Neurodevelopmental Disorders Research Articles

Whole-exome-based single nucleotide variants and copy number analysis for prenatal diagnosis of compound heterozygosity of SMPD4.

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with neurodevelopmental disorders with microcephaly, arthrogryposis, and structural brain anomalies. SMPD4 encodes a sphingomyelinase that hydrolyzes sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes. For the efficient prenatal diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using whole-exome analysis is required. A physical examination of the parents was performed. Karyotype and whole-exome analysis were performed for the fetus and the parents. A fetus with microcephaly and arthrogryposis; biallelic null variants (c.387-1G>A; Chr2[GRCh38]: g.130142742_130202459del) were detected by whole-exome sequencing (WES). We have reported for the first time the biallelic loss-of-function mutations in SMPD4 in patients born to unrelated parents in China. WES could replace chromosomal microarray analysis and copy number variation sequencing as a more cost-effective genetic test for detecting CNVs and diagnosing highly heterogeneous conditions.

Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome

BackgroundKabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. MethodsSingle-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n=4) versus controls (n=4). FindingsPathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation. InterpretationOur data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders. FundingThis study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children’s Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).

An Exploration of Organoid Technology: Present Advancements, Applications, and Obstacles.

Organoids are in vitro models that exhibit a three-dimensional structure and effectively replicate the structural and physiological features of human organs. This work examines the potential applications of organoid technology, as well as the challenges and future directions associated with its implementation. The manuscript was put together by conducting a comprehensive literature review, which involved an in-depth evaluation of globally renowned scientific research databases. The field of organoids has generated significant attention due to its potential applications in tissue development and disease modelling, as well as its implications for personalised medicine, drug screening, and cell-based therapies. The utilisation of organoids has proven to be effective in the examination of various conditions, encompassing genetic disorders, cancer, neurodevelopmental disorders and infectious diseases. The exploration of the wider uses of organoids is still in its early phases. Research shall be conducted to integrate 3D organoid systems as alternatives for current models, potentially improving both fundamental and clinical studies in the future.

Examining contributing factors for the implementation of inclusion students with disabilities from the perspective of university academics in Saudi Arabia

Inclusive education focuses on implementing education for individuals who do not follow typical learning trajectory and require special educational needs (SEN). Educational systems in many countries around the world, including Saudi Arabia, tend to implement and practise inclusive education in order to fulfill relevant international conventions and achieve educational standards of acceptable quality in educating children and young people with medical and neurodevelopmental conditions. This study seeks to reveal some of the factors that may help to overcome the obstacles faced in the implementation of inclusive education from the point of view of academics of special education in Saudi universities. To achieve this goal, the study used semi-structured interviews as its primary tool for data collection. Sixteen male and female faculty members specialized in special education in several Saudi public universities were interviewed. The data were analysed thematically. Two master themes were derived from the thematic analyses, 1) theoretical factors and 2) applied factors. Both master themes had several sub-themes. A number of factors were identified as helping to implement inclusive education thereby changing the behaviours and attitudes towards including students with disabilities Saudi context. It is suggested here that similar factors might exist in other countries in Middle East and beyond.

Measuring the Replicability of our own Research

In the study of transgenic mouse models of neurodevelopmental and neurodegenerative disorders, we use batteries of tests to measure deficits in behaviour and from the results of these tests, we make inferences about the mental states of the mice that we interpret as deficits in "learning", "memory", "anxiety", "depression", etc. This paper discusses the problems of determining whether a particular transgenic mouse is a valid mouse model of disease X, the problem of background strains, and the question of whether our behavioural tests are measuring what we say they are. The problem of the reliability of results is then discussed: are they replicable between labs and can we replicate our results in our own lab? This involves the study of intra- and inter- experimenter reliability. The variables that influence replicability and the importance of conducting a complete behavioural phenotype: sensory, motor, cognitive and social emotional behaviour are discussed. Then the thorny question of failure to replicate is examined: Is it a curse or a blessing? Finally, the role of failure in research and what it tells us about our research paradigms is examined.

Antioxidants, Hormetic Nutrition, and Autism.

