Current topics
The research of my group is centered around the role of enzymology and metabolism in genetic (malignant) diseases, to develop strategies for diagnosis and treatment of new patients.
(1) Inborn errors of metabolism
My group has been instrumental in the discovery of disease-causing genes in patients with rare Mendelian diseases. Using a detailed clinical and biochemical phenotyping approach, combined with whole genome sequencing our team of clinicians, functional lab specialists, and bioinformaticians identified an expansion of a GCA-repeat tract of the gene encoding glutaminase (GLS) in 3 unrelated patients with progressive ataxia and early onset developmental delay (Published in NEJM). Furthermore, we have been the leading group in the identification of a novel inborn error of pyrimidine metabolism, a hCNT1 deficiency resulting in altered pyrimidine nucleoside homeostasis. Finally, we have recently identified the first cytosolic Fe-S cluster protein assembly disorders associated with lethal neurodegeneration.
Patients suffering from a lysosomal storage disorder often have a variable clinical presentation and with the upcoming possibility of treatment with enzyme replacement therapy, the need for biomarkers that predict or reflect disease progression has increased. We have been able to identify biochemical and imaging parameters in patients with acid sphingomyelinase deficiency and Fabry disease which may function as prognostic factors and surrogate clinical endpoints. In addition, we have been able to develop a model predicting the development of anti-drug antibodies against recombinant alpha-Galactosidase A in male patients with classical Fabry disease. Furthermore, we have shown that early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression.
(2) Pharmacogenetic aspects of inborn errors of metabolism
A particular focus of my group has been the pharmacogenetic aspects of inborn errors of metabolism and we are involved in various national and international studies. Our research efforts have been instrumental in identifying novel genetic mechanisms underlying severe fluoropyrimidine toxicity and we have developed a novel in vivo loading test to diagnose cancer patients at risk of developing severe fluoropyrimidine-associated toxicity. Since 2019, our phenotyping and genotyping approach became part of the routine diagnostic procedures in several hospitals in the Netherlands and has prevented severe toxicity, including death, in patients at risk.
(3) Catecholamine metabolites associated with clinical and genetic characteristics of neuroblastoma
Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system that is characterised by increased production and excretion of catecholamine metabolites. We have shown that analysis of a urinary panel of eight catecholamine can improve neuroblastoma diagnostics and risk assessment. We have identified 3-methoxytyramine as powerful prognostic marker and predicting MYC activity in the tumour. Our findings have gained considerable attention from other international groups. For this reason, two European prospective studies, including patients from 10 different countries, were designed in order to validate and extend our knowledge regarding the clinical implication of catecholamine metabolites in neuroblastoma.
My research is embedded within the research institutes Amsterdam Gastroenterology Metabolism (AGEM) and the Cancer Center Amsterdam (CCA). My ambition is to elucidate the role of enzymes in metabolism of genetic (malignant) diseases and to develop therapeutic strategies to prevent, attenuate, or cure these conditions.
Inherited Metabolic Disorders
Inherited Metabolic Disorders (IMDs) are associated with a broad spectrum of clinical abnormalities and a large inter-patient variation in clinical presentation is often observed. To gain more insight in the pathophysiology of IEMS, including lysosomal storage disorders, glutaminase deficiency and novel cofactor deficiencies (unpublished) my group will use conventional cell lines (fibroblasts), advanced model systems such as human induced pluripotent stems cells (hIPCs), to generate the appropriate affected tissue, and cerebral organoids, combined with multi-omics analyses (metabolomics, lipidomics, proteomics and transcriptomics) and artificial intelligence guided identification of potential targets for therapy.
The first inborn error of metabolism (IEM) caused by a short tandem repeat (STR) expansion in glutaminase (GLS) was published by my group. The pathogenic mechanisms of a GLS deficiency caused by this complex molecular aberration is not yet known. In collaboration between multiple groups of University Medicals Centers, which have specific expertise regarding the functional aspects of repeat-expansions disorders, we will execute an innovative fundamental research project to investigate various pathological mechanism(s), such as glutaminergic and glutamatergic neurotransmission and Repeat-Associated Non-AUG (RAN) translation in GLS-deficient neuronal cells, cerebral organoids as well as retina models.
These studies will increase our understanding of the pathophysiology of IMDs and it will result in the identification of new therapeutic targets and insights and thus pave the way towards the development of customized treatment strategies for individual patients. In addition, the fundamental insights obtained from investigating the impact of short tandem repeats on cellular functioning will increase our understanding of other (repeat expansion) disorders as well.
Oncology
Patients with a complete dihydropyrimidine dehydrogenase (DPD) deficiency present with mainly a neurological phenotype whereas carriers of a DPYD deficiency are at risk of developing severe fluoropyrimidine-associated toxicity. My group has identified numerous novel/rare and potential deleterious variants in the DPYD gene in these patients and we will perform a detailed biochemical characterization of these variants. Furthermore, we will develop new enzymatic assays to identify additional patients at risk.
The relative paucity of recurrent somatic mutations in neuroblastoma challenges therapeutic strategies that rely on frequently altered oncogenic drivers. The insight that many cancer-related pathways have profound effects on metabolism and that many tumors become dependent on specific metabolic processes has boosted interest in targeting cancer metabolism as a promising therapeutic rationale. Therefore, we will characterize tumor cells, plasma and urine from neuroblastoma patients, using multi-omics techniques, to identify key-metabolic enzymes and pathways. These studies will enable the identification of additional specific, sensitive markers needed to stratify low-risk versus high-risk disease, measure the response to therapy, and predict outcome. Furthermore, we will bring, in an international setting, the detection of catecholamine metabolites to the clinic thereby improving diagnosis, risk stratification, and response assessment.
The above mentioned studies will increase our understanding of the underlying causes of fluoropyrimidine-associated toxicity and it will result in the identification of new therapeutic targets in neuroblastoma, enabling the development of therapy and optimal care tailored to the individual patient.
Since my group is internationally recognized for their expertise on IEMs, and we have been leading in the discovery of new IEMs, it provides a unique opportunity to establish (inter)national collaborations to move our understanding of these (new) IEMS forward.
