CURE Discovery: Genetic Research Finds Potential Alternatives to Brain Surgery for Children with Cortical Dysplasia

A Potential Alternative is Already in Clinical Trial

Recent research by CURE grantee Dr. Jeong Ho Lee of the Korea Advanced Institute of Science and Technology has shed important light on the genetic mutations that lead to focal cortical dysplasia, a severe form of pediatric epilepsy that inadequately responds to available treatment options. Genetic mutations were found in the brain tissue of individuals affected by a particular subtype of focal cortical dysplasia (focal cortical dysplasia type II) that is characterized by brain abnormalities, leading to seizures and epilepsy.

Conventional genetic testing methods to identify genetic mutations in those with epilepsy often use blood or saliva from patients. However, these latest results from Dr. Lee and his team suggest that certain epilepsy-related gene mutations may only be detectable when brain tissue is analyzed.

Brain-Only Mutations in Genes that Cause Focal Cortical Dysplasia

By comparing blood and saliva samples to samples of brain tissue from a group of 40 individuals who had previously undergone brain surgery for focal cortical dysplasia type II, Dr. Lee and his team found that a significant number of these individuals (12.5%) had brain-only mutations in genes TSC1 and TSC2. Together with the previous pioneering work of his team to identify brain-only mutations in the MTOR gene in individuals with focal cortical dysplasia type II, they revealed that brain-only mutations in genes within the mTOR brain signaling pathway (including the genes TSC1, TSC2 and MTOR) are found in up to 30% of individuals with focal cortical dysplasia. The fact that these mutations were found only in the brain means that these mutations would be undetectable by conventional genetic testing methods, suggesting that investigation of brain-only mutations should be explored to a greater extent.

In addition to identifying brain-only mutations leading to focal cortical dysplasia, Dr. Lee and his team also addressed the current lack of adequate animal models to better study the disorder. The team was able to successfully recreate the brain-only mutations in genes TSC1 and TSC2 in developing mice, providing a much-needed animal model for further examination of the ways in which gene mutations can lead to focal cortical dysplasia type II.

Clinical Trials for the Treatment of Focal Cortical Dysplasia

Furthermore, the team provided evidence that mTOR inhibitors, such as rapamycin or everolimus, are promising anti-epileptic drugs for the treatment of focal cortical dysplasia. In fact, everolimus is currently under phase II clinical trial for the treatment of focal cortical dysplasia.

As noted by Dr. Lee, because focal cortical dysplasia is a drug-resistant epilepsy, many children with the disorder require invasive brain surgery as treatment. However, even in cases where surgery is performed, up to 40% of these children may still have seizures. By identifying genes associated with focal cortical dysplasia as well as creating a new way of studying the genetic mechanisms behind the disorder, Dr. Lee and his team have made progress towards the creation of novel, non-surgical targets at which to aim treatments for this devastating form of drug-resistant childhood epilepsy.

[1] Lim et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Human Genet 2017; 100(3):454-472.
[2] Guerrini et al. Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia 2015; 56(11):1669-86.
[3] Gaitanis and Donahue. Focal cortical dysplasia. Ped Neurol 2013; 49:79-87.
[4] Poduri et al. Genetic testing in the epilepsies – developments and dilemmas. Nat Rev Neurol 2014; 10(5):293-299.
[5] Lim et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015; 21(4):395-400.

New Testing Provides Better Information for Parents of Children with Epileptic Encephalopathy

Advances in genetic testing offer new insights to parents who have a child with a rare but serious form of epilepsy, epileptic encephalopathy (EE), found in one of about every 2,000 births and characterized by developmental disabilities as well as horrible seizures.

“New ways of sequencing the human genome mean geneticists and genetic counselors have much more to say to parents who wonder if future children might carry the disease,” says Dr. Heather Mefford, associate professor of pediatrics (genetic medicine) at University of Washington School of Medicine and Deputy Scientific Director of the Brotman Baty Institute for Precision Medicine, co-senior author of findingspublished this week in the New England Journal of Medicine.

