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 freqently observed in common developmental disorders (e.g. speech dyspraxia, attention deficit hyperactivity disorder (ADHD) and developmental coordination disorder (DCD)). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genomewide 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 (hELP4) in two independent datasets; the strongest evidence was with rs986527 in intron 9 of hELP4, providing a Likelihood Ratio of 629:1 (p=0.0002) in favor of an association. Resequencing of hELP4 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 hELP4. hELP4 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 hELP4 impairs brain-specific Elongator mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

SummaryPurpose-Associations between rolandic epilepsy (RE) with reading disability (RD) and speech sound disorder (SSD) have not been tested in a controlled study. We conducted a case-control study to determine whether (1) RD and SSD odds are higher in RE probands than controls and (2) an RE proband predicts a family member with RD or SSD, hence suggesting a shared genetic etiology for RE, RD, and SSD.Methods-Unmatched case-control study with 55 stringently defined RE cases, 150 controls in the same age range lacking a primary brain disorder diagnosis, and their siblings and parents. Odds ratios (OR) were calculated by multiple logistic regression, adjusted for sex and age, and for relatives, also adjusted for comorbidity of RD and SSD in the proband.Results-RD was strongly associated with RE after adjustment for sex and age: OR 5.78 (95% CI: 2. 86-11.69). An RE proband predicts RD in family members: OR 2.84 (95% CI: 1.38-5.84), but not independently of the RE proband's RD status: OR 1.30 (95% CI: 0.55-12.79). SSD was also comorbid with RE: adjusted OR 2.47 (95%CI: 1. 22-4.97). An RE proband predicts SSD in relatives, even after controlling for sex, age and proband SSD comorbidity: OR 4.44 (95% CI: 1.93-10.22).Conclusions-RE is strongly comorbid with RD and SSD. Both RD and SSD are likely to be genetically influenced and may contribute to the complex genetic etiology of the RE syndrome. Siblings of RE patients are at high risk of RD and SSD and both RE patients and their younger siblings should be screened early. KeywordsPhonologic disorder; Articulation disorder; Speech delay; Developmental dysphasia; Developmental dyslexia; Centrotemporal sharp waves; Complex genetic; Familial aggregation; Comorbidity; Cognitive deficit; Family study Address correspondence and reprint requests to Tara Clarke, Mailman School of Public Health, 722 West 168th Street, New York, NY 10032, U.S.A. E-mail: tc2226@columbia.edu. The study was conceived by DKP, LJS, BB and TC. DKP, BB, TC, PLM, JC, SF, GT, BRG, and ND designed the study. BB, TC, JC, SF, and DKP collected the data. TC, LJS, PLM and DKP analyzed the data. TC wrote the first draft. All authors contributed to redrafting. Conflict of Interest:The authors declare that they have no competing financial interests. Rolandic epilepsy (RE) is the most common epilepsy syndrome affecting children . It is a developmental epilepsy with a complex genetic inheritance that has yet to be elucidated (Bali et al., 2005). Centrotemporal spikes (CTS) are the electroencephalographic hallmark of RE. The association of RE or CTS with reading disability (RD) and language impairment has often been suggested (Staden et al., 1998;Vinayan et al., 2005), as has association with impairment in the development of speech motor control, also known as speech sound disorder (SSD) (Bladin, 1987;Doose, 1989;Lundberg et al., 2005;Park et al., 2005). Neither the association between RE and RD nor between RE and SSD has been rigorously tested in a case-control study, and thus association has not been unequivocally e...

SUMMARY

Purpose Children with Rolandic Epilepsy (RE) experience difficulties in reading, language and attention. Their siblings are at high risk of dyslexia but are not otherwise known to have neurocognitive deficits. We therefore sought evidence for a RE-associated neurocognitive endophenotype. Methods Thirteen probands (male:female 9:4) and 11 epilepsy-free siblings (male:female 5:6) completed a neurocognitive evaluation within the domains of reading, language and attention. Frequencies of impairment were compared, and mean standardized scores of children with RE and their siblings were each compared against population means. Key findings Frequency of impairment in each domain was comparable for siblings and probands: 9% of siblings and 31% of probands were reading impaired; 36% of siblings and 54% of probands were language impaired; 70% of siblings and 67% of probands had attention impairments. Comparison of differences between sample and population means revealed evidence of a similar pattern of language deficits in both groups, specifically for picture naming and attention to competing words. For measures of attention, both groups made significantly higher omission errors and were impaired in their ability to sustain attention. Significance Children with RE and unaffected siblings demonstrate neurocognitive impairments in the domains of language and attention that are likely to remain undetected with general clinical protocols. Neurocognitively impaired probands and siblings showed a remarkably similar profile of deficits in language and attention that could explain poor academic performance. Early evaluation and intervention may benefit these children academically.

SUMMARYPurpose: 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 under-went 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. KeywordsCentrotemporal; Rolandic; Focal sharp wave; Epilepsy; Genetic; Family; EEG; Segregation Address correspondence and reprint requests to Dr. Deb K. Pal, Mailman School of Public Health, Columbia University, 722 West 168th Street, Sixth floor, New York, NY 10032. E-mail: dkp28@columbia.edu. DECLARATIONS The authors declare that they have no competing financial interests. The study was conceived and designed by DKP. Data collection and processing was performed by BB, TC, LLK, and CIA. BB, LS, TC, DKP conducted the analysis. BB wrote the first draft. All authors took part in revising the manuscript for the final draft. Focal sharp waves (FSWs) on the surface electroencephalogram (EEG) are a common (1.6-3.5%) finding in early to mid-childhood (Eeg-Olofsson et al., 1971;Okubo et al., 1994). Although they can be found in asymptomatic children, they are particularly associated with idiopathic focal epilepsy syndromes and have been noted in other epileptic encephalopathies including Landau-Kleffner syndrome (Doose et al., 1996). FSWs are inconstant: they may disappear from one location or other in serial EEGs, and appear to migrate from posterior to anterior regions with maturation (Gibbs et al., 1954). They may occur only in non-rapid eye movement (NREM) sleep, not in a waking state or in rapid eye m...