Overview

• Spectrum of Seizure Disorders
  • Varying severity
  • Diagnosed in families with:
    • Febrile seizures (triggered by high fever)
    • Recurrent seizures (epilepsy) of other types, including afebrile seizures
  • Seizure Types:
    • Generalized seizures
    • Partial seizures 
  • Common Seizure Types:
    • Myoclonic seizures (involuntary muscle twitches)
    • Atonic seizures (sudden episodes of weak muscle tone)
    • Absence seizures (short periods of loss of consciousness appearing as staring spells)

Features of the GEFS+ Spectrum

• Simple Febrile Seizures
  • Most common and mildest feature
  • Begin in infancy
  • Usually stop by age 5
• Febrile Seizures Plus (FS+)
  • Condition when febrile seizures continue after age 5 or other types of seizure develop
  • Seizures usually end in early adolescence

Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy - SMEI)

• Part of the GEFS+ spectrum
• Most severe disorder in this group
• Features:
  • Prolonged seizures (status epilepticus) triggered by fever
  • Afebrile seizures begin in early childhood (myoclonic or absence seizures)
  • Difficult to control with medication
  • Can worsen over time
  • Decline in brain function is common
  • Normal development in the first year, followed by developmental regression
  • Difficulty in coordinating movements (ataxia) and intellectual disability

Intermediate Severity Seizure Disorders in GEFS+

• Some people with GEFS+ have seizure disorders that do not fit classical diagnoses of:
  • Simple febrile seizures
  • FS+
  • Dravet syndrome

Family Variability in GEFS+

• Family members may have different combinations of febrile seizures and epilepsy
  • Example: One family member with only febrile seizures, another with myoclonic epilepsy
• Can occur in individuals without a family history of the condition

Prevalence

• GEFS+ is a rare condition. Its prevalence is unknown.

Genetic Basis of GEFS+

• Mutations and Genes Involved

  • Several genes, including unidentified ones, can cause GEFS+
  • Most commonly associated gene: SCN1A
    • Over 80% of Dravet syndrome cases
    • About 10% of other GEFS+ cases
  • Mutations in other genes: found in a small number of affected individuals or families

• Function of Associated Genes

  • SCN1A gene:
    • Provides instructions for making subunits of sodium channels
    • Sodium channels transport positively charged sodium ions into cells
    • Helps generate and transmit electrical signals between neurons
  • Other GEFS+-associated genes:
    • Encode subunits of GABAA receptor ion channels
    • GABAA receptor channels inhibit signaling between neurons
    • Involved in nerve signaling

Effects of SCN1A Gene Mutations

• Variety of Effects on Sodium Channels

  • Many mutations causing Dravet syndrome: reduce the number of functional channels
  • Milder GEFS+ disorders: likely alter channel structure
  • Affect the ability of channels to transport sodium ions into neurons
  • Some mutations: reduce channel activity, others may increase it

• Unclear Mechanisms

  • Studies show certain SCN1A mutations cause constant stimulation of neuron signaling
  • Overstimulation may trigger abnormal brain activity associated with seizures
  • Not all SCN1A mutations have the same effect

Changes in GABAA Receptor Subunit Genes

• Impaired Channel Function
  • Causes uncontrolled signaling between neurons
  • Likely leads to seizures

Understanding GEFS+ Variability

• Range of Seizure Disorders
  • Variability even among family members
  • Researchers believe other genes and environmental factors influence severity
  • Unclear how changes in any one gene lead to the spectrum of disorders

Conclusion

• Complex Interaction
  • Combination of genetic mutations and environmental factors
  • Results in the varied presentation of seizure disorders in GEFS+

Inheritance of GEFS+

• Autosomal Dominant Pattern

• Inheritance Mechanisms

  • Inherited Mutations
    • Affected person inherits the mutation from one affected parent
  • De Novo Mutations
    • New mutations in the gene with no family history of the disorder

• Dravet Syndrome Inheritance

  • Almost always caused by de novo mutations
  • Can be inherited from a parent with a milder form of GEFS+

• Other Forms of GEFS+

  • Usually inherited from an affected parent
  • Rarely inherited from a parent with somatic mosaicism
    • Somatic mosaicism: some cells have the gene mutation, others do not
    • Parent with mosaicism may be less severely affected or asymptomatic

Cite this: CNKE contributors.Genetic Epilepsy with Febrile Seizures Plus (GEFS+). CNKE.org, The Child Neurology Knowledge Environment. 06 January 2025. Available at: https://cnke.org/articles/276 Accessed  06 January 2025.