Daryl Efron

A novel pericentric inversion of chromosome 3 cosegregates with a developmental-behavioural phenotype

Current advances in genetic knowledge and analysis have facilitated the shift in emphasis from single gene disorders to complex traits such as cancer and atopic disorders where changes in more than one gene usually contribute to the disease phenotype. A challenging area of complex trait research is the determination of the genetic basis of behavioural phenotypes. Early studies in this area focused on classical linkage analysis in pedigrees which segregated the trait of interest and led to the identification of genes for intellectual disability, such as fraX(A).1,2 In this disorder, mutations in a single gene are sufficient to generate the disease phenotype. In contrast, with other neurodevelopmental disorders, results to date have been much more complex. With ADHD, for example, a large number of genes affecting neurotransmitter function, particularly dopamine, have been implicated. However, results from linkage or association studies have not been reliably replicated. Even the most promising gene candidates are implicated in only a small percentage of ADHD cases.3,4 Identification of the genes involved is a challenging task. Firstly, accurate phenotype definition is crucial to successful outcomes in these pooled studies. Secondly, neurodevelopmental disorders such as ADHD are multifactorial, with a number of different genes, likely to be of varying effect and interacting with environmental influences, presumably contributing to the development of the observed phenotypes. We have identified an extended family where the proband, a child with moderate intellectual disability as well as severe conduct disturbance, was found to have a pericentric inversion of chromosome 3. The inversion was found to cosegregate with developmental-behavioural problems in other members of the family. In order to describe the phenotype, a developmental-behavioural paediatrician undertook a standardised clinical evaluation of eight of the juvenile members of the extended family. The findings are presented in this paper. ### Participants The parents/guardians …

Complementary and alternative medicine use in children with attention deficit hyperactivity disorder

Objectives:  The use of complementary and alternative medicines (CAM) is increasing in the general population. Attention deficit hyperactivity disorder (ADHD) is a chronic condition that has a major impact on childrens functioning and has no cure, therefore many families may try CAM at some stage. We aimed to determine (i) the lifetime incidence of CAM use in a clinical sample of children with ADHD; (ii) parents’ perceptions of the effectiveness of CAM for ADHD; and (iii) the proportion who informed their paediatrician.

Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype

Background: Attention deficit hyperactivity disorder (ADHD) is a complex condition with high heritability. However, both biochemical investigations and association and linkage studies have failed to define fully the underlying genetic factors associated with ADHD. We have identified a family co-segregating an early onset behavioural/developmental condition, with features of ADHD and intellectual disability, with a pericentric inversion of chromosome 3, 46N inv(3)(p14:q21). Methods: We hypothesised that the inversion breakpoints affect a gene or genes that cause the observed phenotype. Large genomic clones (P1 derived/yeast/bacterial artificial chromosomes) were assembled into contigs across the two inversion breakpoints using molecular and bioinformatic technologies. Restriction fragments crossing the junctions were identified by Southern analysis and these fragments were amplified using inverse PCR. Results: The amplification products were subsequently sequenced to reveal that the breakpoints lay within an intron of the dedicator of cytokinesis 3 (DOCK3) gene at the p arm breakpoint, and an intron of a novel member of the solute carrier family 9 (sodium/hydrogen exchanger) isoform 9 (SLC9A9) at the q arm. Both genes are expressed in the brain, but neither of the genes has previously been implicated in developmental or behavioural disorders. Conclusion: These two disrupted genes are candidates for involvement in the pathway leading to the neuropsychological condition in this family.

Impact of a behavioural sleep intervention on symptoms and sleep in children with attention deficit hyperactivity disorder, and parental mental health: randomised controlled trial

