Epilepsy through the eyes of a geneticist

Assoc. Dr. Elitza Betcheva-Krajcir: At ‘Heart and Brain’ every patient with epilepsy can receive a multidisciplinary approach, individual treatment plan and follow-up

Epilepsy is a group of diseases in which, due to brain involvement, there is a persistent predisposition to epileptic seizures of different nature. It is one of the most common pathological conditions in neurological practice, affecting more than 50 million people worldwide of different ages, genders and ethnic backgrounds. According to recent scientific data, up to about 10% of people in the general population in industrialized countries have at least one epileptic seizure in their lifetime, and at least 3% develop a disease in the epilepsy group. At the same time, over 80% of epilepsy-associated mortality is found in low- and middle-income countries. Over 13 million people per year develop varying degrees of disability as a result of epilepsy.

Few people know that genetics plays an important role in the diagnosis and treatment of the disease. At ‘Heart and Brain’ Pleven, medical genetics specialists work together with paediatricians, neurologists, imaging specialists, clinical laboratory doctors and immunologists. It is this multidisciplinary approach that allows the most appropriate individual treatment and follow-up plan to be determined in the shortest possible time.

On the International Day of People with Epilepsy, we talk to Dr. Elitsa Becheva-Kraichir, Head of the Medical Genetics Laboratory at ‘Heart and Brain’ Pleven and Burgas.

– Assoc. Betcheva, please tell us a bit more about epilepsy and epileptic seizures.

– By definition, seizures are the symptoms of an irregular release of electrical charges from a large group of nerve cells in the brain, resulting in tingling sensations, smells, altered consciousness or twitching of muscles, entire limbs or convulsions of the whole body. The occurrence of such seizures at different points in time, with or without immediate provocation, is epilepsy. When, in addition to epileptic seizures, there is also involvement of higher functions of the cerebral cortex, we speak of epileptic encephalopathy. And when symptoms from other organs and systems are found in addition to epilepsy (so-called co-morbidity), we speak of syndromic epilepsy.

The diseases in the group of epilepsies are diverse – they differ in the type and duration of seizures, the severity of symptoms, the presence of concomitant other complaints and causes of occurrence. Epilepsy may be due to severe brain trauma, intoxication, infectious diseases, congenital structural defects, brain tumors, brain degenerative diseases, metabolic diseases, vascular problems (stroke), genetic predisposition. But even with a thorough analysis of the causes, nearly half of the cases remain with an unknown etiology.

– What is the role of genetic factors in the occurrence of epilepsy?

– A significant proportion of genetically determined cases of epilepsy have a multifactorial basis, with only part of the causes of the disease being in our genetic information – DNA – while another part is due to environmental and lifestyle factors. In such cases, simple diagnostic genetic analyses will not be able to provide us with clinically relevant information.

When genetically determined epilepsy is due to individual genetic variants, these can already be detected by diagnostic genetic tests, but they are inherently different types, necessitating the use of different types of genetic analyses, because there is no method that covers all possible variations. In some patients we use molecular cytogenetic methods (e.g. microarray for variants called ‘copy number changes’), in others molecular genetic methods (sequencing or genotyping of single nucleotide variants), and in others, although rarely, specific ways of analysing DNA misrepeats (dynamic mutations) or defects in mitochondrial DNA.

– Tell us how you, the geneticists at Heart and Brain, work together with other specialists and what the multidisciplinary, individual approach you take entails.

– In the heterogeneous group of epilepsies, two main groups of patients stand out – paediatric and non-paediatric, and the approach to them diagnostically and therapeutically is sometimes slightly different.

When it comes to children with epilepsy, with or without encephalopathy and accompanying other symptoms, they are most often patients of the specialised clinic ‘Mom and Me’, part of ‘Heart and Brain’. Alongside the care of the specific health problem for which they are hospitalised, specialist consultations are initiated with a geneticist and a neurologist. Laboratory, immunological, infectious disease tests, imaging, and EEG (electroencephalogram) are performed as needed. Specialists from different specialties discuss the case together and decide on genetic testing.

