By Adam Clatworthy

As a husband to a paediatric nurse, when you enter parenthood, you feel like you have a bit of a head start—that you’ve heard the worst of the stories, that you hope you don’t have to go through yourself.

But that all changes when you go through the challenges we’ve been going through. Having a child diagnosed with a very rare form of intractable epilepsy is devastating for any parent, but to have it happen twice is unimaginable.

CRELD1 (cysteine-rich with EGF-like domains 1) is a protein-coding gene. Sequence changes in the CRELD1 gene are typically associated with the cause of atrioventricular septal defect; h​owever, new types of sequence changes in different parts of the CRELD1 gene can cause an extremely rare genetic disorder, when both copies of the gene don’t function properly (autosomal recessive inheritance).

This manifests as a wide range of neurodevelopmental disorders, ranging from mild movement disorders to severe developmental and cognitive delays.

This newly identified CRELD1-related disorder is also characterised by multiple, frequent, treatment-resistant epileptic seizures, adrenal insufficiency, severe bilateral neural hearing loss, immature eye development, acute respiratory distress and submucosal cleft palate.

It’s a disease that very few people have had to face. If you Google “CRELD1 and epilepsy”, very little comes up in the search, which means that any parents faced with the same condition are completely lost when given this extremely rare diagnosis.

The mission to change that

I’ve spent the last four years searching for guidance, answers and support to help families firstly recognise, and then deal with this ever-challenging condition. The only mention of epilepsy and CRELD1 is a publication that discusses precision medicine and COVID-19, where a person with CRELD1 and seizures is mentioned in passing.¹

I first heard about CRELD1 when our daughter Lola started having frequent seizures at just three months old. Lola had severe developmental delay, was struggling with feeding and mobility and often experienced upwards of 80–100 “twitches” and prolonged seizures every day. By pure chance, a mother in one of the epilepsy Facebook groups I had joined, recognised Lola’s seizures from those that her son was having. We quickly established many similarities in our children’s symptoms and experiences. This proved to be a far more reliable source of intel than what we gathered from the geneticist who initially brushed off our suggestions saying, “We’ve not seen any links between epilepsy and CRELD1, so it’s highly unlikely to be that…” This was one of the big issues—no-one believed me that it could be CRELD1, and they wouldn’t test for it. This made us feel like we didn’t know what we were talking about because we’re “just parents”.

We were desperate to get a diagnosis to not only give us more direction on potential treatment options for Lola, but also because we wanted to have another child. We were told by our neurologist that Lola was “a lightning bolt” and that they’d done all the testing they could. 

“We were told the chances of us having another child with the same condition were less than 3%.”

A few weeks before Lola’s third birthday, and just four days after her little brother Alfie was born, every parent’s worst nightmare became a reality when we tragically lost Lola. Her cause of death was put down to sudden unexpected death in epilepsy (SUDEP), a tragic outcome for many children diagnosed with severe epilepsy. 

We quickly learned that Alfie started having the exact same seizures at three months old and soon had confirmation that Lola and Alfie were both diagnosed with the same CRELD1 gene sequence variation after pushing our geneticist to test for CRELD1 again. 

Shortly after our hospital visit with Alfie’s first seizure, Lola’s full exome sequencing, as part of the 100,000 genomes project was finally completed, but didn’t come back with any conclusive insights. At this point, I asked the geneticist about CRELD1 again. We provided a raft of information that we’d gathered from the other mum over the past two years, along with contact details for their geneticist and neurologists in Canada. We also provided details for a genetic testing company that is running a study into the CRELD1 mutation in partnership with Yale School of Public Health.

The next day, we received a response to say that they had gone back to Lola’s sequencing and had in fact identified changes in the CRELD1 gene. They now think it is highly likely that this mutation is what caused the issues for Lola, and they want to do further scientific research to prove this and publish in the medical literature, to avoid missing other potential diagnoses.

Both Lola and Alfie are now part of a CRELD1 research study with Yale School of Public Health,² inspiring me to bring together a devoted team of experts in genetics, rare diseases and neurology. Each of them shares the commitment to advancing the understanding of CRELD1-related disorder and improving the lives of children born with this rare genetic disorder.

We were also accepted into a Facebook group—CRELD1 Warriors—which has the parents of just 15 children that have been diagnosed with CRELD1 around the world. This group has been our lifeline and our new extended family, helping us learn as much as possible. We all talk almost every day and share key learnings about our children’s symptoms and different tests / learnings that have then helped us all. 

These conversations led me to creating the CRELD1 Warriors website—a place where other families could find comfort in being connected, where they weren’t alone, and where they had a chance to learn from the experiences we had all been through. Now, if you Google “CRELD1 and epilepsy”, our website is the first site you’ll see. Since launching the site last August, we’ve had over 2,000 unique visitors and we’ve heard directly from families in the UK and in the US that got a CRELD1 diagnosis for their children—simply by finding the website.

Advancing the conversation

Our geneticist has remarked that it’s the first time in her career that a family has used their own knowledge and investigations to help diagnose a rare disease condition and without that information they would not have analysed the CRELD1 gene.

When you think about how much time a doctor, neurologist or geneticist can physically spend with a patient, there is no way that they can fully understand their complex condition or symptoms. We often don’t have the academic or scientific background, but as parents we live with and learn from our children every second of every day.

International collaborative research is underway, and Yale will soon be publishing its scientific paper linking a number of children with similar symptoms and genetic results. Two rare genetic changes have been detected within the gene on chromosome 3 and are considered disease-causing. The gene changes have been found in both parents and therefore the chance of having another affected child is 25%.

And while in the long-term, these steps are hugely encouraging, as a parent you have to look at the short-term as well as the longer-term options available—in a sense, you’re prepared to leave no stone unturned.

Looking at all the options

The link to the family we found on Facebook doesn’t stop at sharing our prognosis. We learned that they (and some of the other CRELD1 children) had seen some success with using cannabidiol (CBD) oil and managed to get their son’s seizures down to one every couple of weeks. When Alfie’s doctors in the UK prescribed the same course of ineffective anti-epilepsy treatment as they had with Lola, we felt intervention was necessary. We weren’t prepared to see history repeat itself.

Thankfully, because of our very supportive neurologist and the positive results seen from some of the other CRELD1 children, Alfie has been accepted for treatment after his second birthday with a drug containing CBD. 

Alfie’s symptoms aren’t quite as severe as Lola’s, but he still can have upwards of 50 seizures a day. Therefore, we also want to explore the option of full-spectrum cannabis for him, having read and heard about the benefits of THC (tetrahydrocannabinol). A number of studies have been conducted by Drug Science, the latest of which, published at the end of last year, revealed that seizure frequency fell by 86% in children with intractable epilepsy who were using medical cannabis.³

But access to cannabis prescriptions in the UK for children with epilepsy is extremely limited—despite its being legalised in 2018. There are very few paediatric neurologists prescribing cannabis in the UK and very few NHS prescriptions have since been written.

Cross-border relations

The battle we face is one of bringing the scientific and parent community together, to form a network of individuals that are all going through the same challenges, helping us focus on identifying the right treatment options, rather than testing multiple drugs that we have no idea will work and bring many damaging side effects.

It also means that we can help make the connections and ensure that the UK and US can learn from each other and share information with families with other potentially undiagnosed children suffering the same challenges across the world.

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