Treatments Options For GRIN
Home /Development of treatments for GRIN disorders is challenging because there is a great range of different mutations and a huge variability in the symptoms caused by the different GRIN variants. So far, most of the treatments that are currently being developed aim to act at the neuroreceptor level but are not curative. Hopefully over the next few years, more researchers, biotechs and pharma companies will focus more on the curative and symptomatic treatment of GRIN disorders.
IMPORTANT: ALWAYS consult with your child’s doctor first before you decide to try any of the following drugs or supplements described below. This warning needs to be taken seriously, since treating a child with a drug that is not suitable for his/her mutation, can cause severe adverse effects!
The first treatments we want to discuss are those which are specific for one of the two general forms of NMDA dysfunctions, GoF or LoF. Later, we will discuss symptomatic treatments aimed at improving some of the many symptoms GRIN patients are affected with.
Treatments directed at modulating the NMDA neuroreceptor
Before considering any treatment directed at modulating the NMDA neuroreceptor, it is very important that you know the functional alteration caused by your child’s specific GRIN mutation. For this reason, it is paramount to have a proper Functional Analysis done prior to deciding on any of the treatment options described as medication for Gain of Function (GoF) can have an adverse effect on Loss of Function (LoF) and vice versa. This effect should never be underestimated!
If your child still does not have a Functional Anlysis or you want to learn more about GoF or LoF please refer to our section on Functional Analysis and GoF and LoF under the ABOUT GRIN tab for more information.
Some of the more well-studied treatments known to modulate the NMDA receptor in GRIN are described below:
Treatments For GoF (Gain of Function)
1. Memantine: This drug has been widely used for Alzheimer’s disease, but its effect on GRIN children varies from patient to patient. Sometimes the beneficial effects of memantine are temporary, but long-time effect has also been reported.
https://www.frontiersin.org/articles/10.3389/fphar.2021.773455/full
2. Perampanel: This is an anti-epileptic drug that acts on the AMPA receptor (which interacts with NMDA) and has been used in a clinical case of a child with GRIN1 GoF.
https://pubmed.ncbi.nlm.nih.gov/33403508/
3. Radiprodil: This is a drug for which a phase 1 clinical trial is currently being conducted in Europe and in the US. Outside of these clinical trials, radiprodil is, unfortunately, not yet approved for use in patients with GRIN. The effect of Radiprodil is directed to the GRIN2B protein, although it is expected to work on other GoF GRIN genes as well.
Radiprodil is expected to have a positive effect on the control of epilepsy and behavioural problems in GoF GRIN disorders. It is important to know that memantine and radiprodil have different modes of action on the NMDA neuroreceptor, broadening their use in different GRIN GoF mutations.
https://onlinelibrary.wiley.com/doi/10.1002/acn3.50998
https://www.sciencedirect.com/science/article/pii/S0028390817302290?via%3Dihub
4. Dextromethorphan: This is the active ingredient in over-the-counter cough medications. Anecdotally, it has had a positive but transient effect in GoF patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283169/
5. Ketamine – This drug is generally used as an anesthetic, and has only been tested at the cellular level, meaning in the laboratory but not in GRIN patients. It is a highly controlled substance, because of its recreational use. It should be used with extreme caution in GRIN children as it can have serious side effects.
https://onlinelibrary.wiley.com/doi/10.1002/acn3.51406
Other Ketamine-like drug derivatives are currently being developed for depression. We hope that in the future these drugs will be considered for the treatment of GRIN disorders.
Treatments for LoF (Loss of Function)
1. L-Serine: This is an amino acid (the building blocks of protein) found in many foods such as corn, soy, chicken, turkey, eggs and almonds. In cells, the active form of L-Serine is D-Serine. At the cellular level in the laboratory, D-serine has been shown to help neurons with LoF mutations to function better. D-Serine is not safe to be given directly, so the L- form is used which is then changed to the more active D- form inside the body.
L-Serine has been studied in detail in a clinical case, but more studies are being carried out to confirm these findings. Only few adverse effects have been described, and it appears to be, overall, well tolerated. However, the erroneous administration to a GoF child was associated with severe epileptic episodes.
The medical team led by Dr. García-Cazorla from the Hospital Sant Joan de Deu, in Barcelona, started in 2020 with the first clinical trial in the world for the food supplement L-Serine, to determine the tolerability and efficacy of this treatment in GRIN children with loss of function (LoF). This study was replicated by several hospitals around Europe. The results of the Spanish clinical trial are expected to be published towards the summer of 2023.