A big question from any parent of a child with EE is, “What are the odds that our other children might have this condition?” For decades, parents whose child had epilepsy were told there’s a 1 to 5 percent chance that other children might inherit the mutation. This was based on clinical evidence – the numbers of reoccurrences physicians saw in the clinic.

But armed with more precise testing, the geneticists found parental mosaicism that wasn’t easily detected before in about 10 percent of families, putting these families at higher risk of passing the mutation to another child. What this means in practical terms is that this small group probably accounts for most of the reoccurrences. For some parents, there’s good news: if this parental mosaicism was not detected, your odds of having another such child with epilepsy could be much less than 1 percent.

Critical Review: Can Mutation?Mediated Effects Occurring Early in Development Cause Long?Term Seizure Susceptibility in Genetic Generalized Epilepsies?

Summary: Epilepsy has a strong genetic component, with an ever?increasing number of disease?causing genes being discovered. Most epilepsy?causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here [researchers] review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub?mesoscopic structural changes in GGE is also reviewed.

Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub?mesoscopic structural changes occur in GGE.

The existence of sub?mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. [Researchers] also propose that presymptomatic treatment may be essential for limiting the long?term consequences of disease?causing mutations in genetic epilepsies.

Study: Effects of [Mutations in Genes] UGT2B7, SCN1A and CYP3A4 on the Therapeutic Response of Sodium Valproate Treatment in Children with Generalized Seizures

PURPOSE: This study aims to evaluate the associations between genetic polymorphisms and the effect of sodium valproate (VPA) therapy in children with generalized seizures.

METHODS: A total of 174 children with generalized seizures on VPA therapy were enrolled. Steady-state trough plasma concentrations of VPA were analyzed. Seventy-six single nucleotide polymorphisms involved in the absorption, metabolism, transport, and target receptor of VPA were identified, and their associations with the therapeutic effect (seizure reduction) were evaluated using logistic regression adjusted by various influence factors.

RESULTS: rs7668282 (UGT2B7, T?>?C, OR?=?2.67, 95% CI: 1.19 to 5.91, P?=?0.017) was more prevalent in drug-resistant patients than drug-responsive patients. rs2242480 (CYP3A4, C?>?T, OR?=?0.27, 95% CI: 0.095 to 0.79, P?=?0.017) and rs10188577 (SCN1A, T?>?C, OR?=?0.40, 95% CI: 0.17 to 0.94, P?=?0.035) were more prevalent in drug-responsive patients compared to drug-resistant patients.

CONCLUSION: In children with generalized seizures on VPA therapy, polymorphisms of UGT2B7, CYP3A4, and SCN1A genes were associated with seizure reduction. Larger studies are warranted to corroborate the results.

‘Missing Mutation’ Found in Severe Infant Epilepsy

Researchers have discovered a “missing mutation” in severe infant epilepsy — long-suspected genetic changes that might trigger overactive, brain-damaging electrical signaling leading to seizures. They also found early indications that specific anti-seizure medications might prevent disabling brain injury by controlling epilepsy during a crucial period shortly after birth.

“These are still early days, but we may be able to use this knowledge to protect the newborn brain and improve a child’s long-term outcome,” said study leader Ethan M. Goldberg, MD, PhD, a pediatric neurologist at Children’s Hospital of Philadelphia.

Goldberg collaborated with European and American researchers in this neurogenetic study of early infantile epileptic encephalopathy, published online Feb. 21, 2018 in Annals of Neurology.

The study focused on mutations in the gene SCN3A. Scientists already knew that the gene had a pattern of high expression in the brain, before and shortly after birth. Variants in SCN3A had also been previously linked to less severe forms of epilepsy, but the current research solidified this link and was the first to establish that SCN3A mutations cause the severe infantile form.

Translating these findings into potential clinical treatments, Goldberg stressed, will require considerable further research — both in nerve cells and in future animal models, in which neurologists can test possible precision-medicine treatments for safety and efficacy before they can be investigated in patients. In addition, the current research allowed the SCN3A gene to be added to an existing diagnostic test, CHOP’s Epilepsy Panel, which uses next-generation sequencing to rapidly test for over 100 genetic causes of childhood epilepsy.

