This report describes the diagnostic and treatment course of an adult woman with the ultra-rare Au-Kline syndrome (AUKS). Since the age of 32 years, when the syndrome was yet undiagnosed, the patient suffered from behavioral decline coinciding with changes in living conditions. At the age of 38, following a bladder infection, she presented with a delirium for which antipsychotic medication was started. The delirium resolved but, while the medication was continued, the pre-existing behavioral symptoms persisted. Clinicpal genetic evaluation revealed a history of congenital hypotonia, developmental delay, and multiple (craniofacial) dysmorphisms. Subsequent trio-based genetic testing demonstrated a novel pathogenic variant in the HNRNPK gene, causative for AUKS. Clinical neuropsychological assessment showed moderate intellectual disability, slow information processing speed, restricted verbal expression, and limited comprehension. Registration of sensory information was severely hampered and there was difficulty in self-modulating the sensory information to be processed. Contextual adaptations and individual psychomotor therapy were then implemented to optimize sensory and motor information processing, to promote daily functioning, and reduce behavioral decline. These interventions, along with the long-term psychotropic medication, had beneficial effects on her functioning, which subsequently returned to near premorbid levels by the age of 45. Overall, this case underscores that the genetic and neuropsychological identification of a neurodevelopmental disorder, together with the integration of tailored psychomotor interventions and contextual adaptations, can improve psychiatric management and daily functioning, and mitigate behavioral decline in adulthood, even following a prolonged diagnostic delay.

Multiple theories describe a relation between different forms of learning and the concept of intelligence. In particular habituation, often considered the simplest form of learning, is linked to general, fluid intelligence. Previous research has established a moderate positive correlation between habituation in infancy and intelligence in childhood. However, no systematic review has explored whether this relation extends beyond infancy. This study presents the results of a systematic literature review aimed at addressing this question. A relatively limited set of published studies, mostly conducted before 1980, was found, exhibiting significant variability in participant characteristics, stimuli, and the measures used to assess both habituation and intelligence. In many instances, effect sizes could not be calculated. The results generally suggest an association between habituation rate and intelligence, though the strength and direction of this relationship are influenced by participant demographics and task specifics. This review explores potential underlying mechanisms and highlights conditions under which a simple measure of habituation rate could serve as an easily obtainable predictor of intelligence beyond infancy.

Kleefstra syndrome (KLEFS1) results from EHMT1 haploinsufficiency and is characterized by variable neurodevelopmental delays and psychopathology. Developmental regression, marked by the sudden loss of previously acquired daily life skills during late puberty or early adulthood, has emerged as a severe complication in individuals with KLEFS1. To investigate the clinical and molecular mechanisms underlying developmental regression and assess the therapeutic potential of olanzapine, we conducted a sequential study in an international cohort of 54 individuals with KLEFS1. Among 16 individuals treated with olanzapine, 10 exhibited a beneficial response based upon improvement of their adaptive functioning, and 4 showed temporary improvement. These clinical findings informed preclinical studies using human induced pluripotent stem cell-derived and ex-vivo cortical slices from a mouse model of KLEFS1. We identified hyperactivity in EHMT1+/- neuronal networks cocultured with EHMT1+/- astrocytes, a dysfunction reversible by olanzapine. Mechanistically, EHMT1+/- astrocytes displayed elevated levels of S100B, a neuroinflammatory marker contributing to neuronal network hyperactivity. Notably, olanzapine treatment reduced S100B levels, and pharmacological inhibition or genetic knockdown of S100B in EHMT1+/- astrocytes was sufficient to rescue the neuronal hyperactivity phenotype. These findings underscore a critical role for astrocytes in KLEFS1 pathophysiology and identify a potential cellular target for olanzapine in mitigating developmental regression.

