2.0 CE Credits - Special Issue: The Neuropsychology of Neurodevelopmental Disorders (JINS 24:9, 2018): CE Bundle 1
- Describe the clinical features of Pitt-Hopkins Syndrome (PTHS).
- Discuss the unique phenotype of the present PTHS case study.
- Describe why a young child with sickle cell anaemia should be considered for early baseline neuropsychological assessment.
- List the subdomains of executive function where a child with sickle cell anaemia might show delay or deficits at preschool age.
- List the genes that have a critical influence on the cognitive, behavioural and adaptive profile of people with Williams syndrome.
- Discuss how genes influence cognitive, behavioural and adaptive characteristics in people with Williams syndrome.
- Describe verbal fluency abilities in youth with sex chromosome aneuploidies.
- Compare performance across groups as they differ as a function of extra X number and X vs. Y status.
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Neurodevelopmental disorders are conditions that involve early insult or abnormality in the developing central nervous system and are associated with a wide spectrum of abilities. These conditions begin during the early developmental period (usually conceptualized as prenatally though the first 3 years of life), affect day-to-day functioning, and are often lifelong. Because the “typical” development of the nervous system has been altered in individuals with neurodevelopmental disorders, reorganization and competition for function occur, usually resulting in skill patterns that are less efficient than among individuals without such conditions. The timing of these alterations or developmental disruptions is also relevant, as different neural systems are selectively vulnerable to injury at different phases of prenatal and post-natal development. As a result, the behavioral and cognitive dysfunction associated with early neural damage can range from subtle (or absent) to diffuse and profound. Moreover, the functional impairments can be observed immediately in some individuals, while in others, the full range of deficits may not manifest until later in life, even though the neurobiological basis of the condition is present earlier (Rudel, 1981).
Among children with neurodevelopmental disorders, the trajectory is often “off developmental track” relative to the trajectory of typically developing children. Developmental delays (i.e., patterns of skill development that should have occurred earlier in life) are often observed early in life. While functional catch-up is possible, it is often incomplete, and the resulting maturational timelines based on typical development become less applicable (Mahone, Slomine, & Zabel, 2018).
Neurodevelopmental disorders are highly prevalent. Recent estimates from the Centers for Disease Control and Prevention (CDC) in the United States show that around one in six, or approximately 17%, of children ages 3 through 17 years have one or more neurodevelopmental disabilities (Boyle et al., 2011). The rates also are increasing, and the CDC reports may underestimate the actual prevalence worldwide. In the past 25 years, medical advances have improved the life course of several genetic, medical, and neurodevelopmental conditions, making them more survivable and compatible with life (e.g., very low birth weight preterm infants, congenital hydrocephalus) and extending the expected lifespan of others (e.g., cystic fibrosis, sickle cell disease). Due to higher survival rates and lifespans extending into adulthood, increased attention has been given to the development of self-management and independence skills and the transition into older adolescence and young adulthood (Tarazi, Mahone, & Zabel, 2007; Warschausky, Kaufman, Evitts, Schutt, & Hurvitz, 2017; Zabel, Jacobson, & Mahone, 2013). Given these considerations, the assessment and study of individuals with neurodevelopmental disorders is of significant interest to neuropsychologists.
Classification of neurodevelopmental disorders can be conceptualized using two primary approaches, one emphasizing behavior (without explicit reference to etiology), and the other emphasizing etiological medical, genetic, and neurological factors (Mahone et al., 2018). In the field of neuropsychology, those neurodevelopmental disorders defined on the basis of behavior (including attention-deficit/hyperactivity Disorder, ADHD; learning disabilities, LDs; autism spectrum disorders, ASDs; and intellectual disability, ID) have received considerable emphasis, in part because of their prevalence and overall public health relevance (Leigh & Du, 2015; Mahone & Denckla, 2017; Mahone & Mapou, 2014). Neurodevelopmental disorders diagnosed on the basis of known or presumed medical etiologic factors have received somewhat less emphasis among neuropsychologists. Such conditions include those with genetic, environmental (injury, infection, teratogens), or multi-factorial medical etiologies.
This special issue of the Journal of the International Neuropsychological Society focuses upon such conditions with known medical or genetic etiologies, and includes 11 papers presenting innovative and novel data related to the neuropsychology (including identification of biomarkers) of specific neurodevelopmental disorders. Included in the issue are seven studies reporting new empirical findings, two critical reviews, and two case reports. The timing of this special issue follows on the heels of the 50th anniversary of the implementation of US PL-88-164 (“Mental Retardation Facilities Construction Act”), which, in 1967, provided financial support for the development 18 University Affiliated Programs (emphasizing treatment for neurodevelopmental disorders), and 12 Research Centers dedicated to research of neurodevelopmental disorders, all of which have contributed to the scientific innovations that have improved the lives of individuals with neurodevelopmental disorders and their families.
