By: Shree Rath
SCN1A gene function:
SCN1A, or sodium channel protein type 1 subunit alpha, mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming open or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na (+) ions may pass in accordance with their electrochemical gradient. Basically, it helps in the generation and propagation of action potentials along a nerve via depolarization. Sodium channels consist of a large central pore, surrounded by alpha and beta subunits. SCN1A forms the alpha subunit of this transmembrane channel.
Mutations in SCN1A gene:
Due to its role in neuronal impulse transmission and the brain being the central organ where millions of impulses are transmitted, SCN1A mutations most severely impact the brain. In fact, studies of epilepsy led to the discovery of mutations in the SCN1A gene. The SCN1A gene has been linked with the following disorders:
- Dravet Syndrome
- Familial Hemiplegic Migraine 3
- Generalized epilepsy with febrile seizures plus, type 2(GEFSP2)
- Developmental and epileptic encephalopathy-6B(DEE6B)
Of all, what SCN1A is famously known for is its association with Dravet syndrome. It was actually one of the first genetic breakthroughs in epilepsy, correlating a typing electroclinical epilepsy syndrome with a de novo genetic mutation.
What is Dravet syndrome?
It is a group of symptoms that begins in infancy (typically 1st year of life). It is a rare form of epilepsy that typically presents in the first year of life, affecting more infants and children. Children have normal development, i.e., they achieve all developmental milestones normally before the advent of a seizure episode. Once they start getting seizures, their development slows, and they fail to achieve further milestones at an appropriate age. They also often show features of autism spectrum disorder.
Genetics:
It is an autosomal dominant disease, with only one copy of the mutated allele from either parent enough to cause the disease in offspring. The mutation inherited is that of the SCN1A gene. However, parents need not be suffering from Dravet syndrome per se for the child to inherit it. As discussed above, the SCN1A mutation is associated with a wide spectrum of diseases, from milder manifestations like migraine to full-blown epilepsy. There may be a few cases as well, which may not be based on inheritance but are sporadic mutations that appear in the genes. Nearly 80% of children diagnosed with Dravet syndrome have the SCN1A gene mutation.
But only between 4% and 10% of SCN1A mutations in children with Dravet syndrome are inherited from a parent. About 90% of SCN1A mutations aren’t found in the child’s parents and are new gene mutations only present in the child.
Signs to look out for:
Before the onset of seizures, children with Dravet syndrome reach developmental milestones on time. However, with symptom onset, children exhibit developmental delays and features of autism spectrum disorder.
Symptoms of Dravet syndrome:
These symptoms usually manifest between the ages of 4 months and 12 months. These seizures could be febrile seizures, associated with a high body temperature, or tonic clonic seizures (in which the whole body first stiffens, followed by jerking movements). After the first episode of seizure, other episodes may follow concurrently, even with mild stimuli like bright light or a slight rise in temperature. Along with seizures, as explained above, children often show developmental delays and intellectual disability; hence, it is also considered a prototype for “developmental encephalopathy with epilepsy.”
At the Doctors:
Doctors would ask about when the first episode occurred and the details of subsequent episode. They would also inquire about the child’s developmental history and may detect challenges in achieving developmental milestones. They may also consider genetic tests to detect the mutated SCN1A allele.
Management and Treatment:
The management and treatment of Dravet syndrome typically involve a multi-faceted approach. It’s important to note that there is no cure for Dravet syndrome, and the goal of treatment is often to control seizures, manage associated symptoms, and improve the individual’s quality of life. Here are key components of the management and treatment plan:
- Anti-epileptic Medications:
- Sodium channel blockers, such as stiripentol, clobazam, and valproic acid, are commonly prescribed to help control seizures in Dravet syndrome.
- Medication regimens are often tailored to the individual, and a combination of drugs may be used.
- Rescue Medications:
- Buccal midazolam or rectal diazepam may be prescribed as rescue medications to be administered during prolonged seizures, helping to shorten or stop seizure activity.
- Ketogenic Diet:
- A high-fat, low-carbohydrate ketogenic diet may be considered, as it has shown effectiveness in reducing seizures in some individuals with Dravet syndrome.
- Physical and Occupational Therapy:
- These therapies can help manage developmental delays and improve motor skills in individuals with Dravet syndrome.
- Behavioral and Educational Support:
- Behavioral interventions and educational support are often necessary to address the developmental challenges and cognitive delays associated with the syndrome.
- Monitoring and Regular Check-ups:
- Regular monitoring of seizure activity, medication effectiveness, and overall health is crucial.
- Genetic testing and counseling may be recommended for a more accurate diagnosis and to assess the risk of recurrence in other family members.
- Avoidance of Triggers:
- Individuals with Dravet syndrome may be sensitive to certain triggers, such as fever and overheating. Taking measures to avoid these triggers can help manage the condition.
- Supportive Care:
- Supportive care, including attention to nutrition, sleep, and overall well-being, is important for individuals with Dravet syndrome.
- Investigational Treatments:
- Given the complex nature of Dravet syndrome, some individuals may be enrolled in clinical trials to explore new treatments or therapies.
It’s essential for individuals with Dravet syndrome to have a comprehensive care team, including neurologists, genetic counselors, physical and occupational therapists, and other specialists. Regular communication and collaboration among healthcare providers, caregivers, and families are crucial for effective management and support. As treatment options and research continue to evolve, individuals with Dravet syndrome may benefit from advances in precision medicine tailored to their specific genetic and clinical profile.
Resources:
Children’s Hospital of Philadelphia (2023). Dravet Syndrome. Children’s Hospital of Philadelphia. Retrieved from: https://www.chop.edu/conditions-diseases/dravet-syndrome
Cleveland Clinic (2022). Dravet Syndrome. Cleveland Clinic. Retrieved from: https://my.clevelandclinic.org/health/diseases/22517-dravet-syndrome
National Library of Medicine (2023). SCN1A sodium voltage-gated channel alpha subunit 1 [Homo sapiens (human)]. National Institute of Health, National Library of Medicine. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/6323
Richards, K.L. et al. (2018). Selective Nav1.1 activation rescues Dravet syndrome mice from seizures and premature death. PNAS. Retrieved from: https://doi.org/10.1073/pnas.1804764115
