Dick Lindhout

Dick Lindhout
University Medical Center Utrecht | UMC Utrecht · Department of Genetics

MD, PhD

About

407
Publications
37,438
Reads
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22,332
Citations
Additional affiliations
June 2000 - June 2016
University Medical Center Utrecht
Position
  • Professor of medical genetics
June 2000 - present
Utrecht University
Position
  • Professor of medical genetics
June 2000 - December 2011
University Medical Center Utrecht
Position
  • Professor of medical genetics, Head of Department

Publications

Publications (407)
Article
Full-text available
Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy c...
Article
Wat zijn de mogelijke oorzaken van het ziektebeeld van onchocerciasis-geassocieerde epilepsie? Moeten zowel nature als nurture meegenomen worden bij het zoeken naar oorzaken van aandoeningen, mede vanwege de implicaties voor counseling, preventie en behandeling? In deze bijdrage wordt een overzicht gegeven van mogelijke complex-genetische factoren...
Article
Is de ernstige epilepsie van kinderen in de dorpen van Tanzania, die vaak diep in de binnenlanden liggen, het gevolg van een parasiet of toch een autoimmuun aandoening? In deze bijdrage een verslag van de mogelijke oorzaken en gevolgen van deze vorm van epilepsie voor de kinderen die hierdoor worden getroffen.
Article
Full-text available
Objective: To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine- or oxcarbazepine-induced hyponatremia (COIH). Methods: We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people wi...
Article
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Objective To examine neurocognitive functioning of children exposed prenatally to carbamazepine, lamotrigine, levetiracetam or valproate monotherapy.Methods In a prospective observational study, children aged 6 or 7 years, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in The Netherlands, were assessed using the...
Article
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Purpose The purpose of the study was to examine different aspects of well-being in mothers with epilepsy with school-aged children. Methods In an observational study, mothers, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in the Netherlands, completed questions on epilepsy, the impact of epilepsy on daily func...
Article
Objective: Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP). Methods: EURAP is an observational prospective cohort study designed to...
Article
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Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the 'fetal methotrexate syndrome'. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The ob...
Article
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Objective: To examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy. Methods: In collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observat...
Article
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We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disabi...
Article
The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most lik...
Article
Full-text available
Objective To ascertain the clinical and genetic factors contributing to carbamazepine and oxcarbazepine induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross‐sectional cohort of people with epilepsy. Methods We collected data on serum sodium levels and anti‐epileptic drug levels in people with ep...
Article
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Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from...
Article
Purpose: Children exposed to antiepileptic drugs (AEDs) in utero are at risk for developmental problems. Maternal epilepsy, its impact on the family system, and other family factors may also contribute. We reviewed the possible associations between family factors and developmental outcome in children who had been exposed to AED during pregnancy....
Article
Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from...
Preprint
Full-text available
Background: Children exposed to antiepileptic drugs (AEDs) in utero are at higher risk for congenital malformations. Less is known about the long-term association with neurocognition and behavior. Research into family factors related to long-term developmental outcomes of children of women with epilepsy is also rare. We present a protocol to invest...
Article
Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudin...
Article
Objective: To access the effect of vagus nerve stimulation (VNS) on the outcome of pregnancy. Methods: We used the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) and its network to search for women receiving adjunctive VNS during pregnancy. Data on maternal and fetal outcomes were extracted from the registry databases and ou...
Article
The development of high-throughput sequencing technologies has led to remarkable progress in understanding the genetic basis of human epilepsies. Over the last 5 years, more than 20 genes have been identified through genome-first approaches, identifying novel genes first and then working backwards to understand the associated phenotypes. This appro...
Article
Full-text available
Objective: To ascertain possible determinants of carbamazepine (CBZ)- and oxcarbazepine (OXC)-induced hyponatremia in a large cohort of people with epilepsy. Methods: We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤1...
Article
Women with epilepsy (WWE) have increased risk of adverse pregnancy outcomes for both the mother and child.1,2 Some of these risks can be reduced by planning prior to pregnancy. Risks of major congenital malformations and adverse cognitive/behavioral outcomes are higher for certain antiepileptic drugs (AEDs). For example, guidelines recommend avoidi...
Article
The use of carbamazepine (CBZ) and oxcarbazepine (OXC) as first-line antiepileptic drugs in the treatment of focal epilepsy is limited by hyponatremia, a known adverse effect. Hyponatremia occurs in up to half of people taking CBZ or OXC and, although often assumed to be asymptomatic, it can lead to symptoms ranging from unsteadiness and mild confu...
Article
Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnan...
Article
Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized...
Article
Objective: To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS). Methods: We retrospectively analyzed data from hospital medical files, child health clinics, and the v...
Article
Full-text available
Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function mis-sense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized...
Article
To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitore...
Article
