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  Disease summary:

  
  
  
  
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    Epilepsy is a common condition affecting 0.5% to 1% of the world’s population in which genetics play an important role. Genetic factors play a predominant role in about 40% of all epilepsies. Common epilepsies are believed to have complex genetic inheritance, influenced by variation in several susceptibility genes with or without an acquired or environmental component. Idiopathic generalized epilepsy (more recently called genetic generalized epilepsy [GGE]) represents 20% to 30% of all epilepsies, and the designation of genetics is based on evidence from family history patterns, twin studies, and known monogenic epilepsies, though the latter represent only a small minority of the epilepsies.

  
  
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  Differential diagnosis:

  
  
  
  
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    Syncope, nonepileptic seizures, migraine, movement disorders, metabolic disturbances, and sleep disorders

  
  
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  Monogenic forms:

  
  
  
  
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    Mutated genes may encode components of neuronal voltage-gated ion channels (sodium and potassium channels) or ligand-gated ion channels (acetylcholine and g-aminobutyric acid type A [GABA-A] receptors) or nonion channel genes LGI1 (leucine-rich glioma-inactivated 1).

  
  
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  Family history:

  
  
  
  
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    There is 8% to 12% risk for developing epilepsy among first-degree relatives of individuals when compared to the risk of approximately 0.5% in the general population. Both generalized and focal epilepsy can be caused by genetic mutations.

  
  
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  Twin studies:

  
  
  
  
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    There is a high concordance of epilepsy for monozygous twins compared to dizygotic twins for generalized epilepsies (~0.8), evidence for the influence of genetic factors in epilepsy especially GGE.

  
  
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  Environmental factors:

  
  
  
  
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    The role of environmental factors and other epigenetic factors in epilepsy is suspected but not well characterized, although fever can be a precipitating factor in some epilepsy syndromes.

  
  
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  Genome-wide associations:

  
  
  
  
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    GWAS failed to identify common genetic variants that contribute to the risk of focal epilepsy.

  
  
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  Pharmacogenomics:

  
  
  
  
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    None known.

The diagnosis of epilepsy is made clinically and relies largely on a detailed clinical history. The history should include triggers, prodromal symptoms, complete description of the event, and postevent symptoms but history may need to be confirmed by appropriate tests, including an electroencephalogram (EEG) when the clinical suspicion for epilepsy is high (note, however, that a normal EEG does not rule out a clinical diagnosis of epilepsy).

The differential diagnosis of epilepsy includes syncope, nonepileptic seizures, migraine (epileptic auras arising from the occipital lobe may be mistaken for typical visual migraine auras), movement disorders (paroxysmal dystonia or hyperplexia), metabolic disturbances, sleep disorders (confusional arousals and other parasomnias, rapid eye movement [REM] sleep behavior disorder, cataplexy).

Screening

When assessing a patient for a potential genetic cause of epilepsy, one should undertake a detailed history starting with the gestational and birth history and focusing on the timing of onset of epilepsy and specific seizure types that occurred at each stage. When seeing an adult with epilepsy, particularly if the individual is intellectually disabled, it is important to attempt to obtain detailed records or to speak with a parent or caregiver for information about the early presentation of the seizures. One should ask about the presence of febrile seizures in childhood, accurate seizure phenotype, significant past medical history (PMH) including trauma, meningitis, prematurity, and other potential factors that would predispose to epilepsy. It is also important to ask about comorbidities such as learning disability, intellectual disability, autism, attention deficit hyperactivity disorder (ADHD), and psychiatric comorbidities. A detailed family history including epilepsy, febrile seizures, as well as the cognitive and psychiatric comorbidities of epilepsy is also important.

Counseling

Inheritance

Most idiopathic epilepsies are complex genetic disorders. An autosomal dominant mode of inheritance is seen in families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), autosomal dominant lateral temporal lobe epilepsy (ADLTE), and genetic epilepsy with febrile seizures plus (GEFS+). An unusual pattern of inheritance occurs in pedigree with mutations in PCDH19

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