Research Berten Ceulemans

Abstract

Dravet syndrome (DS) is a genetically caused severe neurodevelopmental disease with drug-resistant epilepsy, cognitive impairment and a strongly increased risk of premature death already at young ages. The occurrence of sudden death is most probably facilitated by sustained susceptibility to cardiorespiratory dysfunction. Our primary hypothesis is that the alterations of autonomic functions observed in DS result from the interplay between the genetically-based neurodevelopmental disorder and effects of recurrent seizures. Epilepsy might thus progressively aggravate the autonomic abnormalities and risk of sudden death related to the underlying genetic disease, through an effect on central control of vegetative functions, a direct effect on cardiac functioning or both. Here, we will: (i) analyze in a DS animal model and in DS patients the temporal relationship between evolution of epilepsy and alteration of autonomic cardiorespiratory functions; (ii) distinguish in rodents the relation between these evolutions of the alterations of the central regulation, the cardiac functioning, and the risk of sudden death; and (iii) evaluate in rodents and in DS patients if the evolution of autonomic dysfunction can be monitored with functional imaging targeting the serotonin pathway. The anticipated findings will be used to stratify DS patients at very high risk of sudden death and may allow novel approaches for pharmacological modulation of the risk of sudden death in DS.

Researcher(s)

• Promoter: Verhulst Stijn
• Co-promoter: Ceulemans Berten
• Co-promoter: Jansen Anna

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Genetic causes of cerebral palsy Abstract Cerebral palsy (CP) is a clinical descriptive term that defines a heterogeneous group of non-progressive, neurodevelopmental disorders of motor impairment, which co-occur with a wide range of medical conditions such as epilepsy, autism, mental disorder, etc. It is the most frequent cause of motor impairment in children with an important impact on quality of life. It's prevalence ranges between 1.5 and 2.5 in 1000 live births. The causes of cerebral palsy are quite variable. Known causes are preterm birth, congenital (brain) abnormalities, intrauterine infection, thrombophilia etc. It was thought that asphyxia at birth was the most frequent cause of cerebral palsy. However, large population-based studies have shown that it is a causative factor in only 10% of CP patients. Recent studies demonstrate an important contribution of genetic factors in the etiology of CP. However, the genetic causes are heterogeneous and the mechanisms of action of these genes related to CP pathology are largely unknown. Genetic investigations in CP patients in Belgium were limited until recently. In this research project, we make a gene panel for CP that can be diagnostic in a cost-effective manner. Furthermore, we want to gain insight into the pathophysiology of CP and associated pathways, which can lead to better insight into the condition itself, early intervention and development of treatment and therapeutic interventions in the future. We performed diagnostic genetic studies in CP-patients that are followed at the Pediatric Neurology department of the University Hospital of Antwerp using (1) SNP-array to exclude chromosomal anomalies and (2) a whole exome sequencing (WES) based gene panel consisting of 200 genes associated with CP and CP-mimics. When no genetic diagnosis can be made in diagnostic setting, WES data are further studied in research setting. The found genetic variants are saved in a custom-made database that allows us to make genotype-phenotype correlations. This research strategy has led to the identification of de novo variants in the KIF1A gene in a relatively large proportion of our CP-population (6/100). These variants are localized in the KIF1A motor domain and can't be found in control databases. In silico prediction programs classify the variants as (probably) pathogenic. KIF1A is a kinesin motor protein, that is responsible for cargo transport along microtubule tracts. It is for example responsible for the transportation of ATG9, a key component in the autophagy pathway. It was demonstrated in C. Elegans that ATG9 regulates autophagy-induction at the synapse. We believe that pathogenic KIF1A-variants inhibit the induction of autophagy. The same mechanism has been described in the AP4-deficiency syndrome, one of the first identified genetic causes of cerebral palsy, caused by a mutation in a subunit of the AP4-complex. AP4 is involved in the transportation of ATG9A. Other mutations in autophagy genes have been described in association with neurological symptoms such as developmental delay, intellectual disability, spasticity, hypotonia, ataxia, epilepsy etc. The clinical characteristics seen in these gene mutations resemble those of CP. It is therefore thought that the presence of genetic variants that dysregulate autophagy, cause a reduced neuroprotective capacity against environmental factors such as hypoxic ischemia or inflammation. Because of this, an increased vulnerability for the development of cerebral palsy occurs. This hypothesis will be further investigated in our research project. Furthermore, we will analyze our population for new genetic variants that can cause cerebral palsy or cerebral palsy mimics. Key words Cerebral palsy, Single Nucleotide Polymorphism-array, Whole exome sequencing

Researcher(s)

• Promoter: Ceulemans Berten

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Methylphenidate (MPH, e.g. Rilatine, Medikinet, Concerta), the first choice medication for Attention-Deficit Hyperactivity Disorder (ADHD), is associated with several adverse effects like insomnia and decreased appetite. In addition, ADHD has been associated with immune and oxidantantioxidant imbalances, which offer potential for certain nutritional supplements as ADHD therapy. A commercially available extract from Pinus pinaster, Pycnogenol®, has antioxidant and immunomodulatory activities. One small randomised trial suggests therapeutic benefit from Pycnogenol® in ADHD, though this study had several limitations. This project is therefore a randomised, double blind, parallel multicenter trial to compare the effect of Pycnogenol® to MPH and placebo over a ten week period on the behaviour of 144 ADHD and Attention-Deficit Disorder (ADD) patients. The ability of Pycnogenol® to improve ADHD or ADD behaviour will be evaluated in week 5 and 10. Evaluations of effects on immunity, oxidative stress and other psychiatric/physical complaints (to investigate mechanism of action) will be performed in week 10 as compared to baseline. Acceptability evaluations will be performed in week 10, based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account. Patients will be recruited from the university hospitals of Antwerp and Ghent, as well as ZNA Erasmus hospital (Antwerp).

Researcher(s)

• Promoter: Hermans Nina
• Co-promoter: Ceulemans Berten

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to improve understanding of immune and oxidative stress aberrancies in ADHD and to evaluate the effects of supplementation with Pinus pinaster bark extract on behaviour and comorbid symptoms and on immune, oxidative stress and antioxidant biomarkers, as compared to placebo, no intervention and MPH treatment.

Researcher(s)

• Promoter: Hermans Nina
• Co-promoter: Ceulemans Berten
• Co-promoter: Pieters Luc
• Fellow: Verlaet Annelies

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to detect novel genome disorders in mental retardation by performing SNP arrays on a series of selected patients with a mental handicap. It can be anticipated that novel deletions will be discovered. The size of the deletions will be determined and analysis of breakpoints will increase our insights in the mechanisms causing the rearrangements. Candidate genes in the deletions will be identified and analyzed using mouse models.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Ceulemans Berten

Research team(s)

Project website

Project type(s)

• Research Project