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Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors.

During adolescence, some individuals with autism spectrum disorder (ASD) engage in severe challenging behaviors, such as aggression, self-injury, disruption, agitation and tantrums. We aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD admitted to a dedicated neurobehavioral unit. We included retrospectively in 2008 and 2009 29 adolescents and young adults with ASD hospitalized for severe challenging behaviors and proposed a guideline (Perisse et al., 2010) that we applied prospectively for 29 patients recruited for the same indications between 2010 and 2012. In total, 58 patients were admitted (n=70 hospitalizations, mean age=15.66 (±4.07) years, 76% male). We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), comorbid organic conditions, etiologic diagnosis of the episode, and treatments. We explored predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge. All but 2 patients exhibited severe autistic symptoms and intellectual disability (ID), and two-thirds had no functional verbal language. During the inpatient stay (mean=84.3 (±94.9) days), patients doubled on average their GAFS scores (mean=17.66 (±9.05) at admission vs. mean=31.4 (±9.48) at discharge). Most common etiologies for acute behavioral crises were organic causes [n=20 (28%), including epilepsy: n=10 (14%) and painful medical conditions: n=10 (14%)], environmental causes [n=17 (25%) including lack of treatment: n=11 (16%) and adjustment disorder: n=6 (9%)], and non-ASD psychiatric condition [n=33 (48%) including catatonia: n=5 (7%), major depressive episode: n=6 (9%), bipolar disorder: n=4 (6%), schizophrenia: n=6 (9%), other/unknown diagnosis: n=12 (17%)]. We found no influence of age, gender, socio-economic status, migration, level of ID, or history of seizure on improvement of GAFS score at discharge. Severity of autism at admission was the only negative predictor (p<.001). Painful medical conditions (p=.04), non-ASD psychiatric diagnoses (p=.001), prior usage of specialized ASD care programs (p=.004), functional language (p=.007), as well as a higher number of challenging behaviors upon admission (p=.001) were associated with higher GAFS scores at discharge. Clinical severity at admission, based on the number of challenging behaviors (r=.35, p=.003) and GAFS score (r=-.32, p=.008) was correlated with a longer inpatient stay. Longer hospitalization was however correlated (r=.27, p=.03) with higher GAFS score at discharge even after adjustment for confounding factors. Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Catatonia is a complex neuropsychiatric syndrome involving a constellation of psychomotor disturbances including catalepsy, waxy flexibility, stupor, mutism, negativism, agitation, posturing, stereotypes, mannerisms, grimacing, echolalia, and echopraxia. Catatonia occurs in several conditions including psychotic, affective and neurodevelopmental disorders such as autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by persistent deficits in communication, social interaction, restricted interests, repetitive behaviours and sensory sensitivities. Catatonia can occur in response to life stressors such as extreme fear or threat, interpersonal conflict, tragic events or following significant loss. Those with ASD may be particularly vulnerable to the negative impact of stressors and the link between catatonia and ASD is being increasingly recognized. The overlapping features of catatonia and ASD make it difficult to differentiate often resulting in delayed or missed diagnosis. Catatonia in ASD remains a significant clinical challenge; it is difficult to diagnose and can pose debilitating difficulties for those affected. Catatonia is a treatable condition and prompt recognition is vital in securing the best possible outcome. We report a complex and unique case of a 15-year-old boy who presented with severe cognitive and functional decline with a background history of significant bullying and deterioration in his mental state. This case posed a diagnostic conundrum leading to a diagnosis of underlying ASD, anxiety and trauma. [ABSTRACT FROM AUTHOR]

Catatonia is characterized by psychomotor alterations and reduced contact with the environment. Initially linked to schizophrenia, it also occurs in mood disorders or organic conditions. In children, catatonia remains poorly delineated, despite dramatically increasing the risk of premature death. As data on pediatric drug-induced catatonia bears many uncertainties, we aimed to characterize its age-dependent patterns, using real-world data from the WHO safety database (VigiBase®).VigiBase® was queried for all reports of catatonia registered up to December 8th 2022. Reports involving patients <18 years were classified into 3 groups: ≤23 months, 2–11 years, and 12–17 years. Disproportionality analyses relied on the Reporting Odds Ratio (ROR), and the positivity of the lower end of the 95% confidence interval of the Information Component (IC) was required to suspect a signal. Catatonia was evoked in 421 pediatric reports. In infants, vaccines were leading. In children, the main signals involved haloperidol (ROR 104.3; 95% CI 45.6–238.5), ondansetron (ROR 40.5; 95% CI 16.5–99.5), and ciclosporin (ROR 27.4; 95% CI 13.8–54.1). In adolescents, chlorpromazine (ROR 199.1; 95% CI 134.8–294.1), benzatropine (ROR 193; 95% CI 104.1–361.6), and olanzapine (ROR 135.7; 95% CI 104.6–175.9) reached the highest RORs. In infants, catatonia was related to vaccines, it was ascribed to multiple drugs in children, and mainly to psychotropic drugs in adolescents. Less suspected drugs, such as ondansetron, were highlighted. Despite limitations inherent in spontaneous reporting systems, this study supports that a careful anamnesis is warranted to separate catatonia associated with medical conditions from drug-induced catatonia in pediatric patients. [ABSTRACT FROM AUTHOR]

