• Epilepsy is not a single disease. It can result from many diseases, and may be classified into primary genetic, structural/metabolic, or unknown causes.

• Electroclinical syndromes are specific types of epilepsy that have characteristic ages of onset, seizure types, electroencephalographic abnormalities, and other features. Many of these electroclinical syndromes are currently of unknown cause, but most are presumed to be genetic in origin and some have been found to have primary genetic causes.

• Other epilepsies are secondary to other well-defined structural or metabolic diseases or entities, which may also have genetic causes.

• Genetic testing is an increasingly useful way to establish a diagnosis and aid in treatment of epilepsy. An individualized approach to genetic testing should be adapted for each patient.

• Although at present there are limitations and challenges to genetic testing, ongoing and future research may expand the utility and applications of genetics in epilepsy.

Box 1   2010 ILAE classification of seizure types

Table 1

Electroclinical syndromes with known genetic causes

Syndromes with onset in the neonatal period and infancy

Benign familial neonatal epilepsy is an autosomal dominant electroclinical syndrome with an 85% penetrance linked to a mutation in a voltage-gated potassium channel.4,5 This syndrome may occur in otherwise developmentally normal infants, with age of onset during the first 3 months of life. These seizures may be of multiple types but are usually characterized as tonic, and may occur up to 30 times daily.6 Resolution occurs 1 to 6 months after onset, but as many as 14% of neonates develop other seizure types later.6 Benign familial neonatal-infantile epilepsy is an autosomal dominant sodium channelopathy with onset in the first 7 months, usually resolving by 12 months.7 The seizures are brief, usually with focal features such as eye and head deviation, occur in clusters of 5 to 10 per day, and occur in the setting of normal development.8

Benign infantile epilepsy presents similarly with an onset between 3 and 20 months of age and is characterized by focal, brief seizures occurring in clusters during the day. These seizures may consist of behavioral arrest, head or eye deviation, or unilateral clonic activity.8 It has been linked to regions in chromosome 19.9 Of note, benign infantile epilepsy may occur with familial hemiplegic migraine owing to missense mutations in the ATP1A2 transporter gene,10 or with choreoathetosis caused by a mutation in PRRT2 in chromosome 16.11,12 In all 3 of these epilepsy syndromes, an interictal EEG obtained between seizures is normal and the long-term prognosis is relatively good.

Early infantile epileptic encephalopathy with suppression-burst (EIEE or Ohtahara syndrome), on the other hand, is a severe epilepsy occurring during the first 3 months of life characterized by tonic spasms occurring during wakefulness and sleep. Affected infants have abnormal neurologic examinations and a high risk of mortality, and a corresponding EEG showing a suppression-burst pattern.6 This electroclinical syndrome has been linked to mutations in ARX,13,14 CDKL5,15 STXBP1,16–18 PLB1,19 and KCNQ2,20 and affected infants who survive may have seizures that evolve into infantile spams.6

Just as different genotypes may produce a shared epilepsy phenotype, mutations affecting a single gene may result in different phenotypes. SCN1A sodium channel–related disorders include generalized epilepsy with febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (Dravet syndrome), and myoclonic-astatic epilepsy (myoclonic epilepsy of Doose). These syndromes may show incomplete penetrance or variable expressivity, and may also occur de novo.21–23

GEFS+ is a syndrome typically affecting multiple family members with different generalized seizure...