What is SCN8A Related disorder?
· SCN8A is a gene that encodes a sodium channel in the brain known as Nav1.6, which functions to regulate neuron excitability in the nervous system.
· SCN8A gene variants (mutations) often cause disorders of the brain, including epilepsy and other related disorders that begin in early childhood. The spectrum of epilepsy and brain involvement can be quite variable.
· Disease-causing (pathogenic) variants in SCN8A may affect the NaV1.6 sodium channel in different ways. In most cases, variants in SCN8A lead to overactivity of the NaV1.6 sodium channel (gain of function or GOF); in other cases, a variant will lead to decreased activity of NaV1.6 (Loss of function or LOF).
· Variants causing increased activity of NaV1.6 in the brain lead to epilepsy that may range from mild childhood epilepsy to severe epilepsy with developmental and epileptic encephalopathy (DEE), which is characterized by developmental delay and periods of developmental regression. Decreased activity of NaV1.6 in the brain is associated with cognitive impairment (intellectual disability), autism spectrum disorder, and movement disorders with or without epilepsy.
· Treatments vary according to the type of genetic variant, the severity, and the type of seizures. Many cases benefit from sodium channel blockers, which work by blocking the excessive activity of the sodium channels in the brain.
· Most SCN8A GOF variants result in moderate to severe developmental and epileptic encephalopathy, which is the most common presentation of this genetic condition. DEE associated with SCN8A variants has been classified as Early Infantile Epileptic Encephalopathy type 13 (EIEE13)
· Individuals affected by SCN8A DEE may present with developmental delay, difficult to control seizures of various types, intellectual disability, low muscle tone (hypotonia), autistic features, movement disorders, improper regulation of the autonomic nervous system (dysautonomia), and blindness due to cortical visual impairment.
· Subjects carrying milder GOF variants may present with relatively benign infantile-onset seizures and paroxysmal dyskinesia, which is characterized by intermittent involuntary abnormal movements that may look like seizures. Children with this type of presentation have normal cognition (SeL(F)IE) and seizures are often outgrown. Some children may have seizures that are partially or fully controlled with typical neurocognitive development.
· Patients with LOF variants generally have a mild cognitive impairment, movement disorders, and/or autistic features. Not all individuals with SCN8A LOF variants have seizures; many present with the absence of seizures.
· Children with SCN8A-related epilepsy may develop different types of seizures, including focal seizures or focal seizures that evolve into generalized tonic-clonic seizures, infantile or epileptic spasms, tonic seizures, atonic seizures, myoclonic seizures, and absence seizures
· Unlike Dravet syndrome, febrile seizures are infrequent. Spontaneous non-febrile, prolonged seizures or status epilepticus, with or without visible convulsions, may occur in some cases.
· Seizure frequency is variable ranging from many seizures a day to a few seizures a month. Although some children may have seizure-free periods that may last for years, seizures are typically difficult to control with medical therapy and may evolve over time.
· The main epilepsy type in subjects with LOF variants is the absence of seizures.
· In the vast majority of cases the pathogenic SCN8A variant is not inherited, that is, it occurs as a new mutation (de novo). This happens when the mutation occurs in one of the parent’s gametes (sperm or egg) before the egg is fertilized at conception.
· Occasionally the pathogenic variant is inherited from a mildly affected or unaffected parent. The latter case may be the result of genetic mosaicism in which the variant is present in a subset of the parent’s cells.
· An SCN8A genetic variant substitutes an amino acid at a specific site in the chain of amino acids in the Nav1.6 sodium channel protein (missense variant). While most missense variants are unique to single patients (singletons), the same variant can be found in a few to dozens of individuals across the world (recurrent variant).
· Nearly all GOF variants are missense; while LOF can be associated with either missense or truncating variants. The latter are genetic variants that lead to reduced or lack of expression of that copy of the Nav1.6 protein.
· Symptoms that may suggest SCN8A-related epilepsy include seizures beginning in infancy or early childhood, especially when combined with developmental delay, intellectual disability, autistic features, or movement disorders.