Background/Objectives: Chronic alcohol use accelerates biological and cognitive aging, yet it remains unclear how cognitive aging progresses during abstinence in alcohol use disorder (AUD). It is also unknown to what extent this follows models such as accelerated aging or the age-related decline as proposed by the vulnerability hypothesis. This study examined age-related changes and cognitive recovery during abstinence in patients with AUD. Methods: A total of 197 clinically admitted patients, referred for detoxification and extensive neuropsychological examination, were included. Neuropsychological testing was administered in the second and sixth week of admission using well-normed instruments. Using both multi-assessment and cross-sectional data, relationships between age and normed cognitive outcome scores were examined. Results: After six weeks of abstinence, age-related deviations were observed for perceptual reasoning (PRI), verbal comprehension (VCI), and short-term memory (SMI) but not for ten other cognitive indices. During admission, age significantly influenced the change in belonging to a specific recovery category. Each additional year of age reduced the odds of showing no cognitive impairment by 5% and reduced the odds of cognitive recovery by approximately 4%, compared to non-improvers. Conclusions: Age-related influences appear limited to specific cognitive functions and do not follow a uniform or easily interpretable pattern. Perceptual reasoning seems negatively affected after age 60 for participants with six weeks of abstinence. Older participants showed a reduced likelihood of cognitive recovery and a reduced likelihood of having no cognitive problems at all. The findings do not support accelerated aging and are still too weak to be considered evidence for the vulnerability hypothesis. Implications for future research are discussed.

Introduction: Parenti-Mignot neurodevelopmental syndrome is caused by pathogenic variants of the CHD5 gene - involved in brain development - and is characterized by developmental delay, intellectual disability, and behavioral disturbances (i.e., autism spectrum disorder or related social problems, obsessive-compulsive tendencies, and aggressive behavior) as well as subtle facial dysmorphisms, epilepsy, hypotonia, and craniosynostosis. To date, cognition, behavior, and psychopathology in patients are either scarcely studied (in children, adolescents, and young adults) or not studied at all. Therefore, this case report aimed to provide additional insights into the cognitive and behavioral phenotype of Parenti-Mignot neurodevelopmental syndrome and discuss possibilities for support and treatment. Case Presentation: This study presents the case of a 54-year-old male with Parenti-Mignot neurodevelopmental syndrome (nonsense variant in the CHD5 gene), who struggles with mood problems and aggressive behaviors. Intelligence, cognitive functioning, and psychopathology are described by using neuropsychological assessment. Moderate to mild intellectual disability was found. Levels of adaptive functioning and performance on measures of attention, executive functioning, and memory were within the expected range considering intelligence level, whereas social cognition constituted a weakness within the profile. Additionally, results indicated internalizing and externalizing behavioral problems and deficits in emotion regulation skills. Conclusion: It is hypothesized that behavioral disturbances of patients with the Parenti-Mignot neurodevelopmental syndrome are likely to result from an underlying cognitive profile that is characterized by low intelligence, social cognitive impairments, and poor emotion regulation. CHD5 involvement in cortical brain development may be an explanation for these cognitive deficits. In clinical practice, neuropsychological assessment can provide helpful pointers for treatment and support in daily functioning.

Explicit memory dysfunction, such as in Alzheimer’s dementia, impairs learning and daily functioning, requiring effective rehabilitation strategies to promote functional independence. Relational learning paradigms such as stimulus equivalence learning (SEL) imply the formation of networks of relations in which trained relations give rise to emergent relations, potentially providing a novel approach to addressing deficits in remembering and stimulus control. We evaluated the scope and nature of research on the application of relational learning paradigms for memory rehabilitation. In particular, we outline the evidence for the efficacy of identity matching and SEL in specific disorders, the associated effective strategies, and challenges to guide future research. A systematic search following the PRISMA-ScR guidelines identified 23 reports categorized into identity matching, arbitrary matching, and differential outcome procedure (DOP) paradigms. Findings were mixed regarding the success of training procedures. Studies indicate particularly positive outcomes under the DOP and overall efficacy seemed to depend on impairment severity. However, current evidence on the efficacy of relational learning paradigms in individuals with explicit memory dysfunction remains inconclusive due to uncontrolled designs and methodological weaknesses in statistical analysis and patient reporting. Nevertheless, insights from the reviewed studies can inform more rigorous future research. The focus should be on identifying the necessary and sufficient conditions for training stimulus equivalence relations in this population, within meaningful and well-controlled experimental designs to validate the preliminary findings and assess SEL’s potential as a cognitive intervention.

