Dravet syndrome: what is it, symptoms, etiology, prognosis

What is Dravet syndrome?

Dravet syndrome (SD) is a severe form epilepsycharacterized by frequent, prolonged seizures, often caused by high body temperature (hyperthermia), developmental delay, speech impairment, ataxia, hypotension, sleep disturbances and other problems with health. Diabetes mellitus is believed to be at the severe end of the spectrum of disorders associated with changes (mutations) in the sodium ion channel genes. The sodium ion channel is a gated porous structure in the cell membrane, regulating the movement of sodium ions in and out of the cell, helping to propagate electrical signals along the neurons. Sodium ion channels are critical components of any tissue that requires electrical signals, including the brain and heart.

More than 80% of patients with Dravet syndrome have a mutation in the gene SCN1Abut not all mutations SCN1A lead to Dravet syndrome. SD is considered

epileptic encephalopathy or convulsive disorder. Diabetes mellitus appears during the first year of life in a healthy child, usually with a generalized tonic clonic or hemiclonic seizure that often lasts (> 5 minutes). Status epilepticus or a seizure lasting more than 5 minutes, and sometimes 30 minutes or more, is common, especially in the early years, and requires urgent medical attention. Additional seizure types, including myoclonic, atypical, and complex partial seizures, appear before age 5 years

EEG, imaging, and development are usually normal at first, but abnormal EEGs and developmental delays often appear at 2 and 3 years of age. Delay can range from mild (rare) to moderate / severe (common), and most adult patients need someone to care for them.

Inconsistency (ataxia) and low muscle tone (hypotension) often appear in the early years and remain characteristic of the syndrome throughout life. Gait may deteriorate over time, leading to decreased mobility during adolescence. Delayed speech is often seen before the age of 2 years. Physical, occupational and speech therapy are recommended. Other common traits and health problems include behavioral problems, growth and nutritional problems, and also disorders of the autonomic nervous system, which regulates things like body temperature and sweating.

Mortality is higher in Dravet syndrome than in the general population of epilepsy patients. Mortality estimates range from 15% to 20% in adulthood. Sudden death syndrome in epilepsy (SEDS) is the most common cause of death and usually occurs during sleep. The second most common cause of death is status epilepticus (status epilepticus) and status epilepticus complications.

Other states suspected to be present in the spectrum disorders, gene-related SCN1A, include (in ascending order of severity):

• Febrile seizures (FS);
• Febrile seizures plus (FS +);
• Generalized epilepsy with febrile seizures plus (GEFS +);
• Intolerable childhood epilepsy with generalized tonic clonic seizures (NDE-GTKP);
• Dravet syndrome (DM).

Signs and symptoms

The median age at onset of seizures is 5.2 months, with a range of 1 to 18 months, but most often up to 12 months. The first attack often lasts, with either generalized tonic clonic or semi-clonic changes, and may be associated with fever. Short seizures can also occur. Hyperthermia or overheating is a common trigger in diabetes, and patients show increased sensitivity to warm baths, fever, exertion and other forms of enhancement temperature.

Myoclonic seizures, when they occur, are usually seen by age 2 years, but they are not required for a diagnosis. Focusing seizures without convulsive status with impaired awareness and attacks of atypical absence usually occur after 2 years. Typical absence seizures and epileptic spasms are uncommon. Initial EEG, CT, MRI, and lumbar puncture are often normal, although background slowing may be evident if performed after an attack. Subsequent EEGs may show diffuse deceleration and / or generalized shocks while other images remain normal. MRI may show mild generalized atrophy or sclerosis of the hippocampus later in life. Development usually occurs during the first year, but the delay often appears in the 2nd and 3rd years of life and usually appears between the ages of 18-60 months.

In older children and adults, seizures persist, although status epilepticus becomes less frequent over time. Obvious:

• developmental delay;
• speech impairment;
• hypotension;
• lack of coordination;
• impaired mobility.

Any patient with a clinical history suggesting diabetes should be genetically tested for SCN1A and / or other genes associated with epilepsy. The presence of a mutation SCN1A may help confirm the diagnosis, but the presence of a mutation alone is not enough to make a diagnosis, and the absence of a mutation does not exclude a diagnosis. Most experts believe that a child with two or more prolonged generalized tonic clonic or hemiclonic seizures with or without fever, genetic testing.

Causes (etiology)

Dravet syndrome is associated with a mutation in a gene SCN1A in 80-90% of cases. Improved genetic testing, including duplication, removal and identification of mosaicism, continues to increase this percentage. Missense (40%), nonsense (20%), frame shifting (20%), duplications / deletions (7%), and splice site mutations (10%) were associated with Dravet syndrome.

Easier manifestations (phenotypes) of conditions associated with SCN1Aare more likely to be associated with erroneous mutations, but neither the type of mutation nor the location on the gene is consistent with the clinical severity of diabetes.

