LGI1 mutations in autosomal dominant partial epilepsy with auditory features

Abstract

Objective: S: Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations.

Methods: The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously.

Results: Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies.

Conclusions: LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.

Figure 1

(A) Positions of LGI1 mutations in published families with autosomal dominant partial epilepsy with auditory features, counted from the first nucleotide of the LGI1 mRNA sequence from GenBank accession no. NM_005097. In the reports of the European collaborative group,, the mutations were counted from the initiation codon; these have been renumbered from the first nucleotide. In addition, the 1320C>T mutation was corrected to 1420C>T (counting from the initiation codon; J. Perez-Tur, personal communication); this is shown as 1644C>T counting from the first nucleotide. (B) Positions of the amino acid substitutions on the multiple alignments of Lgi proteins in human, mouse, and rat.

Figure 2

Families with newly identified mutations in LGI1. M/+indicates mutation carrier; +/+ indicates no mutation. Symbol definitions: □ ○ = Unaffected; ▪^A •^A = Idiopathic partial epilepsy with auditory features; ⊡ ⋅ = Unaffected mutation carrier; ▥ ◍ = Idiopathic generalized epilepsy; ◨ ◑ = Idiopathic partial and generalized epilepsy.