Deb K. Pal

Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

Summary: Purpose:Conflicting evidence about impairment of attention systems and the absence of a working model of attention has contributed to lack of clarity about comorbidity of attention problems in rolandic epilepsy (RE). Impairments in distributed attention systems may inform a disease model for RE, as well as direct interventions.Methods:We used a systematic review of the relevant literature published in English from 1990 to 2006 to evaluate impairment in attention in RE. The Mirsky and Posner models of attention were evaluated for applicability, and studies were reviewed for design, instrumentation, and congruence with the Posner model of attention.Results:Fourteen studies were identified: seven using a cross‐sectional design (six active EEG abnormalities; one EEG remission) and seven longitudinal studies (abnormal EEGs and follow‐up until normalized). According to the Posner model of attention, 12 studies employed measures that tapped the alerting network, 11 studies the orienting network, and eight the executive network. Nearly all controlled studies demonstrated impairments in all tested attention networks. In contrast, uncontrolled studies uniformly did not demonstrate impairments. Follow‐up studies demonstrated complete or near complete resolution of attention impairments.Discussion:The weight of evidence, defined as the majority of studies evaluated, suggests that all three attention systems are impaired in children with active centrotemporal spikes (CTS), implying a more widespread functional cortical disturbance in RE than previously held. These impairments resolve upon EEG remission, suggesting a common pathological basis to the autosomal dominant CTS trait. Sources of methodological variation are discussed with recommendations for future investigations.

Very few genetic associations for idiopathic epilepsy have been replicated and this has tempered enthusiasm for the results of genetic studies in epilepsy. What are the reasons for lack of replication? While type 1 error, population stratification, and multiple testing have been discussed extensively, the importance of genetic heterogeneity has been relatively neglected. In the first part of this review, we explore the sources of genetic heterogeneity and their importance for epilepsy genetic studies. In the second part, we review alternatives to the simple law of replication, revisiting Bradford Hill's guidelines for evidence of causality. A coherence perspective is applied to three examples. We conclude that adopting the perspective of integrating coherent and consistent evidence from different experimental approaches is a more appropriate requirement for proceeding to functional studies.

Summary: Purpose: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population. The inheritance of CTS is presumed autosomal dominant but this is controversial. Previous studies have varied considerably in methodology, especially in the control of bias and confounding. We aimed to test the hypothesis of autosomal dominant inheritance of CTS in a well‐designed family segregation analysis study. Methods: Probands with rolandic epilepsy were collected through unambiguous single ascertainment. Siblings in the age range 4–16 years underwent sleep‐deprived EEG; observations from those who remained awake were omitted. CTS were rated as present or absent by two independent observers blinded to the study hypothesis and subject identities. We computed the segregation ratio of CTS, corrected for ascertainment. We tested the segregation ratio estimate for consistency with dominant and recessive modes of inheritance, and compared the observed sex ratio of those affected with CTS for consistency with sex linkage. Results: Thirty siblings from 23 families underwent EEG examination. Twenty‐three showed evidence of sleep in their EEG recordings. Eleven of 23 recordings demonstrated CTS, yielding a corrected segregation ratio of 0.48 (95% CI: 0.27–0.69). The male to female ratio of CTS affectedness was approximately equal. Conclusions: The segregation ratio of CTS in rolandic epilepsy families is consistent with a highly penetrant autosomal dominant inheritance, with equal sex ratio. Autosomal recessive and X‐linked inheritance are rejected. The CTS locus might act in combination with one or more loci to produce the phenotype of rolandic epilepsy.

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