Scientists at University of Utah (U of U) Health report that they have developed high-tech tools to uncover the genetic cause of early infantile epileptic encephalopathy (EIEE). Their study (“Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy”) appears online in Nature Genomic Medicine.

“Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE,” write the investigators.

“The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, three of the 12 patients received nondiagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.”

“These tools let us peek in the dark corners and under the rug of the genome that other methods do not,” says Aaron Quinlan, Ph.D., associate professor of human genetics and biomedical informatics at U of U Health and senior author on the paper. “With this approach rather than undergoing multiple tests, families can receive results faster, limiting their medical odyssey, at ultimately a lower cost.”

Genomic findings are emerging rapidly in 2 large, closely related epilepsy research consortia: the Epilepsy Phenome/Genome Project and Epi4K. Disclosure of individual results to participants in genomic research is increasingly viewed as an ethical obligation, but strategies for return of results were not included in the design of these consortia, raising complexities in establishing criteria for which results to offer, determining participant preferences, managing the large number of sites involved, and covering associated costs. Here, researchers describe the challenges faced, alternative approaches considered, and progress to date.

Experience from these 2 consortia illustrates the importance, for genomic research in epilepsy and other disorders, of including a specific plan for return of results in the study design, with financial support for obtaining clinical confirmation and providing ongoing support for participants. Participant preferences for return of results should be established at the time of enrollment, and methods for allowing future contacts with participants should be included. In addition, methods should be developed for summarizing meaningful, comprehensible information about findings in the aggregate that participants can access in an ongoing way.

Focal malformations of cortical development (FMCDs) are a heterogeneous group of brain cortical abnormalities. These conditions are the most common causes of medically refractory epilepsy in children and are highly associated with intellectual disability, developmental delay, and autism-spectrum disorders. Despite a broad spectrum of cortical abnormalities in FMCDs, the defective migration of neuronal cells is considered a key pathological hallmark.

A Korean research team led by [CURE grantee] Professor Jeong Ho Lee at the Korea Advanced Institute of Science and Technology (KAIST) has recently investigated the molecular mechanism of defective neuronal migration in FMCDs.

The research team previously demonstrated that brain-only mutations in the mechanistic target of rapamycin (MTOR) gene causes focal cortical dysplasia, one major form of FMCDs leading to intractable epilepsy in children. However, the molecular mechanisms by which brain-only mutations in MTOR lead to cortical dyslamination and defective neuronal migration in FMCDs remain unclear.

Next-generation sequencing (NGS) can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy (DRE), according to a study published CNS Neuroscience & Therapeutics.

Jing Peng, Ph.D., from Central South University in China, and colleagues conducted genetic testing on 273 pediatric DRE patients with no obvious acquired etiology; 74 underwent whole-exome sequencing (WES), 141 had epilepsy-related gene panel testing, and 58 had clinical WES gene panel testing. Frequency of seizures, outpatient visits, and hospitalization was also assessed.

The researchers found that a genetic diagnosis was made in 86 patients (31.5 percent; 93 likely disease-causing mutations in 33 genes). By testing type, detection rates were 32.6% for the epilepsy-related gene panel, 44.8% for the clinical WES gene panel, and 17.3% for WES. Also, 34 patients accepted therapy based on their mutant genes, after which 52.9% became seizure-free and 38.2% experienced seizure reduction. Hospitalization incidents were significantly lower for patients after testing than before regardless of positive or negative genetic results.

SIGNIFICANCE: Our results indicate that there is disruption of the blood brain barrier in POLG-related disease, as evidenced by a raised cerebrospinal fluid protein and a raised CSF/serum ratio of albumin. We also find that raised cerebrospinal fluid protein is a common finding in patients with POLG disease. Our data suggest that the presence of blood brain barrier dysfunction predicts a poorer outcome, and elevated cerebrospinal fluid protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.

OBJECTIVE: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients.

METHODS: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries–Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF barrier.

RESULTS: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months).

Approximately 25% of child patients have Rolandic Epilepsy or RE, also known as Benign Epilepsy with Centrotemporal Spikes (BECTS). RE has a complex genetic basis, probably made up of combinations of susceptibility variants in different genes. Children with RE quite often have other symptoms that affect their speech, attention, reading ability or coordination. The goal of this study is to find the genetic basis for susceptibility to seizures and associated comorbidities for RE using genomewide association approaches.

We know that RE has a genetic basis and we recently discovered the genetic cause of the EEG pattern seen in RE. The goal of REGAIN is to now find the genetic basis for susceptibility to seizures and the associated symptoms above. Our hope is to be able to improve diagnosis and understand why each child with RE is different, and perhaps point us towards new treatments that are more effective and have fewer side effects.

We will compare the genetic code of 3,000 children with RE against a similar number of people not affected by epilepsy. With the proposed large sample of participants, we will be able to pinpoint the exact changes that might lead to seizures or attention problems for example. Learning the genetic basis for these problems will deepen our understanding of the mechanisms and lead to new treatments or cures.

Estimated study start date: June 1, 2018
Estimated study completion date: December 31, 200

Eligibility Criteria

Ages Eligible for Study: 6 Years to 25 Years (Child, Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Sampling Method: Non-Probability Sample

Inclusion Criteria:

• Diagnosis of Rolandic Epilepsy in accordance with the following international criteria:
  • Age of first afebrile seizure 3-12 years
  • Seizures comprising focal sensorimotor seizures affecting the vocal tract and face, with or without involvement of the arm
  • Predominant sleep-related seizures
  • EEG interictal centro-temporal spikes with normal background
• Current age 6-25 years

Exclusion Criteria:

• No history of focal seizure
• Normal EEG or abnormal background features on EEG
• Known structural causes (stroke, tuberous sclerosis, infection, post-infectious or metabolic)
• Primary diagnosis of autism or global learning disability
• Focal central neurological deficit on clinical exam,
• Unable to provide informed consent
• Unable to provide blood sample