4. Familial generalized seizures due to LGI1 mutation: Importance of family history for genetic testing

Abstract

Background It is well known that patients with temporal lobe epilepsy may present with generalized seizures, and the temporal localization depends on further investigation. We present a family with five individuals in three generations where the clinical pattern consisted largely of generalized seizures, but who were then shown to have epilepsy due to an LGI1 mutation. We wish to discuss the clinical and EEG findings in these patients, and to compare these with families with autosomal dominant partial epilepsy with auditory features (ADPEAF) or familial lateral temporal lobe epilepsy (FLTLE) reported in the literature. Family report The proband is a 46-year-old female college graduate who had normal development and no history of head trauma, central nervous system infection or febrile seizures. She had four nocturnal generalized tonic-clonic seizures (GTCS), all occurred around 5–6 am, the first one at age 19years. Diphenylhydantoin was prescribed and later replaced by carbamazepine CR. She has been seizure free since adequate compliance with treatment. Her first EEG performed at 19 years showed an excess of slow waves at 2–4Hz over both posterior head regions without epileptic activity. Her second EEG at 22years showed spikes and slow spike waves alternating over both temporal regions, mostly during drowsiness, and increased during hyperventilation. During intermittent photic stimulation, a photomyoclonic response appeared. Her 40-year-old sister had her first GTCS at 12years which was generalized from the onset. All but one of her subsequent attacks occurred during sleep. Before the only seizure that occurred while awake, she felt numbness of her whole body and heard a whooshing sound suggestive of neocortical temporal lobe involvement. The third sister is 52years old; she had her first GTCS at 19years. A year prior to this, she had transient symptoms of a tingling sensation associated with a whooshing noise. She later had other generalized attacks preceded by this aura. A diagnosis of neocortical or lateral temporal lobe epilepsy, possibly ADPEAF or FLTLE, was suggested. Although the proband only had nocturnal GTCS, LGI1 sequencing was performed on the basis of the family history. A c.611delC mutation leading to a frameshift and premature termination of the protein was identified. Discussion Generalized nocturnal and diurnal seizures associated with interictal generalized spike-wave activity occurring in a family with ADPEAF is unusual. They may represent secondarily generalized seizures or primary generalized seizures or both. In addition, photosensitivity in the proband is unusual as well. Among the reported patients with LGI1 mutation, there are several who have had GTCS and interictal generalized spike-wave and/or polyspike-wave discharges [Ottman et al., 2004]. This family further illustrates that patients with ADPEAF or FLTLE may present with generalized seizures and generalized spike and wave epileptic discharges. Intensive monitoring and attention to aura with auditory features should lead to accurate diagnosis of this genetically determined epileptic syndrome. This report points to the importance of detailed family history to help orient the diagnosis by genetic testing.