Objective To examine whether behavioural strategies designed to improve children’s sleep problems could also improve the symptoms, behaviour, daily functioning, and working memory of children with attention deficit hyperactivity disorder (ADHD) and the mental health of their parents. Design Randomised controlled trial. Setting 21 general paediatric practices in Victoria, Australia. Participants 244 children aged 5-12 years with ADHD attending the practices between 2010 and 2012. Intervention Sleep hygiene practices and standardised behavioural strategies delivered by trained psychologists or trainee paediatricians during two fortnightly consultations and a follow-up telephone call. Children in the control group received usual clinical care. Main outcome measures At three and six months after randomisation: severity of ADHD symptoms (parent and teacher ADHD rating scale IV—primary outcome), sleep problems (parent reported severity, children’s sleep habits questionnaire, actigraphy), behaviour (strengths and difficulties questionnaire), quality of life (pediatric quality of life inventory 4.0), daily functioning (daily parent rating of evening and morning behavior), working memory (working memory test battery for children, six months only), and parent mental health (depression anxiety stress scales). Results Intervention compared with control families reported a greater decrease in ADHD symptoms at three and six months (adjusted mean difference for change in symptom severity −2.9, 95% confidence interval −5.5 to −0.3, P=0.03, effect size −0.3, and −3.7, −6.1 to −1.2, P=0.004, effect size −0.4, respectively). Compared with control children, intervention children had fewer moderate-severe sleep problems at three months (56% v 30%; adjusted odds ratio 0.30, 95% confidence interval 0.16 to 0.59; P<0.001) and six months (46% v 34%; 0.58, 0.32 to 1.0; P=0.07). At three months this equated to a reduction in absolute risk of 25.7% (95% confidence interval 14.1% to 37.3%) and an estimated number needed to treat of 3.9. At six months the number needed to treat was 7.8. Approximately a half to one third of the beneficial effect of the intervention on ADHD symptoms was mediated through improved sleep, at three and six months, respectively. Intervention families reported greater improvements in all other child and family outcomes except parental mental health. Teachers reported improved behaviour of the children at three and six months. Working memory (backwards digit recall) was higher in the intervention children compared with control children at six months. Daily sleep duration measured by actigraphy tended to be higher in the intervention children at three months (mean difference 10.9 minutes, 95% confidence interval −19.0 to 40.8 minutes, effect size 0.2) and six months (9.9 minutes, −16.3 to 36.1 minutes, effect size 0.3); however, this measure was only completed by a subset of children (n=54 at three months and n=37 at six months). Conclusions A brief behavioural sleep intervention modestly improves the severity of ADHD symptoms in a community sample of children with ADHD, most of whom were taking stimulant medications. The intervention also improved the children’s sleep, behaviour, quality of life, and functioning, with most benefits sustained to six months post-intervention. The intervention may be suitable for use in primary and secondary care. Trial registration Current Controlled Trials ISRCTN68819261.

Relationship between symptoms of attention-deficit/hyperactivity disorder and family functioning: a community-based study

This study examined the relationship between family functioning and attention-deficit/hyperactivity disorder (ADHD) symptoms in an Australian community-based sample. Children were screened for ADHD in their second year of formal schooling. Two hundred and two (202) primary caregivers completed validated measures of family quality of life (QoL), parent mental health, parenting styles and parental relationship quality. Compared with controls, parents of children screening positive for ADHD reported poorer family QoL in the domains of emotional impact (mean difference [MD] −20.1; 95% CI −38.2 to −1.9, p = 0.03) and impact on family activities (MD −17.2; 95% CI −27.9 to −6.5, p = 0.002), less parental warmth (MD −3.4; 95% CI −6.0 to −0.9, p = 0.01) and higher parental depression (MD 6.8; 95% CI 1.8 to 11.7, p = 0.009) and anxiety (MD 6.2; 95% CI 1.7 to 10.6, p = 0.008) after adjusting for socio-demographic characteristics and child conduct symptoms. Parents of children screening positive for ADHD reported higher stress (MD 4.5; 95% CI 1.2 to 7.1, p = 0.007) and more inconsistent (MD 3.0; 95% CI 1.2 to 4.8, p = 0.002) and hostile (MD = 2.2; 95% CI 1.0 to 3.4, p = 0.001) parenting after adjusting for socio-demographic factors only. No difference in parental relationship quality and parental inductive reasoning was identified. Conclusion: These findings suggest a strong association between poor family functioning and ADHD symptoms and carry implications for comprehensive ADHD management and the importance of seeing the child within the family context.

Child and parent perceptions of stimulant medication treatment in attention deficit hyperactivity disorder

To evaluate child and parent perceptions of treatment with stimulant medication in a sample of children with attention deficit hyperactivity disorder (ADHD).

Managing sleep problems in school aged children with ADHD: A pilot randomised controlled trial

OBJECTIVE To evaluate the feasibility and helpfulness of a behavioral sleep program for children with ADHD, and explore the impact of different program dosages on child and family outcomes. METHODS Randomised trial comparing a brief (1 session, n=13) and extended (2-3 sessions, n=14) sleep program in children with ADHD (aged 5-14 years) and at least one behavioral sleep disorder (American Academy of Sleep Medicine Criteria). Outcomes included helpfulness and use of interventions, child sleep (parent-reported sleep problem; Child Sleep Habits Questionnaire), ADHD symptoms (ADHD IV Rating Scale), daily functioning (Daily Parent Rating of Evening and Morning Behavior), quality of life (Pediatric Quality of Life Inventory), and caregiver mental health (Depression Anxiety Stress Scales). RESULTS Twenty-seven families (63% of those eligible) took part. Most parents would recommend the program to others (95%) and found the strategies helpful. Five months post-randomisation, 67% of parents in both groups reported that their childs sleep problems had resolved. Child quality of life, daily functioning, and parental anxiety also improved in the extended group only (Cohens d: 0.39, 0.47 and 0.50, respectively). There was minimal change in ADHD symptom scores from baseline to 5 months in either group. CONCLUSIONS A behavioral sleep intervention in children with ADHD is feasible to deliver and improves child sleep by parent report. The extended program resulted in greater improvements in child and caregiver outcomes.

