What is Dravet syndrome?

What is Dravet Syndrome?

Dravet syndrome is a severe, rare developmental and epileptic encephalopathy that begins in infancy, characterized by drug-resistant seizures (initially triggered by fever), progressive cognitive decline, motor impairment, and behavioral abnormalities, caused in approximately 85% of cases by mutations in the SCN1A gene. 1

Clinical Characteristics

Dravet syndrome affects approximately 1 in 16,000 live births 1 and presents with a distinctive clinical pattern:

Seizure Features

• Initial presentation: Prolonged febrile and afebrile seizures beginning in the first year of life in previously normally developing infants 2
• Fever sensitivity: The hallmark feature—seizures are consistently precipitated by fever 3
• Multiple seizure types evolve: Convulsive seizures (most common), myoclonic seizures, atypical absence seizures, complex partial seizures, and frequent status epilepticus 4, 3
• Photosensitivity and pattern-sensitivity are also frequently observed 5
• Drug-resistant epilepsy: Seizures persist despite multiple antiepileptic medications 1

Neurodevelopmental Impact

After the initial seizure onset, patients experience:

• Progressive cognitive impairment 4
• Motor abnormalities and psychomotor delays 1
• Language impairment 1
• Behavioral disorders with hyperactivity and sometimes autistic traits 3

Critical caveat: These neurodevelopmental impairments result from both the underlying genetic mutation AND the epilepsy itself, illustrating the concept of "epileptic encephalopathy" 3. This means that even with optimal seizure control, some developmental issues may persist due to the sodium channel dysfunction itself.

Genetic Basis

SCN1A mutations (encoding the voltage-gated sodium channel NaV1.1) account for approximately 85% of cases 3, 5. The genetic landscape includes:

• Most mutations are de novo (new mutations), though familial mutations occur 3
• Intragenic deletions, duplications, and amplifications are rare mechanisms 3
• Somatic mosaic mutations should be considered when counseling families about recurrence risk 3
• PCDH19 mutations account for approximately 5% of cases, particularly in female patients 5
• Other genes (SCN2A, SCN8A, SCN9A, SCN1B, GABRA1, GABRG2, STXBP1, HCN1, CHD2, KCNA2) can cause similar phenotypes but may represent distinct conditions 2

Diagnosis

Dravet syndrome is diagnosed clinically based on the characteristic seizure pattern and developmental trajectory 4. When the clinical picture is unclear, genetic testing is recommended to confirm SCN1A or other causative mutations 4.

• MRI imaging is typically normal 3
• No specific neuropathologic signature exists 3

Prognosis and Long-term Outlook

The prognosis is unfavorable in most cases 5:

• Seizures persist into adulthood but may become less frequent 3
• Motor and cognitive impairment affects most patients 5
• Increased risk of sudden unexpected death in epilepsy (SUDEP) compared to general epilepsy population 6

Pathophysiology

In heterozygous Scn1a+/- mouse models, GABAergic interneurons show substantially reduced sodium current density with impaired sustained action potential firing 3. This leads to reduced GABAergic (inhibitory) output and increased excitability of downstream targets, explaining the seizure susceptibility.

Important pitfall: Understanding this mechanism helps explain why certain antiepileptic drugs (phenytoin, carbamazepine, lamotrigine) can paradoxically worsen seizures in Dravet syndrome and should be avoided 3.