Background: Inherited metabolic disorders (IEMs) can be represented in children and adolescents by psychiatric disorders. The early diagnosis of IEMs is crucial for clinical outcome and treatment. The aim of this review is to analyze the most recurrent and specific psychiatric features related to IEMs in pediatrics, based on the onset type and psychiatric phenotypes. Methods: Following the PRISMA Statement, a systematic literature review was performed using a predefined algorithm to find suitable publications in scientific databases of interest. After removing duplicates and screening titles and abstracts, suitable papers were analyzed and screened for inclusion and exclusion criteria. Finally, the data of interest were retrieved from the remaining articles. Results: The results of this study are reported by type of symptoms onset (acute and chronic) and by possible psychiatric features related to IEMs. Psychiatric phenomenology has been grouped into five main clinical manifestations: mood and anxiety disorders; schizophrenia-spectrum disorders; catatonia; eating disorders; and self-injurious behaviors. Conclusions: The inclusion of a variety of psychiatric manifestations in children and adolescents with different IEMs is a key strength of this study, which allowed us to explore the facets of seemingly different disorders in depth, avoiding possible misdiagnoses, with the related delay of early and appropriate treatments. [ABSTRACT FROM AUTHOR]

Background: Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10–8), D (p = 1.86×10–4), E (p = 2.92×10–9), J (p = 2.65×10–9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p < 0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage. [ABSTRACT FROM AUTHOR]

A better understanding of the endocannabinoid system and a relaxation in regulatory control of cannabis globally has increased interest in the medicinal use of cannabinoid-based products (CBP). We provide a systematic review of the rationale and current clinical trial evidence for CBP in the treatment of neuropsychiatric and neurodevelopmental disorders in children and adolescents. A systematic search of MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Trials was performed to identify articles published after 1980 about CBP for medical purposes in individuals aged 18 years or younger with selected neuropsychiatric or neurodevelopmental conditions. Risk of bias and quality of evidence was assessed for each article. Of 4466 articles screened, 18 were eligible for inclusion, addressing eight conditions (anxiety disorders (n = 1); autism spectrum disorder (n = 5); foetal alcohol spectrum disorder (n = 1); fragile X syndrome (n = 2); intellectual disability (n = 1); mood disorders (n = 2); post-traumatic stress disorder (n = 3); and Tourette syndrome (n = 3)). Only one randomised controlled trial (RCT) was identified. The remaining seventeen articles included one open-label trial, three uncontrolled before-and-after trials, two case series and 11 case reports, thus the risk of bias was high. Despite growing community and scientific interest, our systematic review identified limited and generally poor-quality evidence for the efficacy of CBP in neuropsychiatric and neurodevelopmental disorders in children and adolescents. Large rigorous RCTs are required to inform clinical care. In the meantime, clinicians must balance patient expectations with the limited evidence available. [ABSTRACT FROM AUTHOR]

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Background. Catatonia is a psychomotor syndrome frequently observed in disorders with neurodevelopmental impairments, including psychiatric disorders such as schizophrenia. The orbitofrontal cortex (OFC) has been repeatedly associated with catatonia. It presents with an important interindividual morphological variability, with three distinct H-shaped sulcal patterns, types I, II, and III, based on the continuity of the medial and lateral orbital sulci. Types II and III have been identified as neurodevelopmental risk factors for schizophrenia. The sulcal pattern of the OFC has never been investigated in catatonia despite the role of the OFC in the pathophysiology and the neurodevelopmental component of catatonia. Methods. In this context, we performed a retrospective analysis of the OFC sulcal pattern in carefully selected homogeneous and matched subgroups of schizophrenia patients with catatonia (N = 58) or without catatonia (N = 65), and healthy controls (N = 82). Results. Logistic regression analyses revealed a group effect on OFC sulcal pattern in the left (2 = 18.1; p < .001) and right (2 = 28.3; p < .001) hemispheres. Catatonia patients were found to have more type III and less type I in both hemispheres compared to healthy controls and more type III on the left hemisphere compared to schizophrenia patients without catatonia. Conclusion. Because the sulcal patterns are indirect markers of early brain development, our findings support a neurodevelopmental origin of catatonia and may shed light on the pathophysiology of this syndrome. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition influenced by a myriad of developmental, biological, psychological, and socio-demographic factors. The ELENA cohort seeks to delineate the intricate interplay of these factors, facilitating the identification of risk factors and the development of targeted interventions. This paper emphasizes the clinical profiles of children and outlines key findings from a biopsychosocial perspective. The ELENA cohort, a multicenter initiative across French regional centers, conducted a systematic prospective analysis on children newly diagnosed with DSM-5 ASD between 2012 and 2019. This encompassed direct assessments and parent-reported questionnaires covering a broad spectrum of developmental, biological, psychological and socio-demographic measures. Embedded case-control studies further examined risk and protective factors, alongside specific environmental and psychosocial influences during pregnancy and early childhood. A subset of participants also contributed biospecimens, with data enhancement via linkage to French National Administrative Healthcare Databases. The study unveils baseline clinical characteristics for 876 children, average age 6 (SD ± 3.3) previously unreported in protocol descriptions. It highlights the study's developmental biopsychosocial approach and its novel findings on children's socio-adaptive functioning, ASD severity, comorbidities, quality of life and interventions. Employing developmental biopsychosocial insights offers a promising pathway to integrating health, social care, and experiential insights, ultimately aiming to enhance the future well-being and outcomes for children with ASD. This approach underscores the need of a holistic, interdisciplinary strategy in encouraging and supporting the ASD community., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primrose syndrome (PS) is a rare genetic disease characterized by developmental delay, intellectual disability, sensorineural hearing loss, and dysmorphic features. PS is caused by de novo pathogenic variants in the ZBTB20 gene, which encodes a transcription factor modulating neurogenesis. We describe resolution with sertraline of neurobehavioral difficulties in a 17-year-old Hispanic male with PS with de novo heterozygous c.1916G > A (p.C639Y) variant of ZBTB20. Neurobehavioral difficulties included aggression towards self and others, irritability, tearfulness, and mood liability that did not respond to behavioral interventions or aripiprazole. Treatment with sertraline, a medication indicated for psychiatric disorders including anxiety and depression, led to the resolution of neurobehavioral difficulties after 2 weeks of initiation of medication. The treatment course suggests that selective serotonin reuptake inhibitors, such as sertraline, may be a useful tool for neurobehavioral difficulties in PS over antipsychotics that are accompanied by complex side effect profiles, and suggest that anxiety is the primary cause of the neurobehavioral difficulties in this patient., (© 2024 Wiley Periodicals LLC.)

