The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures 1 . Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances 2,3 . We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes ( Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.Correspondence should be addressed to R.O. (e-mail: ro6@columbia.edu). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2008 December 22. Published in final edited form as:Nat Genet. 2002 March ; 30(3): 335-341. doi:10.1038/ng832. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn 1995 we mapped the ADPEAF locus to a 10-cM region on chromosome 10q24 in a single extended pedigree 2 . Linkage was subsequently reported to an overlapping interval in another large family, narrowing the minimal genetic region to approximately 3 cM, assuming the causative gene was the same 4 . Analysis of additional pedigrees confirmed the linkage but failed to narrow the region further 5-7 . To screen for disease-related mutations, we resequenced all coding-exon and bordering-intron sequences from positional candidate genes in the overlap interval in one affected individual from each of three ADPEAF pedigrees showing linkage to chromosome 10q24 (families 6610, A and B; Fig. 2) 2,7 . We then genotyped putative diseaserelated mutations in all available family members from the three linked pedigrees, all family members from two smaller families with ADPEAF (families C and D; Fig. 2) and 123 unrelated control individuals.Resequencing of LGI1 identified presumptive mutations in each of the five families with ADPEAF (Table 1 and Fig. 2). All tested affected individuals from the five families harbored a single copy of a putative disease mutation, as did all obligate carriers and individuals classified as 'unknown' who were found to carry the disease-linked haplotype (Fig. 2). Several unaffected individuals also carried the disease haplotype and presumptive mutation. Whether these individuals manifest subclinical signs of disease or have undergone recent changes in affection status is not yet known, but the results are consistent with our previous estimate of 71% disease-gene penetrance in family 6610 (ref.2).To di...

The syndrome known as nocturnal frontal lobe epilepsy is recognized worldwide and has been studied in a wide range of clinical and scientific settings (epilepsy, sleep medicine, neurosurgery, pediatric neurology, epidemiology, genetics). Though uncommon, it is of considerable interest to practicing neurologists because of complexity in differential diagnosis from more common, benign sleep disorders such as parasomnias, or other disorders like psychogenic nonepileptic seizures. Moreover, misdiagnosis can have substantial adverse consequences on patients' lives. At present, there is no consensus definition of this disorder and disagreement persists about its core electroclinical features and the spectrum of etiologies involved. To improve the definition of the disorder and establish diagnostic criteria with levels of certainty, a consensus conference using formal recommended methodology was held in Bologna in September 2014. It was recommended that the name be changed to sleep-related hypermotor epilepsy (SHE), reflecting evidence that the attacks are associated with sleep rather than time of day, the seizures may arise from extrafrontal sites, and the motor aspects of the seizures are characteristic. The etiology may be genetic or due to structural pathology, but in most cases remains unknown. Diagnostic criteria were developed with 3 levels of certainty: witnessed (possible) SHE, video-documented (clinical) SHE, and video-EEG-documented (confirmed) SHE. The main research gaps involve epidemiology, pathophysiology, treatment, and prognosis.

We investigated comorbidity of migraine and epilepsy by using information from structured telephone interviews with 1,948 adult probands with epilepsy and 1,411 of their parents and siblings. Epilepsy was defined as a lifetime history of two or more unprovoked seizures, and migraine as severe headaches with two or more of the following symptoms: unilateral pain, throbbing pain, visual aura, or nausea. Cumulative incidence of migraine to age 40 was 24% in probands with epilepsy, 23% in relatives with epilepsy, and 12% in relatives without epilepsy. Using Cox proportional hazards analysis to control for years at risk and gender, the rate ratio for migraine was 2.4 (95% CI, 2.02 to 2.89) among probands and 2.4 (1.58 to 3.79) among relatives with epilepsy in comparison with relatives without epilepsy. Migraine risk was highest in probands with epilepsy due to head trauma, but it was significantly higher in every subgroup of probands than in unaffected relatives when probands were stratified by seizure type, age at onset, etiology of epilepsy, and history of epilepsy in first-degree relatives. Age-specific incidence of migraine among probands was increased to a greater extent after onset of epilepsy than before, but it was also significantly increased more than 5 years before onset and 1 to 5 years before onset. These results indicate that migraine and epilepsy are strongly associated, independent of seizure type, etiology, age at onset, or family history of epilepsy.

The authors briefly review the current potential and limitations of molecular epidemiology. This approach uses biomarkers to measure the internal and bioeffective dose of toxicants, early biologic effects likely to be predictive of cancer, and variations in individual susceptibility. The most frequent application of biomarkers has been in assessment of exposure/dose and susceptibility due to genetic and nongenetic factors. More research is needed to establish the predictive significance of biomarkers in terms of disease risk. To illustrate that molecular epidemiology has potential in identifying etiologic factors in disease, this article presents data from a recent study of the developmental effects of fetal exposure to polycyclic aromatic hydrocarbons (PAH) via ambient pollution. The study was carried out in an industrialized area of Poland with relatively high levels of PAH pollution from coal burning. PAH-DNA adducts in leukocytes and plasma cotinine were measured in umbilical cord blood as dosimeters of transplacental PAH and cigarette smoke, respectively. The study subjects were 70 newborns from the industrialized city of Krakow and 90 newborns from Limanowa, a rural town with far greater use of coal for home heating. Newborns whose levels of PAH-DNA adducts were above the median (3.85/10[8] nucleotides) had a significantly decreased birth length, weight, and head circumference. Cotinine was significantly inversely associated with birth weight and length. Although preliminary, these results provide a new molecular link between PAH exposure and developmental effects, generating initial data and hypotheses for further study.