Anne O’Hare

Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are >/=1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions).

Associations of HLA alleles with specific language impairment

BackgroundHuman leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals affected by language impairment.MethodsWe perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types.ResultsQuantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD).ConclusionThese preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders.

Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

Drooling Reduction Intervention randomised trial (DRI): comparing the efficacy and acceptability of hyoscine patches and glycopyrronium liquid on drooling in children with neurodisability

Objective Investigate whether hyoscine patch or glycopyrronium liquid is more effective and acceptable to treat drooling in children with neurodisability. Design Multicentre, single-blind, randomised controlled trial. Setting Recruitment through neurodisability teams; treatment by parents. Participants Ninety children with neurodisability who had never received medication for drooling (55 boys, 35 girls; median age 4 years). Exclusion criteria: medication contraindicated; in a trial that could affect drooling or management. Intervention Children were randomised to receive a hyoscine skin patch or glycopyrronium liquid. Dose was increased over 4 weeks to achieve optimum symptom control with minimal side-effects; steady dose then continued to 12 weeks. Primary and secondary outcomes Primary outcome: Drooling Impact Scale (DIS) score at week-4. Secondary outcomes: change in DIS scores over 12 weeks, Drooling Severity and Frequency Scale and Treatment Satisfaction Questionnaire for Medication; adverse events; children’s perception about treatment. Results Both medications yielded clinically and statistically significant reductions in mean DIS at week-4 (25.0 (SD 22.2) for hyoscine and 26.6 (SD 16) for glycopyrronium). There was no significant difference in change in DIS scores between treatment groups. By week-12, 26/47 (55%) children starting treatment were receiving hyoscine compared with 31/38 (82%) on glycopyrronium. There was a 42% increased chance of being on treatment at week-12 for children randomised to glycopyrronium relative to hyoscine (1.42, 95% CI 1.04 to 1.95). Conclusions Hyoscine and glycopyrronium are clinically effective in treating drooling in children with neurodisability. Hyoscine produced more problematic side effects leading to a greater chance of treatment cessation. Trial registration numbers ISRCTN75287237; EUDRACT: 2013-000863-94; Medicines and Healthcare Products Regulatory Agency: 17136/0264/001-0003

Correction: Exome Sequencing in an Admixed Isolated Population IndicatesNFXL1 Variants Confer a Risk for Specific Language Impairment (PLoS Genet, 11(6), (2015))

Pía Villanueva, Ron Nudel, Alexander Hoischen, María Angélica Fernández, Nuala H. Simpson, Christian Gilissen, Rose H. Reader, Lillian Jara, María Magdalena Echeverry, Clyde Francks, Gillian Baird, Gina Conti-Ramsden, Anne O’Hare, Patrick F. Bolton, Elizabeth R. Hennessy, SLI Consortium, Hernán Palomino, Luis Carvajal-Carmona, Joris A. Veltman, Jean-Baptiste Cazier, Zulema De Barbieri, Simon E. Fisher, Dianne F. Newbury

PC.21 Eye-tracking methodology for the assessment of social function in infancy

Background Eye-tracking has provided new insights into the development of infant cognition and is currently being explored as a potential way to identify early biomarkers of later difficulty. We aimed to assess social cognitive ability across levels of stimulus complexity in infancy. Methods Participants were 32 typically-developing (TD) infants aged 6–12 months, recruited with ethical approval (from University of Edinburgh). We measured 3 aspects of social cognition using stimuli of increasing complexity: attention distributed across faces; attention to faces in a grid-like array; and attention to faces embedded in naturalistic scenes. Results In each task we found evidence of longer fixation duration on socially informative content compared with other regions (i.e. eyes versus mouths, faces versus other objects; Wilcoxon signed-ranks all p Conclusions Each task showed evidence of infant interest in social information. Evidence from first fixation data reveals that these social preferences are mediated by stimulus complexity. Caution must therefore be taken when examining early biomarkers in social cognition because stimulus complexity may influence infants’ capacity to demonstrate social attentional preferences. These findings have implications for development of eye-tracking tasks as biomarkers of later difficulty.

