An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure.

BACKGROUND: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. METHODS: We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. RESULTS: 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. CONCLUSIONS: DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population.

Global developmental delay and a de novo deletion of the 16p13.13 region.

Many rare genetic variants are associated with the risk of atypical neurodevelopmental trajectories. In this study, we report a patient with developmental delay, autistic traits and multiple congenital anomalies, including congenital heart anomalies and orofacial cleft, with a 0.832 Mb de novo deletion of the 16p13.13 region classified as a variant of uncertain significance. Comparison of similar sized deletions and duplications overlapping the same genes in the DECIPHER database, revealed seven reports of copy number variants (CNVs), four duplications and three deletions. A neurodevelopmental phenotype including learning disability and intellectual disability was noted in some of the DECIPHER entries where phenotype was provided. Although the association between a deletion in this region and an atypical neurodevelopmental trajectory remains to be elucidated, the overlapping CNVs with neurodevelopmental phenotypes suggests possible candidate genes within the 16p13.13 region.

Characterizing the ASD-ADHD phenotype: measurement structure and invariance in a clinical sample.

BACKGROUND: Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) have considerable overlap, supporting the need for a dimensional framework that examines neurodevelopmental domains which cross traditional diagnostic boundaries. In the following study, we use factor analysis to deconstruct the ASD-ADHD phenotype into its underlying phenotypic domains and test for measurement invariance across adaptive functioning, age, gender and ASD/ADHD clinical diagnoses. METHODS: Participants included children and youth (aged 3-20 years) with a clinical diagnosis of ASD (n = 727) or ADHD (n = 770) for a total of 1,497 participants. Parents of these children completed the Social Communication Questionnaire (SCQ), a measure of autism symptoms, and the Strengths and Weaknesses of ADHD and Normal Behaviour (SWAN) questionnaire, a measure of ADHD symptoms. An exploratory factor analysis (EFA) was performed on combined SCQ and SWAN items. This was followed by a confirmatory factor analysis (CFA) and tests of measurement invariance. RESULTS: EFA revealed a four-factor solution (inattention, hyperactivity/impulsivity, social-communication, and restricted, repetitive, behaviours and interests (RRBI)) and a CFA confirmed good model fit. This solution also showed good model fit across subgroups of interest. CONCLUSIONS: Our study shows that a combined ASD-ADHD phenotype is characterized by two latent ASD domains (social communication and RRBIs) and two latent ADHD domains (inattention and hyperactivity/impulsivity). We established measurement invariance of the derived measurement model across adaptive functioning, age, gender and ASD/ADHD diagnoses.

Latent Structure of Combined Autistic and ADHD Symptoms in Clinical and General Population Samples: A Scoping Review.

Background: Many phenotypic studies have estimated the degree of comorbidity between Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), but few have examined the latent, or unobserved, structure of combined ASD and ADHD symptoms. This is an important perquisite toward better understanding the overlap between ASD and ADHD. Methods: We conducted a scoping review of studies that examined the factor or latent class structure of ASD and ADHD symptoms within the same clinical or general population sample. Results: Eight studies met final inclusion criteria. Four factor analysis studies found that ASD and ADHD domains loaded separately and one found that some ASD and ADHD domains loaded together. In the three latent class studies, there were evidence of profiles with high levels of co-occurring ASD and ADHD symptoms. Conclusions: Our scoping review provides some evidence of phenotypic overlap between ASD and ADHD at the latent, or unobserved, level, particularly when using a "person-centered" (latent class analysis) vs. a "variable-centered" (factor analysis) approach.

Inattention and hyperactive/impulsive component scores do not differentiate between autism spectrum disorder and attention-deficit/hyperactivity disorder in a clinical sample.