The issue begins with seven empirical studies, emphasizing disorders (both rare and more common) with genetic and associated medical etiologies, with samples ranging in age from early childhood through young adult. Williams syndrome is a rare genetic condition, often associated with intellectual disability and significant visuospatial dysfunction. In the first paper, Prieto-Corona and colleagues report on neuropsychological and functional outcomes in children with Williams syndrome, with and without the additional (even rarer) deletion of the GTF2IRD2 gene. They showed that those individuals with the additional genetic deletion had even greater dysfunction in visuospatial and social cognition, compared to those with without the deletion.
Antschel et al. report findings from a rich, 9-year longitudinal dataset of individuals with 22q11.2 deletion syndrome, a disorder associated with high risk for functional impairment and psychosis. They found that early executive function, especially working memory deficits, were associated with later functional impairment, but that the association was seen in both those with and without the disorder, highlighting the importance of early assessment of executive and cognitive control skills as predictors of later outcome.
There is considerable sexual dimorphism observed among individuals with neurodevelopmental disorders. The study of individuals with sex chromosome aneuploidies—conditions characterized by abnormal numbers of X or Y chromosomes, for example, Klinefelter syndrome (XXY) or Turner syndrome (XO)—provides a highly relevant framework to investigate the etiology of some sex differences in development and function. In this issue, Udhnani and colleagues and Maiman and colleagues report on a less studied variant of sex chromosome aneuploidies—those with trisomies, tetrasomies, and pentasomies—showing an association between these variants and reductions in verbal fluency, with severity of deficits related linearly to the number of supernumerary X chromosomes.
The dystrophinopathies (including Duchenne and Becker muscular dystrophies) are X-linked muscle diseases associated with abnormal expression of the protein dystrophin. These conditions affect primarily males and result in a wide range of functional cognitive deficits. Fee and colleagues report on neuropsychological performance in a sample of 50 boys with muscular dystrophy, grouped by gene mutation position relative to exon 43. They found that boys with mutation downstream from exon 43 showed greater academic deficits, relative to those with mutation upstream of exon 43.
Medical and surgical advances contribute to an increasing number of individuals surviving congenital heart disease (CHD) and its treatment. King et al. report on neuroimaging findings in a sample of adolescents and young adults with CHD, showing reduced cerebellar volumes, with reductions predictive of executive and cognitive control functions.
The manifestation of neurobehavioral dysfunction among children with neurodevelopmental disorders often occurs early in life. Downes and colleagues present a case control study of executive functions in preschoolers with sickle cell disease (SCD). In their sample, performance-based reductions in inhibitory control and cognitive flexibility were more pronounced than parent reports of similar functions, highlighting the importance of direct assessment of executive control skills in preschoolers with SCD.
Down syndrome (DS) represents the most common genetic etiology of intellectual disability, and is associated with a wide range of medical complications and skill difficulties, especially those implicating hippocampally mediated functions. Edgin and colleagues reported minimal effects of a fast-mapping strategy, hypothesized to incrementally improve word retention, but instead showed that individuals with DS do retain novel words effectively, but only when presented during learning trials in small groups. In a related review, Hammer and colleagues provide a succinct overview of structural anatomic neuroimaging studies of individuals with DS, highlighting widespread reductions in cerebral volume early in life, with smaller effects (relative reductions) observed by adolescence.
Neurofibromatosis type 1 (NF1) is a genetic neurocutaneous disorder associated with learning disabilities, ADHD, and an increased risk for brain tumors. Beaussart and colleagues provide a meta-analysis of 19 studies of individuals with NF1, emphasizing executive control skills. They concluded that, in general, working memory and planning skills were relatively more affected than inhibitory control in this population, and that relative difficulties (compared to those without NF1) tend to increase with age through adolescence.
The two final papers in this issue highlight the utility of case studies, especially in rare conditions. Tan et al. report on an individual with Pitt-Hopkins syndrome (PHS), a rare genetic disorder caused by insufficient expression of the TCF4 gene. Nearly all of the few prior published reports on PHS highlight severe intellectual and functional deficits and minimal language use. This case report instead presents findings from an individual who, despite many cognitive limitations, showed some relatively spared language function. In the final paper for this special issue, Kim et al. report on an intervention using different spacing methods to improve word list learning in a young adult with congenital amnesia secondary to premature birth and associated hypoxic-ischemic injury. They found that word recognition improved with repetitions spaced, rather than massed.
As illustrated in this set of papers, neuropsychological studies of neurodevelopmental disorders typically are conducted from a developmental perspective with an increasingly interdisciplinary approach that frequently draws upon (and informs) a refined understanding of endophenotypes and biomarkers. The ultimate hope, of course, is that these research approaches will inform more effective treatment and optimal developmental outcomes for the target populations.
It was a pleasure organizing these papers into this special issue, and we thank the authors for their contribution to this unique collection of studies demonstrating the importance of rigorous neuropsychological inquiry into neurodevelopmental conditions. It is our hope that the readers of the Journal of the International Neuropsychological Society find this collection valuable and are able to build off of the innovative and novel neuropsychological findings in the specific neurodevelopmental disorders presented within.
Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder caused by insufficient expression of the TCF4 gene. Most cases are characterized by severe intellectual disability, absent speech, motor delays, and autism spectrum disorder. Many have abnormal brain imaging,dysmorphic facial features, and medical comorbidities: myopia, constipation, epilepsy, and apneic spells. The present case study expands existing understanding ofthis disorder by presenting a unique phenotype with higher cognitive abilities and fewer medical comorbidities.
The present casestudy reports on a 13-year-old, Caucasian male with a recent diagnosis of PTHS following genetic testing (i.e., whole exome sequencing). He was referred for a neuropsychologicalevaluation to document his neurocognitive functioning to assist with intervention planning.
Evaluation of intellectual, attention/executive,memory, visual-motor/fine-motor, academic, adaptive, and emotional/behavioral functioning revealed global impairment across all areas of functioning. However, he demonstratedabilities beyond what has been detailed in the literature, including use of full sentences, capacity to learn and solve novel problems, basic academic functioning,and independent ambulation.
Children with PTHS may demonstrate a spectrum of abilities beyond what has been documented in theliterature thus far. Failure to recognize this spectrum can result in late identification of an accurate diagnosis. (JINS, 2018,
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Children with sickle cell anemia (SCA) are commonly reported to experience executive dysfunction. However, the development of executivefunction (EF) in preschool-age children without stroke in this patient population has not been investigated so it is unclear when and how these deficits emerge.
This case-control study examines the feasibility of assessing the early development of executive functioning in 22 preschool children years with SCAin the domains of processing speed, working memory, attention, inhibitory control, and cognitive flexibility, as well as everyday function, in comparison to matchedcontrol children.
A pattern of potential deficits in early emerging executive skills was observed in the domains of inhibitorycontrol and cognitive flexibility. Parents reported no differences for everyday EF and no significant differences were observed for working memory and processingspeed.
Results suggest that deficits in everyday executive difficulties, working memory, and processing speed, as commonlyreported for older children with SCA, may not yet have emerged at this early developmental stage, despite specific deficits in cognitive flexibility and inhibitorycontrol on behavioral measures. The feasibility of using available executive measures with preschool age children to characterize the development of early EF skillsis discussed. (JINS, 2018, 24, 949–954)
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Williams syndrome (WS) is a neurodevelopmental disorder that results from a heterozygous microdeletion on chromosome 7q11.23. Most of the time, the affected region contains~1.5 Mb of sequence encoding approximately 24 genes. Some 5–8% of patients with WS have a deletion exceeding 1.8 Mb, thereby affecting two additional genes, includingGTF2IRD2. Currently, there is no consensus regarding the implications of GTF2IRD2 loss for the neuropsychologicalphenotype of WS patients.
The present study aimed to identify the role of GTF2IRD2 in the cognitive,behavioral, and adaptive profile of WS patients.
Twelve patients diagnosed with WS participated, four with GTF2IRD2 deletion (atypical WS group), and eight without this deletion (typical WS group). The age range of both groups was 7–18 years old. Each patient’s 7q11.23 deletionscope was determined by chromosomal microarray analysis. Cognitive, behavioral, and adaptive abilities were assessed with a battery of neuropsychological tests.
Compared with the typical WS group, the atypical WS patients with GTF2IRD2 deletion had more impaired visuospatial abilities and more significant behavioralproblems, mainly related to the construct of social cognition.
These findings provide new evidence regarding the influenceof the GTF2IRD2 gene on the severity of behavioral symptoms of WS related to social cognition and certain visuospatial abilities. (
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Past research suggests that youth with sex chromosome aneuploidies (SCAs) present with verbal fluency deficits. However, most studieshave focused on sex chromosome trisomies. Far less is known about sex chromosome tetrasomies and pentasomies. Thus, the current research sought to characterize verbalfluency performance among youth with sex chromosome trisomies, tetrasomies, and pentasomies by contrasting how performance varies as a function of extra X number andX versus Y status.
Participants included 79 youth with SCAs and 42 typically developing controls matchedon age, maternal education, and racial/ethnic background. Participants completed the phonemic and semantic conditions of a verbal fluency task and an abbreviated intelligencetest.
Both supernumerary X and Y chromosomes were associated with verbal fluency deficits relative to controls. These impairmentsincreased as a function of the number of extra X chromosomes, and the pattern of impairments on phonemic and semantic fluency differed for those with a supernumeraryX versus Y chromosome. Whereas one supernumerary Y chromosome was associated with similar performance across fluency conditions, one supernumeraryX chromosome was associated with relatively stronger semantic than phonemic fluency skills.
Verbal fluency skills in youth withsupernumerary X and Y chromosomes are impaired relative to controls. However, the degree of impairment varies across groups and task condition. Further research intothe cognitive underpinnings of verbal fluency in youth with SCAs may provide insights into their verbal fluency deficits and help guide future treatments. (JINS,2018, 24, 917–927)
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