The diagnosis of Dravet syndrome is based on the patient’s clinical picture. He/she usually has no history of any significant brain injury to explain the epilepsy such as birth asphyxia or meningitis. Standard investigations such as blood biochemistry and brain imaging studies (CT and MRI) are at this point normal.
Molecular Diagnosis – Pr Le Guern
Genetics of Dravet Syndrome – Dr Christel Depienne
Since 2001, it has become clear that Dravet syndrome is caused in most cases by a genetic mutation that alters the normal electrical functioning of brain cells.
More than 70% of patients with Dravet syndrome have a mutation in the SCN1A gene on chromosome 2. Other Dravet patients may also have a mutation in other genes.
Boys and girls are equally affected by SCN1A mutations since it is not located on a sexual chromosome.
Patients with Dravet syndrome often have no family history of the disease and are in this case qualified as “sporadic” or “isolated”. This is due to the fact that the mutation has happened « de novo » in the patient, meaning that it is absent from any of their parents.
Examples of families with a child suffering from Dravet syndrome
When the mutation is “de novo”, there is little chance that future siblings of the Dravet child will be affected by Dravet syndrome. Despite this fact, it is recommended to undergo genetic testing, because siblings may also be affected in some rare cases.
The identification of the mutation is performed through molecular diagnosis as shown below:
Genetic counselling may help parents understand the risk of recurrence of Dravet syndrome in their other children.
If genetic testing is not available in your country, you may visit the following website which offers, under certain conditions, a genetic test free of charge. http://www.testdravet.info
In 2001, a Belgium team showed that Dravet syndrome is in most cases due to a genetic mutation in the SCN1A gene on chromosome 2.
The SCN1A gene encodes the alpha 1 subunit of the voltage-dependant sodium channel, also called Nav1.1. channel. This channel is located on the postsynaptic membrane and permeable to sodium ions.
A mutation in this gene either modifies the proper working of the sodium ion channel or leads to a reduction in the number of these channels in brain cells.
The Nav1.1. channel is directly involved in the electrical signals generated by brain cells and the mutation is therefore suspected to have an impact on brain cell discharges, leading to epilepsy.
The SCN1A mutations are inherited in an autosomal dominant fashion, meaning that one mutation is sufficient to cause the disease.
The mutation can occur anywhere in the SCN1A gene. So far, more than 500 different mutations have been identified throughout this gene. These mutations are usually private, with each patient having a different mutation. If you wish to get more information on the SCN1A gene we invite you to visit the following websites:
Mutations found in patients with Dravet syndrome are of all types, including point DNA substitutions or small deletions-insertions (68% of patients). They are also large-scale microrearrangements (deletions or, more rarely, duplications) encompassing one or several exons or the whole gene.
A specific method can be needed to detect SCN1A microrearrangements depending on the method used to perform the genetic test.
Examples of GEFS+ families including a child with Dravet syndrome
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 of prenatal diagnosis should undergo ethics approval.
In 2009, a French team showed that mutations or deletions in PCDH19, located on chromosome X, lead to a severe epilepsy that resembled Dravet syndrome.
Mutations in PCDH19 mainly affect females who have a normal and a mutated copy of the gene, whereas males who only have one copy of the mutated gene are unaffected. For this reason, the epilepsy related to PCDH19 mutations was first described in 2008 as Epilepsy in Females with Mental Retardation (EFMR) by an Australian team.
The PCDH19 gene encodes a transmembrane protein called Protocadherin 19. This protein is probably involved in cell adhesion and the establishment of synaptic connections during brain development, although this has not yet been demonstrated.
PCDH19 mutations follow an unusual X-linked inheritance mode.
For diseases caused by mutations on the X chromosome, mutated males are usually more affected than mutated females since they only carry one copy of the gene while females carry two copies. For some diseases, only males are affected and females are unaffected (recessive X-linked inheritance).
The expression mode of PCDH19 related disease is different:
Males carrying the mutation are usually unaffected (or asymptomatic).
Females carrying one normal and one mutated X chromosome are affected.
Example of pedigree with several family members affected with PCDH19-related epilepsy
Characteristics of the unusual inheritance associated with PCDH19-related epilepsy
It is important to keep in mind that a little girl affected by a PCDH19-related Dravet syndrome may have inherited it through an asymptomatic father, but it can also be a de novo mutation.
Examples of family with a girl affected with PCDH19-related epilepsy
Males carrying a PCDH19 mutation in a mosaic state can also be affected like mutated girls, although such cases are probably rare.
Twenty to thirty per cent of diagnosed Dravet patients do not carry the SCN1A mutation. Research is ongoing worldwide in order to identify other genes and/or factors which may cause this type of epilepsy.
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 in two parts:
Not all genetic diseases show their effect 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.
For severe diseases with no possibility of treatment or cure, individuals undergoing presymptomatic testing should be aged ≥18 years. The process includes a time for reflection and a psychological support.
It can require the advice of an ethical committee in some countries.
Prenatal testing is done on foetal cells sampled from chorionic villus (i.e. baby’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.
The issue of prenatal testing is the interruption of the pregnancy in case the foetus has the mutation causing the disease
The following illustration shows the risk of recurrence of Dravet syndrome related to a SCN1A mutation, according to the origin of the mutation.
The following illustration shows the risk of recurrence of Dravet syndrome/EFMR related to a PCDH19 mutation, according to the origin of the mutation.