New Report Shows Rare Disease More Common Than Previously Thought

Approximately one in forty-two thousand children are born with a disease called CDKL5 Deficiency Disorder, according to a new medical report recently published in the journal Brain and presented last month at the 13th European Paediatric Neurology Society Congress in Athens, Greece. This means that each year there are over 100 new children born with the disease in the EU alone, and over 3,000 in the world.

The disease leads to frequent seizures shortly after birth and severe impairment in neurological development, with most affected people being unable to walk, talk or care for themselves. “When our daughter was diagnosed in 2009 they told us there were approximately 200 cases in the world”, says Carol-Anne Partridge, chair of CDKL5 UK and the International CDKL5 Alliance, which represents patient organizations from 18 countries. “Today we know that these children were simply not being diagnosed correctly,” she adds.

The study, by a medical team from the Royal Hospital for Children in Glasgow, kept track of all births in Scotland during three years and applied genetic testing to all children under 3 years of age who developed epilepsy. “We found that as many as 1 in 4 children with epilepsy have a genetic syndrome”, explains Professor Sameer Zuberi, corresponding author for the study, “and a small group of genes explains most of the cases.”

Among these genes is CDKL5, which encodes a protein necessary for proper brain functioning. Mutations in the CDKL5 gene produce CDKL5 Deficiency Disorder, with one of the first symptoms being early-onset epilepsy. There is no therapy approved for treating the disease now known to affect thousands of people.

NeuCyte to Advance Novel Compound for Treatment of Refractory Epilepsy and Related Neurological Disorders

NeuCyte, Inc. announced that it has entered into an exclusive license agreement with Trillium Therapeutics to advance an undisclosed preclinical compound with potential utility in treating refractory epilepsy in the form of Dravet syndrome and related disorders.

The compound covered by this agreement has demonstrated highly encouraging activity during studies conducted by the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP). It demonstrates a superior safety and anti-seizure efficacy profile over NINDS benchmark anti-epileptic drugs (AEDs) in eleven animal models. It has also demonstrated broad efficacy in NIH animal studies for pharmaco-resistant epilepsy. As a result, this novel agent has gained the prestigious NINDS Red Book status and been selected as a promising lead drug candidate.

“This compound is an exceedingly promising antiseizure drug which, although in preclinical development, is quite efficacious in a wide variety of highly predictive seizure models,” said Roger J. Porter, MD, Adjunct Professor of Neurology at the University of Pennsylvania, former Deputy Director of NINDS, former Chairman of the White House Committee on Brain and Behavioral Sciences, and former President of American Epilepsy Society. “It may prove very effective for patients with epilepsy.” As a first-in-class compound with unique mechanism of action profiles, this drug candidate is likely to have activity across a variety of indications. The favorable efficacy and safety profile has also been validated by NeuCyte’s proprietary in vitro human iPSC-derived models.

Complex Neurocognitive Skills Delayed in Youth With SCN8A Variant Epilepsy

Complex neurocognitive skills, typically acquired later in development, are the most delayed skills in youth with SCN8A?related epilepsy, according to results published in Epilepsia.

Researchers analyzed 91 patients with SCN8A-related epilepsy. Analyses were conducted to identify correlations between age at seizure onset and neurodevelopmental growth. Parents and guardians provided information pertaining to their child’s medications, seizure history, comorbidities, and developmental skills based on Denver II items. Twenty-five skills were chosen, six to seven from each category (fine motor, gross motor, social motor, and language).

Researchers carried out a retrospective analysis of data from an online SCN8A community registry and used the canonical transcript to map all genetic variants collected. Spearman rank tests were used to evaluate pairwise relationships between certain seizure characteristic variables and development score.

A limitations of this study included the potential for recall error in questionnaires completed by parents and guardians. Further, cohort included was not large enough to produce statistically significant tests and prevented further stratification based on subphenotypes or mutational type.

Researchers concluded that variants of uncertain significance should be taken into consideration when evaluating children with SCN8A-related epilepsy. Researchers believe these findings provide “a clinical context at initial presentation that may be prognostic for developmental outcome.”