We present the case of a 16-year-old female patient who experienced the loss of her mother to suicide, leading to post-traumatic stress disorder and prominent mood symptoms. She developed catatonic features during her inpatient psychiatric hospitalization following her own suicide attempt. Over her hospital course, she began to demonstrate signs of co-occurring obsessive-compulsive disorder (OCD) and affective psychotic disorder obfuscated by the severity of her catatonia. After initial workup including neurologic evaluation, laboratory tests, imaging (EEG, MRI), the patient was stabilized on a combination of benzodiazepines, antipsychotics, mood stabilizers, and selective serotonin reuptake inhibitors. The diagnostic challenges of disambiguating multiple concurrent diagnoses in the presence of a syndrome with unclear pathophysiology are discussed. Recommendations are made to thoroughly evaluate thought content during periods of catatonic remission to guide diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Individuals with developmental disorders exhibit a broad spectrum of aggressive behaviors, including self-directed actions and those directed toward others. These behaviors can lead to physical harm, disruptions in daily life, caregiver stress, and an increased risk for abuse and institutionalization. An integrated and multidisciplinary approach, including psychosocial approaches and pharmacotherapy, has been attempted to treat self-injurious and aggressive behaviors, but has shown limited effectiveness in reducing those behaviors. Recently, the use of electroconvulsive therapy has increased as an alternative treatment for pediatric and adolescent patients with treatment-resistant behavior problems in developmental disorders. This review elucidates the indications and clinical effectiveness of electroconvulsive therapy in the management of self-injurious behavior and catatonia in patients with developmental disorders such as autism spectrum disorders and intellectual disabilities. [ABSTRACT FROM AUTHOR]

Background: Recent literature has shown that a considerable percentage of patients with severe mental disorders can develop, over time, full-blown or subthreshold catatonia. Some studies corroborate the model of an illness trajectory in which different mental disorders would be arranged along a continuum of severity until the development of catatonia. In such an illness pathway, autistic traits (AT) and borderline personality disorder (BPD) may represent important steps. In order to further explore the association between AT, BPD, and catatonia, the aim of this study was to compare catatonic spectrum symptoms and AT among patients with major depressive disorder (MDD), BPD, and healthy controls (CTL), also evaluating possible predictive dimensions of the different diagnoses. Methods: A total of 90 adults affected by BPD, 90 adults with a diagnosis of MDD, and 90 CTL, homogeneous in terms of gender and age, were recruited from six Italian university departments of psychiatry and assessed with the SCID-5-RV, the Catatonia Spectrum (CS), and the Adult Autism Subthreshold Autism Spectrum (AdAS Spectrum). Results: The total CS score was significantly higher in the BPD and MDD groups than in the CTL group, while the majority of CS domain scores were significantly higher in the BPD group than in the MDD group, which scored significantly higher than the CTL group. The total AdAS Spectrum score and the AdAS Spectrum domain scores were significantly higher in the BPD group than in the MDD group, which in turn scored significantly higher than the CTL group. The CS domains "psychomotor activity" and "impulsivity", and AdAS Spectrum domains "verbal communication", "empathy", and "hyper-/hyporeactivity to sensory input" were associated with the risk of presenting a diagnosis of BPD. [ABSTRACT FROM AUTHOR]

Inclusive education policies stimulate children with special educational needs, including autism, to attend regular education. We aimed to explore change over time in school placement and transitions of autistic children since the introduction of an inclusive education policy in the Netherlands (2014) and to examine the role of individual child characteristics. This study used longitudinal data from 2013 to 2021 on autistic children (N = 1463, aged 5-16 years). We expected an increase in regular school placements and transitions to regular schools. Surprisingly, the proportion of children with autism in regular schools slightly decreased. Special school placement was more likely for boys and autistic children with lower intelligence scores, co-occurring conditions or behavioral and peer relation problems. Younger autistic children and those with lower intelligence scores more often transferred from a regular to a special school. The opposite transition was more common in older autistic children and those with higher intelligence scores. The likelihood of special-to-regular transitions did not change, but regular-to-special transitions were more prevalent during the years just after the policy change than in later years. The inclusive policy had little impact on the school placement, and at most led to a delayed drop in referrals to special schools., (© 2024. The Author(s).)