· Seizure onset is typically from birth to 18 months with an average age of onset of 4-5 months. However, there is a range of onset times with nearly 20% of patients experiencing a first seizure in the neonatal period, and about 12% with an onset time at >10 months.
· Because there are other multiple genetic disorders with similar symptoms, clinical findings alone cannot establish a firm diagnosis.
· The diagnosis of SCN8A-related disorder is established by the identification of a pathogenic variant in the SCN8A gene through molecular genetic testing, either through multi-gene epilepsy panels or whole exome sequencing (WES).
· Additional medical tests such as electroencephalogram (EEG) or magnetic resonance imaging (MRI) may yield evidence of abnormalities and lead to diagnoses such as Lennox-Gastaut Syndrome or West Syndrome
· Treatment strategies are guided by the type and severity of seizures and the type of variant carried by a patient. The GOF mechanism predicts that seizures are likely to respond to sodium channel blockers.
· Sodium channel blockers (SCBs) are usually very effective in individuals with mild to moderate manifestations. Subjects with more severe GOF variants or seizure clusters tend to require combinations of medications, including anti-seizure medications that alter neuronal excitability by other mechanisms such as GABAergic drugs, e.g., clobazam.
· Favorable responses to SCBs such as oxcarbazepine, phenytoin, and carbamazepine are common, while more variable responses have been reported with lacosamide, valproate, lamotrigine, topiramate, zonisamide, and rufinamide. Cannabidiol (CBD) may also be effective.
· Epileptic spasms may respond favorably to high dose corticosteroids or adrenocorticotrophic hormone, or in some cases vigabatrin, but control of spasms can be difficult and may not be sustained.
· There is a growing consensus that seizures may be exacerbated with the use of levetiracetam, although ~10% of patients do well with this medication.
· Rescue medications such as diazepam, clonazepam, and midazolam are often required to help stop or shorten clusters of seizures when they occur.
· When medications are not effective in controlling seizures, implantable devices such as vagus nerve stimulation (VNS) are an option. Other options include dietary therapies such as a ketogenic diet or a modified Atkins diet.
· Physical, occupational and speech therapies are recommended to be started as soon as possible in cases with cognitive and developmental delays or autism spectrum disorder
· In addition to different manifestations of GOF and LOF properties of individual variants, multiple factors likely contribute to the wide phenotypic spectrum, including genetic background (i.e., modifier genes), environmental influences and the particular functional changes brought about by missense variants at various sites across the NaV1.6 channel.
· In the case of recurrent variants, the available data indicate heterogeneity in genotype-phenotype correlation. Subjects with the same gene variant may vary in their clinical presentation, progression, response to treatment, and prognosis.
· On the other hand, some variants are invariably associated with mild disease whereas others are found only in patients with severe DEE.
· Individuals with the typical form of SCN8A DEE have significant developmental impairments, mild to severe intellectual disability, and features of autism. Refractory seizures will likely require ongoing treatment, possibly with the use of alternating or multiple medications.
· For individuals with moderate GOF variants, anti-seizure medications are more effective and fewer developmental delays and regressions are expected over time. These individuals may also be ambulatory and develop some speech and language functions.
· For all individuals with DEE, developmental regression events may reoccur in association with increases in seizures, illnesses, vaccinations, changes in medication, or with unknown causes.
· While early mortality in SCN8A-related epilepsies is estimated to be relatively high (~5.3%), the majority of these patients suffer a gradual worsening of their neurologic and overall condition, and only a minority (estimated at 1.6%) experience sudden unexplained death in epilepsy (SUDEP).
· Individuals with milder GOF variants are expected to have a more benign course as seizures are more easily controlled. These individuals often have relatively normal cognition and motor abilities, although language delays are more likely.
· Less is known about treatment or long-term outcome in patients with LOF variants who show variable intellectual disability, movement disorder, ataxia, and seizure activity.
· In the case of recurrent variants, the available data indicate heterogeneity in genotype-phenotype correlation. Subjects with the same gene variant may vary in their clinical presentation, progression, response to treatment, and prognosis.
· On the other hand, some variants are invariably associated with mild disease whereas others are found only in patients with severe DEE.