Autism spectrum disorder (ASD) includes a heterogeneous group of complex neurodevelopmental disorders characterized by atypical behaviors with two core pathological manifestations: deficits in social interaction/communication and repetitive behaviors, which are associated with disturbed redox homeostasis. Modulation of cellular resilience mechanisms induced by low levels of stressors represents a novel approach for the development of therapeutic strategies, and in this context, neuroprotective effects of a wide range of polyphenol compounds have been demonstrated in several in vitro and in vivo studies and thoroughly reviewed. Mushrooms have been used in traditional medicine for many years and have been associated with a long list of therapeutic properties, including antitumor, immunomodulatory, antioxidant, antiviral, antibacterial, and hepatoprotective effects. Our recent studies have strikingly indicated the presence of polyphenols in nutritional mushrooms and demonstrated their protective effects in different models of neurodegenerative disorders in humans and rats. Although their therapeutic effects are exerted through multiple mechanisms, increasing attention is focusing on their capacity to induce endogenous defense systems by modulating cellular signaling processes such as nuclear factor erythroid 2 related factor 2 (Nrf2) and nuclear factor-kappa B (NF-&#954;B) pathways. Here we discuss the protective role of hormesis and its modulation by hormetic nutrients in ASD.

Human-specific insights into candidate genes and boosted discoveries of novel loci illuminate roles of neuroglia in reading disorders.

Reading disorders (RD) are human-specific neuropsychological conditions associated with decoding printed words and/or reading comprehension. So far only a handful of candidate genes segregated in families and 42 loci from genome-wide association study (GWAS) have been identified that jointly provided little clues of pathophysiology. Leveraging human-specific genomic information, we critically assessed the RD candidates for the first time and found substantial human-specific features within. The GWAS candidates (i.e., population signals) were distinct from the familial counterparts and were more likely pleiotropic in neuropsychiatric traits and to harbor human-specific regulatory elements (HSREs). Candidate genes associated with human cortical morphology indeed showed human-specific expression in adult brain cortices, particularly in neuroglia likely regulated by HSREs. Expression levels of candidate genes across human brain developmental stages showed a clear pattern of uplifted expression in early brain development crucial to RD development. Following the new insights and loci pleiotropic in cognitive traits, we identified four novel genes from the GWAS sub-significant associations (i.e., FOXO3, MAPT, KMT2E and HTT) and the Semaphorin gene family with functional priors (i.e., SEMA3A, SEMA3E and SEMA5B). These novel genes were related to neuronal plasticity and disorders, mostly conserved the pattern of uplifted expression in early brain development and had evident expression in cortical neuroglial cells. Our findings jointly illuminated the association of RD with neuroglia regulation-an emerging hotspot in studying neurodevelopmental disorders, and highlighted the need of improving RD phenotyping to avoid jeopardizing future genetic studies of RD.

Autism spectrum disorder identification with multi-site functional magnetic resonance imaging

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by enduring difficulties in social interaction and communication. People analyzed with ASD may display repetitive behaviors and limited interests. Autism is classified as a spectrum disorder, implying that the symptom intensity might range from mild to severe depending on the individual. To detect ASD in this paper an attribute feature graph approach is designed by using the stastical dependencies features that necessarily accomplish the diagnosis of ASD. In the first phase the features extracted are designed based on the functional magnetic resonance imaging (fMRI) data, in the next-step the attribute feature graph layer learns the features of the node information of various nodes by ASD classification. Further, in the third step, it is employed to independently extract distinguishing features from the functional connectivity matrices of the brain that are derived from fMRI. The custom convolutional neural network (CNN) used in this study is trained on a comprehensive dataset comprising individuals diagnosed with ASD and typically developing individuals. In the fourth stage, a prototype learning is developed to augment the classification performance of the custom-CNN. The experimental analysis further carried out states that the proposed model works efficiently in comparison with the existing system.

