Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.

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Reduction of cortical parvalbumin expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition

Development ◽

10.1242/dev.198390 ◽

2021 ◽

Author(s):

Till Scheuer ◽

Elena auf dem Brinke ◽

Sabine Grosser ◽

Susanne A. Wolf ◽

Daniele Mattei ◽

...

Keyword(s):

Preterm Birth ◽

Psychiatric Symptoms ◽

Autism Spectrum ◽

Morphological Properties ◽

Behavioral Deficits ◽

Hyperactivity Disorder ◽

Spectrum Disorders ◽

The Brain ◽

Psychiatric Problems ◽

Behavior And Cognition

The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the mechanisms underlying are not known. In a translational hyperoxia model, exposing mice pups at age P5 to 80% oxygen for 48 hours to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin expressing interneurons until adulthood. Developmental delay of cortical myelin was observed together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor being involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning, and attention. These results elucidate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.

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Characterizing Daily-Life Social Interactions in Adolescents and Young Adults with Neurodevelopmental Disorders: A Comparison Between Individuals with Autism Spectrum Disorders and 22q11.2 Deletion Syndrome

Journal of Autism and Developmental Disorders ◽

10.1007/s10803-021-05423-9 ◽

2022 ◽

Author(s):

Clémence Feller ◽

Laura Ilen ◽

Stephan Eliez ◽

Maude Schneider

Keyword(s):

Autism Spectrum Disorders ◽

Social Interactions ◽

Subjective Experience ◽

Daily Life ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Mobile App ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Spectrum Disorders

AbstractSocial impairments are common features of 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). The Ecological Momentary Assessment (EMA) allowed access to daily-life information in order to explore the phenomenology of social interactions. 32 individuals with 22q11DS, 26 individuals with ASD and 44 typically developing peers (TD) aged 12–30 were assessed during 6 days 8 times a day using a mobile app. Participants with 22q11DS and ASD did not spend more time alone but showed distinct implication in the social sphere than TD. Distinct profiles emerged between the two conditions regarding the subjective experience of aloneness and the subjective experience of social interactions. This study highlights distinct social functioning profiles in daily-life in 22q11DS and ASD that points towards different therapeutic targets.

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Characterizing daily-life social interactions in adolescents and young adults with neurodevelopmental disorders: a comparison between individuals with Autism Spectrum Disorders and 22q11.2 deletion syndrome

10.21203/rs.3.rs-506720/v1 ◽

2021 ◽

Author(s):

Clémence Mathilde Feller ◽

Laura Ilen ◽

Maude Schneider

Keyword(s):

Autism Spectrum Disorders ◽

Social Interactions ◽

Subjective Experience ◽

Daily Life ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Social Impairments ◽

Spectrum Disorders

Abstract Background: Social impairments are common features of several neurodevelopmental conditions, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). However, little is known about social interactions in daily-life. The Ecological Momentary Assessment (EMA) was used to have access to daily-life information and to distinguish the phenomenology of social interactions between the two conditions, often considered as presenting a similar profile of social impairments.Methods: 32 individuals with 22q11DS, 26 individuals with ASD and 44 healthy controls (HC) aged 12-30 were recruited. All participants were assessed during 6 days 8 times a day using a mobile app. The EMA protocol assessed positive and negative affect, social context (alone versus in company) and the subjective experience of aloneness and social interactions.Results: Participants with 22q11DS and ASD did not spend more time alone, but spent less time with familiar individuals such as friends, and more time with people they live with, compared to HC. However, distinct profiles emerged between the two conditions regarding the subjective experience of aloneness, with more intense feelings of exclusion in participants with ASD compared to participants with 22q11DS and HC. The subjective appreciation of interactions revealed that individuals with ASD felt more judged and more nervous than both 22q11DS and HC. Nevertheless, both conditions expressed a higher desire to be alone when in company of other people than HC.Conclusions: This study highlights distinct social functioning profiles in daily-life in 22q11DS and ASD, giving new intel regarding the social phenotype in these conditions, and pointing towards different therapeutic targets.

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Autism Spectrum Disorders and Symptoms in Children with Molecularly Confirmed 22q11.2 Deletion Syndrome

Journal of Autism and Developmental Disorders ◽

10.1007/s10803-005-5036-9 ◽

2005 ◽

Vol 35 (4) ◽

pp. 461-470 ◽

Cited By ~ 150

Author(s):

Sarah E. Fine ◽

Alison Weissman ◽

Marsha Gerdes ◽

Jennifer Pinto-Martin ◽

Elaine H. Zackai ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Spectrum Disorders

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Axis I psychiatric diagnoses in adolescents and young adults with 22q11 deletion syndrome

European Psychiatry ◽

10.1016/j.eurpsy.2013.06.002 ◽

2013 ◽

Vol 28 (7) ◽

pp. 417-422 ◽

Cited By ~ 5

Author(s):

O.Y. Ousley ◽

E. Smearman ◽

S. Fernandez-Carriba ◽

K.A. Rockers ◽

K. Coleman ◽

...

