I have been working on nonketotic hyperglycinemia (NKH) since 1991 and in as a primary of my research since 1998. Throughout these years, NKH has remained my passion.
View the bio of Johan Van Hove, MD, PhD
NKH is a disorder that affects the glycine cleavage enzyme system. Patients have mutations in components of the system usually with mutations in the GLDC or the AMT genes. Most children present in early infancy with an epileptic brain disorder. Some children present later with developmental delays and other problems. A brief outline of NKH, can be found at the NORD website: https://rarediseases.org/rare-diseases/nonketotic-hyperglycinemia/. A more extensive explanation for the care of NKH patients can be found at the GeneReviews website at https://www.ncbi.nlm.nih.gov/books/NBK1357/.
Our current studies involve four areas, each directed towards the development of an effective therapy for NKH:
1. Describe changes in the biochemistry that make the brain cells sick, and develop therapeutic measures to improve this.
--We are looking at the changes in the methylation status of the folates, the end product of the glycine cleavage action. Folate is an essential vitamin in the biochemistry of the brain. There is no shortage of folate but its metabolism is ineffective in NKH by having insufficient methylation. We will evaluate and optimize the way to regenerate the methylation of the folates.
--We are evaluating the mechanisms by which excessive glycine causes toxicity in the brain. By evaluating each critical step, we aim to identify specific steps where the toxicity can be mitigated.
By combining these two approaches, we hope to develop a better environment for the brain to grow in. We investigate these approaches in samples from human patients with NKH and in a mouse model of NKH.
2. About half the patients with NKH have at least one mutation that makes the P-protein unstable We are developing a compound that stabilizes the P-protein and increases the amount of protein that is present in every cell, and thus making the disease less severe. Such a compound is called a chaperone. Chaperones have been developed for other conditions and can provide a substantial improvement in the clinical condition. We have developed a method to identify candidate chaperones and then evaluate these compounds for therapeutic potential in human patients. We have done a first screen, but need to continue doing a larger screen targeted at compounds that have access to the brain. This will be followed by extensive testing and, as needed, optimization with medicinal chemistry.
3. We are developing a clinical study of children with NKH. This study is aimed at optimizing the current therapy to the best of our knowledge of today, and at measuring the most relevant clinical parameters. This will provide the best care of today, and provide a good start to implement future studies on new therapies not yet in practice.
4. To support future clinical trials and to provide families with information about the impact of the mutation in their family, we aim to express all the known missense mutations and measure the impact of those mutations upon enzyme activity.
We aim to work in collaboration with other investigators who have an interest in NKH. How You Can Help Clinical support: NKH patients can support our work by visiting us in the clinic at Children’s Hospital Colorado. Please contact either Linda at Linda.Polivka@childrenscolorado.org or Danielle at Danielle.Komlo@childrenscolorado.org for scheduling. NKH patients can also donate a sample. Should a child die, they can donate the brain to the Brain and Tissue Bank at the University of Maryland (https://www.medschool.umaryland.edu/btbank/).
Financial support: Our current work is primarily funded by donations from families and donors interested in supporting our work in NKH. These gifts are essential to continue our work, and without your support, this progress would not be possible. Funding from philanthropy is essential to keep our work going, and we are very grateful to our donors.
We can accept your support for these endeavors through the University of Colorado Foundation. Checks can be made out to the CU Foundation with “0221975 Nonketotic Hyperglycinemia Fund” in the memo line and mailed to Deborah Beckworth, University of Colorado Denver, Mail Stop 8313, RC1 North, P18-3101, 12800 East 19th Avenue, Aurora, CO 80045.
You can also donate online at https://giving.cu.edu/nkh.
If you have questions about other types of gifts (example: estate commitments, wire transfers, gifts of stocks or other appreciated securities, etc.) or if you wish to create a memorial fund to accept gifts following the passing of a loved one, please contact Jerry Sinning at 303-724-7825 or firstname.lastname@example.org