Valsamma Eapen

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

The international prevalence, epidemiology, and clinical phenomenology of Tourette syndrome: A cross-cultural perspective

The overall international prevalence of Tourette syndrome (TS) is 1% in the majority of cultures of the world. Both TS and tics are certainly more obvious and may be more common in younger people. Moreover, TS is seen less frequently in some cultures. However, in all cultures where it has been reported, the phenomenology is similar, highlighting the biological underpinnings of the disorder. This article reviews the international prevalence, epidemiology, and clinical phenomenology of TS, from a cross-cultural perspective.

Clinical features and associated psychopathology in a Tourette syndrome cohort

Objective – This study explored in detail the association between tic symptomatology, related clinical variables, and psychopathology in 91 consecutive adult TS subjects from a UK clinic.

Obsessive compulsive symptoms in Gilles de la Tourette syndrome and obsessive compulsive disorder

The distribution of obsessive compulsive symptoms was compared in 16 individuals with primary obsessive compulsive disorder (OCD) and 16 individuals with Gilles de la Tourette syndrome (GTS) and associated obsessive compulsive behaviors (OCB). The two groups showed significant differences in the distribution of OC symptomatology. Furthermore, those OCD probands who shared a similar symptom profile with GTS individuals all had a positive family history of OCD. All of the other OCD probands were isolated cases. Implications of this finding on the etiology and pathogenesis of the two disorders are discussed.

International comparisons of behavioral and emotional problems in preschool children: Parents' reports from 24 societies

International comparisons were conducted of preschool childrens behavioral and emotional problems as reported on the Child Behavior Checklist for Ages 1½–5 by parents in 24 societies (N = 19,850). Item ratings were aggregated into scores on syndromes; Diagnostic and Statistical Manual of Mental Disorders–oriented scales; a Stress Problems scale; and Internalizing, Externalizing, and Total Problems scales. Effect sizes for scale score differences among the 24 societies ranged from small to medium (3–12%). Although societies differed greatly in language, culture, and other characteristics, Total Problems scores for 18 of the 24 societies were within 7.1 points of the omnicultural mean of 33.3 (on a scale of 0–198). Gender and age differences, as well as gender and age interactions with society, were all very small (effect sizes < 1%). Across all pairs of societies, correlations between mean item ratings averaged .78, and correlations between internal consistency alphas for the scales averaged .92, indicating that the rank orders of mean item ratings and internal consistencies of scales were very similar across diverse societies.

Bilineal transmission in Tourette's syndrome families

We assessed the frequency of bilineal (from maternal and paternal sides) transmission of Tourettes syndrome (TS) in two groups of pedigrees: (1) 39 high-density families in which five or more relatives were reported to have TS, and (2) the families of 39 consecutively ascertained probands referred for evaluation of TS. We used two designations for the TS phenotype (tics, tics or obsessive-compulsive behavior [OCB]), and we attempted to verify bilineal transmission with direct examinations. For the high-density pedigrees, bilineal transmission was evident in 33% (considering tics) and 41% (considering tics or OCB) of families, which was confirmed by examination in 77% of the kindreds. For the consecutive pedigrees, bilineal transmission was seen in 15% (tics) and 26% (tics or OCB) of families, which was verified by examination in 66% of the kindreds. Both parents of the proband were affected (tics or OCB) in 38% of the high-density pedigrees and 10% of the consecutive pedigrees. For the high-density families only, the frequency of bilineal transmission appeared to be related to the probands severity of TS, and for both pedigree groups, the frequency of both parents being affected was higher in families in which the probands symptoms were most severe. Our findings support the contention that bilineal transmission and homozygosity are common in TS. These genetic phenomena might play a role in determining severity of illness and may explain current difficulties in localizing the gene defect by linkage analysis.

Obsessive compulsive behaviour and depressive symptoms in young people with Tourette syndrome. A controlled study.

Abstract. Tourette syndrome (TS) is characterised by multiple motor and one or more vocal tics. There have been no controlled studies using standardised instruments of depressive symptoms and obsessive compulsive symptomatology (OCS) in young people with TS. We completed a study of phenomenology and psychopathology in children with TS, including a controlled evaluation of the association between depressive symptoms, OCS, and TS. 57 people aged 15 or under with TS were recruited. Phenomenology and psychopathology were assessed using standardised instruments. The association between TS, depressive symptoms and obsessionality was investigated using 75 age- and gender-matched controls. There were high levels of depressive symptomatology and OCS in the TS group. Twenty-three (40 %) had carried out self-injurious behaviours and 34 (60 %) met criteria for Attention Deficit Hyperactivity Disorder (ADHD). Depressive symptoms and obsessionality were higher in the TS cohort compared with the control group; this excess persisted after adjustment for the effects of age, gender and comorbidity between depression and obsessionality. This study demonstrates high levels of psychopathology in children with TS, including ADHD, OCS and depressive symptoms. The findings illustrate the potentially complex, challenging combination of difficulties encountered by children with TS and those who care for them.

