The diagnosis of Dravet syndrome is based on the child’s history of seizures and other symptoms that emerge as the seizures progress. Typically, when Dravet syndrome is diagnosed there is no history of significant brain injury, such as birth asphyxia or meningitis, to explain the epilepsy (Dravet and Guerrini, 2011).
Standard investigations such as Magnetic Resonance Imaging (MRI) and electroencephalography (EEG) appear normal at first.
In 2001 it became clear that Dravet syndrome is caused by a defect in the electrical function of brain cells (Claes et al. 2001).
Chromosomes, genes and DNA
In every cell, humans have 22 pairs of chromosomes and 1 pair of sexual chromosomes (males are XY and females are XX), as shown below on the karyotype (image of chromosomes under the microscope).
Each chromosome is made up of tightly coiled strands of DNA (DeoxyriboNucleic Acid). Genes are segments of DNA that determine specific traits, such as eye or hair colour. Humans have more than 20,000 genes.
A gene mutation is an alteration in DNA, that may be inherited or acquired over a person’s lifetime, as cells age or are exposed to certain chemicals. These DNA changes can result in genetic disorders.
In 2001, a Belgian team showed that Dravet syndrome is in most cases due to a genetic mutation in the SCN1A gene (de Claes et al. 2001). About 85% of Dravet syndrome cases are associated with a mutation in the SCN1A gene (Rosander et al. 2015).
The SCN1A gene, located on chromosome 2, encodes the alpha 1 subunit of the voltage-dependant sodium channel, also called Nav1.1. channel. This channel, permeable to sodium ions, is directly involved in the electrical signals generated by brain cells.
Human karyotype and voltage dependant sodium channel schema
A mutation in this gene can modify the proper functioning of the sodium ion channel and/or reduce the number of these channels in brain cells.
Mutations found in patients with Dravet syndrome are of all types (truncating, missense). To date, more than 1,448 different mutations have been identified throughout this gene (Jiang et al. 2018). This leads to different forms of SCN1A-related disorders from a mild form (familial hemiplegic migraine) to a very severe form (Dravet syndrome) as shown on the figure below.
The spectrum of SCN1A disorders
95% of SCN1A mutations (Harkin et al. 2007) appear to be “de novo” (or new to the patient), meaning the mutation is not inherited from parents, but that the mutation occurs in the germ cell (egg or spermatozoid) of one of the parents. It occurs independently of the rank of birth in the family and affects children of both sexes.
Genetic testing of the parents is recommended to confirm that the mutation is de novo. The identification of the mutation is performed through molecular diagnosis as shown below:
When the mutation is de novo, the chance to have another child with Dravet syndrome is minimum. However, genetic counselling is recommended, with the aim of helping families understand the risk of recurrence of Dravet syndrome in their other children.
Genetic testing steps
Examples of GEFS+ families with inherited SCN1A mutation
The same mutation can lead to severe epilepsy in a child while other family members and parents may be unaffected or only mildly affected compared to the child with Dravet syndrome. The reason for this clinical variability remains unknown, but genetic or non-genetic factors other than the mutation itself may contribute to this difference (Escoyg et al. 2010).
A prenatal diagnosis can be carried out in GEFS+ families. However, since missense mutations found in GEFS+ families are usually associated with benign phenotypes, the request for prenatal diagnosis should undergo ethical approval (Escoyg et al. 2010).
About 15% of patients diagnosed with Dravet syndrome do not carry a SCN1A mutation. Research is ongoing worldwide in order to identify other genes and/or factors which may cause this type of epilepsy. Several other genes have been reported in patients with Dravet syndrome who test negative for SCN1A mutations (Steel 2017). However, the clinical presentation in most of these cases is atypical for Dravet syndrome (Wirrell et al. 2017).
Genes involved in Dravet Syndrome (adapted from Steel et al. 2017)
Genetic counselling is the process by which patients and relatives are advised of the nature and consequences of the disorder, the probability of developing or transmitting it, and the options available for family planning.
This counselling can be separated into two parts:
In some countries, this may require the advice of an ethical committee.
Prenatal testing is done on foetal cells sampled from chorionic villus (i.e. the foetus’s developing placenta) at ~12 weeks or from cells present in the amniotic fluid (the fluid surrounding the baby) after 15-16 weeks of pregnancy.
Not all genetic diseases manifest themselves immediately at birth or early in childhood. Although the gene mutation is present at birth, some diseases do not appear until adulthood. If a specific mutated gene responsible for a late-onset disease has been identified, a person from an affected family can be tested before symptoms appear.