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.
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/.
My studies in the past have described:
- Outlining the clinical stories and features of
the NKH condition and the conditions that look like NKH but are not the same
(variant NKH and related disorders). We have recognized the differences between
severe NKH and attenuated NKH and classified the various subgroups within
- The use of benzoate and optimized the dosing
that is needed to bring the glycine down (https://www.ncbi.nlm.nih.gov/pubmed/16151895),
and the clinical effect in NKH in particular that in attenuated NKH treatment
early improves outcome (https://www.jpeds.com/article/S0022-3476(15)01539-5/fulltext)
- The genetic basis of NKH describing all the
genetic changes that were known in 2017 providing a large database for
laboratories, clinicians and families to use in interpreting the results of
genetic testing (https://www.nature.com/articles/gim201674)
- The relation between genetic changes and the
outcome of children with NKH. All children have two mutations in NKH, one
inherited from their mother and one from their father. If both mutations do not
leave any activity of the enzyme, then the child has severe NKH. If at least
one of the two mutations has some activity of the enzyme, then there is an
opportunity that the child will have attenuated NKH. (https://onlinelibrary.wiley.com/doi/full/10.1002/ana.24485)
- The biochemical values that can help predict if
a baby will have a severe or an attenuated form of NKH. (https://onlinelibrary.wiley.com/doi/full/10.1002/ana.24485)
- The changes on brain magnetic resonance imaging
(MRI) in NKH. Recognizing these MRI changes helps physicians tremendously with
diagnosing the child at an early age within the first months of life, and
differentiating it from other conditions that can be confused with NKH. It also
provided insight into brain growth problems. (https://onlinelibrary.wiley.com/doi/full/10.1002/jimd.12072)
- We have provided care guidelines for children
with NKH, which are available on the GeneReviews website. (https://www.ncbi.nlm.nih.gov/books/NBK1357/)
These studies have formed a solid basis on the clinical,
biochemical, and genetic description of NKH. They have laid the foundation for
studies on treatment.
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 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
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.