Berten Ceulemans - Academia.edu (original) (raw)
Papers by Berten Ceulemans
Neurotherapeutics, 2019
Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for wh... more Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.
The early infantile epileptic encephalopathies (EIEE) are a group of rare, severe neurodevelopmen... more The early infantile epileptic encephalopathies (EIEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 novel putative transcript models. The extended transcriptional footprint of these genes allowed for 294 intronic or intergenic variants, found in human mutation databases, to be reclassified as exonic, while a further 70 intronic variants were reclassified as splice-site proximal. Using SCN1A as a case study due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome, or a similar phenotype, with a pa...
Abstracts of the 44th Annual Meeting of the Society for Neuropediatrics, 2018
The American Journal of Human Genetics, 2018
Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterize... more Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs. 1-3 This suggests that unknown genetic etiologies exist, potentially in the $98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a ''poison'' exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons, 4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly. 6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.
European Journal of Paediatric Neurology, 2018
Aim: Sleep problems are often reported in patients with a Dravet Syndrome (DS). In this study we ... more Aim: Sleep problems are often reported in patients with a Dravet Syndrome (DS). In this study we explored the sleep behavior in DS and compared the prevalence of sleep problems with other epilepsy patients. Methods: An online questionnaire based on the 'Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP)' was distributed amongst DS parents and a control group (parents from children with epilepsy). Completed questionnaires were evaluated by factor scores and Composite Sleep Index (CSI). Results: Fifty-six responses were recorded in the DS group (42 were 18 year). Caregivers reported an overall frequency of sleep problems in 42.3% (22/52). Severe sleep problems, measured by CSI, were found in 28.3% (13/46) mainly related to night waking or daytime sleepiness. In the control group (n ¼ 66, 62 were 18 year), sleep problems were reported by 21.2% (14/52) of the parents. Comparison analysis between pediatric DS and epilepsy patients revealed no significant differences between the prevalence of different types of sleep disorders, except for daytime sleepiness (p ¼ 0.042). However, the parent (or caregiver)reported quality of sleep was significantly lower in the DS group (p ¼ 0.011). Interpretation: Sleep problems are frequent in DS patients and are mainly related to daytime sleepiness and night waking. Compared with other epilepsy patients, severe sleep problems are not more common in patients with a DS. However DS patients tend to have more mild night waking problems, which may explain the worse parental-reported sleep quality in DS patients.
2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2015
Home monitoring of refractory epilepsy patients has become of more interest the last couple of de... more Home monitoring of refractory epilepsy patients has become of more interest the last couple of decades. A biomedical signal that can be used for online seizure detection at home is the electrocardiogram. Previous studies have shown that tonic-clonic seizures are most often accompanied with a strong heart rate increase. The main issue however is the strong patient-specific behavior of the ictal heart rate features, which makes it hard to make a patient-independent seizure detection algorithm. A patient-specific algorithm might be a solution, but existing methods require the availability of data of several seizures, which would make them inefficient in case the first seizure only occurs after a couple of days. Therefore an online method is described here that automatically converts from a patient-independent towards a patient-specific algorithm as more patient-specific data become available. This is done by using online feedback from the users to previously given alarms. By using a simplified one-class classifier, no seizure training data needs to be available for a good performance. The method is already able to adapt to the patient-specific characteristics after a couple of hours, and is able to detect 23 of 24 seizures longer than 10s, with an average of 0.38 false alarms per hour. Due to its low-complexity, it can be easily used for wearable seizure detection at home.
