The three new families with LGI1
mutations had clinical features consistent with those of previously reported families ( and Tables e-1 and e-2
). In Family I (), we identified a missense mutation in exon 8 (1477G>A counting from the initiation codon) resulting in the substitution of a conserved amino acid residue (Gly493Arg). This family contains seven individuals with idiopathic epilepsy, with an average age at onset of 16 years (range 11–35) (Supplementary Table e-1
). Six of these individuals were classified as having focal epilepsy and the remaining one was unclassifiable. All six of those with focal epilepsy had either ictal auditory symptoms (N=3), ictal receptive aphasia (N=2), or both (N=1) (Supplementary Table e-2
Family J () has a mutation in exon 6 (598delT) predicted to cause protein truncation. The family contains five individuals with idiopathic focal epilepsy (age at onset: average 15, range 8–35 years), four of whom had both auditory symptoms and receptive aphasia. One additional individual (II:2), who also carried the mutation, had an isolated unprovoked seizure associated with multiple sclerosis, and also reported auditory symptoms. One other individual (I:1) had an acute symptomatic seizure as an allergic reaction to penicillin, and another (I:2) was reported to have had epilepsy but could not be classified further.
In Family K (), we identified a mutation in exon 8 (1636-1637delCA) predicted to cause protein truncation. This family contains 11 individuals with idiopathic epilepsy (age at onset: average 18, range 11–38 years), but information was sufficient for further classification in only six of them, all of whom had focal epilepsy. Among these six individuals, two had auditory symptoms and one had both auditory symptoms and receptive aphasia. In addition, one individual (III:9) had an isolated unprovoked seizure, and another (III:18) had symptomatic epilepsy associated with a traumatic brain injury with loss of consciousness lasting more than 30 minutes. Although mutation status in III:18 is unknown because he declined to donate blood for the study, he reported both auditory symptoms and aphasia (Supplementary Table e-2
). Finally, four individuals (IV:13, IV:15, IV:16, and IV:21) were reported by other family members to have had seizures, but this information could not be confirmed because they declined to participate.
To analyze the risk of depression, we included eight previously reported families with LGI1
mutations in addition to the three new families reported here (Kalachikov et al., 2002
; Ottman et al., 2004
). In these 11 families, 121 individuals met inclusion criteria (46 AC, 15 UC, and 60 NC), of whom 94 (78%) participated (38 AC, 11 UC, and 45 NC), 10 (8%) refused, eight (7%) had died or were physically unable to participate, and nine (7%) could not be contacted after multiple attempts. After exclusion of the individuals who had died or were unable to participate, the participation rate was 83% (94/113), a rate that was not significantly associated with gender, education, age, ethnicity, or comparison group (AC, UC, or NC).
shows the demographic characteristics and depression outcomes of the participating subjects. Among the 45 participating NC, 12 (27%) were married-in relatives who were not genetically-related to LGI1 carriers. The three comparison groups did not differ in the distribution of gender or number of family members with epilepsy. Although NC were older than carriers (average age: AC 45 years, UC 44 years, NC 52 years, p=0.03 for carriers vs. noncarriers), age at interview was not associated with current depression. Therefore, none of these would confound the relationship between carrier status and depression in this sample.
Demographic and depression variables in affected carriers, unaffected carriers (UC), and non-carriers (NC)
Tests of hypotheses
Current depressive symptom severity scores were significantly higher in carriers than in NC, both in the analysis of the two carrier groups combined (p=0.01, ) and in the analysis restricted to AC (p=0.002, ). However, current symptom severity scores were not higher in UC than in NC (p=0.96). shows the distribution of depression symptoms by LGI1 carrier group and severity categories (e.g., mild, moderate, severe). Scores in the moderate to severe range (score ≥10) were found in 16% of AC, 7% of NC and none of UC.
One possible explanation for the increase of depressive symptoms in AC is the use of antiepileptic drugs (AEDs), since side-effects of some AEDs may mimic depressive symptoms. To evaluate this possibility, we repeated the analysis after excluding five items in the PHQ-9 that appeared most likely to be associated with AED use: sleeping difficulties, feeling tired or having little energy, appetite changes, concentration difficulties, and moving or speaking slowly or feeling restless. In this analysis the risk remained higher in all carriers vs. NC (p=0.015) and in AC vs. NC (p=0.007).
Since depressive symptoms were increased in AC but not in UC, we considered whether depressive symptom scores were associated with epilepsy severity, as measured by the lifetime history of secondarily generalized tonic-clonic seizures (SGTCs). Among AC whose diagnostic interviews were completed ≥5 years after epilepsy onset (N=33), those who had a history of ≥4 SGTCs (N=24) had higher depressive symptom scores than those with <4 SGTCs (N=9) (4.9 vs. 2.3, p=0.15). When this analysis was restricted to 22 individuals interviewed for depressive symptoms <5 years after the diagnostic interviews were done (so that the information on number of SGTCs was more current), the difference was larger (5.6 vs.1.2, p=0.05).