Diacomit is Effective as Add-on Therapy to Reduce Refractory Seizures in Dravet, Review Study Finds

Diacomit (stiripentol) is an effective add-on oral therapy to reduce the frequency and duration of seizures in patients with Dravet syndrome, a review study has found.

The study, “Stiripentol: A Novel Antiseizure Medication for the Management of Dravet Syndrome,” was published in the journal Annals of Pharmacotherapy.

Diacomit, marketed by Biocodex, is a new type of anticonvulsive medication that has been shown to reduce the frequency of seizures in patients with Dravet syndrome, especially when administered in combination with other antiseizure medications, such as Onfi (clobazam), Depacon (valproate), and topiramate (sold as Topamax among other names), or with dietary interventions such as the ketogenic diet (low-carbohydrate, high-fat diet).

This new antiseizure therapy received the designation of orphan drug in 2001 from the European Medicines Agency, followed by its approval in Europe as an add-on therapy in 2007. The U.S. Food and Drug Administration approved Diacomit in 2018 as an add-on therapy for the treatment of seizures in children with Dravet syndrome who are 2 years of age or older and already taking Onfi.

Better Seizure Control with Ketogenic Diet in Infants with Genetic Epilepsy

Infants and young children with epilepsy due to a confirmed genetic abnormality had a better response to treatment with ketogenic diet compared to patients with other types of epilepsy, according to a review of 10-year experience at Ann & Robert H. Lurie Children’s Hospital of Chicago. Results were published in Scientific Reports.

“Overall, we observed that ketogenic diet continues to be a safe, effective and well-tolerated treatment for patients under 3 years of age with drug-resistant epilepsy,” says study author John Millichap, MD, an epilepsy specialist at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Based on our experience, clinicians could consider offering ketogenic diet earlier to infants diagnosed with genetic epilepsy, perhaps even before it becomes clear that the patient is not responding to anticonvulsant medication.”

Ketogenic diet is a high fat, low carbohydrate and protein restricted diet that is rigorously medically supervised. It is widely recognized as an effective treatment for epilepsy that does not respond to medications.

“The ketogenic diet helps control seizures by reducing fluctuations of blood sugar, which reduces hyper-excitability in the brain,” explains Dr. Millichap. “At Lurie Children’s we have used it since 1963.”

Possible Role of SCN4A Skeletal Muscle Mutation in the Loss of Breathing During Seizure

SCN4A gene mutations cause a number of neuromuscular phenotypes including myotonia. A subset of infants with myotonia-causing mutations experience severe life-threatening episodic laryngospasm [a spasm of the vocal cords that makes it difficult to speak or breathe] with apnea.

This research team recently identified similar SCN4A mutations in association with sudden infant death syndrome. Laryngospasm has also been proposed as a contributory mechanism to some cases of sudden unexpected death in epilepsy (SUDEP). The team reports an infant with EEG-confirmed seizures and recurrent apneas. Whole-exome sequencing identified a known pathogenic mutation in the SCN4A gene that has been reported in several unrelated families with myotonic disorder.

This study proposes that the SCN4A mutation contributed to the apneas in our case, irrespective of the underlying cause of the epilepsy. They suggest this supports the notion that laryngospasm may contribute to some cases of SUDEP, and implicates a possible shared mechanism between a proportion of sudden infant deaths and sudden unexpected deaths in epilepsy.

Stoke Therapeutics Observational Study of Children and Adolescents Living with Dravet Syndrome

Stoke Therapeutics, Inc. announced enrollment of the first patient in an observational study of children and adolescents ages 2 to 18 with Dravet syndrome. BUTTERFLY is a two-year observational study that is designed to evaluate seizure frequency and non-seizure comorbidities associated with the disease, including motor and speech impairment, intellectual and developmental disabilities, behavioral deficits and abnormal sleep patterns. Data from the study will support clinical development plans for the company’s lead therapeutic candidate, STK-001, an investigational new treatment for Dravet syndrome.

