Neuropsychological Profile of an Adolescent Female With Ectodermal Dysplasia With Hypohidrosis.

The ectodermal dysplasias are a group of rare genetic disorders that are caused by abnormalities in cell and tissue development of the embryonic ectoderm. A paucity of research has systematically examined the cognitive, academic, and psychological phenotype of individuals with ectodermal dysplasia. We describe the neuropsychological profile of a female adolescent with ectodermal dysplasia with hypohidrosis. Using a battery of standardized tests, we assessed the adolescent's intellectual functioning, language processing, visuospatial and visuomotor functioning, perceptual reasoning, sensory-motor functioning, memory, executive functioning, academic functioning, emotional and behavioral functioning, and adaptive functioning. Results from the testing indicated that the adolescent possessed relative verbal strengths, with scores generally falling in the low average to average range. However, she exhibited severe deficits in visuospatial functioning, visuomotor construction/organization, visuomotor integration, visual memory, executive functioning, reading, and math. She also presented with symptoms of anxiety and depression but had relatively strong adaptive skills. Based on the testing results from our evaluation, the adolescent met the criteria for specific learning disorders with impairment in reading and math, generalized anxiety disorder, and major depressive disorder. To our knowledge, this is the first case report to comprehensively characterize the full neuropsychological and academic profile of an adolescent female with ectodermal dysplasia with hypohidrosis. Recommendations from the evaluation are presented to inform clinical practice with, and future research of, this population.

Neurofibromatosis Type 1 Implicates Ras Pathways in the Genetic Architecture of Neurodevelopmental Disorders.

The genetic architecture of neurodevelopmental disorders is largely polygenic, non-specific, and pleiotropic. This complex genetic architecture makes the search for specific etiological mechanisms that contribute to neurodevelopmental risk more challenging. Monogenic disorders provide an opportunity to focus in on how well-articulated signaling pathways contribute to risk for neurodevelopmental outcomes. This paper will focus on neurofibromatosis type 1 (NF1), a rare monogenic disorder that is associated with varied neurodevelopmental outcomes. Specifically, this paper will provide a brief overview of NF1 and its phenotypic associations with autism spectrum disorder, attention-deficit/hyperactivity disorder, and specific learning disorders, describe how variation within the NF1 gene increases risk for neurodevelopmental disorders via altered Ras signaling, and provide future directions for NF1 research to help elucidate the genetic architecture of neurodevelopmental disorders in the general population.

An executive functioning perspective in neurofibromatosis type 1: from ADHD and autism spectrum disorder to research domains.

PURPOSE: Neurofibromatosis type 1 (NF1) is a rare monogenic disorder associated with executive function (EF) deficits and heightened risk for attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The goal of this paper is to understand how EFs provide a common foundation to understand vulnerabilities for ADHD and ASD within NF1. METHODS: A literature review and synthesis was conducted. RESULTS: EF difficulties in working memory, inhibitory control, cognitive flexibility, and planning are evident in NF1, ADHD, and ASD. However, relatively little is known about the heterogeneity of EFs and ADHD and ASD outcomes in NF1. Assessment of ADHD and ASD in NF1 is based on behavioral symptoms without understanding neurobiological contributions. Recent efforts are promoting the use of dimensional and multidisciplinary methods to better understand normal and abnormal behavior, including integrating information from genetics to self-report measures. CONCLUSION: NF1 is a monogenic disease with well-developed molecular and phenotypic research as well as complementary animal models. NF1 presents an excellent opportunity to advance our understanding of the neurobiological impact of known pathogenic variation in normal and abnormal neural pathways implicated in human psychopathology. EFs are core features of NF1, ADHD, and ASD, and these neurodevelopmental outcomes are highly prevalent in NF1. We propose a multilevel approach for understanding EFs in patients with NF1.This is essential to advance targeted interventions for NF1 patients and to advance the exciting field of research in this condition.

Pre- and Perinatal Ischemia-Hypoxia, the Ischemia-Hypoxia Response Pathway, and ADHD Risk.

