The research of Dr. van Karnebeek’s (MD, PhD in pediatrics and biochemical genetics) focuses on improving diagnosis and treatment of intellectual disability. Characterized by deficits in cognitive functioning and adaptive skills, intellectual disability is associated with significant behavioral problems including epilepsy and other neurological disabilities. Affecting 2-3% of children worldwide, its economic impact and emotional suffering is significant. The underlying causes of intellectual disability vary from environmental to genetic. Inborn errors of metabolism, due to a defect in a single gene that codes for an enzyme responsible for converting one substance into another, are the only genetic conditions for which treatment is available. Although the individual conditions are rare, Dr. van Karnebeek’s research is showing that collectively this group may account for more than 5% of all intellectual disability cases.
“ID is often regarded as an unchangeable fate, but recent research is changing this paradigm. Treatment (medical diets, vitamins, medication, stem cell transplants) is available for a large number of inborn errors of metabolism, and can prevent or halt brain damage and significantly improve neurologic functioning”, says Dr. van Karnebeek, “the sooner these are identified in affected children, the better their health outcomes.”
After conducting a comprehensive review with Dr. Sylvia Stockler (Professor in Pediatrics, UBC) of the known treatable genetic disorders causing intellectual disability, the Treatable Intellectual Disability Endeavor in B.C. was established. Dr. van Karnebeek spearheaded the development of a diagnostic protocol supported by digital tools that help physicians identify and treat 89 treatable inborn errors of metabolism (www.treatable-id.org). During the first 2 years of TIDE protocol implementation at BCCH, a treatable condition was identified in more than 5% of 400 children.
Together with her team at TIDE BC and at CMMT, Dr. van Karnebeek continues to research new treatable genetic causes of intellectual disability, and to promote the early detection and treatment of these disorders. One example is the successful development and implementation of a medical diet to improve cognitive outcomes and seizure control in patients with Pyridoxine Dependent Epilepsy due to an inborn error in lysine metabolism.
Another striking example of this high-impact research, Dr. van Karnebeek recently collaborated with international colleagues (including Dr. Wyeth Wasserman, also at CMMT) to perform genomic studies on four children with hyperammonemia. This medical emergency affects about one in 1,000 infants, and often results from the body’s inability to detoxify by-products of converting proteins into energy. Dr. van Karnebeek’s team discovered a new cause for this condition: mutations in the gene that encodes carbonic anhydrase VA, a liver enzyme that plays an essential role in this energy production and detoxification process. Dr. van Karnebeek’s findings also demonstrated that this form of hyperammonemia – which manifests itself shortly after birth – can be treated effectively using carglumic acid, thereby preventing irreversible brain damage.
Broadening the scope of her research on inborn errors of metabolism, Dr. van Karnebeek now leads the Omics2TreatID initiative, which is funded by Genome BC and CIHR. This integrated and multidisciplinary approach combines phenomics, genomics and metabolomic technologies to discover treatable genetic defects in children with developmental delays and intellectual disability.
“In some cases, the treatment we offer can prevent or reverse intellectual disability and completely change a child’s life,” says Dr. van Karnebeek. “It’s a powerful motivation to move forward with our research and its translation into clinical practice.”