallinn, Estonia; Clinic for Neuropediatrics and Neurorehabilitation (G.K., C.B., H.H.), Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Germany; Paracelsus Medical Private University (G.K.), Salzburg, Austria; Neuropeadiatric Department (L.L.F.), Hospices Civils de Lyon; Department of Genetics (G.L., N.C.), Lyon University Hospitals; Claude Bernard Lyon I University (G.L., N.C.); Lyon Neuroscience Research Centre (G.L., N.C.), CNRS UMR5292, INSERM U1028; Epilepsy, Sleep and Pediatric Neurophysiology Department (J.d.B.), Lyon University Hospitals, France; Clinic for Pediatric Neurology (S.B.), Pediatric Department, University Hospital, Herlev, Denmark; Kleinwachau (N.H.), Sächsisches Epilepsiezentrum Radeberg, Dresden; Department of Neuropediatrics/Epilepsy Center (J.J.), University Medical Center Freiburg; Department of General Paediatrics (S.S.), Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg; Department of Women and Child Health (S.S.), Hospital for Children and Adolescents, University of Leipzig Hospitals and Clinics, Germany; Department of Pediatrics (C.T.M., H.C.M.), Division of Genetic Medicine, University of Washington, Seattle; Amplexa Genetics (L.H.G.L., H.A.D.), Odense, Denmark; Northern German Epilepsy Center for Children and Adolescents (S.v.S.), Schwentinental-Raisdorf, Germany; Wilhelm Johannsen Centre for Functional Genome Research (Y.M., N.T.), Department of Cellular and Molecular Medicine, University of Copenhagen; Danish Epilepsy Center (G.R.), Filadelfia/University of Copenhagen, Denmark; Department of Diagnostics (J.R.L.), Institute of Human Genetics, University of Leipzig; and Svt. Luka's Institute of Child Neurology and Epilepsy (K.M.), Moscow, Russia. Dr Maljevic is currently at the Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.

Objective: To examine the role of mutations in GABRB3 encoding the β subunit of the GABA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes.

Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs.

Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant β, together with α and γ subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations.

Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.
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http://dx.doi.org/10.1212/WNL.0000000000003565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278942PMC
January 2017

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies.

Mol Syndromol 2016 Sep 20;7(4):210-219. Epub 2016 Aug 20.

Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark.

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including and . Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.
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http://dx.doi.org/10.1159/000448369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073625PMC
September 2016

CDKL5 Gene-Related Epileptic Encephalopathy in Estonia: Four Cases, One Novel Mutation Causing Severe Phenotype in a Boy, and Overview of the Literature.

Neuropediatrics 2016 Dec 6;47(6):361-367. Epub 2016 Sep 6.

Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia.

Cyclin-dependent kinase-like 5 () gene mutations have mainly been found in females with early infantile epileptic encephalopathy (EIEE), severe intellectual disability, and Rett-like features. To date, only 22 boys have been reported, presenting with far more severe phenotypic features. We report the first cases of gene-related EIEE in Estonia diagnosed using panels of epilepsy-associated genes and describe the phenotype-genotype correlations in three male and one female patient. One of the mutations, identified in a male patient, was a novel de novo hemizygous frameshift mutation (NM_003159.2:c.2225_2228del (p.Glu742Afs*41)) in exon 15 of All boys have a more severe phenotype than the female patient. In boys with early onset of seizures and poor development with absent or poor eye contact, gene-related EIEE can be suspected and epilepsy-associated genes should be analyzed for early etiological diagnosis. Early genetic diagnosis would be the cornerstone in personalized treatment in the future.
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http://dx.doi.org/10.1055/s-0036-1586730DOI Listing
December 2016

Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy.

Am J Med Genet A 2016 08 2;170(8):2173-6. Epub 2016 Jun 2.

Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.