This review focuses on how measured pre- and perinatal environmental and (epi)genetic risk factors are interrelated and potentially influence one, of many, common developmental pathway towards ADHD. Consistent with the Developmental Origins of Health and Disease hypothesis, lower birth weight is associated with increased ADHD risk. Prenatal ischemia-hypoxia (insufficient blood and oxygen supply in utero) is a primary pathway to lower birth weight and produces neurodevelopmental risk for ADHD. To promote tissue survival in the context of ischemia-hypoxia, ischemia-hypoxia response (IHR) pathway gene expression is altered in the developing brain and peripheral tissues. Although altered IHR gene expression is adaptive in the context of ischemia-hypoxia, lasting IHR epigenetic modifications may lead to increased ADHD risk. Taken together, IHR genetic vulnerability to ischemia-hypoxia and IHR epigenetic alterations following prenatal ischemia-hypoxia may result in neurodevelopmental vulnerability for ADHD. Limitations of the extant literature and future directions for genetically-informed research are discussed.

Association of Multidimensional Schizotypy with PID-5 Domains and Facets.

The underlying vulnerability for schizophrenia-spectrum disorders is expressed across a continuum of clinical and subclinical symptoms referred to as schizotypy. Schizotypy is a multidimensional construct with positive, negative, and disorganized dimensions. The present study examined associations of positive, negative, and disorganized schizotypy with pathological personality traits and facets assessed by the Personality Inventory for DSM-5 (PID-5) in 1,342 young adults. As hypothesized, positive schizotypy was associated with the PID-5 psychoticism domain and facets, negative schizotypy was associated with the detachment domain and facets and the restricted affectivity facet, and disorganized schizotypy's strongest associations were with the distractibility and eccentricity facets and the negative affect domain. The PID-5 facets accounted for upwards of two thirds of the variance in each schizotypy dimension. The authors conclude by providing regression-based algorithms for computing positive, negative, and disorganized schizotypy scores based on the PID-5 facets.

COMT and anxiety and cognition in children with chromosome 22q11.2 deletion syndrome.

The COMT gene is thought to contribute to the cognitive/psychiatric phenotypes in 22q11.2 deletion syndrome. We measured these manifestations against the Val/Met alleles of the COMT gene, in 40 nonpsychotic 22q11DS children. The Val allele was associated with poor IQ, processing speed, executive function and a higher frequency of anxiety disorders, underscoring the importance of the COMT gene in the childhood psychopathology in 22q11DS.

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.

Socioeconomic status and psychological function in children with chromosome 22q11.2 deletion syndrome: implications for genetic counseling.

The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes in the 22q11.2 interval is primarily responsible for the psychological manifestations, little is known about the role of the environment in either mitigating or contributing to these problems. We examined the association of parental socio-economic status (SES) with cognition and behavior in children with 22q11DS (n = 65) and matched healthy control subjects (n = 52), since SES is a component of family resources. We found that in children with 22q11DS, higher SES correlated with better overall functioning (p < .01) and social skills (p < .01), and less frequent oppositional defiant behavior (p < .001). These findings were in contrast to the control subjects in whom SES correlated with cognition and achievement, but not behavior. Our results indicate that environmental factors influence the behavioral phenotype in children with 22q11DS, providing a framework for developing appropriate interventions. As such, genetic counseling for families with 22q11DS may include consideration of family resources and inclusion of other health professionals, such as social workers, to explore with the family available social supports and resources.

Neurological soft signs in psychometrically identified schizotypy.

Patients with schizophrenia often exhibit structural brain abnormalities, as well as neurological soft signs (NSS), consistent with its conceptualization as a neurodevelopmental disorder. NSS are mild, presumably nonlocalizing, neurological impairments that are inferred from performance deficits in domains such as sensory integration, motor coordination, and motor sequencing. The vulnerability for schizophrenia is presumed to be expressed across a broad continuum of impairment referred to as schizotypy. It is hypothesized that nondisordered people along the schizotypy continuum should exhibit elevated rates of NSS. The present study examined the relation of psychometrically identified positive and negative schizotypy with NSS using the Neurological Evaluation Scale in a nonclinically ascertained sample of young adults (n=177). As hypothesized, negative, but not positive, schizotypy was related to increased NSS in tasks that assessed fine and gross motor coordination, motor sequencing, eye movement abnormalities, and memory recall. However, positive schizotypy was associated with increased NSS in tasks related to sensory integration dysfunction. In general, the positivexnegative schizotypy interaction term was unrelated to individual NSS tasks. The findings support: a) the theory that the vulnerability for schizophrenia is expressed across a broad continuum of subclinical and clinical impairment referred to as schizotypy; b) the multidimensional structure of schizotypy; and c) the notion that schizotypy is an appropriate construct for understanding the etiology and development of schizophrenia-spectrum disorders.