BackgroundThe recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders.ObjectiveTo define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.MethodsWe collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.ResultsWhen compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations.ConclusionsThe 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

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Purpose:To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. Methods:Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging.Results: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers.Conclusions: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.

Chromosome 16p11.2 deletions and duplications are among the most frequent genetic etiologies of autism spectrum disorder (ASD) and other neurodevelopmental disorders, but detailed descriptions of their neurologic phenotypes have not yet been completed. We utilized standardized examination and history methods to characterize a neurologic phenotype in 136 carriers of 16p11.2 deletion and 110 carriers of 16p11.2 duplication-the largest cohort to date of uniformly and comprehensively characterized individuals with the same 16p copy number variants (CNVs). The 16p11.2 deletion neurologic phenotype is characterized by highly prevalent speech articulation abnormalities, limb and trunk hypotonia with hyporeflexia, abnormalities of agility, sacral dimples, seizures/epilepsy, large head size/macrocephaly, and Chiari I/cerebellar tonsillar ectopia. Speech articulation abnormalities, hypotonia, abnormal agility, sacral dimples, and seizures/epilepsy are also seen in duplication carriers, along with more prominent hyperreflexia; less, though still prevalent, hyporeflexia; highly prevalent action tremor; small head size/microcephaly; and cerebral white matter/corpus callosum abnormalities and ventricular enlargement. The neurologic phenotypes of these reciprocal 16p11.2 CNVs include both shared and distinct features. Reciprocal phenotypic characteristics of predominant hypo- versus hyperreflexia and macro- versus microcephaly may reflect opposite neurobiological abnormalities with converging effects causing the functional impairments shared between 16p11.2 deletion and duplication carriers (i.e., abnormal motor agility and articulation). While the phenotypes exhibit overlap with other genetically-caused neurodevelopmental disorders, clinicians should be aware of the more striking features-such as the speech and motor impairments, growth abnormalities, tremor, and sacral dimples-when evaluating individuals with developmental delay, intellectual disability, ASD, and/or language disorders. © 2016 Wiley Periodicals, Inc.

OBJECTIVE-We have previously described patterns of neonatal brain injury that correlate with global cognitive and motor outcomes. We now examine, in survivors of neonatal encephalopathy (presumed secondary to hypoxia-ischemia) without functional motor deficits, whether the severity and neuroanatomical involvement on neonatal magnetic resonance imaging (MRI) are associated with domain-specific cognitive outcomes, verbal (VIQ) and performance IQ (PIQ), at four years of age.METHODS-In this prospective study, neonatal MRIs of 81 term infants with neonatal encephalopathy were scored for degree of injury in two common patterns: watershed-distribution (WS) and basal ganglia-distribution (BG). Follow-up evaluation at four years of age by examiners blinded to clinical history and MRIs included a five-point neuromotor score and the Wechsler Preschool and Primary Scale of Intelligence -Revised. In 64 subjects with no functional motor impairment, test of trend was used to examine the association of ordered WS and BG MRI scores with mean VIQ and PIQ. RESULTS-LowerVIQs and PIQs were seen with increasing degree of injury on both WS and BG scales in univariate analyses (p≤0.05, all four analyses). When each MRI pattern score was adjusted for the other, only the association of decreasing VIQ with increasing WS injury remained significant (p=0.01; VIQ means across WS scores: 105-84). A suggestion of decreasing VIQ with increasing BG injury was also seen in the multivariate model (p=0.06; means across BG scores: 100-80), while no association was seen between PIQ and severity of injury in either MRI pattern.CONCLUSIONS-In survivors of neonatal encephalopathy without functional motor deficits at 4 years of age, an increasing severity of watershed-distribution injury is associated with more impaired language-related abilities.

Klinefelter (47, XXY) syndrome (KS), the most common form of sex-chromosomal aneuploidy, is characterized by physical, endocrinologic, and reproductive abnormalities. Individuals with KS also exhibit a cognitive/behavioral phenotype characterized by language and language-based learning disabilities and executive and attentional dysfunction in the setting of normal general intelligence. The underlying neurobiologic mechanisms are just now beginning to be elucidated through structural and functional neuroimaging. Here, we review the literature of structural and functional neural findings in KS identified by neuroimaging and present preliminary results from a functional magnetic resonance imaging study examining brain activity during a verb generation task in KS. KeywordsKlinefelter syndrome; XXY; MRI; neuroimage; Magnetic Resonance Imaging; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-PhotonThe 47, XXY karyotype is the most common form of sex-chromosomal aneuploidy, with an estimated prevalence in the general population between one in 500 and one in 1000 [Lanfranco et al., 2004]. The clinical manifestations associated with this genotype are referred to as Klinefelter syndrome (KS). Characteristic physical and medical attributes of infertility, small testes, gynecomastia, and tall body habitus with long legs are thought to result from testosterone deficiency [Wattendorf and Muenke, 2005]. Individuals with KS also exhibit a characteristic pattern of cognitive and behavioral dysfunction [Geschwind et al., 2000], which is reviewed NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in depth in another article in this issue [Boada et al., 2009]. In brief, the cognitive/behavioral phenotype includes language and language-based learning disabilities (similar to that observed in cytogenetically-normal children with dyslexia) as well as executive and attentional dysfunction [Lanfranco et al., 2004]. General intelligence appears to be within the typical range in men with KS, though global developmental delays in childhood include delayed language and (gross and fine) motor development [Wattendorf and Muenke, 2005].Though a characteristic KS cognitive phenotype is now recognized, relatively little is known about the underlying neural mechanisms [Geschwind et al., 2000;Reiss et al., 2000;Geschwind and Dykens, 2004;Giedd et al., 2007;van Rijn et al., 2008]. In this article, we review the current literature of studies beyond case-report status that used structural and functional neuroimaging techniques to further understanding of the neurobiologic mechanisms underlying cognitive and behavioral differences in KS. We begin by presenting studies of volumetric differences in KS, organized by neuroanatomic level of the brain findings, including (1) widespread brain differences and differences in ventricular size; (2) cerebral lobar and cerebellar differences; (3) differences in intra-individual asymmetries; and (4) regional differences. This is followed by a section discussing f...

Apraxia traditionally refers to impaired ability to carry out skilled movements in the absence of fundamental sensorimotor, language, or general cognitive impairment sufficient to preclude them. The child neurology literature includes a much broader and varied usage of the term developmental dyspraxia. It has been used to describe a wide range of motor symptoms, including clumsiness and general coordination difficulties, in various developmental disorders (including autistic spectrum disorders, developmental language disorders, and perinatal stroke). We argue for the need to restrict use of the term developmental dyspraxia to describe impaired performance of skilled gestures, recognizing that, unlike acquired adult-onset apraxia, coexisting sensory and motor problems may also be present.

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