BACKGROUND: Although there is high co-occurrence between ASD and ADHD, the nature of this co-occurrence remains unclear. Our study aimed to examine the underlying relationship between ASD and ADHD symptoms in a combined sample of children with a primary clinical diagnosis of ASD or ADHD. METHODS: Participants included children and youth (aged 3-20 years) with a clinical diagnosis of ASD (n = 303) or ADHD (n = 319) for a total of 622 participants. Parents of these children completed the social communication questionnaire (SCQ), a measure of autism symptoms, and the strengths and weaknesses of ADHD and normal behavior (SWAN) questionnaire, a measure of ADHD symptoms. A principal component analysis (PCA) was performed on combined SCQ and SWAN items, followed by a profile analysis comparing normalized component scores between diagnostic groups and gender. RESULTS: PCA revealed a four-component solution (inattention, hyperactivity/impulsivity, social-communication, and restricted, repetitive, behaviors, and interests (RRBI)), with no overlap between SCQ and SWAN items in the components. Children with ASD had higher component scores in social-communication and RRBI than children with ADHD, while there was no difference in inattentive and hyperactive/impulsive scores between diagnostic groups. Males had higher scores than females in social-communication, RRBI, and hyperactivity/impulsivity components in each diagnostic group. LIMITATIONS: We did not formally assess children with ASD for ADHD using our research-criteria for ADHD, and vice versa. High rates of co-occurring ADHD in ASD, for example, may have inflated component scores in inattention and hyperactivity/impulsivity. A disadvantage with using single informant-based reports (i.e., parent-rated questionnaires) is that ASD and ADHD symptoms may be difficult to distinguish by parents, and may be interpreted differently between parents and clinicians. CONCLUSIONS: ASD and ADHD items loaded on separate components in our sample, suggesting that the measurement structure cannot explain the covariation between the two disorders in clinical samples. High levels of inattention and hyperactivity/impulsivity were seen in both ASD and ADHD in our clinical sample. This supports the need for a dimensional framework that examines neurodevelopmental domains across traditional diagnostic boundaries. Females also had lower component scores across social-communication, RRBI, and hyperactivity/impulsivity than males, suggesting that there may be gender-specific phenotypes related to the two conditions.

Stimulant Withdrawal in a Child with Autism Spectrum Disorder and ADHD - A Case Report.

OBJECTIVE: To consider whether the concepts of tolerance and withdrawal to stimulant medications apply to a preadolescent female, affected by autism spectrum disorder (ASD) and treated for associated attention-deficit/hyperactivity disorder (ADHD). METHODS: We describe the case history and review scientific English language literature pertaining to acute withdrawal effects associated with methylphenidate and amphetamine derivatives in children. RESULTS: An 11-year-old female with ASD and ADHD referred to our clinic experienced vomiting, headaches, and light sensitivity following abrupt discontinuation of methylphenidate; she subsequently presented with migraines and marked malaise immediately after a dose reduction in lisdexamfetamine. Evidence supports the notion that ADHD symptoms in children with ASD can be effectively treated with methylphenidate; however, beneficial effects are less robust relative to children with a primary ADHD diagnosis. Children affected by ASD are also more susceptible to adverse effects. Literature on withdrawal from stimulants in children is limited to case studies; in contrast, in the adult population more information is available, especially in adults with substance abuse disorders. Adults experiencing stimulant withdrawal often experience depression, fatigue, changes in appetite, and insomnia or hypersomnia. CONCLUSIONS: We argue that tolerance to stimulants was conceivably developing in this young female, and consequently discontinuation of methylphenidate and dose reduction of lisdexamfetamine resulted in withdrawal symptoms. Children with ASD are more sensitive to stimulant medications and we wonder whether this extends to an increased sensitivity to developing tolerance to stimulant medication. Clinicians ought to be vigilant about the emergence of symptomology suggestive of withdrawal phenomena following stimulant discontinuation.