European Journal of Paediatric Neurology, 2015
Objective Dravet syndrome is a severe epileptic encephalopathy beginning in infancy. The characte... more Objective Dravet syndrome is a severe epileptic encephalopathy beginning in infancy. The characteristic electroclinical picture is well known. With the discovery of SCN1A, molecular confirmation is possible in 75% of the patients. In approximately 70% a mutation is found and in 3–5% a copy number variant (CNV). CNVs frequently involve deletions, which not only contain SCN1A but the whole SCN gene cluster. This cluster contains five sodium channel genes (SCN3A, SCN2A, SCN1A, SCNC9A and SCN7A) along with GRB14 and GALNT3. The aim of this study was to determine whether patients with a SCN cluster deletion show a more severe form of the Dravet syndrome or have a specific continuous gene deletion syndrome. Methods We retrospectively reviewed the files of children with a deletion of the SCN gene cluster. Results We report six patients with a SCN cluster deletion (5 confirmed by aCGH, one with MLPA). All patients have a large de novo deletion (mean 5.6 Mb, SD 2.5). The mean age of presentation was 14.8 w (SD 7.3 w). Four infants presented with myoclonus, one with a febrile status epilepticus and one with an afebrile focal seizure with secondary generalization. Three had dysmorphic features and an abnormal development prior to the onset of convulsions. All patients showed a disastrous course with a severe mental retardation, hypotonia, failure to thrive and therapy resistant epilepsy in infancy. Two patients died around the age of one year, one at the age of 15 years. Three patients (8m, 20m and 4y of age) are still in follow-up. Conclusion Patients with a SCN cluster deletion frequently show a more severe form than the classic Dravet syndrome phenotype. The slightly earlier presentations with myoclonic seizures, abnormal development prior to the onset of convulsions, severe developmental delay or dead in infancy are suggestive for the SCN cluster deletion syndrome.
Acta Neurologica Belgica, 2013
Over the past decades, it has become clear that the most efficient way to prevent status epilepti... more Over the past decades, it has become clear that the most efficient way to prevent status epilepticus is to stop the seizure as fast as possible, and early treatment of prolonged convulsive seizures has become an integral part of the overall treatment strategy in epilepsy. Benzodiazepines are the first choice drugs to be used as emergency medication. This treatment in the early phases of a seizure often implies a 'pre-medical' setting before intervention of medically trained persons. In this paper, we propose "good practice points" for first line management of prolonged convulsive seizures in children and adults in a 'pre-medical' setting.
JIMD Reports
Monosialotetrahexosylganglioside (GMI) gangliosidosis and Morquio type B (MorB) are two lysosomal... more Monosialotetrahexosylganglioside (GMI) gangliosidosis and Morquio type B (MorB) are two lysosomal storage disorders (LSDs) caused by the same enzyme deficiency, β-galactosidase (βgal). GMI gangliosidosis, associated with GMI ganglioside accumulation, is a neurodegenerative condition characterized by psychomotor regression, visceromegaly, cherry red spot, and facial and skeletal abnormalities. MorB is characterized by prominent and severe skeletal deformities due to keratan sulfate (KS) accumulation. There are only a few reports on intermediate phenotypes between GMI gangliosidosis and MorB. The presentation of two new patients with this rare intermediate phenotype motivated us to review the literature, to study differences and similarities between GMI gangliosidosis and MorB, and to speculate about the possible mechanisms that may contribute to the differences in clinical presentation. In conclusion, we hypothesize that GMI gangliosidosis and MorB are part of one phenotypic spectrum of the same disease and that the classification of LSDs might need to be revised.
Acta Neurologica Belgica, 2004
Peer reviewe
Acta Neurologica Belgica, 2004
Epilepsia, 2020
5 CRMR malformations et maladies congénitales du cervelet et déficiences intellectuelles de cause... more 5 CRMR malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares,
2015 Computing in Cardiology Conference (CinC), 2015
Previous studies have shown that during several types of seizures, the heart rate increases stron... more Previous studies have shown that during several types of seizures, the heart rate increases strongly towards a maximal patient-specific epileptic heart rate HR ep. This ictal peak heart rate is one of the most important features for classifying epileptic heart rate increases. We therefore try to estimate HR ep , which is done by using least squares support vector machines. The found estimation had a mean square error of 18bpm, which is an improvement compared to age-based estimators. Adding this information to an online seizure detector led to an increased performance (F1-score: 14.65% to 18.72%) with a decreased detection delay (23.8s to 11.9s).