Epilepsy Research Findings: August 2019

The past month has been filled with interesting research discoveries, including work done by CURE Grantee Dr. William Nobis and colleagues to advance our understanding of the areas of the brain that may be important in Sudden Unexpected Death in Epilepsy (SUDEP). In the field of epilepsy genetics, a large-scale study identified new epilepsy-associated genetic variants by examining the genetic make-up of more than 17,000 people with epilepsy. There is also intriguing research news looking at why cilantro, used in traditional medicine, may work to combat seizures.

Summaries of these research discoveries are below.

Plus, get epilepsy research news all month by downloading the new CURE mobile app! Find the details here.

Research Discoveries

SUDEP: A study featuring the work of CURE Grantee Dr. William Nobis and colleagues suggests that an area of the brain called the amygdala plays a role in dysfunctional breathing during seizures and possibly SUDEP. Learn More
Epilepsy Genetics: In one of the largest studies of its kind to examine the genetic make-up of individuals with epilepsy, scientists discover rare genetic variants associated with epilepsy. Learn More
Herbal Treatments: A study examines how the molecular action of cilantro, which is used as a traditional anticonvulsant medication, can help combat seizures. Learn More
Dementia and Epilepsy: Patients with dementia who are registered in the Swedish dementia registry were found to have increased rates of epilepsy. Learn More
Multiple Sclerosis and Epilepsy: Patients with multiple sclerosis have a higher risk of developing seizures compared with the general population. Learn More
SCN8A-Related Epilepsy: A study featuring the work of CURE Grantee Dr. Gemma Carvill and colleagues identified a set of neurons in the brains of mice that have a SCN8A gene mutation similar to humans that may be critical targets for therapeutic intervention. Learn More

Introducing the CURE Epilepsy Research Mobile App for research updates in the palm of your hand! Download today. iOS | Android

FDA-Approved Donepezil Protects Against Seizures in a Mouse Model of Dravet Syndrome

De novo loss-of-function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early-life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. This research team previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants.

In the present study, the team evaluated the therapeutic potential of donepezil, a reversible acetylcholinesterase inhibitor approved by the FDA, in a mouse model of Dravet syndrome (Scn1a +/-). The team found that donepezil conferred robust protection against induced seizures in Scn1a +/- mutants.

Study on Challenges in Patients with Juvenile Myoclonic Epilepsy Points to a Need of Closer Follow-Up

BACKGROUND: Patients with juvenile myoclonic epilepsy (JME) may have uncontrolled seizures. The purpose of this study was to investigate the use and challenges with antiepileptic drugs (AEDs) and the patients’ view of these challenges.

METHOD: A questionnaire about the use of AEDs, adherence to therapy, and quality of life was given to patients with JME recruited from Drammen Hospital. Data regarding AEDs were confirmed from medical records at Drammen Hospital, Norway (2007-2018). Additional clinical interviews were performed, and a mixed method approach was applied.

RESULTS: Ninety patients with defined JME diagnosis, 54/36 women/men aged 14-39 (mean: 25) years, were included. Only 29 (33%) were seizure-free. Within the last year, 21% experienced generalized tonic-clonic seizures (GTCS), and 68% had myoclonic jerks. Seventy-six (84%) used AEDs, 78% in monotherapy. A total of 10 AEDs were used;: most commonly valproate (n = 33), lamotrigine (n = 27), and levetiracetam (n = 21). Two-thirds of valproate users were men while all other AEDs were used more in females than in men. Valproate and levetiracetam displayed better efficacy against GTCS than lamotrigine. One-third often/sometimes forgot their medication nonintentionally while 14% had intentional poor adherence. The majority reported good quality of life (76%). No significant correlations between the use of AEDs, use of valproate, poor adherence, quality of life score, and seizure freedom were demonstrated. Half of the patients had serum concentrations measured every year, and two-thirds thought this was important. Qualitative interviews elucidated treatment challenges in JME;, adverse effect burden, adherence, and activities of daily life.

CONCLUSION: Despite the use of antiepileptic drugs in the majority of patients, only one-third were seizure-free. Other challenges included polypharmacy, the use of valproate in women, and variable adherence. This points to a need for closer follow-up in patients with juvenile myoclonic epilepsy.