OBJECTIF: Examiner si les concepts de tolérance et de sevrage des médicaments stimulants s'appliquent à une pré-adolescente souffrant d'un trouble du spectre de l'autisme (TSA) et traitée pour un trouble de déficit de l'attention avec hyperactivité (TDAH) associé. MÉTHODES: Nous décrivons les antécédents du cas et examinons la littérature scientifique en anglais relative aux effets de sevrage associés au méthylphénidate et aux dérivés d'amphétamine chez les enfants. RÉSULTATS: Une fillette de 11 ans souffrant de TSA et de TDAH envoyée à notre clinique éprouvait des vomissements, des maux de tête et une sensibilité à la lumière par suite d'une cessation abrupte de méthylphénidate; elle a ensuite présenté des migraines et un malaise marqué immédiatement après la réduction d'une dose de lisdexamfétamine. Les données probantes soutiennent la notion que les symptômes du TDAH chez les enfants souffrant du TSA peuvent être efficacement traités par méthylphénidate; cependant, les effets bénéfiques sont moins intenses chez les enfants dont le diagnostic primaire est le TDAH. Les enfants souffrant du TSA sont également plus susceptibles aux effets indésirables. La littérature sur le sevrage des stimulants chez les enfants se limite aux études de cas; par contre, il y a plus d'information dans la population adulte, spécialement chez les adultes souffrant de troubles d'abus de substances. Les adultes vivant un sevrage de stimulant présentent souvent dépression, fatigue, changements d'appétit, et insomnie ou hypersomnie. CONCLUSIONS: Nous alléguons que la tolérance aux stimulants se développait probablement chez cette jeune fille et que par conséquent, la cessation de méthylphénidate et la réduction de la dose de lisdexamfétamine ont entraîné des symptômes de sevrage. Les enfants souffrant de TSA sont plus sensibles aux médicaments stimulants et nous nous demandons si cela s'étend à une sensibilité accrue au développement d'une tolérance aux médicaments stimulants. Les cliniciens doivent être vigilants devant l'apparition d'une symptomatologie suggestive d'un phénomène de sevrage suivant la cessation d'un stimulant.

Functional independence measure at rehabilitation admission as a predictor of return to driving after traumatic brain injury.

OBJECTIVE: To examine the utility of three common measures as predictors of return to driving after traumatic brain injury (TBI): Glasgow Coma Score (GCS) within the first 24 hours of injury and both Functional Independence Measure (FIM) and Disability Rating Scale (DRS) at rehabilitation admission. METHODS: Seventy-two participants with TBI completed a questionnaire that assessed return to driving post-TBI, as measured by reinstatement of the driver's license. Participants who did not return to driving for non-medical reasons or who had not driven pre-injury and did not obtain a driver's license post-injury were excluded from analysis. This produced a final sample of 59 participants. Scores on GCS, FIM and DRS, leveraged from an existing database, were compared between participants who had and those who had not returned to driving post-injury. Multiple logistic regression analysis was performed to determine the relationship of each predictor variable to return to driving. RESULTS: Only the FIM score at rehabilitation admission was significantly associated with return to driving (p < 0.01). FIM score had a sensitivity of 72% and specificity of 73% with respect to return to driving. CONCLUSIONS: This study supports the use of FIM at rehabilitation admission as a predictor of return to driving. Future studies should be directed at identifying other measures to be used in combination with FIM to accurately predict return to driving post-TBI.

Early neuropsychological tests as correlates of return to driving after traumatic brain injury.

OBJECTIVE: To assess the ability of neuropsychometric tests administered during inpatient rehabilitation to predict return to driving after traumatic brain injury (TBI). DESIGN: Retrospective, matched case-controlled study. METHODS: Sixty-seven participants with TBI, drawn from an existing database, completed a questionnaire that assessed return to driving post-TBI, as measured by reinstatement of the driver's license. Drivers were individually case-matched to non-drivers on age, Glasgow Coma Scale (GCS), Disability Rating Scale (DRS) and the rehabilitation admission interval (RAI). Scores on four neuropsychological tests (Trail-Making A, Trail Making B, Digit Span-forward and Digit Span-backward), administered during the rehabilitation stay, were compared between case-matched drivers and non-drivers. OUTCOME MEASURE: Return to driving, as defined by reinstatement of the driver's license. RESULTS: Participants who had returned to driving were comparable to those who had not returned to driving with respect to demographic variables, initial injury severity and baseline functioning. Scores on two neuropsychological assessments were significantly better in participants who had returned to driving than in those who had not: Trail-making A (p < 0.01) and Trail-making B (p < 0.01). CONCLUSIONS: The results suggest that neuropsychological measures of processing speed and cognitive flexibility may predict return to driving after TBI.