Precise, early diagnosis, added Goldberg, will be crucial, because of the highly regulated timetable of early-life neurological events. “The mutation’s activity in the Nav1.3 sodium ion channel occurs during a short period in newborns, but if we can intervene during that window, we may be able to help prevent long-term neurological injury and benefit patients,” he said.

Variants in one gene account for 7% of juvenile myoclonic epilepsy cases

An extremely rare genetic variant that affects the maturation, migration, and death of neurons appears to be responsible for about 7% of cases of juvenile myoclonic epilepsy.

Variants of the intestinal-cell kinase gene (ICK) occurred in 12 members of a family affected by the disorder and were confirmed in 22 of 310 additional patients, Julia N. Bailey, PhD , of the University of California, Los Angeles, and her colleagues reported in the March 15 issue of the New England Journal of Medicine .

But among these 34 patients, the variant manifested as different epileptic phenotypes, suggesting genetic pleiotropism, the investigators said.

The investigators drew data from the GENESS (Genetic Epilepsies Studies) consortium, which has study sites in the United States, Mexico, Honduras, Brazil, and Japan. The current study from the databank analyzed information from 334 families with genetic generalized epilepsies. Among these, 310 patients had adolescent-onset myoclonic seizures and polyspike waves, or had a diagnosis of JME.

Genetic Testing to Develop Personalized Medicine for Epilepsy

This webinar recorded at Columbia University in New York City, focuses on “Genetic Testing to Develop Personalized Medicine in Epilepsy”. In this webinar, learn more about the importance of genetic testing in epilepsy, the different diagnoses you can receive from genetic testing, and what options are available after your testing results. Also, learn how CURE’s Signature Program, the Epilepsy Genetics Initiative or EGI, is helping push the precision medicine movement in epilepsy forward.

The webinar is presented by Dr. David Goldstein, Director of the Institute of Genomic Medicine at Columbia, and also features a Q&A portion. Some of the questions you might hear addressed include:

  • What is the value of genetic testing?
  • How do I go about getting testing ordered for me and/or my child?
  • What type of results can I expect if I do have genetic testing completed?
  • How can knowing the cause of my/my child’s epilepsy help with the available treatment options?
  • How is epilepsy research, like that involved in EGI, helping end the diagnostic odyssey that many patients face?

PPP3CA Gene Mutations Cause a Severe Neurodevelopmental Disease and Seizures

The discovery is credited to data from CURE’s Epilepsy Genetics Initiative

De novo mutations in the PPP3CA gene lead to a severe form of neurodevelopmental disease characterized by seizures. These mutations are not inherited from an individual’s parents.

The discovery was based on genomic data from CURE’s Epilepsy Genetics Initiative.

The identification of PPP3CA as an epilepsy-associated gene provides new insight into the possible causes and mechanisms behind epilepsy, opening a new research target for potential PPP3CA-related therapeutics.

The discovery also provides much-needed information to the individuals and families affected by PPP3CA-associated epilepsies because that diagnosis can potentially be used to inform decisions regarding treatments.

Identifying the genes in which mutations can lead to epilepsy can be challenging, especially for the severe and rare forms. The rarity of these disorders is often associated with a lack of sufficient data. However, in pooling genetics data from several different sources, including those from CURE’s Epilepsy Genetics Initiative, Principal Investigator Dr. Erin L. Heinzen and senior co-author Dr. Heather Mefford had the statistical power to successfully identify mutations in the PPP3CA gene as a lead factor in the development of one severe type of PPP3CA-associated neurodevelopmental disease characterized by childhood-onset epilepsy.

The PPP3CA gene is typically responsible for the production of a protein called calcineurin, which is an essential component of proper signaling between neurons in the brain.[1] As the results of the current study demonstrate, mutations interfering with proper neuronal transmission, such as mutations in PPP3CA, can lead to neurodevelopmental disorders and epilepsy. Using a combined genomic dataset, Dr. Heinzen and her team found de novo mutations in PPP3CA in six individuals: 6/6 of these individuals had developmental delays, 5/6 had childhood-onset epilepsy, and 3/6 had an atypical physical appearance.