Introduction:Levocarnitine is essential for brain functioning and fatty acid metabolism and stems largely from dietary sources. The Epsilon-Trimethyllysine Hydroxylase (TMLHE) gene encodes the enzyme N-Trimethyllysine hydroxylase (TMLH) which catalyses the first step in the biosynthesis of carnitine. Lack of TMLH enzyme activity is associated with developmental delay and autistic behaviours described as X-linked recessive autism, type 6 (OMIM#300872). Patient and Methods:Here, an institutionalized adult male patient with intellectual disability, autism, and challenging behaviours is presented in whom genetic analysis disclosed a novel pathogenic variant in the TMLHE gene. Extensive somatic, neurological, psychiatric, and neuropsychological investigations were performed next to examination of hematological and biochemical parameters including plasma carnitine status. Also, Whole Exome Sequencing (WES) and Next-Generation Metabolic Screening (NGMS) were performed. Results:Moderate intellectual disability along with obsessive and aggressive behaviour in the context of autism spectrum disorders was established as well as symptoms from the catatonic spectrum. With WES, a novel variant in the TMHLE gene was identified and using NGMS, increased concentration of trimethyllysine and decreased concentration of γ-butyrobetaine were found resulting in a significantly decreased BB/TML ratio, confirming the pathogenicity of this variant. Conclusion:X-linked autism type 6 is characterized by moderate intellectual disability and symptoms from the autism spectrum in the absence of any dysmorphisms. To prevent regressive autistic episodes in young children, it is highly recommended to consider next-generation sequencing techniques as the first step in the differential diagnostic process of autism.

Purpose This study aims to investigate the distinctive personality traits and characteristics of individuals with borderline intellectual functioning (BIF) and mild intellectual disability (MID) within specialized centers for MID-BIF treatment and care compared with individuals without MID-BIF diagnosis gathered from general mental health care (GMH) settings. Design/methodology/approach Patients classified with MID-BIF ( n = 58), most with comorbid psychopathology, were thoroughly interviewed by trained clinicians who afterward completed the Shedler–Westen Assessment Procedure (SWAP-200) about the patient. The authors compared SWAP-200 profiles of MID-BIF patients with profiles of GMH individuals. In addition, the authors have compared these profiles for the MID and BIF groups (differentiated based on previously known intelligence quotient scores). Findings Results show significantly higher scores for the MID-BIF group than the GMH group on scales encompassing emotional instability, impulsivity and antagonism. On scales containing constraint and healthy traits, significantly lower scores were found for the MID-BIF group than for the GMH group. Importance of including SWAP-200 personality assessment for a more comprehensive understanding and treatment planning for individuals with MID-BIF is discussed. Originality/value This study offers insights into personality within individuals with an MID-BIF diagnosis, compared with individuals in a GMH setting.

This case report aims to alert physicians to neuropsychological features and chromosomal variants that may underly resistant hypertension. We present a 35-year-old female patient with hypertensive crisis (BP 260/160 mmHg), initially treated with a combination of calcium antagonists, beta blockers, diuretics and angiotensin-converting enzyme (ACE)-inhibitors, though with little improvement. Cushing's syndrome, Conn's syndrome, and glucocorticoid receptor deficiency were ruled out. Multidisciplinary examination of medical history and (hetero)anamneses including psychosocial factors revealed mild dysmorphic body features, developmental delay, early diagnosis of autism spectrum disorder, a history of being bullied at school, little peer contact, learning disabilities, and special education. Neuropsychological assessment demonstrated below average to low average intelligence quotient, cognitive impairments, and psychopathology. Parallel genetic analyses revealed a rare 16p11.2 microdeletion syndrome. These concurrent examinations explained the patient's life-long high stress levels. After psychological treatment, with additional support at home, her blood pressure lowered to normal levels and antihypertensive drugs were no longer needed.