The CACNA1A gene encodes the transmembrane pore-forming alpha-1A subunit of the Cav 2.1 P/Q-type voltage-gated calcium channel. Several heterozygous mutations within this gene, including nonsense mutations, missense mutations, and expansion of cytosine-adenine-guanine repeats, are known to cause three allelic autosomal dominant conditions-episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. An association with epilepsy and CACNA1A mutations has also been described. However, the link with epileptic encephalopathies has emerged only recently. Here we describe two patients, sister and brother, with compound heterozygous mutations in CACNA1A. Exome sequencing detected biallelic mutations in CACNA1A: A missense mutation c.4315T>A (p.Trp1439Arg) in exon 27, and a seven base pair deletion c.472_478delGCCTTCC (p.Ala158Thrfs*6) in exon 3. Both patients were normal at birth, but developed daily recurrent seizures in early infancy with concomitant extreme muscular hypotonia, hypokinesia, and global developmental delay. The brain MRI images showed progressive cerebral, cerebellar, and optic nerve atrophy. At the age of 5, both patients were blind and bedridden with a profound developmental delay. The elder sister died at that age. Their parents and two siblings were heterozygotes for one of those pathogenic mutations and expressed a milder phenotype. Both of them have intellectual disability and in addition the mother has adult onset cerebellar ataxia with a slowly progressive cerebellar atrophy. Compound heterozygous mutations in the CACNA1A gene presumably cause early onset epileptic encephalopathy, and progressive cerebral, cerebellar and optic nerve atrophy with reduced lifespan. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37678DOI Listing
August 2016

Clinical Phenotype of De Novo Mutation: Case Report and Review of Literature.

Child Neurol Open 2015 Apr-Jun;2(2):2329048X15583717. Epub 2015 May 5.

Department of Pediatrics, University of Tartu, Tartu, Estonia.

Mutations in the guanine nucleotide-binding protein (G protein), α activating activity polypeptide O () gene have recently been described in 6 patients with early infantile epileptic encephalopathies. In the present study, we report the phenotype and the clinical course of a 4-year-old female with an epileptic encephalopathy (Ohtahara syndrome) and profound intellectual disability due to a de novo mutation (c.692A>G; p.Tyr231Cys). Ohtahara syndrome is a devastating early infantile epileptic encephalopathy that can be caused by mutations in different genes, now also including . The mutation was found using a targeted next generation sequencing gene panel and demonstrates targeted sequencing as a powerful tool for identifying mutations in genes where only a few de novo mutations have been identified.
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http://dx.doi.org/10.1177/2329048X15583717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417033PMC
May 2015

Monosomy 1p36 - a multifaceted and still enigmatic syndrome: four clinically diverse cases with shared white matter abnormalities.

Eur J Paediatr Neurol 2014 May 25;18(3):338-46. Epub 2014 Jan 25.

Department of Pediatrics, Faculty of Medicine, University of Tartu, Tartu, Estonia; Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.

Monosomy 1p36 is the most common subtelomeric deletion syndrome seen in humans. Uniform features of the syndrome include early developmental delay and consequent intellectual disability, muscular hypotonia, and characteristic dysmorphic facial features. The gene-rich nature of the chromosomal band, inconsistent deletion sizes and overlapping clinical features have complicated relevant genotype-phenotype correlations. We describe four patients with isolated chromosome 1p36 deletions. All patients shared white matter abnormalities, allowing us to narrow the critical region for white matter involvement to the deletion size of up to 2.5 Mb from the telomere. We hypothesise that there might be a gene(s) responsible for myelin development in the 1p36 subtelomeric region. Other significant clinical findings were progressive spastic paraparesis, epileptic encephalopathy, various skeletal anomalies, Prader-Willi-like phenotype, neoplastic changes - a haemangioma and a benign skin tumour, and in one case, sleep myoclonus, a clinical entity not previously described in association with 1p36 monosomy. Combined with prior studies, our results suggest that the clinical features seen in monosomy 1p36 have more complex causes than a classical contiguous gene deletion syndrome.
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http://dx.doi.org/10.1016/j.ejpn.2014.01.008DOI Listing
May 2014

De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders.

J Child Neurol 2014 Dec 18;29(12):NP202-6. Epub 2013 Dec 18.