Unlike other tests, genetic analyses take some time (1-2 months). We invite the family for a secondary consultation, during which we explain in detail all our actions, tests, changes found, their consequences, preventive and therapeutic options in a language that people understand. The relatives of the sick child have the opportunity to ask all their questions. After the consultation, we provide a detailed written conclusion with recommendations according to the most current professional guidelines.

Often, the child needs long-term follow-up – not only from the pediatrician and neurologist, but also from other specialists such as the cardiologist and endocrinologist.

Sometimes the necessary preventive checkups are many in number, highly specialized and annual. To reduce the time and stress for children and their families, we have made arrangements for them to take place in just 2-3 days at one location. Children don’t have to ‘go to the doctors’, the specialist doctors come to them.

Like our young patients, adults with epilepsy or other neurological conditions that might have a genetic cause have the opportunity to have a genetic consultation on-site – in their hospital room, during their stay in the neurology clinic. The most common concern of these patients is what is the risk that their (now born, grown or future) children may also have a genetic disorder.

– What does the genetic consultation involve?

– At the first meeting of the genetic doctor with the patient (and his/her family), the specialist explains in understandable language the principles of genetic information, genetic testing and the genetic components of diseases. It is important for the patient to overcome the fear of the unknown and stigma, and for the doctor to understand and feel his patient psychologically.

The secondary consultation consists of one or more discussions between the geneticist and the patient and a written conclusion. The focus here is understanding the results and discussing next steps. Often, with chronic and complex diseases, patients and their families maintain contact with their doctor for years and have multiple, for example annual, secondary consultations.

– What specific tests are needed?

– As I mentioned, there is no method in genetics (yet) that allows us to test for all types of genetic changes with one test. However, there are already methods developed that allow searching for several types of genetic defects at the same time.

In general, in most cases the indication for genetic analysis is reached when other causes of the disease have been ruled out by more conventional methods. In the case of epilepsies, laboratory, infectious disease, imaging, physiological and other studies have already been performed, but the suspicion of a genetic etiology remains.

On the basis of the clinical picture, the presumed clinical diagnosis of the neurologist and the results of other investigations, the geneticist considers which method is most likely to identify the cause. In most cases, as a first step, we apply analysis for small DNA variants combined with analysis for copy-number changes, preferably covering nuclear and mitochondrial genetic material. We can examine only genes known to be associated with the development of epilepsy as well as all of a person’s protein-coding genes or even their entire genome. If we do not identify a genetic cause with these generally general methods, we undertake more specific investigations – for example, for dynamic mutations, epigenetic changes, etc.

– What is the point of genetic analyses in epilepsy and what are the benefits for the patient?

– This is a question that people often ask – “what’s the use when my gene can’t be fixed?”. There are several forms of epilepsy where identifying a specific genetic defect is key to the choice of therapy. For example, some forms of epilepsy are significantly affected by a special dietary regimen. In other forms of epilepsy, a specific genetic defect may cause the disease not to improve but, on the contrary, to worsen significantly with classical therapy (e.g. valproates). The genetic result helps us to understand why this is so and what medications are appropriate.

For other people with epilepsy, the most important question is what is the risk that the next child in the family will be affected by the same disease. When it comes to severe syndromic epilepsy with encephalopathy, determining the risk for recurrence and offering options for prenatal or preimplantation diagnosis is of great importance to parents.

Not least among the benefits for many families is the sense of relief that they finally know why their child, for example, is ill and the lifting of guilt, especially from mothers who often think they did something wrong during pregnancy.

Knowing the exact genetic diagnosis does not always allow an etiological treatment (treatment of the cause), but increasingly it allows the choice of a much better, more adequate treatment for the specific patient, a better quality of life and a system of measures to avoid the development of complications and disability.