This retrospective chart review examines the safety, tolerability and effectiveness of long acting injectable paliperidone palmitate (P-LAI) targeting irritability in twenty-six youth and transition-aged individuals with autism spectrum disorder (ASD) and/or intellectual disability (ID) over a 3-year window. Clinical response was evaluated via prospectively assigned Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) scales as well as number of hospital presentations. P-LAI was well tolerated with only 3 patients stopping P-LAI due to side effects. The average duration of P-LAI treatment was 21.1 months. Difficulty with medication compliance was the most common reason for initiating P-LAI. There was a statistically significant improvement in CGI-I, CGI-S and hospital visits and no change in BMI noted. Given the potential difficulty of medication administration in this population, this evidence of safety, tolerability as well as preliminary data supporting effectiveness is an important addition to the literature regarding psychopharmacologic management of irritability in youth with ASD and ID., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mental health assessment in autistic individuals with intellectual disabilities may be challenging. Findings from non-autistic samples indicate overlap between obsessive-compulsive disorder (OCD) and psychotic disorder/schizophrenia, but little is known about this potential overlap in autistic people. Explorative, retrospective chart study involving comprehensive, multimodal assessments for 18 autistic individuals with suspected OCD in a specialized mental health department. All participants had an intellectual disability (12) or significant impairments in adaptive behavior (6). While no participants had been diagnosed with psychotic disorder at referral, 7/18 participants were diagnosed with a psychotic disorder following assessment (schizophrenia or unspecified psychotic disorder). OCD symptoms may overshadow psychotic symptoms in autistic individuals with intellectual disabilities. A combination of conventional assessment tools and assessment tools developed for autistic people may be helpful in differentiating OCD and psychosis in this population, as well as prototypical symptom considerations and exploring the developmental trajectories of symptoms. [ABSTRACT FROM AUTHOR]

Although animal dispersal is known to play key roles in ecological and evolutionary processes such as colonization, population extinction and local adaptation, little is known about its genetic basis, particularly in vertebrates. Untapping the genetic basis of dispersal should deepen our understanding of how dispersal behaviour evolves, the molecular mechanisms that regulate it and link it to other phenotypic aspects in order to form the so‐called dispersal syndromes. Here, we comprehensively combined quantitative genetics, genome‐wide sequencing and transcriptome sequencing to investigate the genetic basis of natal dispersal in a known ecological and evolutionary model of vertebrate dispersal: the common lizard, Zootoca vivipara. Our study supports the heritability of dispersal in semi‐natural populations, with less variation attributable to maternal and natal environment effects. In addition, we found an association between natal dispersal and both variation in the carbonic anhydrase (CA10) gene, and in the expression of several genes (TGFB2, SLC6A4, NOS1) involved in central nervous system functioning. These findings suggest that neurotransmitters (serotonin and nitric oxide) are involved in the regulation of dispersal and shaping dispersal syndromes. Several genes from the circadian clock (CRY2, KCTD21) were also differentially expressed between disperser and resident lizards, supporting that the circadian rhythm, known to be involved in long‐distance migration in other taxa, might affect dispersal as well. Since neuronal and circadian pathways are relatively well conserved across vertebrates, our results are likely to be generalisable, and we therefore encourage future studies to further investigate the role of these pathways in shaping dispersal in vertebrates. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by social impairments and restricted, repetitive behaviors. Treatment of ASD is notoriously difficult and might benefit from identification of underlying mechanisms that overlap with those disturbed in other developmental disorders, for which treatment options are more obvious. One example of the latter is attention-deficit hyperactivity disorder (ADHD), given the efficacy of especially stimulants in treatment of ADHD. Deficiencies in catecholaminergic systems [dopamine (DA), norepinephrine (NE)] in ADHD are obvious targets for stimulant treatment. Recent findings suggest that dysfunction in catecholaminergic systems may also be a factor in at least a subgroup of ASD. In this review we scrutinize the evidence for catecholaminergic mechanisms underlying ASD symptoms, and also include in this analysis a third classic ascending arousing system, the acetylcholinergic (ACh) network. We complement this with a comprehensive review of DA-, NE-, and ACh-targeted interventions in ASD, and an exploratory search for potential treatment-response predictors (biomarkers) in ASD, genetically or otherwise. Based on this review and analysis we propose that (1) stimulant treatment may be a viable option for an ASD subcategory, possibly defined by genetic subtyping; (2) cerebellar dysfunction is pronounced for a relatively small ADHD subgroup but much more common in ASD and in both cases may point toward NE- or ACh-directed intervention; (3) deficiency of the cortical salience network is sizable in subgroups of both disorders, and biomarkers such as eye blink rate and pupillometric data may predict the efficacy of targeting this underlying deficiency via DA, NE, or ACh in both ASD and ADHD. [ABSTRACT FROM AUTHOR]

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia with an estimated prevalence of 1/10,000. Schizophrenia and Autism spectrum disorder (ASD) have shared phenotypic features and shared genetic etiology. There is growing research surrounding the co-occurrence of psychomotor syndromes like catatonia with neurodevelopmental disorders like ASD or psychiatric disorders like schizophrenia. In 2013, Shorter and Wachtel described a phenomenon of the 'Iron Triangle' where COS, ASD, and catatonia often co-occur. The Iron Triangle theory is based on observation of historical case literature, which showed that all three diagnoses in the Iron Triangle were routinely assigned to children and adolescents. The pattern of this "Iron Triangle" suggests there may be a single underlying pathology resulting in a unique mixed form of catatonia, autism, and psychosis. We describe the case of a boy with sequential development of COS, ASD, and catatonia who also has syndromic facial and musculoskeletal features. This case highlights overlapping diagnostic features of these three disorders and can help us better understand how "hidden" features of catatonia may occur in patients with COS or ASD but go unrecognized, because they are grouped as features under autism/schizophrenia rather than a distinct diagnosis of catatonia. Further study is warranted to elucidate if this phenotypic pattern constitutes a new single diagnosis that is not well understood, an endophenotype of schizophrenia, or if this is the result of phenomenological overlap between catatonia, ASD, and COS. [ABSTRACT FROM AUTHOR]