Proceedings of the …, 2007
AbstractThe first aim of the project is to construct an acquisition system for four acceleromete... more AbstractThe first aim of the project is to construct an acquisition system for four accelerometer sensors, fixed to the extremities. The information is transmitted to a data-gatheringsystem which synchronizes the accelerometer signals with the video-...
European Journal of Paediatric Neurology, 2019
Objective: To quantify gait abnormalities in people with Dravet syndrome (DS). Methods: Individua... more Objective: To quantify gait abnormalities in people with Dravet syndrome (DS). Methods: Individuals with a confirmed diagnosis of DS were enrolled. They were stratified according to knee flexion at initial contact (IC) and range of motion (ROM) during stance [crouch gait if knee flexion >20° at IC and knee range of motion (ROM) >15°; straight gait: knee flexion <20° at IC]. A 1D ANOVA (α = 0.05) was used to test statistical differences among the joint kinematics and spatio-temporal parameters of the cohort and an age-matched control group. Clinical (neurological and orthopedic evaluation) and anamnestic data (seizure type, drugs, genetic mutation) were collected; distribution between the two gait phenotypes was assessed with the Fisher exact test and, for mutation, with the chi-squared test (p-value < 0.05). Results: Seventy-one subjects were enrolled and evaluated with instrumented gait analysis. Fifty-two were included in the final analysis (mean age 13.8 ± 7.3; M 26). Two gait patterns were detected: an atypical crouch gait (34.6%) with increased ankle, knee and hip flexion during stance, and reduced walking speed and stride length without any muscle-tendon retraction; and a pattern resembling those of healthy age-matched controls, but still showing reduced walking speed and stride length. No difference in clinical or anamnestic data emerged between the two groups. Significance: Objectively quantified gait in DS shows two gait patterns with no clear-cut relation to clinical data. Kinematic parameters abnormalities are likely due to stabilization issues. These findings may guide rehabilitative and preventive measures.
Neurotherapeutics, 2019
Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for wh... more Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.
The early infantile epileptic encephalopathies (EIEE) are a group of rare, severe neurodevelopmen... more The early infantile epileptic encephalopathies (EIEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 novel putative transcript models. The extended transcriptional footprint of these genes allowed for 294 intronic or intergenic variants, found in human mutation databases, to be reclassified as exonic, while a further 70 intronic variants were reclassified as splice-site proximal. Using SCN1A as a case study due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome, or a similar phenotype, with a pa...
Abstracts of the 44th Annual Meeting of the Society for Neuropediatrics, 2018
The American Journal of Human Genetics, 2018
Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterize... more Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs. 1-3 This suggests that unknown genetic etiologies exist, potentially in the $98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a ''poison'' exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons, 4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly. 6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.
European Journal of Paediatric Neurology, 2018
Aim: Sleep problems are often reported in patients with a Dravet Syndrome (DS). In this study we ... more Aim: Sleep problems are often reported in patients with a Dravet Syndrome (DS). In this study we explored the sleep behavior in DS and compared the prevalence of sleep problems with other epilepsy patients. Methods: An online questionnaire based on the 'Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP)' was distributed amongst DS parents and a control group (parents from children with epilepsy). Completed questionnaires were evaluated by factor scores and Composite Sleep Index (CSI). Results: Fifty-six responses were recorded in the DS group (42 were 18 year). Caregivers reported an overall frequency of sleep problems in 42.3% (22/52). Severe sleep problems, measured by CSI, were found in 28.3% (13/46) mainly related to night waking or daytime sleepiness. In the control group (n ¼ 66, 62 were 18 year), sleep problems were reported by 21.2% (14/52) of the parents. Comparison analysis between pediatric DS and epilepsy patients revealed no significant differences between the prevalence of different types of sleep disorders, except for daytime sleepiness (p ¼ 0.042). However, the parent (or caregiver)reported quality of sleep was significantly lower in the DS group (p ¼ 0.011). Interpretation: Sleep problems are frequent in DS patients and are mainly related to daytime sleepiness and night waking. Compared with other epilepsy patients, severe sleep problems are not more common in patients with a DS. However DS patients tend to have more mild night waking problems, which may explain the worse parental-reported sleep quality in DS patients.