90% of the mutations appear to be new to the child and not inherited from the parent. In documented cases of inherited mutations SCN1A parent has more easy the form of epilepsy or neurological symptoms are absent, while the child develops diabetes mellitus. Advanced testing found mosaic mutations in parents who had previously tested negative for SCN1A mutations. Mosaism is a condition in which some cells in a person are genetically different from other cells in that person. This can happen shortly after fertilization, when a single cell in a cluster of cells undergoes spontaneous mutation. Only cells originating from this mutated cell will carry the mutation: non-mutant cells will produce healthy cells, and thus a developed individual may have slightly different structures in their cells.

The risk of recurrence is 50% in families with inherited mutations SCN1A. Due to the detection of mosaicism and the possibility of mutations in the eggs or sperm (germ line mutations), the risk of recurrence even for apparently new mutations is increased compared to the normal population, and therefore a genetic counseling.

Other genes associated with diabetes, including SCN2A, SCN8A, GABRA1, GABARG2, PCDH19, STXBP1 and SCN1B, but the clinical picture in these cases is often somewhat atypical for the syndrome.

Affected populations

Dravet syndrome affects approximately 1 in 15,700 people, or 0.0064% of the population. Approximately 80-90% of them, or 1: 20,900 people, have both a mutation SCN1Aand the clinical diagnosis of diabetes. It accounts for approximately 0.17% of all epilepsies.

Related disorders

Patients with Dravet syndrome may be misdiagnosed with myoclonic atonic epilepsy, Lennox-Gastaut syndrome, myoclonic epilepsy of infancy, genetic epilepsy with febrile seizures plus, atypical febrile seizures, and mitochondrial disorders.

In addition, some children may be diagnosed with focal epilepsy. Conversely, in patients with myoclonic atonic epilepsy, myoclonic epilepsy of infancy and associated PCDH19 epilepsy may be misdiagnosed with Dravet syndrome.

A careful study of the medical history and characteristic progression of Dravet syndrome is important for the differential diagnosis.

Several genes including SCN2A, SCN8A, GABRA1, GABARG2, STXBP1, PCDH19 and SCN1Bhave been reported in diabetic patients who gave negative for mutation SCN1A. However, the clinical picture in most of these cases is not typical for diabetes mellitus.

Diagnostics

Dravet syndrome is a clinical diagnosis. The presentation is a unique characteristic and, according to the consensus of North American neuroscientists with experience with diabetes in 2017, includes:

• Typical onset is 1 to 18 months, most often <12 months, with an average of 5.2.
• Recurrent generalized tonic-clonic or hemiconvulsive seizures are often prolonged but may be short-lived.
• Myoclonic seizures onset by age 2 years, accompanied by flow status, focal seizures with impaired awareness, and atypical seizures of absence.
• Hyperthermia causes seizures in most patients (due to illness, vaccinations, warm baths, exercise, etc.). Other factors may include visual features or photosensitivity, food intake and bowel movements.
• Normal development, neurologic examination, MRI, and normal or non-specific EEG results at the start.

In older children and adults:

• Persistent seizures that may or may not continue. Status epilepticus becomes less common over time and may not show up in adulthood.
• Hyperthermia as a trigger attack may decrease with the age of the patient.
• Exacerbation of seizures with the use of sodium channels.
• Intellectual disability manifests itself by 18-60 months.
• Crouching gait, hypotension, impaired coordination of movements and impaired dexterity.
• MRI may be normal or show mild generalized atrophy and / or sclerosis of the hippocampus.
• EEG may show diffuse background slowing with multifocal and / or generalized interventricular discharges.

Standard treatments

While there is no cure for Dravet's syndrome, there are treatments to reduce seizures. First-line seizure medications include clobazam and valproic acid. Second line treatments include Diakomite, Topiramate, and a ketogenic diet. Third-line treatments include Clonazepam, Levetiracetam, Zonisamide, Ethosuximide, and a vagus nerve stimulant.

In 2018, Epidiolex was approved for the treatment of seizures associated with Dravet syndrome in patients aged two years and older. It is the first FDA approved for the treatment of Dravet syndrome.

Also in 2018, Diakomite was approved for the treatment of seizures associated with Dravet syndrome in patients two years of age or older who are also taking clobazam. Diakomite is manufactured by Biocodex.

Medicines that IT DOES NOT FOLLOW use for diabetes, include sodium channel blockers such as carbamazepine (tegretol), oxcarbazepine (trileptal), lamotrigine (lamictal), vigabatrin (sabril), rufinamide (banzel), phenytoin (dilantin), fosfenistin) cefosfenitin. Note, that phenytoin and phosphenytoin should be avoided as daily medications, but their effectiveness in the emergency treatment of status epilepticus is unclear.

Status epilepticus is common in patients with diabetes, and caregivers should be trained in home-based medication to control long-term seizures. Rectal diazepam and buccal (by mouth) or intranasal (nasal) midazolam are often used.

Forecast

As children with Dravet syndrome get older, their cognitive functions stabilize. The degree of mental retardation ranges from mild to severe, but most adolescents and adults with Dravet syndrome depend on their caregivers. Gait abnormalities seem to worsen during adolescence. Seizures tend to decrease in number and duration with age. People with Dravet syndrome have a higher risk of sudden death than the general population, but this risk is still low.