Usually, a patient with idiopathic epilepsy has no family history of epilepsy or febrile seizures. Nevertheless, it is always essential to take a detailed family history, which, if positive, can provide important clues to the type of epilepsy affecting the family. A cursory history in a busy clinic setting may miss important pointers to a genetic etiology unless the extended family history is taken in detail and a pedigree is routinely constructed. It is unusual to obtain a strong family history of epilepsy affecting many members across multiple generations that unequivocally suggests a single-gene inheritance pattern. Much more common is when the patient reports a few distant relatives (such as a skipped generation or once-removed cousins or uncles or aunts) with a diagnosis of epilepsy. These affected family members illustrate how genetic factors may be relevant to the patient’s epilepsy. It is often difficult to obtain detailed electroclinical data about affected relatives, but in some instances, such as ADNFLE, these data may be key to making the diagnosis. In other cases, the family history is not relevant, and epilepsy could be a result of “acquired factors.” When these acquired factors are explored, however, they may not be convincing and the genetic etiology may not have been appreciated (or was denied); therefore, it is always helpful to obtain as much information as possible. Furthermore, investigations to uncover a genetic etiology may be hampered by the family’s reluctance to cooperate owing to the stigma attached to the diagnosis of epilepsy and the potential of having inherited this disorder. On the other hand, when five or six family members over multiple generations report seizures, the possibility of single-gene disorders should not be dismissed if a few key individuals are unaffected, as they may be nonpenetrant carriers of a genetic mutation (5). Incomplete penetrance is usual in autosomal dominant disorders.

In all cases, a pedigree will highlight the degree of relationship between affected family members. A pedigree should identify the index patient, or proband, and clearly show the proband’s relationship to affected and unaffected members on both the maternal and paternal sides. The clinician should always ask about parental consanguinity, which is vital in determining inheritance patterns. It is also good practice to obtain the names and dates of birth of affected individuals, any consanguinity elsewhere in the family, and obstetric history (miscarriages, stillbirths, neonatal deaths). The presence of multiple miscarriages may suggest X-linked dominant inheritance or other genetic causes. The clinician should always specifically inquire about a family history of epilepsy and febrile convulsions because, not recognizing that these two entities may be related genetically, many families will fail to mention febrile seizures. Obtaining age of seizure onset, course, semiology, and provoking factors in affected family members is helpful, and it is worth asking whether precise data can be secured from other family members. It is also important to update the pedigree as new information on family members becomes available at future consultations (5).

A genetic etiology is suspected in a patient with epilepsy who has multiple congenital anomalies with a known cytogenetic abnormality, imaging data and/or a clinical phenotype suggestive of a known single-gene disorder such as tuberous sclerosis or Rett syndrome, or clinical and laboratory findings of a genetically determined inborn error of metabolism or a mitochondrial cytopathy. In most of these instances, however, epilepsy is only one component of several complicated medical issues these patients and families face.

Accurate diagnosis of an underlying genetic etiology is of paramount importance for the patient with epilepsy and the family. A specific diagnosis often carries implications for appropriate antiepileptic drug (AED) selection, prognosis, and genetic counseling. In terms of the idiopathic epilepsies, clinical genetic factors may guide diagnosis and thus management. An example is a child presenting with nocturnal frontal lobe epilepsy and a normal magnetic resonance imaging scan of the brain. If that child has three other family members with nocturnal frontal lobe epilepsy that follows an autosomal dominant inheritance pattern, a diagnosis of ADNFLE can be made and guide AED selection based on the previous experience (6). Genetic counseling could also be performed in view of the clinical genetics of this disorder. Because the genes currently known for ADNFLE account for only a small proportion of families, the diagnosis more frequently relies on the clinical genetics and seizure semiology than on a molecular defect (7). Similarly, clinical genetics guides recognition of generalized epilepsy with febrile seizures plus (GEFS+) (8). Although a number of genes have been identified for GEFS+, they relate to only a minority of patients and families with this disorder. Diagnosis of a mild phenotype such as febrile seizures plus helps the clinician predict a good prognosis and potentially opt for no AED treatment for an 8-year-old child who continues to have a few febrile seizures.

Just as important, but to date relatively infrequent, genetic mutations have major implications for management. At present, there are two main situations in which a genetic defect will significantly influence clinical care. The first is the mild disorder of benign familial neonatal convulsions (BFNC) (see below). This idiopathic epilepsy is the only autosomal dominant epilepsy syndrome in which most families have mutations of the potassium-channel gene KCNQ2. The finding of a mutation in a neonate with seizures guides prognosis and reassures the family about
the likely good outcome (9). The first molecular lesion to have major diagnostic implications for a patient with a severe epileptic encephalopathy is represented by mutations in the sodium-channel α₁ subunit gene SCN1A in severe myoclonic epilepsy of infancy (SMEI) (see below) (10). SCN1A mutations arise de novo in approximately 70% of patients with SMEI and, if considered pathogenic, mean that the clinician does not need to pursue other invasive diagnostic tests; confirmation of diagnosis by DNA tests, however, does not influence the choice of AEDs at this time (11).

Accurate genetic diagnosis also helps in the management of patients by timely investigation, treatment, and institution of surveillance for anticipated involvement of other organs and systems, particularly when symptomatic epilepsy occurs as part of a multisystem disorder. For example, in patients with tuberous sclerosis, surveillance and treatment are indicated for hydrocephalus, renal cysts or tumors, cardiac rhabdomyomas, cardiac conduction defects, ocular abnormalities, and pulmonary involvement (12,13). Precise genetic testing and counseling of family members at risk are also possible when an accurate genetic diagnosis is made. Furthermore, new epilepsy syndromes and brain malformations of genetic origin will be recognized only if families and patients with familial disorders are identified.

Sometimes, a genetic etiology has implications for the treatment of epileptic seizures. For example, in several genetically determined disorders, specific metabolic therapy is indicated: lifelong oral pyridoxine for B₆-dependent seizures (14), the ketogenic diet for glucose transporter defects (15), biotin supplementation in biotinidase deficiency-related seizures (16), and folinic acid for folinic acid-responsive seizures (17). In other situations, a specific AED may show superior efficacy in treating the seizures of a genetic condition, as, for example, vigabatrin for infantile spasms caused by tuberous sclerosis (18). New trials of drugs designed to ameliorate a genetically determined channel dysfunction are also on the horizon; an example is the potassium-channel drug retigabine for benign neonatal febrile convulsions caused by mutations in a potassium-channel gene(s) (19).