Pleiotropic effects of the 11p13 locus on developmental verbal dyspraxia and EEG centrotemporal sharp waves

Abstract

We recently showed genomewide linkage of centrotemporal sharp waves (CTS) in classic Rolandic epilepsy (RE) families to chromosome 11p13, and fine-mapped this locus to variants in the ELP4 gene. Speech sound disorder (SSD) is a common comorbidity in RE subjects, of unknown etiology, which co-aggregates in family members in a manner that could hypothetically be explained by shared underlying genetic risk with CTS. Furthermore, the neural mechanism of SSD is unknown, although individuals with rare, Mendelian forms of RE are described with severe verbal and oromotor apraxia. We therefore first performed genomewide linkage analysis for SSD, operationally defined as clinical history consistent with ICD-10 speech articulation disorder, in 38 families singly ascertained through a proband with RE. We tested the hypothesis of shared genetic risk with CTS at the 11p13 locus. In the second part of the study we used computerized acoustic analysis of recorded speech to test the hypothesis of dyspraxia as a mechanism for SSD in a smaller subset of RE probands and relatives. In two-point and multipoint LOD score analysis, we found that evidence for linkage to the 11p13 locus increased substantially when the phenotype was broadened from CTS to CTS/SSD. In multipoint analysis, the LOD score rose by 3.2 to HLOD 7.54 at D11S914 for CTS/SSD, the same marker at which multipoint linkage maximized for CTS alone. Non-parametric, affected-only methods in a sub-set of the data provide further confirmatory evidence for pleiotropy. In acoustic analysis there were voice-onset time abnormalities in 10/18 RE probands, 8/16 siblings and 5/15 parents, providing evidence of breakdown in the spatial/temporal properties of speech articulation consistent with a dyspraxic mechanism. The results from genetic and physiological studies suggest a pleiotropic role for the 11p13 locus in the development of both SSD and CTS, and also indicate a dyspraxic mechanism for the SSD linked to 11p13. Taken together, these data strongly support a neurodevelopmental origin for classic RE.

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

“…We hypothesized that as has been found for a number of complex neurodevelopmental disorders (eg, autism), 6,34 intellectual disability, 35,36 and schizophrenia, 37 rare CNVs in genomic DNA may be associated with increased risk for CAS. Consistent with this hypothesis, array comparative genomic hybridization analyses identified 16p11.2 deletions in two patients with CAS in the same approximate region as reported for other patients with this syndrome.…”

“…Emerging genomic studies have begun to report that speech impairment consistent with CAS is associated with several genes and loci for epilepsy, including FOXP1, 34,38 FOXG1, 39 ELP4, 36 and RAI1. 40 CAS and epilepsy may have common neurogenetic substrates associated with 16p11.2 deletions or they may co-segregate as separate traits.…”

Neurodevelopmental disorders in children with epilepsy

“…При обследовании 36 пациентов с роландической эпилепсией U. Stephani и G. Carlsson [39] не обнаружили у них корреляции между выраженностью изменений на ЭЭГ и показателями IQ, однако у каждого пациента от-мечалось хотя бы одно из нарушений: дискалькулия, от-ставание в развитии речи, СДВГ, расстройство координа-ции, зрительно-пространственные нарушения. Генетиче-ские исследования в 38 семьях, в которых у пробанда была подтверждена роландическая эпилепсия, показали плейо-тропный эффект локуса 11p13, который детерминирует и речевые нарушения, и ЭЭГ-паттерн заболевания [40].…”

A Review of the Not So Benign- Benign Childhood Epilepsy with Centrotemporal Spikes

“…In this study evidence for linkage to chromosome 15q14 was obtained with a maximal LOD score of 3.56 under an autosomal recessive mode of inheritance but no mutation was identified. Similarly in other recent studies despite promising logarithm of odds (LOD) scores, no genetic mutations have been identified [31,32]. Recent studies in some families has shown an overlap between epileptic encephalopathy with CSWS, atypical benign partial epilepsy, and BECTS which has led to the concept of a spectrum of epilepsy-aphasia disorders with BECTS at the lower end, the broad less well-defined group of epilepsy-aphasia children in the middle, and classical LKS and the syndrome of CSWS at the extreme end [30,[33][34][35].…”