CDKL5: Understanding rare epilepsies, patient by patient, neuron by neuron

CDKL5 epilepsy
Haley with her parents and neurologist Heather Olson (right)

Nine-year-old Haley Hilt has had intractable seizures all her life. Though she cannot speak, she communicates volumes with her eyes. Using a tablet she controls with her gaze, she can tell her parents when her head hurts and has shown that she knows her letters, numbers and shapes.

Haley is one of a growing group of children who are advancing the science around CDKL5 epilepsy, Haley’s newly recognized genetic disorder. When Boston Children’s Hospital geneticist Joan Stoler, MD, diagnosed Haley in 2009, there were perhaps 100 cases known in the world; today, there are estimated to be a few thousand. Haley’s neurologist, Heather Olson, MD, leads a CDKL5 Center of Excellence at the hospital that is bringing the condition into better view.

A ‘challenging disorder’

The seizures started when Haley was just 4 weeks old. At first, her parents were told they were night terrors, but what they saw didn’t seem normal. “She would wake up out of sleep — her whole body would stiffen, her eyes would roll back, her arms would go up,” says her mother, Melissa Hilt.

After her parents showed videos of the episodes to their pediatrician, Haley was admitted to a hospital in New York State for overnight EEG monitoring. That began a series of trips back and forth from Albany to Boston Children’s and a series of seizure medications.

Nothing worked for long — in fact, the seizures would come back even stronger. They also kept changing, going from spasms to full-blown tonic clonic (grand mal) seizures to ticks on one side of Haley’s face.

CDKL5 epilepsyAt about 18 months, Haley’s development began abruptly regressing, which the Hilts later learned is typical of children with CDKL5 epilepsy. “Within a two-week period, she went from standing and cruising — she would hold onto furniture and try to move — to not being able to sit up or hold her head up,” says Melissa.

In 2008, Haley had an epilepsy surgery evaluation including EEG, PET and SPECT scans of her brain. “We were told that the seizures were happening throughout her entire brain and that surgery was not an option,” says Melissa. “Her treatment options were the ketogenic diet or a vagus nerve stimulator.“

They tried both. The diet improved Haley’s seizures somewhat, but caused liver and gastrointestinal problems, so they had to discontinue it after couple of years. The vagus nerve stimulator, a pacemaker-like device implanted below Haley’s collarbone, has reduced the tonic-clonic seizures but not the spasms.

“CDKL5 epilepsy is a very challenging disorder,” says Olson. “Most kids have difficult-to-control seizures, severe developmental and cognitive challenges, visual impairment and various other medical challenges including sleep and gastrointestinal symptoms. Our goal in the Center of Excellence is to provide disease-specific, high-quality multidisciplinary care, to better define the disorder and improve patients’ quality of life. Simultaneously, we hope to engage the scientific community to help us understand the disorder’s underlying biology and work toward targeted treatments.”

Neurons and evoked potentials: Delving into CDKL5

As one of about 25 patients enrolled at the Center, Haley is eligible for several research studies. Through Boston Children’s Human Neuron Core, some of her skin cells will be transformed into stem cells and then into living, functioning neurons that embody her condition in miniature.

Neuron_in_tissue_culture

The neurons can mature to some extent in the dish, forming connections, or synapses, of both the excitatory and inhibitory kind. Since epilepsy involves an imbalance of excitatory versus inhibitory signaling, the patient-derived neurons will hopefully help investigators understand how CDKL5 mutations tip the brain into seizures. “We can study electrical function in these neurons and compare the results with those in CDKL5 mouse models,” says Olson.

Michela Fagiolini, PhD, of Boston Children’s F.M. Kirby Neurobiology Center, is leading the scientific research. She notes that the CDKL5 protein is found at the synapses, and that mice lacking CDKL5 indeed show evidence of an altered balance of excitatory and inhibitory synapses.

“We can now study neurons from CDKL5 patients and the mice in parallel,” she says. “We can look at how excitatory and inhibitory synapse markers change during development, how neurons connect and when and how circuits are altered.”

Neurons derived from CDKL5 patients can also be used to screen batteries of candidate drugs, essentially enabling researchers to conduct a “clinical trial in a dish.” Such trials can sometimes provide a better clue to what treatments will work than traditional animal testing. This may be particularly helpful in CDKL5, since mice with CDKL5 mutations don’t have seizures.

Haley will also eventually have specialized brain EEG recordings called visual evoked potentials (VEPs) to measure cortical visual impairment, a prominent feature in CDKL5 patients that affects their vision. (Recent studies in two CDKL5 mouse models also indicate abnormal visual responses.) Fagiolini and the lab of Charles A. Nelson, PhD, have been studying vision in patients with Rett syndrome, a condition related to Haley’s disorder, and have found that VEPs track with disease severity and overall brain function.

“We plan to evaluate VEP and EEG over time in both CDKL5 patients and in animal models,” says Fagiolini. “We can use these techniques to map the trajectory of brain function and evaluate drug efficacy in pre-clinical studies — and eventually clinical trials.”

Comparing notes and patients

Most immediately, the CDKL5 clinic is helping clinicians understand the disorder’s variable features and its trajectory over time, establishing a baseline for medical research and helping families know what to expect. Some children, for example, require tube feeding or have orthopedic problems related to low muscle tone. Patients are also monitored for the possibility of heart rhythm problems.

Haley with mom and Heather Olson

“We’re definitely learning as we go along,” says Olson. “For example, some but not all our kids have microcephaly. Gastrointestinal problems seem to be a big part of the disorder, similar to other neurodevelopmental syndromes. We’re also doing sleep surveys on the kids, and our neuro-ophthalmologist is helping to understand their visual impairment. We’re finding that with aggressive therapies, kids can do better than expected.”

Currently, Haley has five to seven clusters of seizures a day, with 20 to 30 mini-seizures in each cluster. Two to three times a week, she has a tonic-clonic seizure. Low muscle tone has kept her wheelchair-bound, though lately she’s able to kneel, rock back and forth on her hands and knees, and, when supported, stand and take steps.

The Hilts may, on their own initiative, join a medical marijuana program starting in New York State. “Haley has tried 15 different medications and still has hundreds of seizures a day,” says Melissa. “I think I’m more optimistic than our doctors in Boston and Albany are, but they’re not denying that it’s worth a try.”

Fagiolini hopes that the scientific research will eventually lead to treatments that prevent or reverse the damage done by CDKL5 mutations, just as parallel research is doing for Rett syndrome.

“Can we reverse what CDKL5 does in the human brain and recover brain function?” she asks. “How much function can you recover? How late in development? In Rett syndrome, brain cells don’t die, so there is hope that if you could re-express the gene you could reverse children’s symptoms, as is already possible in the animal models. Similar work needs to be done for CDKL5.”

  • Filippe S. Vieira

    Hi, my name is Filippe. I´m from Brazil and I´m father to Natalia, 6. She has te CDKL5 disorder. I´ll be in Boston in May and I would like to know to be possible a conversation
    about what’s new in the treatment of cdkl5. Best Regards.

  • nansona

    Thanks for writing, Filippe. You can call our Department of Neurology at 1-617-355-6388 and ask to speak with Dr. Heather Olson. Good luck! –Nancy Fliesler, Vector editor