To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose. The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which th...
Article
Full-text available
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confide...
Article
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Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associa...
Article
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Objectives: This study was an assessment of the incidence, course, and etiology of epilepsy with vaccination-related seizure onset in a population-based cohort of children. Methods: The medical data of 990 children with seizures after vaccination in the first 2 years of life, reported to the National Institute for Public Health and Environment i...
Article
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Background: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loc...
Article
Full-text available
A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies a...
Article
Full-text available
Objective: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. Methods: We mapped a quantitative trait locus (QTL1) fo...
Article
Mitochondrial Ca(2+) uptake has key roles in cell life and death. Physiological Ca(2+) signaling regulates aerobic metabolism, whereas pathological Ca(2+) overload triggers cell death. Mitochondrial Ca(2+) uptake is mediated by the Ca(2+) uniporter complex in the inner mitochondrial membrane, which comprises MCU, a Ca(2+)-selective ion channel, and...
Article
Mitochondrial Ca2+ uptake has key roles in cell life and death. Physiological Ca2+ signaling regulates aerobic metabolism, whereas pathological Ca2+ overload triggers cell death. Mitochondrial Ca2+ uptake is mediated by the Ca2+ uniporter complex in the inner mitochondrial membrane1, 2, which comprises MCU, a Ca2+-selective ion channel, and its reg...
Article
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Generalized epilepsy with febrile seizures plus (GEFS+) is an early onset febrile epileptic syndrome with therapeutic responsive (a)febrile seizures continuing later in life. Dravet syndrome (DS) or severe myoclonic epilepsy of infancy has a complex phenotype including febrile generalized or hemiclonic convulsions before the age of 1, followed by i...
Article
Full-text available
A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies a...
Article
Objectives To evaluate prospectively the influence of cyclic oral contraceptive (OC) use on lamotrigine (LTG) serum levels when used in combination therapy. Methods Women with epilepsy using LTG in combination with valproate (VPA; n = 7), carbamazepine (CBZ; n = 3) or oxcarbazepine (OXC; n = 1) were evaluated during two periods of 28 days cyclic OC...
Article
Full-text available
ALDH7A1 and PNPO deficiencies are rare inborn errors of vitamin B6 metabolism causing perinatal seizure disorders. The phenotypic variability, however, is broad. To assess the frequency of these deficiencies in unexplained infantile epilepsy, we screened 113 patients for mutations in both genes. We identified 1 patient with an epilepsy phenotype re...
Article
To analyze seizure control, dose adjustments, and other changes of antiepileptic drug (AED) treatment during pregnancy in a large cohort of women with epilepsy entering pregnancy on monotherapy with carbamazepine, lamotrigine, phenobarbital, or valproate. Seizure control and AED treatment were recorded prospectively in 3,806 pregnancies of 3,451 wo...
Article
Data sharing is essential for a better understanding of genetic disorders. Good phenotype coding plays a key role in this process. Unfortunately, the two most widely used coding systems in medicine, ICD-10 and SNOMED-CT, lack information necessary for the detailed classification and annotation of rare and genetic disorders. This prevents the optima...
Article
Full-text available
To determine the prevalence of Dravet syndrome, an epileptic encephalopathy caused by SCN1A-mutations, often with seizure onset after vaccination, among infants reported with seizures following vaccination. To determine differences in characteristics of reported seizures after vaccination in children with and without SCN1A-related Dravet syndrome....
Data
Vaccination schedules from 1997–2006. (DOC)
Data
Clinical features of children with Dravet syndrome. (DOCX)
Data
Follow-up results of children according to classification of seizures at stage 1. (DOC)
Article
Full-text available
Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible auti...
Article
Full-text available
Background Most pregnant women with chronic active epilepsy need to use antiepileptic drugs (AEDs) during pregnancy to prevent epileptic seizures that may threaten maternal and fetal well-being. Valproic acid (VPA) and carbamazepine (CBZ) have been associated with an increased risk of neural tube defects (NTDs) in the exposed fetus. Aim To investig...
Article
Full-text available
Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown t...
Article
Full-text available
Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) in...
Article
Full-text available
To describe the questions addressed by participants and physicians to the International Registry of Antiepileptic Drugs and Pregnancy centre in The Netherlands (EURAP-NL). All incoming questions during the study period were systematically inventoried. Characteristics of the inquirer, antiepileptic drugs (AEDs) indicated, question topic, indication...
Article
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Dental agenesis is the most common, often heritable, developmental anomaly in humans. Mutations in MSX1, PAX9, AXIN2 and the ectodermal dysplasia genes EDA, EDAR and EDARADD have been detected in familial severe tooth agenesis. However, until recently, in the majority of cases (∼90%) the genetic factor could not be identified, implying that other g...
Article
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Aims: Pyridoxine dependent epilepsy (PDE) and pyridoxal-5'-phosphate deficiency are rare autosomal recessive enzyme defects in vitamin B6 metabolism due to mutations in the ALDH7A1 and PNPO gene. These disorders are typically characterized by severe, neonatal seizures that are resistant to anticonvulsant drugs but can be controlled by pyridoxine/py...
Article
Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2...
Article
Full-text available
Electrical status epilepticus in sleep syndrome is the association of the electroencephalographic pattern and deficits in language or global cognitive function and behavioral problems. The etiology is often unknown, but genetic risk factors have been implicated. Array-based comparative genomic hybridization was used to identify copy number variatio...