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SYNGAP1 Epilepsy

????Most people with?SYNGAP1?syndrome develop epilepsy, usually from around 2 years of age. However some people develop epilepsy earlier during infancy while others develop it later on in childhood or during early adulthood.

????SYNGAP1 seizures are commonly atypical absence seizures (staring spells) and/or eyelid myoclonia (eye flutters) as well as atonic (drop attacks due to loss of muscle tone). Tonic clonic or what were previously called “grand mal” seizures have been reported in a few people. Prior to their genetic diagnosis, people with SYNGAP1 may have been given clinical diagnoses of Doose syndrome or Jeavons syndrome. Some people with specific EEG patterns may receive a diagnosis of?Lennox-Gastaut syndrome.

????SYNGAP1 seizures have commonly been reported to be triggered by eating or chewing. Some other triggers include sounds and noises, light (photosensitivity), and patterns.?

????You can learn more about?types of seizures in SYNGAP1?in our webinar with Dr ángel Aledo-Serrano.

EEG monitoring in SYNGAP1

????Some clinicians recommend regular EEG monitoring for people with SYNGAP1, particularly if cognition plateaus or seizures change or worsen. Since seizures in SYNGAP1 can be irregular and hard to identify, it is recommended to have a lengthy video EEG where possible.

Seizure control

????Currently there is no specific?course of treatment?that targets the underlying cause of SYNGAP1 epilepsy, so it is up to caregivers to work with their neurology teams to apply the most appropriate medication protocols and therapies that work for their child.

????In addition, there is no one particular anti-epileptic drug (AED) or specific combination of drugs which is known to work well for all people with SYNGAP1. However, one SYNGAP1 clinician has noted that some AEDs such sodium channel blockers, oxcarbazepine, lacosamide and rufinamide do not work particularly well for their SYNGAP1 patients’ epilepsy. AEDs that work well for some people may not work well for others. Families have reported side effects with various AEDs including muscle weakness, fatigue, cognitive plateaus, loss of appetite and adverse behaviors.

????When SYNGAP1 epilepsy is well controlled families have reported fewer seizures, improved sleep and behavior.

????Anecdotally, some families have worked with their clinicians to implement?the ketogenic diet or Modified Atkins Diet (MAD)?with some degree of success. This has enabled them to reduce the number or dosage of medications administered to the person with SYNGAP1.

????Despite this, a number of SYNGAP1 patients remain resistant to medications and dietary approaches and are unable to achieve seizure control. For those people,?Vagus nerve stimulation (VNS)?or epilepsy surgery may be considered.

????One of the un-answered questions about SYNGAP1 epilepsy is why some people are able to achieve seizure control with existing medications and others aren’t. It could be that there are other genetic factors or environmental factors involved that improve or worsen symptoms.

????You can learn more about studying and?treating SYNGAP1?in our webinar with?Dr. Jimmy Holder Jr.?of Texas Children’s Hospital.

Research into mechanisms that may be causing seizures in SYNGAP1 and potential treatments

????The?SynGAP protein?is one of the most highly abundant proteins found at the synapses (the connections between neurons). One of SynGAP’s most well-documented functions is that it plays a key role in enabling synaptic plasticity (the ability of a synapse to become stronger or weaker). Plasticity is important for healthy brain function, particularly for learning and acquiring new memories. SynGAP enables plasticity by regulating the strength of the synapses. It does this by signaling for the recruitment of receptors called AMPA receptors. For people without enough SynGAP protein, the brain’s signalling mechanisms are weakened and the synapses end up recruiting too many AMPA receptors. This causes dysfunction in the synapses and results in reduced synaptic plasticity and the symptoms of SYNGAP1-related disorder.

????Dr. Shilpa Kadam of The Kennedy Krieger Institute and Johns Hopkins University School of Medicine has studied SYNGAP1 patient EEGs and found seizures occur when the brain is transitioning between sleep stages, for example from non-REM to REM sleep and from REM to non-REM sleep. During normal sleep the brain’s gamma frequency oscillates in a certain rhythm but that rhythm was found to be completely disrupted in both mice and people with SYNGAP1. Both seizures and altered cognition are thought to occur due to these disrupted gamma oscillations and in turn, these disrupted oscillations are thought to be caused by too many AMPA receptors.

????Dr. Kadam’s lab treated SYNGAP1 heterozygous mice with a low dose of the AED perampanel (Fycompa), which is an AED that acts to block AMPA receptors. This medication at low dosage helped correct seizures in SynGAP mice, however this low dose approach has not yet been studied in people with SYNGAP1.

????Dr Gavin Rumbaugh?of The Scripps Research Institute also?demonstrates?that EEG changes in mice can be improved with correction of SynGAP expression.

????For more information see?Dr. Rick Huganir’swebinar on SynGAP, Dr. Shilpa Kadam’s webinar on?studying SYNGAP1 EEGs?and Dr Gavin Rumbaugh’s webinar on?developing treatments for SYNGAP1.

Epilepsy Treatment

There are a number of treatments available to treat epilepsy in general:

Anti-epileptic drugs (AEDs): many broad and narrow spectrum anticonvulsants are available. In a significant portion of the SYNGAP1 population, one or several in combination are effective in reducing seizures. However, some SYNGAP1 patients have a drug-resistant form of epilepsy and do not benefit from AEDs.

Cannabinoids: Although not tested in SYNGAP1 specifically,?CBD?has been shown to have antiepileptic efficacy in?trials of other epilepsies. A number of SYNGAP1 patients use cannabinoids as an add-on therapy for seizure reduction.

Special Diets: the?ketogenic diet?is now accepted as an approach for reducing seizures.

Surgery: surgical procedures such as?Vagus Nerve Stimulation (VNS)?or Corpus Callosotomy may benefit carefully selected epilepsy patients with AED-resistant seizures.