The results of early intervention neurodevelopmental therapy in premature infants at the age of four, according to the Bayley's III assessment tool

Introduction: The main goal of modern Neonatology is the survival of premature infants with as few problems as possible. The purpose is to preserve and care for the brain potential of Brain Care (Als H. 2006). Neurodevelopmental Care is provided to infants from birth to the age of three. It concerns infants who have developmental deficits or are at risk of developing neurodevelopmental disorders. The goal of Early Intervention is to promote child health, enhance existing and emerging abilities, minimize developmental delay, address existing or emerging motor, cognitive, and emotional deficits, as well as prevent cognitive, functional, and limited parents and the entire family environment. Purpose: The purpose of this research is to study the necessity and possibilities of early intervention and physiotherapeutic rehabilitation of premature infants, according to the Bayley III assessment scale. A clinical trial demonstrating the effect of Neurodevelopmental Education on premature infants, according to the measurements of the Bayley Scale. Method: This study was designed as a clinical trial between September 2017 and August 2023. It included one hundred premature infants who were recorded and equally divided between premature infants who received simple counseling according to early intervention therapy and not any type of Neurodevelopmental Education (Group A, 25 boys, 25 girls aged 1 month and 15 days) and premature infants who received Neurodevelopmental Education therapy immediately after their discharge from the NICU (Group B, 25 boys, 25 girls aged 1 month and 15 days). Both groups received Early Intervention Neurodevelopmental Care during their stay in the NICU. Therapy will be administered by the researcher and the staff trained by the researcher himself for a period of the last 12 years. The groups were evaluated at the age of 4 years using the Bayley Scale for Infant and Toddler Development, Third Edition (BayleyIII). It should be noted that the Bayley Scales for infant and toddler development will be examined and will serve as the research instrument of the current project. Finally, conclusions will be drawn based on the statistical analysis of the results obtained from the evaluation and comparison of the two groups.

Exome sequencing in four families with neurodevelopmental disorders: genotype-phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN.

Neurodevelopmental disorders (NDDs) are a clinically and genetically heterogeneous group of early-onset pediatric disorders that affect the structure and/or function of the central or peripheral nervous system. Achieving a precise molecular diagnosis for NDDs may be challenging due to the diverse genetic underpinnings and clinical variability. In the current study, we investigated the underlying genetic cause(s) of NDDs in four unrelated Pakistani families. Using exome sequencing (ES) as a diagnostic approach, we identified disease-causing variants in established NDD-associated genes in all families, including one hitherto unreported variant in RELN and three recurrent variants in VPS13B, DEGS1, and SPG11. Overall, our study highlights the potential of ES as a tool for clinical diagnosis.

A meta-analysis of the efficacy and safety of trofinetide in patients with rett syndrome.

Rett syndrome (RTT) is an uncommon inherited neurodevelopmental disorder that affects brain development, mostly in females. It results from mutation in MECP2 gene in the long arm (q) of the X chromosome. Trofinetide is a recently developed drug that has a neuroprotective effect on neurons, and it is our aim in this meta-analysis to evaluate its efficacy and safety in treating Rett syndrome patients. We searched 5 databases (PubMed, Scopus, Embase, Web of Science, and Cochrane Library databases) to identify randomized controlled trials (RCTs) comparing Trofinetide and placebo in patients with Rett syndrome until August 13, 2023.Our primary outcomes were the Clinical Global Impression-Improvement (CGI) and the Rett syndrome Behavior Questionnaire (RSBQ). We used Risk of Bias Assessment tool-2 (ROB2) to assess the methodological quality of the included randomized controlled trials. Three RCTs with a total of 325 patients were included with a follow-up duration ranging from one month to three months. 186 patients received the intervention drug (Trofinetide) and 138 received the placebo. Trofinetide was found to reduce CGI and RSBQ significantly more than placebo (MD = -0.35, 95% CI [-0.52 to -0.18], P 0.0001), (MD = -3.40, 95% CI [-3.69 to -3.12], P 0.00001) respectively. Most adverse events did not show any statistical difference between Trofinetide and the placebo. Trofinetide offers promise as a potential effective and safe therapeutic opportunity for a population without many available treatments, with improvements seen on both CGI and RSBQ assessments and no severe adverse effects reported.

