University of Washington Regional Epilepsy Center at Harborview Medical Center

Does your patient have a genetic epilepsy?

By Nicholas Poolos, MD, PhD

Nicholas Poolos, MD, PhD Research advances in the last decade show that certain human epilepsy syndromes have a genetic cause. Genetic epilepsy means that the fundamental cause is gene mutation. "Genetic" is not synonymous with "inherited," especially not in the Mendelian sense with dominant or recessive inheritance patterns. Some gene mutations causing epilepsy may occur de novo, thus will lack a pattern of inheritance. Also, most epilepsy that is inherited shows a complex, non-Mendelian pattern implying interplay of multiple genes. Nonetheless, a small number of syndromes do have Mendelian inheritance and have been associated with mutations of single genes that can be identified with genetic testing. I will briefly review some of the recently characterized genetic epilepsy syndromes, divided into disorders with and without brain lesions on MRI, with the goal of identifying these patients in your practice.

Non-lesional genetic epilepsy
The most recently characterized genetic epilepsy syndromes are all non-lesional in nature. A fascinating feature in common is that the causative gene mutation in every case identified so far affects the expression of neuronal ion channels, or a protein associated with ion channels, underscoring the importance of ion channel dysfunction in the pathogenesis of epilepsy. Three typical syndromes are--

Generalized epilepsy with febrile seizures-plus (GEFS+) is a syndrome characterized by a diversity of seizure types within a family, all with a history of febrile seizures during early childhood. GEFS+ shows autosomal dominant (AD) inheritance, but with incomplete penetrance (about 50%), meaning that about 25% of family members are likely to be affected in any given generation. In addition to febrile seizures, afebrile generalized tonic-clonic seizures can occur during childhood and in later life, along with myoclonic and even partial-onset seizures. GEFS+ has been linked predominantly to point mutations of voltage-gated sodium channel genes (SNC1Aand SCN1B).More extensive mutations of one of these same genes can lead to the devastating syndrome of severe myoclonic epilepsy of infancy (SMEI). Estimates of the frequency of GEFS+ have been increasing as new mutations are discovered, thus a careful family history in any patient with a history of febrile seizures should be undertaken to discover a pattern of inheritance.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE ) was the first non-lesional epilepsy syndrome to be tied to a specific gene mutation, in this case genes encoding the nicotinic acetylcholine receptor (CHRNA4, CHRNB2). This syndrome shows much less phenotypic variability than GEFS+, but similar to GEFS+ shows AD inheritance with incomplete penetrance. ADNFLE is characterized by the onset around ten years of age of stereotyped nocturnal frontal lobe seizures, with bicycling or thrashing movements of the lower extremities. Like other frontal lobe seizures, they can be misdiagnosed as a sleep disorder or as psychogenic in origin.

Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare genetic epilepsy with a distinctive phenotype. Complex partial seizures of temporal origin are preceded by an auditory aura, sometimes of identifiable music or voices; at other times the aura consists of ringing or a machinery-like sound that gradually increases in volume. Secondarily generalized seizures are common. Affected patients are often well-controlled on antiepileptic medications, and a significant fraction experience spontaneous remission of seizures in their 30s or beyond, an important consideration that may obviate life-long therapy. A gene previously implicated as a brain tumor suppressor (LGI1) is mutated in ADPEAF; it appears to modulate excitatory neurotransmission, and does not appear to be associated with an increased risk for brain tumors in epilepsy patients.

Lesional genetic epilepsy
Mutations in several genes produces epilepsy syndromes associated with mental retardation and abnormalities of brain structure evident on MRI. These lesional syndromes are more common than the non-lesional genetic syndromes described above, and are far easier to diagnose because of their characteristic neuroimaging findings. Three of the more common syndromes are described below.

Tuberous sclerosisis an AD disorder producing mental retardation and seizures, as well as causing cardiac, renal, and pulmonary pathology. Brain pathology consists of calcified subependymal nodules, giant cell astrocytomas, and other areas of focal cortical dysgenesis. This disorder is attributable to mutation of two genes (TSC1 and TSC2) that cause similar phenotypes, but significant phenotypic variability is seen even within individual families. Screening for involvement of other organ systems is essential as cardiac and renal dysfunction are a significant source of morbidity.
Subcortical band heterotopia (SBH) or "double cortex syndrome" is an X-linked disorder of neuronal migration in which bands of gray matter are found embedded in the subcortical white matter, often with malformation of the overlying cerebral cortex. This disorder shows wide phenotypic variability in affected females, with some affecteds seizure-free and of normal intelligence. Affected males typically are severely affected and show lissencephaly on brain imaging. Mutation of the DCX gene is responsible for this disorder.

Periventricularnodular heterotopia (PNH) is manifested by islands of gray matter in periventricular areas. Intelligence is usually normal, but the seizure disorder can be medically intractable. Like SBH, this disorder is also X-linked, and in females mutation of the FLNA gene can often be demonstrated. Males with PNH rarely show this gene mutation and presumably their syndrome results from a different genetic cause.

Evaluation and treatment of genetic epilepsy
Identification of possible genetic epilepsy is important both for the patient and the patient's family. Genetic testing for all of the above disorders is commercially available, with the exception of ADPEAF, which at present is performed only on a research basis. Many patients with genetic epilepsy express an understandable concern that they may pass the disorder on to future generations. Genetic testing—with appropriate counseling—can help to stratify this risk. More importantly, most of these disorders, particularly the X-linked migrational disorders, show highly variable penetrance. This means that an affected patient often has seemingly unaffected relatives who are carriers for the disorder. Genetic testing and neuroimaging may help identify these carriers at risk of having affected offspring.
Treatment considerations for genetic epilepsy mostly concern the possibility of surgical treatment of intractable epilepsy. There is little evidence that the seizures associated with genetic epilepsy respond differentially to antiepileptic medication, with the exception of exacerbation of SMEI by lamotrigine, and the occasional spontaneous remission of seizures associated with ADPEAF. It would seem that epilepsy surgery for intractable seizures associated with a non-lesional syndrome would be ill-advised, given the diffuse nature of the underlying pathology, although clinical data on this issue are lacking. For lesional genetic epilepsy, while surgical treatment produces a relatively low rate of seizure freedom, appropriate patients for lesion excision can be identified using intracranial EEG monitoring.

Summary
Clinicians should be alert to the possibility of a genetic epilepsy. Genetic testing and counseling may be important for understanding the patient's prognosis, as well as for family planning purposes. Identification of a genetic epilepsy may figure into calculating the risks and benefits of epilepsy surgery for intractable seizures.

Additional resources
www.genetests.org Descriptions of genetic disorders and available diagnostic tests.