Anxiety in Children With Attention-Deficit/Hyperactivity Disorder

OBJECTIVES: Although anxiety is common in children with attention-deficit/hyperactivity disorder (ADHD), it is unclear how anxiety influences the lives of these children. This study examined the association between anxiety comorbidities and functioning by comparing children with ADHD and no, 1, or ≥2 anxiety comorbidities. Differential associations were examined by current ADHD presentation (subtype). METHODS: Children with diagnostically confirmed ADHD (N = 392; 5–13 years) were recruited via 21 pediatrician practices across Victoria, Australia. Anxiety was assessed by using the Anxiety Disorders Interview Schedule for Children—IV. Functional measures included parent-reported: quality of life (QoL; Pediatric Quality of Life Inventory 4.0), behavior and peer problems (Strengths and Difficulties Questionnaire), daily functioning (Daily Parent Rating of Evening and Morning Behavior), and school attendance. Teacher-reported behavior and peer problems (Strengths and Difficulties Questionnaire) were also examined. Linear and logistic regression controlled for ADHD severity, medication use, comorbidities, and demographic factors. RESULTS: Children with ≥2 anxiety comorbidities (n = 143; 39%) had poorer QoL (effect size: –0.8) and more difficulties with behavior (effect size: 0.4) and daily functioning (effect size: 0.3) than children without anxiety (n = 132; 36%). Poorer functioning was not observed for children with 1 anxiety comorbidity (n = 95; 26%). Two or more anxiety comorbidities were associated with poorer functioning for children with both ADHD-Inattentive and ADHD-Combined presentation. CONCLUSIONS: Children with ADHD demonstrate poorer QoL, daily functioning and behavior when ≥2 anxiety comorbidities are present. Future research should examine whether treating anxiety in children with ADHD improves functional outcomes.

The Children's Attention Project: a community-based longitudinal study of children with ADHD and non-ADHD controls

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) affects approximately 5% of children worldwide and results in significant impairments in daily functioning. Few community-ascertained samples of children with ADHD have been studied prospectively to identify factors associated with differential outcomes. The Children’s Attention Project is the first such study in Australia, examining the mental health, social, academic and quality of life outcomes for children with diagnostically-confirmed ADHD compared to non-ADHD controls. The study aims to map the course of ADHD symptoms over time and to identify risk and protective factors associated with differential outcomes.Methods/designThe sample for this prospective longitudinal study is being recruited across 43 socio-economically diverse primary schools across Melbourne, Australia. All children in Grade 1, the second year of formal schooling (6–8 years), are screened for ADHD symptoms using independent parent and teacher reports on the Conners’ 3 ADHD index (~N = 5260). Children screening positive for ADHD by both parent and teacher report, and a matched sample (gender, school) screening negative, are invited to participate in the longitudinal study. At baseline this involves parent completion of the NIMH Diagnostic Interview Schedule for Children IV (DISC-IV) to confirm likely ADHD diagnostic status and identify other mental health difficulties, direct child assessments (cognitive, academic, language and executive functioning; height and weight) and questionnaires for parents and teachers assessing outcomes, as well as a broad range of risk and protective factors (child, parent/family, teacher/school, and socio-economic factors). Families will be initially followed up for 3 years.DiscussionThis study is the first Australian longitudinal study of children with ADHD and one of the first community-based longitudinal studies of diagnostically confirmed children with ADHD. The study’s examination of a broad range of risk and protective factors and ADHD-related outcomes has the potential to inform novel strategies for intervention and prevention.

Language Problems in Children With ADHD: A Community-Based Study

OBJECTIVES: To examine the prevalence of language problems in children with attention-deficit/hyperactivity disorder (ADHD) versus non-ADHD controls, and the impact of language problems on the social and academic functioning of children with ADHD. METHODS: Children (6 to 8 years) with ADHD (n = 179) and controls (n = 212) were recruited through 43 Melbourne schools. ADHD was assessed by using the Conners 3 ADHD Index and the Diagnostic Interview Schedule for Children IV. Oral language was assessed by using the Clinical Evaluation of Language Fundamentals, fourth edition, screener. Academic functioning was measured via direct assessment (Wide Range Achievement Test 4) and teacher report (Social Skills Improvement System). Social functioning was measured via parent and teacher report (Strengths and Difficulties Questionnaire; Social Skills Improvement System). Logistic and linear regression models were adjusted for sociodemographic factors and child comorbidities. RESULTS: Children with ADHD had a higher prevalence of language problems than controls after adjustment for sociodemographic factors and comorbidities (odds ratio, 2.8; 95% confidence interval [CI], 1.5 to 5.1). Compared with children with ADHD alone, those with language problems had poorer word reading (mean difference [MD], −11.6; 95% CI, −16.4 to −6.9; effect size, −0.7), math computation (MD, −11.4; 95% CI, −15.0 to −7.7; effect size, −0.8), and academic competence (MD, −10.1; 95% CI, −14.0 to −6.1; effect size, −0.7). Language problems were not associated with poorer social functioning. CONCLUSIONS: Children with ADHD had a higher prevalence of language problems than controls, and language problems in children with ADHD contributed to markedly poorer academic functioning.