The 94 families collected for genetic linkage analysis contained 322 individuals with idiopathic epilepsy, of whom 169 had partial seizures. Thirty-four percent (58/169) of those with partial seizures had auditory symptoms. Fifty-one percent (48/94) of the families contained 2 or more subjects with idiopathic focal epilepsy, and of those, 19% (9/48) met our criteria for ADPEAF (i.e., 2 or more subjects with ictal auditory symptoms). Two of the nine families had been tested previously and found to have mutations in LGI1
(Families 6610 and C).6
The remaining seven linkage families that met criteria for ADPEAF are reported here.
Given our known interest in this syndrome, we explored the possibility that subjects with auditory symptoms had been referred to us selectively, leading to an overestimate of the proportion of familial focal epilepsy meeting criteria for ADPEAF. For this purpose, we examined separately the subset of 31 families that had been ascertained in our original familial aggregation study, between 1985 and 1988, before publication of the article describing the syndrome in 1995.1
These 31 families were virtually identical to the remaining families, both in the proportion containing two or more subjects with idiopathic focal epilepsy (52%) and in the proportion of those meeting criteria for ADPEAF (19%). The proportion of individuals
with partial seizures who had ictal auditory symptoms was slightly lower in these 31 families than in the others (27% vs 38%), but the difference was not significant.
All 10 families included in the current study (7 from our linkage database and 3 others ascertained because of auditory symptoms) were of European descent. They contained 43 individuals with idiopathic epilepsy (4 primary generalized; 31 focal; 3 focal and primary generalized; and 5 unclassifiable). Seventy-nine percent (27/34) of those with partial seizures had ictal auditory symptoms. Age at onset averaged 14 ± 1.95 years (SE). None of the families contained an individual with glioblastoma.
We sequenced LGI1 in one affected subject from each family and identified mutations in three of them (two from the linkage database and one referred because of auditory symptoms). In the families of these three subjects, we sequenced the gene in all remaining sampled individuals and confirmed that the mutations cosegregated with epilepsy ().
Family F had a missense mutation in exon 1 (348T>C, counting from the first nucleotide), resulting in a cysteine-toarginine substitution in amino acid residue 42 (C42R; see and ). Both affected sisters carried the mutation, as did their unaffected father.
Clinical features in three newly identified ADPEAF families with LGI1 mutations
Family G had a missense mutation in exon 8 (1117T>C), resulting in an isoleucine-to-threonine substitution in amino acid residue 298 (I298T). Five of the six affected individuals in the family had focal epilepsy with auditory symptoms. The remaining affected subject (IV:6) had two nocturnal generalized tonic-clonic seizures (GTCs) at age 10 and 11 years. No myoclonic or absence seizures were noted. An EEG report from the treating physician indicated generalized bursts of 2.5 to 3-Hz spike- and slow-wave activity. She was treated successfully with valproic acid. We classified her syndrome as idiopathic generalized epilepsy (IGE), not otherwise specified (NOS), a category we used for IGE-like syndromes that do not fit clearly into existing IGE categories (e.g., because of atypical age at onset or seizure type constellations, or isolated GTCs that do not occur on awakening).
All four tested affected family members (including the one with IGE NOS) had the mutation. The remaining two affected subjects declined to give blood samples. Three unaffected individuals in the family (one of whom was married in) did not carry the mutation. Two other unaffected subjects did carry the mutation, consistent with reduced penetrance: II:1, aged 76 years, and IV:5, aged 17 years at the time of study.
Family H had a missense mutation in exon 3 (553C>A), resulting in an alanine-to-aspartate substitution in residue 110 (A110D). Three individuals had idiopathic epilepsy, and all had the mutation. Two were classified as having focal epilepsy with auditory symptoms, but both also had generalized-onset (myoclonic) seizures. II:2 had secondarily generalized seizures beginning at age 13 years, preceded by a warning of feeling light-headed and hazy, and complex partial seizures with similar symptoms, also including a high-pitched ringing in his right ear. He also had myoclonic seizures while watching television, beginning at age 21 years, and witnessed by his wife. An EEG tracing from his treating physician, which we reviewed directly, showed 3-Hz generalized spike-wave activity during hyperventilation and photic stimulation. He was classified as having auditory partial epilepsy and juvenile myoclonic epilepsy.
