Non-Ketotic Hyperglycinemia, (NKH), is a rare, genetic disorder that affects only one child in every 60,000.
It is caused by an excess of glycine on the brain that affects development.
The condition can vary in severity, with the more severe forms resulting in frequent seizures, immobility, and global developmental delay.
The condition is life-limiting, and there are only approximately 15 children in the United Kingdom and 500 children worldwide still surviving with NKH.
Huge strides are being made into understanding NKH and what makes our children so sick. MRI scans have been studied and the many genes that can cause the disorder have been mapped. We are now heading towards gene therapy, and a clinical trial is hopefully soon on the horizon.
Joseph’s Goal currently supports financially the research of Dr Nick Greene of UCL Great Ormond Street Institute of Child Health in London, who leads the UK arm of NKH research. Dr Greene is close to a breakthrough in gene replacement therapy, and is also developing a new drug that could help in the management of seizures. There is at last some light at the end of a very dark tunnel!
Research on Non-Ketotic Hyperglycinemia at UCL Great Ormond Street Institute of Child Health
The research group at University College London, led by Prof. Nick Greene, is focusing on studies to better understand the disease process of NKH and to develop new therapies. NKH is caused by a genetic defect that affects a protein complex in the body called the glycine cleavage system. This prevents the breakdown of a small molecule called glycine, which then accumulates to harmful levels in the body.
One hindrance in NKH research has been the lack of an experimental system. For this reason, the UCL group developed a mouse model, with disruption of the mouse equivalent of the gene which is most commonly defective in children with NKH. The mice show features of NKH such as elevated glycine and a range of approaches are now being used to study this model in more detail. For example, sensitive biochemical measurements have shown changes in particular aspects of metabolism. EEG is being used to ask whether NKH mice show altered brain electrical activity and the brain cells are being analysed in to ask where the injury occurs. Importantly, as well as generating new information on the disease process, these studies provide measures for assessing the effects of potential new treatments, such as new or untested drugs. For example, existing NKH treatments such as benzoate have been tested and other approaches are now being investigated.
A major line of research aims to make progress towards gene therapy for NKH. Mouse genetic tools are being used to restore expression of the glycine cleavage system gene in particular tissues and at different stages of development in the NKH mice, to ask whether this ‘rescues’ the disease. These experiments are a step towards testing gene therapy, in which a normal copy of the glycine cleavage system gene is introduced into the NKH mice. These tests are now in progress – if successful, this approach could potentially be developed for use in children with NKH.
In addition to the mouse models, the UCL group are also working to develop new models in zebrafish and in cell lines, each of which has advantages for asking particular research questions. Details on Prof. Greene’s research and publications can be found below.