Machine Learning Approach to Predict Autism Spectrum Disorder

Autism Spectrum Disorder is one of a group of neuro developmental disorders. ASD's are communication , social interactions, range of play and interests, processing and integrating sensory information. In our research we have used the algorithms like Random forest, SVC, ANN, Logistic regression and the Extra trees to predict that which person has the ASD.

A large and diverse brain organoid dataset of 1,400 cross-laboratory images of 64 trackable brain organoids

Brain organoids represent a useful tool for modeling of neurodevelopmental disorders and can recapitulate brain volume alterations such as microcephaly. To monitor organoid growth, brightfield microscopy images are frequently used and evaluated manually which is time-consuming and prone to observer-bias. Recent software applications for organoid evaluation address this issue using classical or AI-based methods. These pipelines have distinct strengths and weaknesses that are not evident to external observers. We provide a dataset of more than 1,400 images of 64 trackable brain organoids from four clones differentiated from healthy and diseased patients. This dataset is especially powerful to test and compare organoid analysis pipelines because of (1) trackable organoids (2) frequent imaging during development (3) clone diversity (4) distinct clone development (5) cross sample imaging by two different labs (6) common imaging distractors, and (6) pixel-level ground truth organoid annotations. Therefore, this dataset allows to perform differentiated analyses to delineate strengths, weaknesses, and generalizability of automated organoid analysis pipelines as well as analysis of clone diversity and similarity.

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role in feedforward and feedback synaptic inhibition, preventing run away excitation in neural networks. Hence, their dysfunction can lead to hyperexcitability and increased susceptibility to seizures. PV+ interneurons are also key players in generating gamma oscillations, which are synchronized neural oscillations associated with various cognitive functions. PV+ interneuron are particularly vulnerable to aging and their degeneration has been associated with cognitive decline and memory impairment in dementia and Alzheimer’s disease (AD). Overall, dysfunction of PV+ interneurons disrupts the normal excitatory/inhibitory balance within specific neurocircuits in the brain and thus has been linked to a wide range of neurodevelopmental and neuropsychiatric disorders. This review focuses on the role of dysfunctional PV+ inhibitory interneurons in the generation of epileptic seizures and cognitive impairment and their potential as targets in the design of future therapeutic strategies to treat these disorders. Recent research using cutting-edge optogenetic and chemogenetic technologies has demonstrated that they can be selectively manipulated to control seizures and restore the balance of neural activity in the brains of animal models. This suggests that PV+ interneurons could be important targets in developing future treatments for patients with epilepsy and comorbid disorders, such as AD, where seizures and cognitive decline are directly linked to specific PV+ interneuron deficits.

Examining the impact of a group treatment using cognitive and social cognition remediation for young offenders: The justice health NSW school-link advantage pilot study.

Young offenders experience higher rates of neurodevelopmental and mental health disorders than the general population, and significant access barriers to health treatment. Treatment combining Cognitive Remediation Therapy (CRT) and Social Cognition Remediation Therapy (SCRT) has demonstrated benefits for functional improvements and social development. However, there is limited information regarding group treatment programs in custodial settings for young offenders. This pilot study explores the effectiveness and feasibility of a group treatment program for youth offenders with cognitive deficits and mental health concerns in youth detention. The School-Link Advantage pilot study designed and tested a 10-week group treatment program combining CRT and SCRT for young offenders in custody. The closed groups incorporated interactive activities focussed on emotional recognition and regulation skills, optimizing executive functioning, understanding values, exploring belief systems, improving relationships, and safety planning. Of the 22 male participants recruited in an Australian Youth Justice Centre, 12 completed all aspects of the treatment program, reflecting a 54.5% completion rate in a typically challenging to engage population cohort. Results demonstrated significant improvements in the ability to store and retrieve information, recognize information, and control emotions. Planning and organizing skills also showed considerable development. This pilot study suggests that a combined CRT and SCRT group treatment program has the potential to effectively target cognitive challenges associated with mental health disorders in young offenders in custody. These promising outcomes suggest exploring randomized controlled trials with increased cultural sensitivity for diverse populations.

Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p &lt; 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A &gt; G (rs889022) and IVS10 + 32T &gt; A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p &lt; 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.

