GRIN Clinical Symptoms

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What are the most common symptoms caused by pathogenic GRIN variants?

Children affected with GRIN disorders can have one or many of the symptoms listed below.  GRIN disorders also share symptoms with other diseases and disorders that affect neurodevelopment, such as Rett syndrome, Angelman syndrome or Dravet syndrome. Usually, there is a delay in the first phases of psychomotor development, which evolves towards an intellectual disability of variable severity. Epilepsy and behavioral disorders similar to autism, are also common.

Even though most of these genetic GRIN mutations affect the central nervous system (CNS), many neurons that carry the NMDA receptor also exist in other parts of the body, including the gastrointestinal system and muscles. This is most likely why some of the children affected by this disorder will have gastrointestinal and other organ-specific symptoms.

Important: The following list of symptoms is very extensive, and could be overwhelming to read, especially for newly diagnosed parents. Please note that not all GRIN children will exhibit all or many of these symptoms nor will your child develop all or many of these symptoms in the future. Keep in mind also that most of these symptoms occur in various degrees of severity. Our intention with this list is to give families the tools necessary to explain some of their kids clinical symptoms, if observed, to their attending physician or pediatric neurologist.  

The most common GRIN symptoms described by families are:

1) Delay in cognitive development, often comparable with behaviors similar to those associated with the autism spectrum. But unlike what we see in autistic kids, GRIN children can be very social. 

2) Epilepsy and absences: some seizures are difficult to control with antiepileptic drugs. Some patients who suffer from epilepsy have also been diagnosed with syndromes such as WEST or Landau-Kleffner syndrome, as well as with infantile spasms. 

3) Non epileptic crisis- moments of hysteria/severe anxiety (still to be differentiated from dysautonomia and so called “neuro-storms”).

4) Movement disorders and delay in psychomotor development: including hypotonia (low muscle tone), hypertonia (high muscle tone), dyskenesia (involuntary movements), stereotypies (repetitive movements), dystonia (combination of high and low muscle tone) and difficulty with fine motor skills, and walking. Dystonia can be hard to diagnose because a child can be more hypotonic than hypertonic and can consequently be diagnosed with hypotonia only

5) Speech and communication disorder: ranging from being non-verbal to having difficulty forming words/sentences. 

6) Visual or eye problems: such as cerebral or cortical visual impairment (CVI), abnormal eye movements like strabismus and nystagmus, problems with binocular vision, etc.

7) Sensory processing problems. Often associated with irritability or increased sensitivity to certain aspects of their environment such as sounds, lights and touch. Some children may experience difficulties in eating because they are unable to tolerate certain food’s tastes, textures and consistencies.

8) Gastrointestinal disorders: constipation, maldigestion, gastroparese (slow emptying of the stomach content), aerophagia (swallowing air), borborigmus (intestinal gas noises), gastric reflux, difficulty burping and vomiting. Gastrointestinal migraines can be considered in some of these patients.

9) Dysphagia: Difficulty swallowing and excessive drooling. It is usually associated with coughing during eating and drinking. In some children excessive drooling can be attributed to weakness of the muscles in the mouth.

10) Sleep disorders: difficulty falling asleep, nocturnal awakenings (crying or laughing), and seeming to need fewer hours of sleep. Best to assess sleep disruption with a 18h- or longer EEG (see section on GRIN Diagnostic tests)

11) Difficulty gaining weight / failure to thrive, low energy levels

12) Altered mental states: irritability, anxiety and/or nervousness. These states can vary rapidly and can come in suddenly without an obvious trigger.

13) Behavioral disorders: aggressive behavior including self-harm (biting hands and wrists), difficulty concentrating, being overly friendly to strangers, extreme impulsivity, no sense of danger, running away (eloping). Compulsive or repetitive behaviors have also been observed. 

14) Dysautonomia: heart rhythm disturbances, excessive sweating, skin color changes in the extremities (blood circulation disturbances), blood pressure alterations, difficulty breathing and thermoregulation issues (body temperature regulation). When a group of these symptoms has a sudden onset, it is termed Paroxysmal Sympathetic Hyperactivity Storms (PHS) or neurostorms

15) Other potential symptoms associated directly or indirectly with GRIN disorders: low thyroid hormone levels, Kidney stones, high levels or ammonia and urea in the blood

16) Migraines: although difficult to prove our GRIN patients suffer from this, there is evidence that the NMDA receptors are involved in the control of migraines, and drugs, targeting the NMDA receptor, are being developed to help control migraines.

17) Respiratory issues and recurrent respiratory infections. Important to rule out problems with dysphagia or muscle weakness that may be the cause of or can contribute to the recurrence of respiratory disease. 

Here you can print the full list of GRIN symptoms so you can share them and discuss them with your medical team.

It is important to mentioned that in most cases children affected by GRIN disorders have been reported to outgrow many or some of their symptoms and will continue to improve (even if it is very slowly) throughout their lives. Some may even outgrow certain symptoms with age, as they mature and become physically stronger. It is also possible to treat and/or control some of these symptoms with appropriate therapy, medication or nutritional supplements. Some kids may respond so well to early stimulation therapies and treatments, that they will manage to reach some developmental milestones.
In our TREATMENT section, under Treatment aimed at regulating some of the GRIN Clinical Symptoms, we have elaborated on a list of potential treatments that have been used, anecdotally, in some GRIN patients. It is very IMPORTANT that you discuss any of these treatments with your child’s physician/neurologist before you try them at home.

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