Mental Health Problems Among Schoolchildren in United Arab Emirates: Prevalence and Risk Factors

OBJECTIVE To examine child psychiatric morbidity in an Arab culture. METHOD Emotional and behavioral problems were investigated in 3,278 schoolchildren aged 6 to 15 years using a two-stage epidemiological study in Al Ain District, United Arab Emirates. Children were screened using standardized questionnaires completed by parents and school physicians in the first stage, and a stratified random sample were interviewed by a child psychiatrist in the second stage. RESULTS 23.9% of children were reported to have a mental health problem by either the parent or the school health physician. Boys were more often reported to be having problems than girls (1.8:1). Using the Rutter A2 scale for parents, the prevalence estimate for behavioral disorders was 16.5%. The weighted prevalence for DSM-IV disorders was 10.4% for the entire population. The presence of certain culture-specific risk factors such as male gender, number of children in the household, polygamy, and low socioeconomic status were identified for psychiatric disorders. A positive family history and consanguinity were the most significant factors associated with learning disorders. CONCLUSIONS The prevalence rates of child psychiatric disorders and the symptomatology observed in this Middle East community are similar to those reported in Western studies.

Clinical outcomes of an early intervention program for preschool children with Autism Spectrum Disorder in a community group setting

BackgroundAvailable evidence indicates that early intervention programs, such as the Early Start Denver Model (ESDM), can positively affect key outcomes for children with Autism Spectrum Disorder (ASD). However, programs involving resource intensive one-to-one clinical intervention are not readily available or deliverable in the community, resulting in many children with ASD missing out on evidence-based intervention during their early and most critical preschool years. This study evaluated the effectiveness of the ESDM for preschool-aged children with ASD using a predominantly group-based intervention in a community child care setting.MethodsParticipants were 26 children (21 male) with ASD with a mean age of 49.6 months. The ESDM, a comprehensive early intervention program that integrates applied behaviour analysis with developmental and relationship-based approaches, was delivered by trained therapists during the child’s attendance at a child care centre for preschool-aged children with ASD. Children received 15–20 hours of group-based, and one hour of one-to-one, ESDM intervention per week. The average intervention period was ten months. Outcome measures were administered pre- and post-intervention, and comprised a developmental assessment - the Mullen Scales of Early Learning (MSEL); and two parent-report questionnaires - the Social Communication Questionnaire (SCQ) and Vineland Adaptive Behaviours Scales–Second Edition (VABS-II).ResultsStatistically significant post-intervention improvements were found in children’s performance on the visual reception, receptive language and expressive language domains of the MSEL in addition to their overall intellectual functioning, as assessed by standardised developmental quotients. Parents reported significant increases in their child’s receptive communication and motor skills on the VABS-II, and a significant decrease in autism-specific features on the SCQ. These effects were of around medium size, and appeared to be in excess of what may have been expected due to maturation. Nonetheless, these results need to be confirmed in a controlled study.ConclusionsThis study suggests community dissemination of the ESDM using predominantly group-based intervention may be an effective intervention. Making the ESDM accessible to the wider ASD community in child care settings has the potential for significant clinical and economic benefits. Further studies are indicated in this area, including those with younger children, and which incorporate a control group and standardised ASD assessments.Trial registrationThis trial is registered with the Australian New Zealand Clinical Trials Registry: Registry number ACTRN12612000461897.

Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism.

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder characterised by motor and vocal tics. Despite decades of research, the aetiology of TS has remained elusive. Recent successes in gene discovery backed by rapidly advancing genomic technologies have given us new insights into the genetic basis of the disorder, but the growing collection of rare and disparate findings have added confusion and complexity to the attempts to translate these findings into neurobiological mechanisms resulting in symptom genesis. In this review, we explore a previously unrecognised genetic link between TS and a competing series of trans-synaptic complexes (neurexins (NRXNs), neuroligins (NLGNs), leucine-rich repeat transmembrane proteins (LRRTMs), leucine rich repeat neuronals (LRRNs) and cerebellin precursor 2 (CBLN2)) that links it with autism spectrum disorder through neurodevelopmental pathways. The emergent neuropathogenetic model integrates all five genes so far found to be uniquely disrupted in TS into a single pathogenetic chain of events described in context with clinical and research implications.