Keyword(s):

Depressive Disorders ◽

Clinical Care ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Deletion Syndrome ◽

Psychiatric Diagnoses ◽

Schizophrenia Spectrum Disorders ◽

Axis I ◽

Dsm Iv ◽

Spectrum Disorders

AbstractBackground22q11.2 deletion syndrome (22q11DS) associates with schizophrenia spectrum disorders (SSDs), autism spectrum disorders (ASDs), and other psychiatric disorders, but co-occurrence of diagnoses are not well described.MethodsWe evaluated the co-occurrence of SSDs, ASDs and other axis I psychiatric diagnoses in 31 adolescents and adults with 22q11DS, assessing ASDs using either stringent Collaborative Program for Excellence in Autism (ASD-CPEA) criteria, or less stringent DSM-IV criteria alone (ASD-DSM-IV).ResultsTen (32%) individuals met criteria for an SSD, five (16%) for ASD-CPEA, and five others (16%) for ASD-DSM-IV. Of those with ASD-CPEA, one (20%) met SSD criteria. Of those with ASD-DSM-IV, four (80%) met SSD criteria. Depressive disorders (8 individuals; 26%) and anxiety disorders (7; 23%) sometimes co-occurred with SSDs and ASDs. SSDs, ASDs, and anxiety occurred predominantly among males and depression predominantly among females.ConclusionsIndividuals with 22q11DS can manifest SSDs in the presence or absence of ASDs and other axis I diagnoses. The results suggest that standard clinical care should include childhood screening for ASDs, and later periodic screening for all axis I diagnoses.

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Developmental course of conversational behaviour of children with 22q11.2 deletion syndrome and Williams syndrome

First Language ◽

10.1177/0142723717713890 ◽

2017 ◽

Vol 37 (6) ◽

pp. 583-611 ◽

Cited By ~ 2

Author(s):

Ellen Van Den Heuvel ◽

Nicola Botting ◽

Inge Boudewijns ◽

Eric Manders ◽

Ann Swillen ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Intellectual Disability ◽

Williams Syndrome ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Conversational Skills ◽

Spectrum Disorders ◽

Over Time

This study investigated three conversational subskills in children with 22q11.2 deletion syndrome (22q11.2DS, n = 8, ages 7–13) and Williams syndrome (WS, n = 8, ages 6–12). The researchers re-evaluated these subskills after 18 to 24 months and compared them to those of peers with idiopathic intellectual disability (IID) and IID and comorbid autism spectrum disorders (IID+ASD). Children with 22q11.2DS became less actively involved over time. Lower assertiveness than in children with IID was demonstrated. They seemed less impaired in terms of accounting for listener’s knowledge than children with IID+ASD. Children with WS showed greater difficulties with discourse management compared to children with IID and 22q11.2DS. They had similar levels of conversational impairments to children with IID+ASD but these were caused by different shortcomings. Over time taking account of listener’s knowledge became challenging for them. Findings suggest that children with 22q11.2DS and those with WS would benefit from conversational skills support and that regular re-evaluation is needed to anticipate conversational challenges.

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Altered kynurenine pathway metabolites in a mouse model of human attention-deficit hyperactivity/autism spectrum disorders: A potential new biological diagnostic marker

Scientific Reports ◽

10.1038/s41598-019-49781-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Yuki Murakami ◽

Yukio Imamura ◽

Kuniaki Saito ◽

Daisuke Sakai ◽

Jun Motoyama

Keyword(s):

Attention Deficit ◽

Neurodevelopmental Disorders ◽

Kynurenine Pathway ◽

Autism Spectrum ◽

Behavioral Deficits ◽

Diagnostic Biomarkers ◽

Hyperactivity Disorder ◽

Spectrum Disorders ◽

Almost All ◽

The Brain

Abstract Deleterious mutations in patchd1 domain containing 1 (PTCHD1) gene have been identified in patients with intellectual disability and/or autism spectrum disorder (ASD). To clarify the causal relationship between Ptchd1 deficiency and behavioral defects relevant to neurodevelopmental disorders, we generated global Ptchd1 knockout (KO) mice. Ptchd1 KO mice displayed hyperlocomotion, increased impulsivity, and lower recognition memory, which resemble attention-deficit hyperactivity disorder (ADHD)-like behaviors. Acute or chronic treatment with atomoxetine ameliorated almost all behavioral deficits in Pthcd1 KO mice. We next determined possible involvement of the kynurenine pathway (KP) metabolites in neurodevelopmental disorders in Ptchd1 KO mice and assessed the potential of KP metabolites as biomarkers for ADHD and/or ASD. Ptchd1 KO mice showed drastic changes in KP metabolite concentrations in the serum and the brain, indicating that the activated KP is associated with ADHD-like behaviors. Our findings indicate that Ptchd1 KO mice can be used as an animal model of human ADHD and/or ASD, and KP metabolites are potential diagnostic biomarkers for neurodevelopmental disorders.