Background: Some genetic neurodevelopmental disorders (NDDs) are linked to a loss of acquired abilities. No universal term or severity measure exists for this phenomenon. This scoping review aims further to define developmental regression in NDDs of genetic etiology. Method: We used the PRISMA checklist and searched PubMed, medRxiv, and Google Scholar for developmental regression literature. After data extraction, qualitative (e.g., assessment methods) and quantitative (e.g., mentioned NDDs) data were analyzed. Results: A total of 59 relevant articles from 2074 unique records were identified, associating 18 NDDs of genetic etiology with developmental regression. Multiple terms (e.g., loss of skills, deterioration) and definitions were used across syndromes. Conclusions: A uniform definition of developmental regression was formulated based on literature diversity and NDD heterogeneity. The study also offers guidance on identifying and monitoring developmental regression and its underlying causes.

PTEN hamartoma tumor syndrome (PHTS) might be associated with a distinct cognitive and psychological profile. However, previous studies are limited, predominantly based on small and pediatric cohorts, likely affected by selection bias, and show a broad range of findings. We aimed to characterize the neuropsychological functioning of adults with PHTS. A total of 40 participants, with intellectual disability as exclusion criterium, completed an extensive clinical neuropsychological assessment including cognitive tasks, questionnaires, and a clinical diagnostic interview. The cognitive tasks and questionnaire data were categorized as below and above average based on 1.5 SD. About 80% of participants showed an average level of intelligence. In addition, 30% and 24% of participants scored below average on immediate memory recall and speed of information processing, respectively. Furthermore, about 25% reported above average scores on the majority of the questionnaires, indicating psychological distress, signs of alexithymia, and cognitive complaints. Personality of participants was characterized by inflexibility, social withdrawal, and difficulties in recognizing and describing their own emotions. Adults with PHTS demonstrate a heterogeneous yet distinct neuropsychological profile that is characterized by slower information processing, psychological problems, and specific personality traits. These findings provide directions on how to optimize the care and daily lives of adults with PHTS.

Cognitive and behavioral measures are used to assess executive functions. Previous research shows that these measures tap different underlying aspects. However, much less is known about this relationship, when assessed in the context of elementary education. The current study aims to contribute to this body of research by examining the relationship between cognitive and behavioral measures (rated by parents and teachers) of executive functioning in an elementary school context, using two study designs. In study 1, the relationship between behavioral measures (using the Behaviour Rating Inventory of Executive Function: BRIEF) and cognitive measures was examined in terms of inhibitory control, planning and organization abilities as well as processing speed using a sample of 51 children (8-10 years old). In study 2, the relationship between behavioral measures and cognitive measures of inhibitory control, cognitive flexibility, and working memory was studied in a sample of 27 children (8-10 years old). Spearman's rho coefficients were calculated between the BRIEF and neuropsychological tasks measuring the aforementioned cognitive functions. Only processing speed appeared to be positively related to parent- and teacher rated executive function problems: lower speed of information processing was associated with more executive function problems in daily life. No other correlation between cognitive and behavioral measures of executive functioning was statistically significant. These findings in the elementary school context confirm that cognitive and behavioral measures reflect different but complementary aspects of executive functioning. Furthermore, they suggest that behavior ratings of executive functioning might reflect general problems, such as slower speed of information processing.

Impaired executive functions (EF) have been found within various mental disorders (e.g., attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia spectrum disorders) as described in DSM-5. However, although impaired EF has been observed within several categories of mental disorders, empirical research on direct relations between EF and broader dimension of psychopathology is still scarce. Therefore, in the current investigation we examined relations between three EF performance tasks and self-reported dimensions of psychopathology (i.e., the internalizing, externalizing, and thought disorder spectra) in a combined dataset of patients with a broad range of mental disorders (N = 440). Despite previously reported results that indicate impaired EF in several categories of mental disorders, in this study no direct relations were found between EF performance tasks and self-reported broader dimensions of psychopathology. These results indicate that relations between EF and psychopathology could be more complex and non-linear in nature. We evaluate the need for integration of EF and dimensional models of psychopathology and reflect on EF as a possible transdiagnostic factor of psychopathology.