2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2015
Home monitoring of refractory epilepsy patients has become of more interest the last couple of de... more Home monitoring of refractory epilepsy patients has become of more interest the last couple of decades. A biomedical signal that can be used for online seizure detection at home is the electrocardiogram. Previous studies have shown that tonic-clonic seizures are most often accompanied with a strong heart rate increase. The main issue however is the strong patient-specific behavior of the ictal heart rate features, which makes it hard to make a patient-independent seizure detection algorithm. A patient-specific algorithm might be a solution, but existing methods require the availability of data of several seizures, which would make them inefficient in case the first seizure only occurs after a couple of days. Therefore an online method is described here that automatically converts from a patient-independent towards a patient-specific algorithm as more patient-specific data become available. This is done by using online feedback from the users to previously given alarms. By using a simplified one-class classifier, no seizure training data needs to be available for a good performance. The method is already able to adapt to the patient-specific characteristics after a couple of hours, and is able to detect 23 of 24 seizures longer than 10s, with an average of 0.38 false alarms per hour. Due to its low-complexity, it can be easily used for wearable seizure detection at home.
European Journal of Paediatric Neurology, 2015
Objective Dravet syndrome is a severe epileptic encephalopathy beginning in infancy. The characte... more Objective Dravet syndrome is a severe epileptic encephalopathy beginning in infancy. The characteristic electroclinical picture is well known. With the discovery of SCN1A, molecular confirmation is possible in 75% of the patients. In approximately 70% a mutation is found and in 3–5% a copy number variant (CNV). CNVs frequently involve deletions, which not only contain SCN1A but the whole SCN gene cluster. This cluster contains five sodium channel genes (SCN3A, SCN2A, SCN1A, SCNC9A and SCN7A) along with GRB14 and GALNT3. The aim of this study was to determine whether patients with a SCN cluster deletion show a more severe form of the Dravet syndrome or have a specific continuous gene deletion syndrome. Methods We retrospectively reviewed the files of children with a deletion of the SCN gene cluster. Results We report six patients with a SCN cluster deletion (5 confirmed by aCGH, one with MLPA). All patients have a large de novo deletion (mean 5.6 Mb, SD 2.5). The mean age of presentation was 14.8 w (SD 7.3 w). Four infants presented with myoclonus, one with a febrile status epilepticus and one with an afebrile focal seizure with secondary generalization. Three had dysmorphic features and an abnormal development prior to the onset of convulsions. All patients showed a disastrous course with a severe mental retardation, hypotonia, failure to thrive and therapy resistant epilepsy in infancy. Two patients died around the age of one year, one at the age of 15 years. Three patients (8m, 20m and 4y of age) are still in follow-up. Conclusion Patients with a SCN cluster deletion frequently show a more severe form than the classic Dravet syndrome phenotype. The slightly earlier presentations with myoclonic seizures, abnormal development prior to the onset of convulsions, severe developmental delay or dead in infancy are suggestive for the SCN cluster deletion syndrome.
Acta Neurologica Belgica, 2013
Over the past decades, it has become clear that the most efficient way to prevent status epilepti... more Over the past decades, it has become clear that the most efficient way to prevent status epilepticus is to stop the seizure as fast as possible, and early treatment of prolonged convulsive seizures has become an integral part of the overall treatment strategy in epilepsy. Benzodiazepines are the first choice drugs to be used as emergency medication. This treatment in the early phases of a seizure often implies a 'pre-medical' setting before intervention of medically trained persons. In this paper, we propose "good practice points" for first line management of prolonged convulsive seizures in children and adults in a 'pre-medical' setting.