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Neurodevelopmental Trajectories and Psychiatric Morbidity: Lessons Learned From the 22q11.2 Deletion Syndrome

Current Psychiatry Reports ◽

10.1007/s11920-021-01225-z ◽

2021 ◽

Vol 23 (3) ◽

Author(s):

Ania M. Fiksinski ◽

Maude Schneider ◽

Janneke Zinkstok ◽

Danielle Baribeau ◽

Samuel J. R. A. Chawner ◽

...

Keyword(s):

Genetic Variants ◽

Clinical Care ◽

Psychiatric Morbidity ◽

Phenotypic Expression ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Lessons Learned ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Variable Expression

AbstractPurpose of ReviewThe 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is relatively common and one of the most extensively studied. This review provides a state-of-the-art overview of current insights regarding associated neurodevelopmental phenotypes and potential implications for 22q11DS and beyond.Recent FindingsWe will first discuss recent findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS, including psychotic disorders, intellectual functioning, autism spectrum disorders, as well as their interactions. Second, we will address considerations that are important in interpreting these data and propose potential implications for both the clinical care for and the empirical study of individuals with 22q11DS. Third, we will highlight variable penetrance and pleiotropy with respect to neurodevelopmental phenotypes in 22q11DS. We will discuss how these phenomena are consistently observed in the context of virtually all rare pathogenic variants and that they pose substantial challenges from both a clinical and a research perspective.SummaryWe outline how 22q11DS could be viewed as a genetic model for studying neurodevelopmental phenotypes. In addition, we propose that 22q11DS research can help elucidate mechanisms underlying variable expression and pleiotropy of neurodevelopmental phenotypes, insights that are likely relevant for 22q11DS and beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.

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Differentiation of Healthy Individuals from Those with Autism Spectrum Disorders using Information Graph of Complementary Opposites

10.32592/ajnpp.2021.8.3.100 ◽

2020 ◽

Keyword(s):

Children With Autism ◽

Autism Spectrum ◽

Brain Signals ◽

Three Stages ◽

The Mean ◽

Spectrum Disorders ◽

Pediatric Psychiatry ◽

The Brain ◽

Optimal Feature ◽

Information Graph

This study aimed to examine the brain signals of children with Autism Spectrum Disorder (ASD) and use a method according to the concept of complementary opposites to obtain the prominent features or a pattern of EEG signal that represents the biological characteristic of such children. In this study, 20 children with the mean±SD age of 8±5 years were divided into two groups of normal control (NC) and ASD. The diagnosis and approval of individuals in both groups were conducted by two experts in the field of pediatric psychiatry and neurology. The recording protocol was designed with the most accuracy; therefore, the brain signals were recorded with the least noise in the awake state of the individuals in both groups. Moreover, the recording was conducted in three stages from two channels (C3-C4) of EEG ( referred to as the central part of the brain) which were symmetrical in function. In this study, the Mandala method was adopted based on the concept of complementary opposites to investigate the features extracted from Mandala pattern topology and obtain new features and pseudo-patterns for the screening and early diagnosis of ASD. The optimal feature here was based on different stages of processing and statistical analysis of Pattern Detection Capability (PDC). The PDC is a biomarker derived from the Mandala pattern for differentiating the NC from ASD groups.

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Episodic Behavioural Regression in an 8-Year-Old Female: Sequelae of 22q11.2 Duplication Syndrome

Case Reports in Psychiatry ◽

10.1155/2018/1394356 ◽

2018 ◽

Vol 2018 ◽

pp. 1-3

Author(s):

A. Bahji ◽

S. Khalid-Khan

Keyword(s):

Case Reports ◽

22Q11.2 Deletion Syndrome ◽

Autism Spectrum ◽

Deletion Syndrome ◽

Medical Illness ◽

22Q11.2 Deletion ◽

Genetic Syndrome ◽

Potential Risk Factors ◽

22Q11.2 Duplication Syndrome ◽

Duplication Syndrome

22q11.2 duplication syndrome is a recently discovered genetic syndrome with unclear neuropsychiatric sequelae. While its connection to 22q11.2 deletion syndrome is actively investigated, case reports on the neuropsychiatric sequelae of affected individuals have been previously described, largely focusing on comorbid autism spectrum disorder. Here, we present the case of an 8-year-old female experiencing episodes of severe behavioural regression following medical illness. We analyze the case and relate it to the available literature and identify potential risk factors.

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