According to Dr. Laura Lubbers, Chief Scientific Officer at CURE, “The powerful discovery that mutations in the PPP3CA gene can lead to this severe form of disease with childhood-onset epilepsy paves the way for the creation of new treatments for epilepsy, and hopefully, a cure.”

This research, recently published in The American Journal of Human Genetics, was led by Dr. Heinzen from the Institute of Genomic Medicine at Columbia University, and involved the efforts of several other Epilepsy Genetics Initiative researchers including Dr. David B. Goldstein, also from the Institute of Genomic Medicine at Columbia University.

At its core, the CURE Epilepsy Genetics Initiative is a program created to use genetic information from people with epilepsy to uncover the causes of epilepsy and advance precision medicine.

Through the Epilepsy Genetics Initiative, individuals with epilepsy undergo Trio Whole Exome Sequencing – a test that analyzes approximately 20,000 genes simultaneously to identify changes in the person’s DNA that are related to their epilepsy.

The results of this powerful study highlight the importance of the continued work of projects like CURE’s Epilepsy Genetics Initiative in advancing towards a better understanding of the genetic causes of epilepsy. “Begun in 2014, CURE’s Epilepsy Genetics Initiative is already helping people understand the cause of their epilepsy” says CURE CEO Kate Carr. “We are excited about this advance in our search for the genetic causes of epilepsy and will continue in our quest for new treatments and our pursuit of a cure.”
[1] Lai MM, Hong JJ, Rugiero Am et al. The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis. J Biol Chem 1999; 274:25963-25966.

Congenica and FutureNeuro unite to deliver more accurate diagnoses for genetic epilepsy

New software to deliver faster and more accurate diagnoses in genetic epilepsies is the ambition of a ground-breaking partnership between Congenica, a global provider of clinical genomics interpretation software, and FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological Diseases, supported by Science Foundation Ireland. The software will be designed to work with electronic health record (EHR) systems, including the Irish electronic health record for Epilepsy, so that the entire diagnostic process, from initial DNA sequencing to determining treatment options, is available to clinicians and patients through their electronic records.

The partnership, operating out of the FutureNeuro Human Genetics lab of Professor Gianpiero Cavalleri in RCSI, Dublin, will build on Congenica’s clinical genomics analysis software, Sapientia™, to assist clinicians in making more tailored treatment decisions for certain types of genetic epilepsy. At the moment, epilepsy is diagnosed using EEGs, CT scans or MRIs, which only provide a limited picture of a person’s epilepsy. Genomics, which focuses on the structure, function, mapping, and editing of genomes, is a new and powerful tool for reaching a molecular diagnosis, which in turn can inform and improve treatment options.

“Genomics is changing clinical medicine,” said Dr Norman Delanty, Clinical Neurologist with FutureNeuro, “neurologists need to embrace it as a new powerful diagnostic tool to allow us to understand the many challenging faces of epilepsy, and lead us to individualising treatment and prognosis in the clinic.”

Gene playing major role in neurological condition found

This genetic discovery included the efforts of CURE grantee Minghsan Xue.

Researchers are closer to solving the puzzle of a complex neurological condition called 15q13.3 microdeletion syndrome. Individuals with this condition are missing a small piece of chromosome 15 that usually contains six genes, but which one of the genes is responsible for the clinical characteristics of patients has not been clear. In this study, a multidisciplinary team of researchers at Baylor College of Medicine and Texas Children’s Hospital has identified in a mouse model OTUD7A as the gene within the deleted region that accounts for many characteristics of the human condition. The researchers also discovered that mice deficient in the gene Otud7a have fewer dendritic spines, small protrusions involved in neuron communication, which might be related to the neurological deficits.

The report appears in the American Journal of Human Genetics.

“Identifying the gene within a deleted region of a chromosome that accounts for the clinical characteristics we see in patients is very important,” said senior author Dr. Christian Schaaf, assistant professor of molecular and human genetics at Baylor College of Medicine and the Joan and Stanford Alexander Endowed Chair for Neuropsychiatric Genetics at Texas Children’s Hospital. “If we want to get to the point where we can treat patients, we need to know which gene or genes to target. That is the big picture question behind this study.”