While the term hikikomori (HKM) has spread internationally to describe a chronic and severe form of social withdrawal, its place in current nosography and its transposition into non-Asian cultures are still debated. A retrospective chart review was conducted to determine the rate and the clinical profiles of HKM among a French sample of adolescent inpatients. Data were obtained from 191 adolescents aged 12–18 years (M = 15.0, 44% boys) consecutively admitted in two inpatient units from January 2017 to December 2019. Using a retrospective diagnosis of HKM based on Teo and Gaw's criteria, we compared socio-demographic characteristics, clinical features, and treatment outcomes between HKM patients and those with other forms of social withdrawal and/or school refusal (SW/SR). At admission, 7% of participants met HKM criteria (n = 14, M = 14.3, 64% boys), one out of six adolescents with SW/SR. Among those with SW/SR, HKM + vs. HKM- participants had higher rates of anxiety disorder (Odd Ratio, OR = 35.2) and lower disruptive behavioral disorder (OR = 0.03). A minority of the participants with anxiety and depressive disorders met the HKM criteria (respectively, 15% and 9%), but those with HKM had a longer duration of symptoms, longer hospitalization, and required more daily care facilities at discharge compared to HKM-. While HKM syndrome could not be delimitated from anxiety disorder, it was associated with specific clinical features and treatment outcomes. The clinical characteristics observed were consistent with the features reported in Asian HKM adults, supporting face validity of this clinical concept in adolescent inpatients with different cultural contexts. [ABSTRACT FROM AUTHOR]

The present study aimed at enhancing the assessment of adaptive behavior in adolescents with Autism Spectrum Disorder trough the Adaptive Behavior Assessment System-Second Edition. To overcome the limits underpinning floor effect, which are commonly observed with the traditional methods, the statistical Hessl method and its revision by Orsini, Pezzuti and Hulbert was adopted. The results showed a more variation using the former method compared to the latter: a greater impairment in Social versus Leisure skills emerged. Regarding the Conceptual domain, a greater deficit in Functional Academics was observed. In the Practical domain, we found a greater impairment in Self-Care skills. Conversely, Home Living skills appeared as a strength compared to other skills. The results are discussed in reference to literature. [ABSTRACT FROM AUTHOR]

The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0–12.0) with 43% of males (55/128), and the median disease duration was 7 months (IQR 1–47). In the whole analysis, the CES diagnostic yield was 55% (70/128). The median test-to-report time was 5 months (IQR 4–7). According to CES indications, the CES diagnostic yields were 81% (21/26) for hyperlipidemia, 75% (6/8) for osteogenesis imperfecta, 64% (25/39) for metabolic disorders, 39% (10/26) for neurological disorders, and 28% (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation. Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients' subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0). [ABSTRACT FROM AUTHOR]

Objective: Catatonia is a neuropsychiatric condition occurring across the age spectrum and associated with great morbidity and mortality. While prospective cohorts have investigated catatonia incidence among psychiatric patients, no studies have comprehensively explored the incidence of catatonia in general hospitals. We examine the incidence of catatonia diagnosis, demographics of catatonia patients, comorbidities, and inpatient procedures utilized among pediatric patients hospitalized with catatonia in the United States. Methods: The Kids' Inpatient Database, a national all-payors sample of pediatric hospitalizations in general hospitals, was examined for the year 2019. Hospitalizations with a discharge diagnosis of catatonia were included in the analysis. Hospitalizations with catatonia as the primary discharge diagnosis were compared to hospitalizations with catatonia as a secondary discharge diagnosis. Results: A total of 900 (95% CI: 850–949) pediatric discharges (291 with catatonia as a primary diagnosis, 609 with catatonia as a secondary diagnosis) occurred during the study year. Mean age was 15.6 ± 2.6 years, and 9.9% were under age 13. Comorbidities were common among patients with catatonia, with psychotic disorders (165; 18.3%), major depressive disorder (69; 7.7%), bipolar disorder (39; 4.3%) and substance-related disorders (20; 2.2%) as the most common primary diagnoses. There was significant comorbidity with neurologic illness, developmental disorders, autism spectrum disorder, and inflammatory conditions. In total 390 catatonia discharges (43.3%) included at least one procedure during admission. Conclusions: catatonia is rarely diagnosed in pediatric patients in general hospitals but is associated with significant and severe psychiatric and medical comorbidities. Further research is needed into the optimal diagnosis, workup, and treatment of catatonia in pediatric patients. [ABSTRACT FROM AUTHOR]