Children's Clinic, Tartu University Hospital, Tartu, Estonia Department of Pediatrics, University of Tartu, Tartu, Estonia.

Epileptic encephalopathies represent a clinically and genetically heterogeneous group of disorders, majority of which are of unknown etiology. We used whole-exome sequencing of a parent-offspring trio to identify the cause of early infantile epileptic encephalopathy in a boy with neonatal seizures, movement disorders, and multiple congenital anomalies who died at the age of 17 months because of respiratory illness and identified a de novo heterozygous missense mutation (c.3979A>G; p.Ile1327Val) in SCN8A (voltage-gated sodium-channel type VIII alpha subunit) gene. The variant was confirmed in the proband with Sanger sequencing. Because the clinical phenotype associated with SCN8A mutations has previously been identified only in a few patients with or without epileptic seizures, these data together with our results suggest that mutations in SCN8A can lead to early infantile epileptic encephalopathy with a broad phenotypic spectrum. Additional investigations will be worthwhile to determine the prevalence and contribution of SCN8A mutations to epileptic encephalopathies.
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http://dx.doi.org/10.1177/0883073813511300DOI Listing
December 2014

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.

Nat Genet 2013 Sep 11;45(9):1067-72. Epub 2013 Aug 11.

Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.

Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.
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http://dx.doi.org/10.1038/ng.2728DOI Listing
September 2013

Newly-diagnosed pediatric epilepsy is associated with elevated autoantibodies to glutamic acid decarboxylase but not cardiolipin.

Epilepsy Res 2013 Jul 25;105(1-2):86-91. Epub 2013 Mar 25.

Department of Pediatrics, University of Tartu, Lunini 6, Tartu 51014, Estonia.

Glutamic acid decarboxylase autoantibodies (GADA) and anti-cardiolipin autoantibodies (ACA) have been detected in adult subjects with epilepsy, though the functional implications of these findings are a matter of debate. This study aimed to determine the prevalence of GADA and ACA and to investigate their clinical significance in pediatric subjects with newly-diagnosed epilepsy. For this purpose GADA and ACA were assessed by enzyme-linked immunosorbent assays in 208 pediatric patients with newly-diagnosed epilepsy and 128 controls. The clinical data (results of electroencephalography, magnetic resonance imaging, 6-month outcome etc.) was compared to antibody test results. Our study revealed GADA in 14 (6.7%) patients with epilepsy and in 1 (0.8%) control, which was a statistically significant difference (P=0.010; Chi-square test). The GADA-positive and -negative patients had similar clinical characteristics. The prevalence of ACA in patients with epilepsy (6.3%) was not significantly different than controls (2.6%). These results suggest that GADA is associated with epilepsy in a subgroup of newly-diagnosed pediatric patients. Further studies are required to determine the prognostic significance and pathogenic role of GADA among pediatric subjects with epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2013.02.009DOI Listing
July 2013

A novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability.

Eur J Med Genet 2012 Mar 21;55(3):178-84. Epub 2012 Jan 21.

Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.

Mutations in the KDM5C gene (lysine (K)-specific demethylase 5C gene; also known as JARID1C and SMCX; MIM 314690) were recently associated with X-linked intellectual disability (XLID). To date only two case reports and five studies that screen for mutations in the KDM5C gene have been published, with 21 mutations reported. Herein we present a large family with XLID caused by a novel mutation c.2T > C in the start codon of the KDM5C gene, presumably leading to loss of gene translation. Six sibs out of seven (two sons and four sisters) and their mother carry this mutation. Two affected males presented the distinctive clinical phenotype, characterized by moderate short stature, clumsy gait, ataxia, increased muscle tone and brisk tendon reflexes. They constantly bore a happy and smiling facial expression, with a protruding tongue. We hereby offer the first thorough description of five affected females with the KDM5C gene mutation. Most frequent clinical features were short stature, facial dysmorphism and developmental problems. X-chromosome inactivation study showed completely skewed inactivation pattern of mutation-carrying chromosome in all affected female patients.
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http://dx.doi.org/10.1016/j.ejmg.2012.01.004DOI Listing
March 2012
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