Grappling with the grey evidence

A number of recent editorials and commentaries have rehearsed the challenges of researching underlying mechanisms and assessing efficacy of treatments in neurodevelopmental clinical practice. As a result of the many barriers to establishing an evidence base, promising approaches may languish in the limbo of ‘grey evidence’ and with research budgets tightening this may become more so. Many interventions in this field are not only complex but have been adopted into everyday management that makes them expensive and ethically fraught to disentangle. Their adoption may take place in other settings such as education and only impinge on medicine when they are presented as clinical investigations and interventions with attendant requests for health services funding such as personal frequency module systems for ‘auditory processing disorders’. However, sometimes support for a grey evidence issue develops at such momentum and is accompanied by such strength of feeling that clinicians face significant challenges when grappling with the consequences for their patients and their families. The literature over the last 10 years on the measles, mumps, and rubella (MMR) and autism debacle encapsulates these and charts how clinicians not only vacillate over wherein lies the truth, but avoid public debate when this is potentially stifled by the strength of feeling engendered towards supporters of the vaccine. In addition, work such as that which highlighted the absence of measles antigen in the peripheral leucocytes of children with autism immunized with MMR might only be published in the peer-reviewed specialist journals and therefore not readily enter the public domain. In the eyes of the critics, this was then considered not readily accessible to families deliberating on whether or not to immunize their children. A recent survey of 102 children aged over 9 years affected with autism spectrum disorder in the city of Edinburgh revealed that whilst they had a 97% uptake of their initial MMR vaccination, only 69.2% had received their booster. We do not know the implications yet of inadequate coverage with MMR. Most paediatric neurologists have never cared for a child with measles encephalitis or subacute sclerosing panencephalitis or experienced the death of the one to two per thousand children dying from measles before the advent of protective immunization. Congenital rubella is a rarity in present-day practice. However, all clinicians working with children from universal to specialist services have been exhorted to take responsibility for discussing and encouraging MMR immunization uptake. Whilst MMR is perhaps one of the most dramatic examples of grey evidence escalating beyond control there are lessons to be learnt. It is salutary to remember that almost all parents acting on the grey evidence that they read about in the media and the internet do so in good faith. Whilst time-consuming to discuss in the busy clinic, it is reasonable that they should expect their clinicians to give them an informed opinion on the validity of the scientific evidence for investigations and interventions that might be relevant to their child’s care. This is particularly challenging for the clinician working in neurodevelopmental medicine as it arises so often. That is why it is particularly helpful to see Developmental Medicine and Child Neurology publish regular systematic reviews and meta-analyses. Another approach is that adopted by the SIGN 98 guidelines on autism spectrum disorders in which all the search questions and terms were appended so that clinicians and other readers could consult them to see whether a putative aetiology or intervention was considered but did not appear in the guideline because of insufficient evidence. This could encompass all the grey evidenced material at the point of drawing up the guidelines, offer transparency to the guideline production and facilitate re-examining the evidence at a future date when further evidence may have emerged, all of which will hopefully provide a useful handle when ‘grappling with the grey evidence’.

Age of onset and outcome in Landau-Kleffner syndrome (1985)

In 1957 Landau and Kleffner described an unusual childhood disorder which they termed ‘syndrome of acquired aphasia with convulsive disorder’, in which language regresses after a period of normal development and seizures develop. Children with this disorder typically have severe receptive language difficulties and often are at first thought to be deaf. However, pure-tone audiometry shows normal peripheral hearing, and usually there are no abnormal neurological signs. Some children do not have seizures but do have an abnormal EEG, typically with spike activity in one or both temporal lobes. Since the original description by Landau and Kleffner several further cases have been reported ...