Objective. We present a narrative review of pediatric catatonia and a case report illustrating the complexity of management of psychosis in a child with catatonia. Method. The literature search used the text terms pediatric, catatonia, and antipsychotics and the search engines PubMed and EBSCO. All references from peer-reviewed journals were reviewed for treatment strategies specific to management in children who are also psychotic. Findings. This 8-year-old girl presented with psychotic symptoms which were initially treated with antipsychotics and evolved into life-threatening catatonia that was eventually stabilized with a total daily dose of 46 mg of lorazepam. Lower doses led to recurrence. Once catatonia improved, she tolerated combined benzodiazepine and antipsychotic treatment. Long-term maintenance over 5 years required maintenance treatment with both benzodiazepines and antipsychotics to prevent relapse. Conclusions. The extraordinary doses of benzodiazepines found to be optimal for management of catatonia in this child led to improved alertness and orientation, without evident sedation. Catatonia did not recur with later management of psychosis using neuroleptics when added to lorazepam. The current literature on pediatric catatonia does not provide guidance on dose maintenance or when and if to rechallenge with antipsychotics. [ABSTRACT FROM AUTHOR]

Background. Catatonic features can appear in autism spectrum disorders (ASDs). There can be overlap in symptoms across catatonia and ASD. The overall aim of this review is to provide evidence for the presence of catatonic features in subjects with ASD. Methods. A systematic literature search using the Web of Science database from inception to July 10, 2021 was conducted following PRISMA, MOOSE guidelines and the PROSPERO protocol. (CRD42021248615). Twelve studies with information about catatonia and ASD were reviewed. Data from a subset was used to conduct meta-analyses of the presence of catatonia in ASD. Results. The systematic review included 12 studies, seven of which were used for the meta-analysis, comprising 969 individuals. The mean age was 21.25 (7.5) years. Two studies (16.6%) included only children and adolescents. A total of 70–100% were males. Our meta-analysis showed that 10.4% (5.8–18.0 95%CI) of individuals with ASD have catatonia. Motor disturb-ances were common in ASD subjects with catatonia. No differences were found in comorbidity. Several treatments have been used in ASD with catatonic features, including benzodiazepines, antipsychotics, and electroconvulsive therapy (ECT). The findings of the systematic review showed that ECT might help manage catatonic symptoms. Conclusions. Different features of catatonia can exist in individuals with ASD and core symptoms of catatonia are reported in ASD. Longitudinal and longer-term studies are required to understand the relationship between catatonia and ASD, and the response of catatonic symptoms to treatment. [ABSTRACT FROM AUTHOR]

Risperidone and aripiprazole, commonly used antipsychotics in children with autism spectrum disorder (ASD), have previously been associated with elevated fracture risk in other populations. The aim of this study was to evaluate and compare the risk of fracture among children with ASD using risperidone or aripiprazole. This was a retrospective, propensity‐score matched cohort study, set between January 2013 and December 2018. We used the MarketScan Medicaid insurance data, which covers multiple states of the United States. We included ASD children aged 2–18 years, who were new users of aripiprazole or risperidone and with no prior history of antipsychotic use or fractures. The main exposure was the continued use of aripiprazole or risperidone. The incidence rates of any fracture during follow‐up were evaluated, and the risk between aripiprazole and risperidone was compared via Cox‐proportional hazard models. Results were stratified by age, sex, duration of exposure and fracture site. In total, 3312 patients (78% male; mean [SD] age 11.0 [3.7] years) were identified for each cohort. Over the full duration of follow‐up, fracture incidence rates per 1000 patient‐years were 23.2 for risperidone and 38.4 for aripiprazole (hazard ratio and 95% confidence interval: 0.60 [0.44–0.83]). Risks were similar between cohorts throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. Extremity fractures drove most of the increased risk, with the biggest differences in lower leg and ankle fractures. Differences widened for children aged 10 years or younger (HR [95% CI]: 0.47 [0.30–0.74]). In conclusion, compared to aripiprazole, risperidone was associated with 40% lower risk of fracture. Further analysis on the mechanism and long‐term bone health of antipsychotic‐treated children with ASD is warranted. Lay summary We compared the risk of bone fractures among 6624 children with autism spectrum disorder (ASD), half of whom used risperidone and half of whom used aripiprazole. Taking other factors into account, risks were similar between the two groups throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. The biggest differences were in lower leg and ankle fractures. Overall, compared with aripiprazole, risperidone was associated with 40% lower risk of fracture. [ABSTRACT FROM AUTHOR]