Neurobehavioral perspectives on autistic spectrum disorder

Understanding genetics and environmental influences in autism has been explored in greater depth in recent decades. However, the mechanism by which they converge that leads to autism still needs to be explored further. An autism diagnosis in DSM-5 results from a neurodevelopmental disorder hurting normal brain function, affecting communication and social interaction combined with restricted or repetitive patterns of behavior and interests. This paper reviews current work investigating how the underlying mechanism of the brain structure and function relates to the complex and aberrant behavioral manifestations of autism. Mapping this connection can provide us with a better understanding of autism signs and symptoms, making the process of accurate diagnosis more straightforward. As a complex neurobehavioral condition, autistic individuals process the environment and their interactions with others differently from those without autism. So, they make different perceptions and connections between themselves and the environment. Consequently, they will have difficulty communicating, forming relationships, and responding appropriately to their environment. It is this lifelong neurobehavioral dysfunction that prevents autistic individuals from adequately understanding what they perceive and the emotional expression of others. There will be differences in their mental states, how their brains work, and how their thinking processes will be affected by a neurodevelopmental disability.

Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo.

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

Harmonizing data on correlates of sleep in children within and across neurodevelopmental disorders: lessons learned from an Ontario Brain Institute cross-program collaboration

There is an increasing desire to study neurodevelopmental disorders (NDDs) together to understand commonalities to develop generic health promotion strategies and improve clinical treatment. Common data elements (CDEs) collected across studies involving children with NDDs afford an opportunity to answer clinically meaningful questions. We undertook a retrospective, secondary analysis of data pertaining to sleep in children with different NDDs collected through various research studies. The objective of this paper is to share lessons learned for data management, collation, and harmonization from a sleep study in children within and across NDDs from large, collaborative research networks in the Ontario Brain Institute (OBI). Three collaborative research networks contributed demographic data and data pertaining to sleep, internalizing symptoms, health-related quality of life, and severity of disorder for children with six different NDDs: autism spectrum disorder; attention deficit/hyperactivity disorder; obsessive compulsive disorder; intellectual disability; cerebral palsy; and epilepsy. Procedures for data harmonization, derivations, and merging were shared and examples pertaining to severity of disorder and sleep disturbances were described in detail. Important lessons emerged from data harmonizing procedures: prioritizing the collection of CDEs to ensure data completeness; ensuring unprocessed data are uploaded for harmonization in order to facilitate timely analytic procedures; the value of maintaining variable naming that is consistent with data dictionaries at time of project validation; and the value of regular meetings with the research networks to discuss and overcome challenges with data harmonization. Buy-in from all research networks involved at study inception and oversight from a centralized infrastructure (OBI) identified the importance of collaboration to collect CDEs and facilitate data harmonization to improve outcomes for children with NDDs.

Functional impairment and quality of life in newly diagnosed adults attending a tertiary ADHD clinic in Ireland.

Attention Deficit-Hyperactive Disorder (ADHD) is a neurodevelopmental disorder, often persisting into adulthood. To investigate the levels of functionality and quality of life (QoL) in adult patients newly diagnosed with ADHD and to compare with those without an ADHD diagnosis. Consecutive patients who were referred to and assessed in a tertiary adult ADHD clinic enrolled in the study. Diagnosis of ADHD was based on DSM-5 criteria. Functionality was measured using the Weiss Functional Impairment Rating Scale (WFIRS) and the Global Assessment of Functioning Scale (GAF). QoL was assessed with the Adult ADHD Quality of Life Questionnaire (AAQoL). Three-hundred and forty participants were recruited, 177 (52.1%) females. Of them 293 (86.2%) were newly diagnosed with ADHD. Those with ADHD had significant lower functionality as it was measured with the WFIRS and GAF, and worse QoL (AAQoL) compared to those without. In addition, a significant correlation between GAF and WFIRS was found. The results show that adults with ADHD have decreased functionality and worse QoL when compared against those presenting with a similar symptomatology, but no ADHD diagnosis. ADHD is not just a behavioural disorder in childhood, but a lifelong condition with accumulating problems that can lead to lower QoL and impaired functioning throughout adulthood.