Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses.

BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. OBJECTIVE: To identify rare, causal CNV in patients with RE. METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

A community-led, harm-reduction approach to chemsex: case study from Australia's largest gay city.

Rates of drug use remain substantially higher among gay and bisexual men (GBM) and people living with HIV (PLHIV) in Sydney, New South Wales, Australia. The use of drugs to enhance sexual pleasure within cultures of Party and Play creates opportunities to discuss sexual health, mental health, consent and wellbeing. Community organisations with a history of HIV prevention, care, treatment are well-placed to respond. ACON's (formerly the AIDS Council of New South Wales) multi-dimensional response to 'chemsex' includes: direct client services support for individuals seeking to manage or reduce their use; health promotion activities that support peer education; partnerships with research institutions to better understand cultures of chemsex; and policy submissions that call for drug use to be approached as a health, rather than a criminal, issue. The approach speaks the language of Party and Play subcultures; employs culturally relevant terminology and imagery; uses content designed, created and delivered by peers; and operates within a pleasure-positive, harm-reduction and community-led framework. These interventions have led to increased service uptake, strong community engagement, robust research partnerships and the recognition of GBM as a priority population in relevant strategies.

Methamphetamine treatment outcomes among gay men attending a LGBTI-specific treatment service in Sydney, Australia.

Gay and bisexual men (GBM) report higher rates of methamphetamine use compared to heterosexual men, and thus have a heightened risk of developing problems from their use. We examined treatment outcomes among GBM clients receiving outpatient counseling at a lesbian, gay, bisexual, transgender and intersex (LGBTI)-specific, harm reduction treatment service in Sydney, Australia. GBM receiving treatment for methamphetamine use from ACON's Substance Support Service between 2012-15 (n = 101) were interviewed at treatment commencement, and after 4 sessions (n = 60; follow-up 1) and 8 sessions (n = 32; follow-up 2). At each interview, clients completed measures of methamphetamine use and dependence, other substance use, injecting risk practices, psychological distress and quality of life. The median age of participants was 41 years and 56.4% identified as HIV-positive. Participants attended a median of 5 sessions and attended treatment for a median of 112 days. There was a significant reduction in the median days of methamphetamine use in the previous 4 weeks between baseline (4 days), follow-up 1 (2 days) and follow-up 2 (2 days; p = .001). There was a significant reduction in the proportion of participants reporting methamphetamine dependence between baseline (92.1%), follow-up 1 (78.3%) and follow-up 2 (71.9%, p < .001). There were also significant reductions in psychological distress (p < .001), and significant improvements in quality of life (p < .001). Clients showed reductions in methamphetamine use and improved psychosocial functioning over time, demonstrating the potential effectiveness of a LGBTI-specific treatment service.

Kenny Caffey syndrome with severe respiratory and gastrointestinal involvement: expanding the clinical phenotype.

Kenny Caffey syndrome (KCS) is a rare syndrome reported almost exclusively in Middle Eastern populations. It is characterized by severe growth retardation-short stature, dysmorphic features, episodic hypocalcaemia, hypoparathyroidism, seizures, and medullary stenosis of long bones with thickened cortices. We report a 10-year-old boy with KCS with an unusually severe respiratory and gastrointestinal system involvement-features not previously described in the literature. He had severe psychomotor retardation and regressed developmentally from walking unaided to sitting with support. MRI brain showed bilateral hippocampal sclerosis, marked supra-tentorial volume loss and numerous calcifications. A 12 bp deletion of exon 2 of tubulin-specific chaperone E (TBCE) gene was identified and the diagnosis of KCS was confirmed. Hypercarbia following a sleep study warranted nocturnal continuous positive airway pressure (CPAP) when aged 6. When boy aged 8, persistent hypercarbia with increasing oxygen requirement and increased frequency and severity of lower respiratory tract infections led to progressive respiratory failure. He became fully dependent on non-invasive ventilation and by 9 years he had a tracheotomy and was established on long-term ventilation. He developed retching, vomiting and diarrhea. Chest CT showed changes consistent with chronic aspiration, but no interstitial pulmonary fibrosis. He died aged 10 from respiratory complications.

Psychopathology in children before and after surgery for extratemporal lobe epilepsy.

AIM: To establish the rates and types of psychiatric disorder in children before and after surgery for extratemporal epilepsy. Relationships between psychiatric morbidity and demographic/clinical variables were examined. METHOD: A retrospective case note review of 71 children undergoing extratemporal focal resection for drug resistant epilepsy in a specialist epilepsy surgery programme between 1997 and 2008. Psychiatric diagnoses were derived from pre- and postoperative assessments according to DSM-IV criteria. RESULTS: Seventy-one children (38 males, 33 females) were eligible for this study. Mean age (SD) at surgery was 9 (5) years. Frontal resections were performed in 73% of the children, parietal in 17%, and occipital in 10%. Mental health problems were present in 37 of 71 (52%) children pre- and/or postoperatively. A similar proportion of children had psychiatric diagnoses pre- and postoperatively: 31 of 71 (44%) and 32 of 71 (45%) respectively. INTERPRETATION: Psychopathology is common in children with extratemporal epilepsy. In this sample, the impact of surgery on psychiatric symptoms was not predictable: some children were unchanged, others improved, and others acquired new psychiatric diagnoses postoperatively. Given the high rates of psychiatric disorder in this group of patients, detection and treatment of mental health needs may be important.

The effects of epilepsy surgery on emotions, behavior, and psychosocial impairment in children and adolescents with drug-resistant epilepsy: a prospective study.

This study examines change in behavioral disorders and psychosocial impairment following epilepsy surgery in 13 children and adolescents with drug-resistant epilepsy. Subjects were screened for emotional and behavioral symptoms four times pre- and postoperatively using the Strengths and Difficulties Questionnaire, and were followed for up to 8.5 years after surgery. The results of this study demonstrated significantly lower scores in emotional and behavioral symptoms after surgery. A downward trend in total difficulty scores for the group was demonstrated over the three postoperative time points. The mean Impact Score showed an initial decrease at the first follow-up time point after surgery with no further improvement subsequently. Our findings suggest that emotional and behavioral symptoms in children undergoing epilepsy surgery may improve following surgery, with reduction in their functional impact, and that these improvements are maintained in the long term.