The first documented pediatric use of Electroconvulsive therapy (ECT) occurred in Europe in 1941. Since then, predominantly successful treatments and reasonable side effects have been reported in severely ill minors. Nevertheless, a shy reluctance determines the controversy about ECT in young patients. This study describes the use of ECT in children and adolescents in Europe. We systematically searched the literature concerning the practice of ECT in minors in all 53 European countries. In addition, we surveyed European experts about national practices and compared guidelines for ECT in minors. The search yielded 79 publications from 18 European countries, mainly from Western Europe, Israel, and Turkey. National data were available from eight countries. These showed an interestingly high relationship between the number of minors treated with ECT and the general use of ECT. No persistent deficits or deaths were reported. On the other hand, no randomized clinical trial was found, and many publications lacked relevant information. Accordingly, the appraisal of the evidence in the guidelines varies considerably. Experts from 13 European countries consistently reported infrequent and unsystematic use of ECT in minors. ECT has been used successfully in minors in Europe with reasonable complications and side effects. Adverse effects on the developing brain, as often suspected, have not been scientifically supported in eight decades. Nevertheless, the use of ECT in Europe is sparse and dependent on accidental circumstances. High-quality evidence is needed, as well as improved knowledge and training of child and adolescent psychiatrists., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Clinically significant attention‐deficit/hyperactivity disorder (ADHD) symptoms are common and impairing in children and youth with autism spectrum disorder(ASD). The aim of this systematic review and meta‐analysis was to (a) evaluate the efficacy and safety of pharmacotherapy for the treatment of ADHD symptoms in ASD and (b) distil findings for clinical translation. Methods: We searched electronic databases and clinical trial registries (1992 onwards). We selected randomized controlled trials conducted in participants <25 years of age, diagnosed with ASD that evaluated ADHD outcomes (hyperactivity/impulsivity and inattention) following treatment with stimulants (methylphenidate or amphetamines), atomoxetine, alpha‐2 adrenergic receptor agonists, antipsychotics, tricyclic antidepressants, bupropion, modafinil, venlafaxine, or a combination, in comparison with placebo, any of the listed medications, or behavioral therapies. Data were pooled using a random‐effects model. Results: Twenty‐five studies (4 methylphenidate, 4 atomoxetine, 1 guanfacine, 14 antipsychotic, 1 venlafaxine, and 1 tianeptine) were included. Methylphenidate reduced hyperactivity (parent‐rated: standardized mean difference [SMD] = −.63, 95%CI = −.95,−.30; teacher‐rated: SMD = −.81, 95%CI = −1.43,−.19) and inattention (parent‐rated: SMD = −.36, 95%CI = −.64,−.07; teacher‐rated: SMD = −.30, 95%CI = −.49,−.11). Atomoxetine reduced inattention (parent‐rated: SMD = −.54, 95%CI = −.98,−.09; teacher/investigator‐rated: SMD = −0.38, 95%CI = −0.75, −0.01) and parent‐rated hyperactivity (parent‐rated: SMD = −.49, 95%CI = −.76,−.23; teacher‐rated: SMD = −.43, 95%CI = −.92,.06). Indirect evidence for significant reductions in hyperactivity with second‐generation antipsychotics was also found. Quality of evidence for all interventions was low/very low. Methylphenidate was associated with a nonsignificant elevated risk of dropout due to adverse events. Conclusions: Direct pooled evidence supports the efficacy and tolerability of methylphenidate or atomoxetine for treatment of ADHD symptoms in children and youth with ASD. The current review highlights the efficacy of standard ADHD pharmacotherapy for treatment of ADHD symptoms in children and youth with ASD. Consideration of the benefits weighed against the limitations of safety/efficacy data and lack of data evaluating long‐term continuation is undertaken to help guide clinical decision‐making regarding treatment of co‐occurring ADHD symptoms in children and youth with ASD. [ABSTRACT FROM AUTHOR]

Catatonia is a psychomotor syndrome with specific clusters of speech, behavioral and motor features. Although potentially life-threatening, especially in its malignant form accompanied with autonomic dysregulation and medical complications, it is a treatable condition, when promptly identified. For a long time catatonia was considered a marker of schizophrenia, thus limiting the possibility of diagnosis and treatment. Due to growing awareness and studies on the subject, it is now known that catatonia can occur in the context of a number of diseases, including psychotic, affective and neurodevelopmental disorders. In recent years, there's been a renewed interest in the recognition and definition of catatonia in neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD), where the differential diagnosis poses great challenges, given the considerable overlapping of signs and symptoms between the conditions. We present the case of a 15 year old boy with High Functioning ASD with a sudden onset of severe catatonic symptoms and the co-existence of psychotic symptoms, whose complex clinical course raises many questions on the differentiation and relation of said disorders. [ABSTRACT FROM AUTHOR]

Copyright of Apuntes Universitarios: Revista de Investigación is the property of Universidad Peruana Union Filiar Tarapoto and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and aims: Children with autism spectrum disorders (ASD) have been found to exhibit difficulties in wh -question production. It is unclear whether these difficulties are pragmatic or syntactic in nature. The current study used a question elicitation task to assess the production of subject and object wh -questions of children with ASD in two different languages (Hebrew and French) wherein the syntactic structure of wh -questions is different, a fact that may contribute to better understanding of the underlying deficits affecting wh -question production. Crucially, beyond the general correct/error rate we also performed an in-depth analysis of error types, comparing syntactic to pragmatic errors and comparing the distribution of errors in the ASD group to that of children with typical development (TD) and children with Developmental Language Disorder (DLD). Results: Correct production rates were found to be similar for the ASD and DLD groups, but error analysis revealed important differences between the ASD groups in the two languages and the DLD group. The Hebrew- and French ASD groups were found to produce pragmatic errors, which were not found in children with DLD. The pragmatic errors were similar in the two ASD groups. Syntactic errors were affected by the structure of each language. Conclusions: Our results have shown that although the two ASD groups come from different countries and speak different languages, the correct production rates and more importantly, the error types were very similar in the two ASD groups, and very different compared to TD children and children with DLD. Implications: Our results highlight the importance of creating research tasks that test different linguistic functions independently and strengthen the need for conducting fine-grained error analysis to differentiate between groups and gain insights into the deficits underlying each of them. [ABSTRACT FROM AUTHOR]

The prevalence of autism spectrum disorder (ASD) has increased in recent decades, much of which is related to changes in diagnostic criteria, and greater awareness among professionals and parents. Using a prospective cross-sectional study design, this study explores the prevalence of ASD among 173 adolescents admitted to two psychiatric facilities in Canada, and its association with some early pre and perinatal risk factors. The overall prevalence of ASD in the psychiatric population was 11.56% compared to 1.52% in children and youth in Canada. While prenatal and perinatal factors were not significantly associated with ASD, we found a frequent association of ASD with different comorbid psychiatric conditions. These findings further our knowledge in planning and management of ASD among this population., (© 2023. The Author(s).)

