Genetic Changes Beyond SCN1A

In a small amount of cases, a clinical diagnosis of Dravet Syndrome is linked to a change (or mutation) in genes other than SCN1A

In some cases, individuals with these non-SCN1A gene mutations show symptoms or characteristics so similar to Dravet Syndrome that no distinction can reliably be drawn on clinical grounds alone. Scientific advances in the understanding of how these genetic mutations might cause Dravet Syndrome, Dravet Syndrome 'mimics' or other epilepsy-related conditions is advancing everyday. Below is an overview of current knowledge in relation to Dravet Syndrome. 

Two medical terms are helpful for understanding the relationship between genetics and a clinical diagnosis of Dravet Syndrome. The term 'phenotype' is used to describe the collection of symptoms and observable characteristics that a neurologist sees in individuals with Dravet Syndrome, and which provides the basis for its clinical diagnosis. In comparison, the term 'genotype' refers to an individual's genetics, which can only be identified through testing. 

Genes in Dravet Syndrome

Gene changes that that have been found in a small number of individuals with a clinical diagnosis of Dravet Syndrome include SCN2A, SCN8A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. 

In most cases, these gene mutations are not usually determined to be the cause of Dravet Syndrome, but may contribute to a Dravet Syndrome phenotype. The authors of a medical article entitled 'Dravet Syndrome and its mimics: Beyond SCN1A' (which includes two members of the DSUK Medical Advisory Board, Professor Sameer Zuberi and Dr Andreas Brunklaus) created the diagram shown below to explain how Dravet Syndrome is usually associated with mutations to the SCN1A gene, but can also be found in individuals with other mutations that may mimic Dravet Syndrome. It additionally shows how the presence of a genetic mutation alone does not necessarily mean the individual has Dravet Syndrome.

Beyond SCn1A

Reference: Steel D, Symonds J, Zuberi SM, Brunklaus A (2017) 'Dravet syndrome and its mimics: beyond SCN1A'. Epilepsia, 58(11):1807-1816

Genotypes beyond SCN1A reported in Dravet Syndrome

SCN2A: This gene codes for the alpha-2 subunit of the sodium ion channel (find out more about the sodium ion channel here). SCN2A mutations have been found in patients with a variety of syndromes, including benign familial neonatal?infantile seizures (BFNIS), early infantile epileptic encephalopathy (EIEE) and autism spectrum disorder.

Recent advances in the understanding of SCN2A-epilepsy phenotypes have helped to improve understanding of which treatments are most likely to improve seizure control in individuals with a SCN2A-related epilepsy. For example, in contrast to those with SCN1A-related Dravet Syndrome, individuals with a SCN2A mutation may respond positively to sodium channel blockers. 

SCN8A: This gene codes for the alpha-8 subunit of the sodium ion channel. Presentation is distinct from Dravet Syndrome in that patients may have epileptic spasms (not seen in Dravet individuals), are not as susceptible to fever-related seizures, usually do not have myoclonic seizures, and patients have been reported to respond to sodium ion channel blockers. 

SCN1B: This gene codes for the beta-1 subunit of the sodium ion channel. SCN1B mutations have been found in several patients with GEFS+ and some with Dravet Syndrome.

PCDH19: This x-linked gene (found on the X chromosome) codes for a protein known as protocadherin-19. This protein helps neurons adhere to one another as they travel between cells. This condition usually occurs in females (who have two X chromosomes, unlike males who have one X chromosome), when one copy of the PCDH19 gene is mutated and the other is normal. The interactions between the faulty and the functional gene are thought to cause symptoms. Although PCDH19 epilepsy is considered to be a distinct syndrome, it mimics Dravet Syndrome in several aspects. Seizure onset is usually later in PCDH19 (average of 11 months vs. 6 months in DS), seizure clusters are more common and often respond to steroids, an approach not used in DS), and photosensitivity is less common.

GABRA1: GABA is an important neurotransmitter. The receptors on the neurons that accept this neurotransmitter are termed “GABR” (R for receptor) and fall into two groups: A and B. GABRA1 encodes the alpha-1 receptor and mutations are found in several epilepsies including childhood absence epilepsy, juvenile myoclonic epilepsy, and genetic generalized epilepsy. Some cases of Dravet Syndrome are associated with GABRA1 mutations.

GABRG2: This gene codes for the gamma-2 GABA receptor and mutations have been found in a small number of individuals with GEFS+ or Dravet Syndrome.

STXBP1: This gene codes for a protein involved in the cell’s process of fusing vessicles (globules containing chemicals such as neurotransmitters) with the membrane. Thus mutations in this gene may affect the cell’s ability to release neurotransmitters. Mutations have been found in patients with Ohtahara syndrome, West syndrome, and non-specific epilepsies with varying components of intellectual disability and movement disorders.

HCN1: This gene codes for a nonselective positive ion channel (meaning it allows calcium, potassium, and other positive ions through), and mutations usually result in a gain of function. In a few individuals, the clinical presentation very closely resembles classic Dravet Syndrome.

CHD2: This gene codes for a protein that modifies gene expression. Individuals with Dravet Syndrome who had CHD2 mutations all experienced seizure onset later than normal (ages 1, 2, and 3), and this appears to be a common feature of CHD2 mutations in general. They have been described in patients with Jeavons syndrome, Lennox-Gastaut, and other epilepsies.

KCNA2: This gene codes for a delayed potassium channel that helps neurons to function properly in the brain. Individuals thought to have Dravet Syndrome with this mutation achieved seizure freedom in adulthood, an outcome not often obtained in classical Dravet Syndrome.

Other gene mutations for Dravet Syndrome have been reported, but there is currently not enough known about these to confirm whether or not they are related to Dravet Syndrome. 

Ultimately, Dravet Syndrome remains a clinical diagnosis and all affected patients, irrespective of genetic status, should have access to appropriate therapies and support services.

Many thanks to our Medical Advisory Board member, Andreas Brunklaus, for his assistance in co-authoring this section of the DSUK website.