Biparental Inheritance in Idiopathic Generalized Epilepsy

We read with interest the report of Marini et al. (1) on two families in which both parents had idiopathic generalized epilepsy (IGE). A paucity of reports exists on unions between two people with epilepsy, but this does not seem to be uncommon. Exposure to other young people with epilepsy may be a factor, as well as acceptance of their epilepsy. Patients often feel that their own epilepsy has given them a better understanding of the other's problems and vice versa. However, the consequences of such unions, with respect to both the increased risk for epilepsy and the possibly more severe epilepsy phenotypes in the offspring are not always appreciated. We report an additional family in which both parents had IGE. The family is of French-Canadian origin. No known consanguinity is present (Fig. 1). Pedigree of the proband's family. The proband (III-1), a 34-year-old woman, started having absence seizures at age 6 years. She had a single generalized seizure at age 12 years. She is treated with valproic acid (VPA) and has fewer than one absence seizures per month. Her recent EEG shows bursts of generalized spike-and-wave at a frequency of 3 to 4 Hz, lasting 1 to 5 s, recorded from both hemispheres, predominantly frontal, during both wakefulness and sleep. She is photo and pattern sensitive. Her 12-year-old son (IV-1) has learning difficulties; his EEG is normal. His younger sister (IV-2) is asymptomatic, but her EEG shows rhythmic sharp waves as well as sharp slow-wave complexes emanating from the right occipital and posterior temporal cortex during sleep. Her younger sister (IV-3) is well; her EEG is normal. The proband's mother (II-4), a 65-year-old woman, has had absence seizures since age 5 years. What Lennox called a Petit Mal Triad developed in her with, in addition, akinetic attacks and myoclonus, both of which subsequently ceased. She had a first generalized tonic–clonic seizure at age 11 years. Despite treatment with VPA and phenytoin (PHT), occasional absences and generalized seizures have persisted into adulthood. EEG shows generalized bursts of three-per-second spike-and-wave discharges with high-voltage spikes. She is photosensitive. She has two sisters (II-2 and II-3) with generalized epilepsy. The oldest sister has generalized tonic–clonic seizures and absence attacks. Seizure frequency always increased with menstrual periods or after childbirth. She has marked photosensitivity. The second sister has major seizures. The proband's father (II-5) had generalized attacks since age 5 years, as well as myoclonic seizures and absences. He was treated with phenobarbital (PB) and PHT. He had occasional absence seizures and approximately one generalized seizure per year until he died of heart disease at age 52 years. His two sisters (II-6 and II-7) had generalized tonic–clonic seizures starting around age 17 years, as well as absence seizures. The paternal grandmother (I-3) had been diagnosed with epilepsy as well, but further details are not available. The presence of myoclonus and photosensitivity may have been underdiagnosed in this family, complicating syndromic diagnosis. Although the proband continued to have some clinical and EEG manifestations in her 30s, she had a less severe phenotype than her affected parents. Thus unlike the families reported by Marini et al. (1), offspring from biparental unions do not necessarily have more severe epilepsy phenotypes. However, this does not exclude the possibility that some offspring from biparental unions may have more severe phenotypes because of a double dose of the same mutation, allelic mutations in the same gene, or nonallelic mutations in different epilepsy genes inherited from both parents. The risk for epilepsy in the offspring of biparental or bilineal epilepsy families has not been studied in detail. Marini et al. (1) mentioned 12 biparental families with 74% of offspring affected, although referral bias may in part explain this high frequency. For IGE in particular, one study mentions that, if both parents have IGE, the risk for epilepsy in the offspring is 33% (2), as compared with 6 to 10% for offspring with only one parent affected (3,4). We support the idea that a larger population-based genetic study is needed to clarify the recurrence risk and epilepsy phenotypes in offspring of biparental IGE families and of bilineal epilepsy families in general.

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