Copyright of Perspectives Psychiatriques is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

(1) Background: Compression garments (CGs) are an adjuvant treatment for generalized joint hypermobility (GJH), including the Ehlers--Danlos syndrome/hypermobility types. The effects of CGs are likely to be related to better proprioceptive control. We aimed to explore the use of CGs in individuals with autism and severe proprioceptive dysfunction (SPD), including individuals with GJH, to control posture and challenging behaviors. (2) Methods: We retrospectively described 14 patients with autism and SPD, including seven with comorbid GJH, who were hospitalized for major challenging behaviors with remaining behavioral symptomatology after the implementation of multidisciplinary approaches, including medication, treatment of organic comorbidities, and behavioral restructuring. Each patient received a CG to wear for at least 1 h (but most often longer) per day for six weeks. We assessed challenging behaviors in these participants with the Aberrant Behavior Checklist (ABC), sensory integration with the Dunn questionnaire, and postural sway and motor performance using a self-designed motricity path at baseline, two weeks, and six weeks. (3) Results: We observed a significant effect on most ABC rating scores at two weeks, which persisted at six weeks (total score, p = 0.004; irritability, p = 0.007; hyperactivity, p = 0.001; lethargy, p = 0.001). Postural control in dorsal and profile positions was significantly improved between before and after wearing the CGs (p = 0.006 and 0.007, respectively). Motor performance was also significantly improved. However, we did not observe a significant change in Dunn sensory scores. During the six-week duration, the treatment was generally well-tolerated. A comorbid GJH diagnosis was not associated with a better outcome. (4) Conclusions: CGs appear to be a promising adjuvant treatment for both behavioral and postural impairments in individuals with autism and SPD. [ABSTRACT FROM AUTHOR]

Background: Behavioral problems are an important issue for people with CHARGE syndrome. The similarity of their behavioral traits with those of people with autism raises questions. In a large national cross-sectional study, we used specific standardized tools for diagnosing autism (Autism Diagnostic Interview-Revised and Diagnostic and Statistical Manual of Mental Disorders, 5th edition, DSM-5) and evaluating behavioral disorders (Developmental Behavior Checklist-Parents, DBC-P) to investigate a series of individuals with CHARGE syndrome, defined by Verloes's criteria. We evaluated their adaptive functioning level and sensory particularities and extracted several data items from medical files to assess as potential risk factors for autism and/or behavioral disorders.Results: We investigated 64 individuals with CHARGE syndrome (35 females; mean age 10.7 years, SD 7.1 years). Among 46 participants with complete results for the Autism Diagnostic Interview-Revised (ADI-R), 13 (28%) had a diagnosis of autism according to the ADI-R, and 25 (54%) had a diagnosis of autism spectrum disorder (ASD) according to the DSM-5 criteria. The frequency of autistic traits in the entire group was a continuum. We did not identify any risk factor for ASD but found a negative correlation between the ADI-R score and adaptive functioning level. Among 48 participants with data for the DBC-P, 26 (55%) had behavioral disorders, which were more frequent in patients with radiological brain anomalies, impaired adaptive functioning, later independent walking, and more sensory particularities.Conclusions: ASD should be considered to be an independent risk requiring early screening and management in children born with CHARGE syndrome. [ABSTRACT FROM AUTHOR]

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Catatonia is a well-established psycho-motor disorder occurring in the background of various psychiatric and medical disorders. Catatonia is commonly associated with psychiatric disorders, especially affective disorders followed by schizophrenia. However, almost 20% occur in the background of different medical and neurological disorders which need to be properly examined and investigated. Catatonia is a serious medical and psychiatric emergency condition; most probably caused by alteration in GABAergic circuits and basal ganglia. If untreated, catatonia can cause life threatening complications like dyselectrolemia, respiratory aspiration, venous thromboembolism, acute renal failure and cardiac arrest because of poor oral intake, immobility and muscular rigidity. The risk of mortality or serious life threatening events further increases in cases of children and adolescents. In children and adolescents, thus, it becomes even more important to diagnose catatonia early and start appropriate treatment. Lorazepam is considered to be the first line treatment and is safe both in adults and children. But evidence is scarce for treatment of lorazepam-resistant adolescent Catatonia. In this report we discuss two adolescent patients diagnosed with catatonia with no medical or neurological disorders in the background. Neither of the patients responded to lorazepam alone or even after augmentation with second generation antipsychotic (olanzapine). Zolpidem, like lorazepam, has a positive allosteric effect on GABA A Receptors (GABAAR) and has been used in some cases successfully to treat resistant catatonia. Here we used zolpidem 30 mg/day in divided doses with marked improvement in few days in all the symptoms. Both cases were discharged on zolpidem extended release (ER) three times a day and maintained well through the next two follow ups in over a two month period. Zolpidem can be a good alternative for children and adolescents in resistant cases. [ABSTRACT FROM AUTHOR]

Background A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia. Methods Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq. Results Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3′ UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS. Conclusion These data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields. [ABSTRACT FROM AUTHOR]