BackgroundNeurofibromatosis Type 1 (NF1) is a congenital neurocutaneous disorder. As NF1 is incurable and presents with a wide range of physical and mental symptoms, knowledge of neurocognitive and behavioral functioning can be an important aid in understanding their functional impact, and developing treatment options. To date, studies in children with NF1 have shown dysfunction in several domains, but much less is known about cognition and behavior in adults with NF1. The present study describes the neuropsychological phenotype of adults with NF1 based on comprehensive clinical examination of cognition and behavior across multiple functions.MethodsParticipants were 62 adults with NF1 (mean age 38.2 years; SD 13.4). All underwent individual clinical neuropsychological assessment at the Center of Excellence for Neuropsychiatry as part of regular care. Scores on all individual measures were standardized into z-scores based on the corresponding normative group data. The proportions of mean z-scores in the NF1 study group were calculated according to cut-off points (±1 to ±1.5 SD; > ±1.5 SD) and compared to the expected proportions in the normal population distribution. Cognition and behavior was tested against population means constructed by bootstrapping.ResultsPerformance on the cognitive measures oral reading speed, visuospatial copying, visuospatial immediate recall, visual learning/imprinting, and visual memory immediate recall in the NF1 group were lower than normative means. The behavioral measures indicated higher levels of dysfunction, including psychopathology. The proportions of the NF1 study group with lower cognitive performance and higher levels of behavioral dysfunction were larger than in the normal population distributions. In addition, domain-level results revealed that intelligence, attention/speed, memory, and social cognition reflect cognitive dysfunction. Moreover, levels of emotion perception problems, experienced executive dysfunction, internalizing psychopathology (e.g., anxiety, depression), and severe fatigue were significantly higher compared to the simulated population sample. The mean level of emotion regulation (coping strategies) did not differ significantly from the population.ConclusionIdentified cognitive and behavioral dysfunction in multiple domains indicates high vulnerability in adults with NF1 and underscores the importance of individualized neuropsychological assessment and treatment. Further research on the relationships between cognition and behavior (including fatigue) in NF1 is warranted.

In psychological assessment, employing a multi-method, multi-informant, and multi-conceptual approach is recommended (Bornstein, 2017). To enrich our understanding in evidence-guided composition of assessment instruments that encompass all these aspects, this study investigates the convergent validity of the SWAP-200 Personality Syndromes (PS) and Trait Dimensions (TD) scales with the MMPI-2-RF PSY-5-r scales, as well as the impact of divergent respondent types on process-focused validity in a clinical sample (n= 52). The study reveals several significant correlations between the SWAP-200 PS scales and MMPI-2-RF PSY-5-r scales that align with conceptual expectations, indicating convergent validity. While significant correlations were observed between TD and PSY-5-r scales, some of these deviated from expectations, most probably due to sample composition and respondent type. In all, results support previous research on the overlap between SWAP-200 scales and trait dimension measures, underscore the usage of both maladaptive dimensional traits (MMPI-2-RF PSY-5-r) and prototypes of personality functioning (SWAP-200 PS), and emphasize their utility as part of a multi-faceted approach in psychological assessment.

Individuals with the genetic disorder neurofibromatosis type 1 (NF1) are typically diagnosed in a medical hospital setting strongly relying on the presence of well-defined physical symptoms such as neurofibromas or pigmentary spots (known as café-au-lait spots). In mental health care settings, however, aside from a few highly specialized centres, the diagnosis and treatment of individuals with NF1 receives little attention, while the need for psychological treatment is increasingly identified, both in clinical practice and in the scientific literature. Occasional referrals of individuals with NF1 to the mental health services are often only targeted at psychological assessment. Subsequent treatment, however, is usually lacking. We describe two individuals with NF1 for whom by means of specialized clinical neuropsychological assessment, participation in a tailored dialectical behavior therapy (DBT) skills training was indicated. We exposit how they were able to develop their skills and how they themselves and their significant others experienced the treatment.

