The causes of dravet syndrome

  • The diagnosis of Dravet syndrome is based on the clinical story. There is no history of a significant brain injury to explain the epilepsy such as birth asphyxia or meningitis.
    Standard investigations such as blood biochemistry and brain imaging studies (
    CT scan Seizures lasting for more than 30 minutes
    and
    MRIMagnetic Resonnance Imaging
    ) are normal. In 2001 it became clear that Dravet syndrome is caused by a defect in the electrical function of brain cells.

1/ Basic science

  • In order to easily understand the basic cause of Dravet syndrome, we invite you to review some basic information on the relation between
    chromosomesThe microscopically visible carriers of the genetic material. They are composed of DNA (deoxyribonucleic acid), proteins and that looks like little rods when watched under a microscope.
    ,
    genes The basic biological units of heredity. Segments of deoxyribonucleic acid (DNA) needed to contribute to a function.
    ,
    DNA DeoxyriboNucleic Acid is a long molecule that encodes genetic information.
    , the brain system and synapses.
  • If you are familiar with these terms you may go directly to the genetic cause.

A/ Brain and neurons

  • The brain is made of billions of interconnected
    [1]neuronsA nerve cell that receives and sends electrical signals over long distances within the body.
    . Each neuron is made up of a cell body, an
    [2]axonA long fiber of a nerve cell (a neuron) that acts somewhat like a fiber-optic cable carrying outgoing messages. The neuron sends electrical impulses from its cell body through the axon to target cells. Each nerve cell has one axon.
    for outgoing transmission of nerve impulses to other neurons, and
    [3]dendritesA short arm-like protuberance from a nerve cell (a neuron). Dendrites from neurons next to one another are tipped by synapses (tiny transmitters and receivers for chemical messages between the cells).
    for incoming nerve impulses from other neurons. These transmissions consist of tiny electrical signals and neurons are connected to each other by
    [4]synapsesA specialised junction at which a neural cell (neuron) communicates with a target cell. At a synapse, a neuron releases a chemical transmitter that diffuses across a small gap and activates special sites called receptors on the target cell.
    .
Brain and neurons
Brain and neurons

b/ Synapse

Mechanism of action

  • A
    synapseA specialised junction at which a neural cell (neuron) communicates with a target cell. At a synapse, a neuron releases a chemical transmitter that diffuses across a small gap and activates special sites called receptors on the target cell.
    is the junction between two neurons.
  • The nerve impulse comes from the
    presynapticLocated before a synapse.
    neuron through its
    [1] axonA long fiber of a nerve cell (a neuron) that acts somewhat like a fiber-optic cable carrying outgoing messages. The neuron sends electrical impulses from its cell body through the axon to target cells. Each nerve cell has one axon.
    . After crossing the synapse, the nerve impulse is transmitted to the
    postsynapticneuron Located after a synapse.
    by its
    [2] dendritesA short arm-like protuberance from a nerve cell (a neuron). Dendrites from neurons next to one another are tipped by synapses (tiny transmitters and receivers for chemical messages between the cells).
Synapse
Synapse

The end of an  [1] axon is enlarged  [4] the presynaptic button. Next to the presynaptic button there is a space called the  [3] synaptic cleft (space between the neurons). On the other side of the synaptic cleft is the part of a  [2] dendrite that receives messages – the  [6] postsynaptic button. The presynaptic button at the end of the axon contains  [5] vesicles filled with chemical messengers, called neurotransmitters. The postsynaptic button is covered by  [7] receptors for these messengers.

When the nerve impulse arrives in the presynaptic button, the vesicles filled of neurotransmitters move down towards the [8] presynaptic membrane and are released in the synaptic cleft.

The neurotransmitters cross the synaptic cleft and bind to the receptors on the postsynaptic button.

This binding enables the nerve impulse to continue its course into the new neurone through its dendrite.

c/ Chromosomes, genes and dna

Chromosomes, genes and DNA
  • The human body is made up of a huge number of
    [1]cellsThe cell is the basic structural, functional and biological unit of all known living organisms. Cells are the smallest unit of life that is classified as a living thing, and are often called the "building blocks of life".
    . Each cell has a core structure (nucleus) that contains
    [2]chromosomesThe microscopically visible carriers of the genetic material. They are composed of DNA (deoxyribonucleic acid), proteins and that looks like little rods when watched under a microscope.
    .
  • Each chromosome is made up of tightly coiled strands of
    [3]DNA(DeoxyriboNucleic Acid) DeoxyriboNucleic Acid is a long molecule that encodes genetic information.
    .
    [4]Genes The basic biological units of heredity. Segments of deoxyribonucleic acid (DNA) needed to contribute to a function.
    are segments of [3]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 the DNA, usually too small to be seen even with the most powerful microscope. The mutation may be inherited or acquired during lifetime, as cells age or are exposed to certain chemicals. These DNA changes can result in genetic disorders.
  • In every cell, humans have 22 pairs of chromosomes+1 pair of sexual chromosomes (males are XY and females are XX)

2/ The genetic cause

  • About 22% of Dravet syndrome patients are mutation-free regarding already identified genes.
  • Around 78% of Dravet syndrome patients have a genetic mutation that appears to cause the associated disease.
  • In most cases this genetic disorder is the result of a “de novo” mutation (meaning that parents did not pass on the mutated gene). Usually there is no significant chance that other children will have Dravet syndrome.
  • Despite this fact, it is recommended that genetic testing be carried out, if the tests are available in your country because in some rare cases siblings may also be affected.
    Genetic counselling An educational counselling process for individuals and families who have a genetic disease or may be at risk for a disease to facilitate informed decision-making.
    should help you to understand the risk if you hope to have more children.

A/ SCN1A gene

70% of Dravet syndrome patients have a mutation in the SCN1A gene located on chromosome 2.

SCN1A genes
SCN1A genes

The SCN1A gene determines how postsynaptic membrane receptors work.

The alteration (mutation) of the SCN1A gene modifies how the gene works. This proper working modification leads to epilepsy.

For Dravet syndrome patients this mutation is nearly always de novo, meaning that the parents did not pass it on to their child. The mutation occurred in the embryo during its intra-uterine life and no other member of the family should be affected. There are rare exceptions to this statement; therefore careful genetic counselling is worthwhile.

b/ Other genes

About 70% of Dravet syndrome patients have a SCN1A gene mutation. Therefore around 30% of patients, clinically diagnosed with a Dravet syndrome may carry mutation on other genes.

1- PCDH19 gene

Recently in 8% of SNC1A negative patients diagnosed as Dravet syndrome, the mutation of the PCDH19 gene on the X chromosome has been identified. Most of these patients are female.

PCDH19 gene
PCDH19 gene

Research is on-going to determine the « how » of the altered PCDH19 gene leads to epileptic seizures.

2- Ongoing research

Twenty to thirty per cent of diagnosed Dravet patients do not carry the SCN1A mutation. Research is ongoing worldwide in order to look for other genes and/or factors which may be linked to this type of epilepsy.