Here are the links for the different publications about L-Serine
L-Serine Clinical Case:
https://www.science.org/doi/10.1126/scisignal.aaw0936
https://link.springer.com/article/10.1007/s13311-021-01173-9
L-Serine Clinical Trial:
https://www.clinicaltrials.gov/ct2/show/NCT04646447?term=Serine&cond=GRIN&draw=2&rank=1
L-Serine Case Reports
https://pubmed.ncbi.nlm.nih.gov/34997442/
2. Piracetam (Nootropil): This is a neurotropic medication that improves the metabolism of neurons. It is available as an over-the-counter supplement in some European countries but in others it is only available with a prescription. Piracetam also affects the NMDA neuroreceptor. The use in GRIN is still anecdotal.
https://www.ptfarm.pl/pub/File/Acta_Poloniae/2005/5/405.pdf
If you want to learn more about the Clinical Trials for GRIN disorders please check our Clinical Trial section under the RESEARCH tab.
Treatment aimed at regulating some of the GRIN Clinical Symptoms
In this section we will describe a few treatments for some of the symptoms mentioned in the previous GRIN Clinical Symptom section. This is a review of symptomatic treatments options discussed by parents. It is intended to be helpful information for parents to discuss with their child’s physician. IMPORTANT: None of these treatments described below has been proven to work specifically on GRIN.
Important: ALWAYS, consult with your doctor before trying any of these treatments on your child.
For Gastrointestinal disorders
Nutrition and diets: For those children affected by gastrointestinal problems, chose easy digestible diets, including diets free of gluten / lactose and / or free of milk / dairy might be beneficial. High caloric foods and specific high caloric food supplements are recommended for children who struggle with gaining weight / suffer from failure to thrive.
For Epilepsy
Ketogenic diet: The ketogenic diet is mostly used in cases where children are affected by drug-resistant epilepsy. A ketogenic diet is in principle low in carbohydrates and proteins, and high in fat. The use of a ketogenic diet in the treatment of certain forms of epilepsy is fairly well known. However, in the case of GRIN disorders, further studies need to be conducted, but it might be an acceptable alternative in cases of drug-resistant epilepsy. However, a close weight control needs to be maintained if putting a GRIN child on a ketogenic diet.
Dr. Amy Ramsey of the University of Toronto, found that her GRIN1 mouse models are less effective at processing glucose in the brain. As a result, the brain lacks fuel /energy, and cannot function optimally. Although the brain accounts for only for 1 to 1.5 kilograms of the total body weight, it is responsible for no less than 20% of the total glucose requirement of the body. By offering a ketogenic diet, glucose as fuel for the brain is replaced by ketones, which can have a positive effect on the functioning of the brain.
Please note that in the case of a complex medical condition such as GRIN, and especially in the case of children, a ketogenic diet should always be offered in consultation with and under the supervision of a doctor.
Vagal Nerve stimulator
Small indwelling device, similar to a pacemaker, that is surgically placed close to the left side of the neck and shoulder area of a patient affected by uncontrollable epilepsy. This device automatically “corrects” the abnormal electrical impulses that happen during an epileptic crisis.
For Sleep disruption
Many drugs and supplements have been recommended for GRIN, with some variable effects.
Melatonin (drops, capsule and slow release)- Helps with the initiation of sleep. It also has an added antioxidant effect.
5-OH tryptophan: Precursor of Serotonin and Melatonin.
Vitamin B12 and Iron supplementation: these important metabolites are associated with good sleep patterns. Deficiencies in B12 or Iron have been related to poor sleep and can easily be assessed by blood tests.
Risperdal: antipsychotic drug known to improve sleep patterns in people affected with schizophrenia. It is a serotonin-dopamine antagonist!
Clonidine: an attention deficit and hyperactivity disorder treatment. Itcan be used to help initiate and maintained sleep, possibly through its effect on the autonomic system, by lowering blood pressure and heart rate.
Neurostorms:
What we believed to be Paroxysmal Sympathetic Hyperactivity Storms (PSH- https://www.uptodate.com/contents/paroxysmal-sympathetic-hyperactivity).
These neurostorms have been treated with some success with different medications aimed at controlling the autonomic nervous system dysregulation, such as Clonidine. Treatments aimed at controlling non epileptic crisis, such as Gabapentin and Carbamazepine, have also worked in some cases.
***More to come***
Until now, none of the above-mentioned treatments have been shown to be curative, but in some cases treatments could improve some of the symptoms described in the GRIN CLINICAL SYMPTOMS section.
Gene therapy
Gene therapy is a “curative” form of treatment, in which the mutated gene is either edited or replaced by a healthy GRIN gene (with all its proper structure and function). This in turn would lead to a functional change also at the cellular (neuron) level. Although gene therapy in GRIN disorders is just getting started, Dr. Amy Ramsey from the University of Toronto is working very hard to develop a suitable model and ways to deliver the “good” GRIN gene to patients affected with GRIN disorders.
To learn more about her work please check out this link:
https://www.sfari.org/funded-project/gene-therapies-for-grin-disorder/