(1) Background: chronic alcohol use is consistently associated with impaired executive functioning, but its profile across the spectrum from mild to major alcohol-related cognitive impairment is, to date, unclear. This study aims to compare executive performances of patients with alcohol-induced neurocognitive disorder, including Korsakoff’s syndrome (KS), by using a computerized assessment battery allowing a fine-grained and precise neuropsychological assessment; (2) Methods: performances of 22 patients with alcohol-related cognitive impairment (ARCI) and 20 patients with KS were compared to those of 22 matched non-alcoholic controls. All participants were diagnosed in accordance with DSM-5-TR criteria and were at least six weeks abstinent from alcohol prior to assessment. Executive function was evaluated using four subtests of Cambridge Neuropsychological Test Automated Battery (CANTAB®); (3) Results: significant differences between groups were found on spatial working memory (updating), sustained attention and inhibitory control, set shifting, and planning. Healthy controls performed significantly better than both patient groups (Games-Howell post hoc; p < 0.05), but no differences in performance were found between the ARCI and KS group; (4) Conclusions: ARCI and KS patients showed significant executive impairments, most prominent in updating, set-shifting and general planning abilities. Findings suggest equivalent levels of executive function in ARCI and KS patients. Our results highlight executive function as a significant hallmark of alcohol-induced neurocognitive disorder and stipulate the importance of early assessment and evaluation of skills to guide treatment.

The maladaptive trait model of personality has gained popularity in the assessment of personality pathology. The Minnesota Multiphasic Personality Inventory (MMPI-2-RF) is a widely used instrument to measure maladaptive traits, by means of the Personality Psychopathology 5 (PSY-5-r) scales. Polarity of these maladaptive trait measures-whether these traits are unipolar or bipolar maladaptive-has not been empirically established in the literature. In a clinical sample (N = 275), we investigated content polarity of these traits in relation to 25 psychological symptoms, measured by the Patient Description Form. Hierarchical regression analyses were applied to compare linear and curvilinear models and determine optimal fit. The results provided evidence for content unipolarity of all five traits, with small exceptions. We conclude that, in practice, the MMPI-2-RF PSY-5-r scales do not assess the PSY-5 theoretical model as expected, such that the higher the score on these scales the more it is likely impairing or impacting daily functioning. Conceptual and clinical implications are discussed.

Objective Studies have reported inconsistent results regarding the extent to which neurocognitive recovery occurs in abstinent patients with alcohol use disorder (AUD). In addition to abstinence, other factors may have influenced this process and contributed to the inconsistencies. This review examines the factors investigated in this regard and describes the possible influence of each factor based on the evidence collected. Methodology PubMed was systematically searched for articles published between January 2000 and July 2023. Longitudinal humane studies investigating neurocognitive recovery in abstinent adult AUD patients were included. Studies with a cross-sectional design were excluded, as were studies that did not classify AUD according to the DSM-IV or 5 criteria, only examined binge use, did not report neuropsychological outcomes or duration of abstinence, or where neurological disorders were present. Results Sixteen categories of factors were distinguished from 31 full-text articles. Consistent patterns were found, indicating an association between neurocognitive recovery and the “smoking” and ‘brain volume” factors. Consistent patterns were also found indicating that there is no relationship with “quantities of alcohol used” and “education level.” A similar consistent pattern was also found for “polysubstance use”, “gender” and “verbal reading”, but the number of studies is considered limited. The association with “age” is studied frequently but with inconsistent findings. The remaining eight factors were regarded as understudied. Conclusion The clearest patterns emerging from the evidence are a predominantly negative influence of smoking on neurocognitive recovery, associations between changes in brain area volume and neurocognitive recovery, and no association between neurocognitive recovery and the amount of alcohol consumed, as measured by self-report, nor with educational attainment. Future research on the understudied factors and factors with inconsistent evidence is needed, preferably through longitudinal designs with multiple assessment periods starting after at least two weeks of abstinence.