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Kleefstra syndrome is a rare genetic neurodevelopmental disorder that is comprehensively studied at the Radboudumc. Despite the enormous increase in novel causes and fundamental mechanisms associated with such disorders, detailed knowledge regarding the clinical course and outcome measures is often limited. Furthermore, a large gap persists between pre-clinical and clinical studies, hindering the optimal utilization of insights from both fields.
Arianne Bouman, MD-PhD candidate from the Department of Human Genetics at Radboudumc, set out to better understand how growth and metabolism manifest in patients with the Kleefstra syndrome. Under guidance of Tjitske Kleefstra, now Head of the Department of Clinical Genetics at Erasmus MC but former coordinator of the ‘Radboudumc Center of Expertise for rare congenital developmental disorders’, and Joyce Geelen, pediatrician Developmental and Genetic Pediatrics at Amalia Children’s Hospital.
The research team studied aspects of height, weight, body composition and endocrine-metabolic biochemical measures in 62 individuals with the Kleefstra syndrome. The results were then correlated with previous pre-clinical findings obtained in a fruit fly model of the Kleefstra syndrome (mutant Drosophila, studied by prof. Annette Schenck). Findings were reported in the American Journal of Medical Genetics on 29 December.
The results revealed a high prevalence of childhood-onset overweight and obesity (60%), with disproportionally high body fat percentage. Furthermore, the researchers identified dysregulated endocrine-metabolic mechanisms, such as hypothyroidism (22%), increased triglycerides, and insulin resistance – consistent with the altered mechanisms observed in mice and Drosophila.
This study concluded that patients with Kleefstra syndrome face a high cardiometabolic risk, thus emphasizing the need for optimal monitoring and lifestyle interventions. Direct clinical recommendations have been formulated and will be integrated into the standard follow-up of patients with Kleefstra syndrome. These recommendations include monitoring weight, thyroid function, lipid status, and glucose metabolism.
Ongoing research in the national consortium BRAINMODEL aims to unravel how these altered endocrine-metabolic mechanisms contribute to the neurodevelopmental and cognitive phenotypes associated with Kleefstra syndrome. Additionally, other genetic neurodevelopmental disorders are studied to enhance the understanding of molecular pathways and their correlation with cognitive and clinical phenotypes. Ultimately, the BRAINmodel team aims to improve diagnostics and treatment for the patients suffering from these genetic neurodevelopmental disorders.
Publication
Bouman, A., et al., Growth, body composition, and endocrine-metabolic profiles of individuals with Kleefstra syndrome provide directions for clinical management and translational studies. Am J Med Genet A, 2023.