JIMD Reports
Monosialotetrahexosylganglioside (GMI) gangliosidosis and Morquio type B (MorB) are two lysosomal... more Monosialotetrahexosylganglioside (GMI) gangliosidosis and Morquio type B (MorB) are two lysosomal storage disorders (LSDs) caused by the same enzyme deficiency, β-galactosidase (βgal). GMI gangliosidosis, associated with GMI ganglioside accumulation, is a neurodegenerative condition characterized by psychomotor regression, visceromegaly, cherry red spot, and facial and skeletal abnormalities. MorB is characterized by prominent and severe skeletal deformities due to keratan sulfate (KS) accumulation. There are only a few reports on intermediate phenotypes between GMI gangliosidosis and MorB. The presentation of two new patients with this rare intermediate phenotype motivated us to review the literature, to study differences and similarities between GMI gangliosidosis and MorB, and to speculate about the possible mechanisms that may contribute to the differences in clinical presentation. In conclusion, we hypothesize that GMI gangliosidosis and MorB are part of one phenotypic spectrum of the same disease and that the classification of LSDs might need to be revised.
Acta Neurologica Belgica, 2004
Peer reviewe
Acta Neurologica Belgica, 2004
Epilepsia, 2020
5 CRMR malformations et maladies congénitales du cervelet et déficiences intellectuelles de cause... more 5 CRMR malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares,
2015 Computing in Cardiology Conference (CinC), 2015
Previous studies have shown that during several types of seizures, the heart rate increases stron... more Previous studies have shown that during several types of seizures, the heart rate increases strongly towards a maximal patient-specific epileptic heart rate HR ep. This ictal peak heart rate is one of the most important features for classifying epileptic heart rate increases. We therefore try to estimate HR ep , which is done by using least squares support vector machines. The found estimation had a mean square error of 18bpm, which is an improvement compared to age-based estimators. Adding this information to an online seizure detector led to an increased performance (F1-score: 14.65% to 18.72%) with a decreased detection delay (23.8s to 11.9s).
Proceedings of the …, 2007
AbstractThe first aim of the project is to construct an acquisition system for four acceleromete... more AbstractThe first aim of the project is to construct an acquisition system for four accelerometer sensors, fixed to the extremities. The information is transmitted to a data-gatheringsystem which synchronizes the accelerometer signals with the video-...
European Journal of Paediatric Neurology, 2019
Objective: To quantify gait abnormalities in people with Dravet syndrome (DS). Methods: Individua... more Objective: To quantify gait abnormalities in people with Dravet syndrome (DS). Methods: Individuals with a confirmed diagnosis of DS were enrolled. They were stratified according to knee flexion at initial contact (IC) and range of motion (ROM) during stance [crouch gait if knee flexion >20° at IC and knee range of motion (ROM) >15°; straight gait: knee flexion <20° at IC]. A 1D ANOVA (α = 0.05) was used to test statistical differences among the joint kinematics and spatio-temporal parameters of the cohort and an age-matched control group. Clinical (neurological and orthopedic evaluation) and anamnestic data (seizure type, drugs, genetic mutation) were collected; distribution between the two gait phenotypes was assessed with the Fisher exact test and, for mutation, with the chi-squared test (p-value < 0.05). Results: Seventy-one subjects were enrolled and evaluated with instrumented gait analysis. Fifty-two were included in the final analysis (mean age 13.8 ± 7.3; M 26). Two gait patterns were detected: an atypical crouch gait (34.6%) with increased ankle, knee and hip flexion during stance, and reduced walking speed and stride length without any muscle-tendon retraction; and a pattern resembling those of healthy age-matched controls, but still showing reduced walking speed and stride length. No difference in clinical or anamnestic data emerged between the two groups. Significance: Objectively quantified gait in DS shows two gait patterns with no clear-cut relation to clinical data. Kinematic parameters abnormalities are likely due to stabilization issues. These findings may guide rehabilitative and preventive measures.