SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

The role of mTOR signalling in neurogenesis, insights from tuberous sclerosis complex.

Understanding the development and function of the nervous system is one of the foremost aims of current biomedical research. The nervous system is generated during a relatively short period of intense neurogenesis that is orchestrated by a number of key molecular signalling pathways. Even subtle defects in the activity of these molecules can have serious repercussions resulting in neurological, neurodevelopmental and neurocognitive problems including epilepsy, intellectual disability and autism. Tuberous sclerosis complex (TSC) is a monogenic disease characterised by these problems and by the formation of benign tumours in multiple organs, including the brain. TSC is caused by mutations in the TSC1 or TSC2 gene leading to activation of the mechanistic target of rapamycin (mTOR) signalling pathway. A desire to understand the neurological manifestations of TSC has stimulated research into the role of the mTOR pathway in neurogenesis. In this review we describe TSC neurobiology and how the use of animal model systems has provided insights into the roles of mTOR signalling in neuronal differentiation and migration. Recent progress in this field has identified novel mTOR pathway components regulating neuronal differentiation. The roles of mTOR signalling and aberrant neurogenesis in epilepsy are also discussed. Continuing efforts to understand mTOR neurobiology will help to identify new therapeutic targets for TSC and other neurological diseases.

Epilepsy and neurodevelopmental disorders of language.

PURPOSE OF REVIEW: Neurodevelopmental disorders of language are increasingly appreciated as part of the phenotype of childhood-onset epilepsy. Here I review studies of the prevalence and prognosis of language impairment in new-onset childhood epilepsy and provide an update of new genetic discoveries that shed light on molecular pathways common to epilepsy and language impairment. RECENT FINDINGS: Three recent papers describe the cognitive and language phenotype of children with new-onset epilepsy and their discrepancy with controls over a 2-3-year period of follow-up. A new study examines the question of pleiotropic effects acting on both electro-encephalographic (EEG) abnormalities and speech sound disorder in rolandic epilepsy families - another study questions the rationale for EEG recording in patients with specific language impairment (SLI) - whereas two studies examine the effect of anti-epileptic drug treatment on speech and language. Two MRI studies indicate the neural basis for language impairment in epilepsy. Three new copy number variant hotspots are reported linking epilepsy and speech or language impairment; and the links between two known genes for developmental verbal dyspraxia, FOXP2 and SRPX2, begin to be elucidated. SUMMARY: Comprehensive neuropsychological and speech pathology assessment need to be factored into the initial evaluation and continued monitoring of children with new-onset epilepsy. EEG recording remains of unknown utility in children with SLI or speech sound disorder (SSD) who do not have epilepsy. Some anti-epileptic drugs may worsen SSD. As the molecular pathways for speech continue to be elucidated, future genetic imaging studies will show how genetic variants map onto to altered structural and connectivity patterns, which could be used as biomarkers for interventions.

Distinct phenotype of early childhood inflammatory bowel disease.

GOALS: Our goals were to answer 2 questions: (1) Is the presentation of early-onset inflammatory bowel disease (IBD) similar to typical adolescent-onset IBD? (2) Is there variability in familial aggregation in childhood IBD? BACKGROUND: The phenotype of IBD in children under 5 years of age (early-onset) is poorly defined. Clinical and genetic studies of IBD, however, generally assume the phenotype to be homogenous throughout childhood. STUDY: We analyzed data from 413 consecutive pediatric IBD outpatients attending our center between 1995 and 2000. Disease type, anatomic distribution, and family history were compared between children presenting before (early-onset) and after the age of five (5 to 15 y). RESULTS: Disease presentation was predominantly colonic in early-onset IBD, most patients presenting with ulcerative colitis (UC). Isolated colonic disease was most frequent in early-onset Crohn disease (colonic 76.5%, ileocolic 24%) compared with ileocolic disease (ileocolic 45.5%, colonic 26%, ileal 19.4%, proximal 6.3%) in the older age group. First-degree family history was highest in early-onset UC 26% versus 11% in the older UC group. CONCLUSIONS: We describe a distinct phenotype of early childhood onset IBD, with a strikingly high familial aggregation in UC and greater tendency to present with colonic disease. As more genetic heterogeneity is identified in IBD, careful definition of phenotype is required to identify further susceptibility genes. The early-onset form of UC presents an ideal group for further genetic analysis. These phenotype differences also suggest that treatment and outcome may vary in early-onset childhood IBD; prospective studies are required to confirm this.