Subject III:1 had complex partial and secondarily generalized seizures preceded by auditory symptoms, and also myoclonic seizures. GTCs began at age 11 years and were preceded by a combination of auditory, visual, olfactory, and autonomic symptoms. In addition to these partial seizures, he had myoclonic seizures, beginning at age 15 years, with rapid jerks of the arms and legs while watching television and occurring most often after sleep deprivation. He also described occasional eyelid twitching with these episodes and had no alteration of consciousness or confusion during or after these events. An EEG report from his treating physician indicated sharp and slow-wave activity with right-sided predominance. He was also classified as having auditory partial epilepsy and juvenile myoclonic epilepsy.
Subject III:2, who was treated at our institution, had pyknolepsy, onset at age 3 years, with 4-Hz generalized spike-wave and polyspike-wave activity on EEG. Absence seizures remitted at age 10 years. At age 22 years, she had two GTCs, the first ~8 months after a moderately severe head injury and the second ~2 months later. Both were nocturnal, with no warning or prodrome, and could not be classified further.
The positions of the three newly identified mutations within LGI1 and the alignments of the mutated Lgi1 proteins with other members of the LGI gene family are shown in . The C42R mutation in Family F affects the beginning of the cysteine-rich N-terminal LRR domain, which has cysteine in this position in all known Lgi proteins. The A110D mutation in Family H changes a highly conserved alanine to aspartate in the second LRR domain. The I298T mutation in Family G localizes to the protein’s putative transmembrane domain and substitutes a polar amino acid (threonine) at a highly conserved position normally occupied by aliphatic amino acids isoleucine or valine.
We estimated penetrance in all eight families in which we have identified mutations so far (five reported previously and three reported here).6
We excluded the probands and their first-degree relatives from this analysis because their epilepsy histories had led to selection of the families for study. The analysis included 76 remaining family members (excluding married-in subjects) aged >20 years with unambiguous diagnoses (15 with idiopathic epilepsy and 61 unaffected). In this group of relatives, the proportion tested for mutations was 87% (13/15) in affected subjects but only 39% (24/61) in unaffected subjects. To correct for this bias, we estimated the number of carriers among the 37 unaffected subjects who were not tested. Among unaffected family members who were tested, 21% (5/24) were carriers. Assuming the same proportion applies to those who were not tested, 7.7 (37 × 0.21) would be expected to carry a mutation. Similarly, we assumed that both of the untested affected subjects had a mutation because all of the tested affected subjects did. Based on these calculations, we estimated that 27.7 relatives had a mutation (i.e., 5 + 15 + 7.7), of whom 15 were affected, giving a penetrance estimate of 54% with an approximate 95% CI of 35 to 73%.
After excluding the family used to define the syndrome initially,1
we compared the clinical features in the seven families with mutations and seven families without (see supplementary data on the Neurology Web site for additional details). The two sets of families were similar in the number of individuals with idiopathic epilepsy, age at onset, and distribution of seizure type. Subjects with partial seizures were more likely to have auditory symptoms in families with mutations than in those without (96% vs 72%; p = 0.049; Fisher’s exact test). Visual symptoms were less common in families with mutations than in families without (29% vs 48%), but this difference was not significant. Autonomic symptoms were less common in families with mutations than in those without (17% vs 56%; p = 0.007; Fisher’s exact test). The two sets of families did not differ significantly in the types of auditory symptoms. In families with mutations, the most common type of auditory symptom was simple, unformed sounds such as buzzing and ringing (often accompanied by other auditory symptom types).