Danielle Williams is a SynGAP parent leader in Australia and a member of the SynGAP Global Network.

Five things you need to know

An important paper which studied 57 SynGAPians was published last month in Neurology. This article summarizes five things you need to know about this paper whether you are a parent, sibling, caregiver or medical professional who cares for a SynGAPian.

1. The genesis story — How this paper began with a parent survey
2. Why this paper matters for both diagnosed & undiagnosed SynGAPians
3. Three emerging findings validated by this & other recent papers
4. Each parent-researcher connection matters
5. Highlights of the cohort of 57 SynGAPians studied

1. THE GENESIS STORY

We received a SynGAP diagnosis for both of our daughters in February 2016. As we struggled with the diagnosis, we were hungry for information about SynGAP. We wanted information about the symptoms we were seeing and what to prepare for. With fellow SynGAP mum, Laura Ma and the support from two of the American Syngap organization founders — Rebecca Kohlhepp and Monica Weldon — we created a survey.

Laura and I spent hours compiling the report which was the first source of useful Syngap patient data we had seen. It began to answer the questions that kept us up at night (if our kids weren’t already!). Questions like: how many have seizures? What types of seizures do they have? What are their triggers? Do they have behavioral issues? Do they have autism? Do they talk? Are they mobile?

In our next appointment with our neurologist Professor Ingrid Scheffer, I proudly presented this report. Ingrid is a globally recognized epilepsy physician-researcher and singing her praises here would make this article too long. Put simply, she is one of the heroes of our medical journey.

On that day, Ingrid looked at the report & rolled her eyes (her version differs). But she said, “I’ll get a team to validate this.” And that is what makes Ingrid so incredible, two years later her ‘validation’ is the largest study of SynGAPians to date in the best Journal for Neurology.

2. WHY THIS PAPER MATTERS FOR PATIENTS

For diagnosed, this paper will help parents & physicians partner to understand how SynGAPians evolve and present. Unique seizures and predictable developments no longer need to be a surprise or the subject of raised eyebrows during valuable clinical conversations.

For undiagnosed patients — and we suspect there are many — the paper will be a critical tool to assist neurologists to make earlier diagnoses, in turn minimizing painful and unnecessary treatment trials for them.

3. THREE EMERGING FINDINGS VALIDATED BY THIS & OTHER RECENT PAPERS

This paper makes many important points but here are three that SynGAP parents and their physicians should be aware of.

First, it identifies a new seizure type: eyelid flutters followed by a drop (eyelid myoclonia followed by myoclonic-atonic seizures). It also validates two other recent SynGAP publications:

Second, it reaffirms the connection between SynGAP and sensory processing issues which was also discussed in November in SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. Michaelson et. al. Nature Neuroscience, 2018.

Third, it notes the correlation between Syngap and eating as a seizure trigger which is the focus of a concurrent paper Chewing induced reflex seizures („eating epilepsy“) and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: review of literature and report of 8 cases by Stülpnagel et. al. Seizure, 2018

4. EACH PARENT-RESEARCH CONNECTION MATTERS

I’m grateful to be involved with Prof. Scheffer and her team on this project. The two young doctors who drove the project Dr Ben Shaw and Dr Danique Vlaskamp, are incredible people. Danique received her PhDs along the way!

We encourage every parent to connect with researchers at every opportunity. If you are visiting their city, ask if you can come to their labs, with your child/patient. Let them know how much their work matters and encourage them to keep going. As this study shows, their work requires our input and our kids require their dedication and talent.

All parties benefit when great doctors believe in the power of driven parents & those parents harness their collective skills.

5. HIGHLIGHTS OF THE COHORT OF 57 SYNGAPIANS STUDIED

Please read this paper. It is full of important information about SynGAP. Please print it out and take it to all your doctors and therapists. But just to give you a taste, to follow are some interesting statistics about the 57 patients reviewed.

• 57 patients (53% male, median age 8 years)
• 56 had epilepsy: generalized in 55, with focal seizures in seven and infantile spasms in one.
• Median seizure onset age was 2 years.
• A new type of drop attack was identified comprising eyelid myoclonia (eyelid flutters) evolving to a myoclonic- atonic (jerk drop) for 5 patients and atonic (drop) seizures in another 8.
• 65% had eyelid flutters with absences (eyelid myoclonia with absences)
• 25% had seizures triggered by eating
• Eating problems, with poor intake or gorging, were also found in more than half of the cohort
• 55 patients had intellectual disability (ID). Moderate to severe in 50.
• 73% had behavioural problems
• 72% had a high pain threshold
• This finding of a high pain threshold may suggest a role for SYNGAP1 in sensory processing
• 68% had eating problems including oral aversion
• 67% had hypotonia (low muscle tone)
• 62% had sleeping problems
• 54% have an autism diagnosis
• 51% have gait abnormalities or ataxia (lack of muscle control / coordination of voluntary movements)
• Developmental plateauing or regression occurred with the onset of seizures in 56 patients
• In 8 patients, developmental regression occurred two months to >3 years prior to the recognition of seizures. Diagnosis of seizures in SYNGAP1 is therefore crucial as appropriate management may potentially improve outcome.
• SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia and myoclonic-atonic seizures, and predilection to seizures triggered when eating.
• Loss-of-function of SYNGAP1 has major consequences for neuronal homeostasis and development, which are crucial for learning and memory.
• A milder outcome of SYNGAP1 DEE was observed significantly more frequently in patients with mutations in exons 1–4, compared with those with mutations in exons 5–19.
• In line with this, Mignot et al. also showed that patients with mutations in exon 4–5 were more pharmaco sensitive compared to those with mutations in exon 6–19
• Recognition of seizures in the context of SYNGAP1 can be challenging, but is crucial to optimising anti-epileptic therapy and improving long term outcome.

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