Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants.

BACKGROUND: Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (> 200 ASD-risk genes), no single gene variant accounts for > 1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. Gene-specific DNAm profiles have been shown to assist in the interpretation of variants of unknown significance. Therefore, we investigated the epigenome in patients with ASD or two of the most common genomic variants conferring increased risk for ASD. Genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450 and MethylationEPIC arrays in blood from individuals with ASD of heterogeneous, undefined etiology (n = 52), and individuals with 16p11.2 deletions (16p11.2del, n = 9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n = 7). RESULTS: DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from each other and from heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n = 9) and CHD8 (n = 13) variants as pathogenic or benign. Our findings that DNAm alterations in each signature target unique genes in relevant biological pathways including neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. CONCLUSIONS: DNAm signatures can provide clinical utility complementary to next-generation sequencing in the interpretation of variants of unknown significance. Our study constitutes a novel approach for ASD risk-associated molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.

Procedural learning and dyslexia.

Three major 'neural systems', specialized for different types of information processing, are the sensory, declarative, and procedural systems. It has been proposed (Trends Neurosci., 30(4), 135-141) that dyslexia may be attributable to impaired function in the procedural system together with intact declarative function. We provide a brief overview of the increasing evidence relating to the hypothesis, noting that the framework involves two main claims: first that 'neural systems' provides a productive level of description avoiding the underspecificity of cognitive descriptions and the overspecificity of brain structural accounts; and second that a distinctive feature of procedural learning is its extended time course, covering from minutes to months. In this article, we focus on the second claim. Three studies-speeded single word reading, long-term response learning, and overnight skill consolidation-are reviewed which together provide clear evidence of difficulties in procedural learning for individuals with dyslexia, even when the tasks are outside the literacy domain. The educational implications of the results are then discussed, and in particular the potential difficulties that impaired overnight procedural consolidation would entail. It is proposed that response to intervention could be better predicted if diagnostic tests on the different forms of learning were first undertaken.

Behavioural and neurophysiological correlates of dyslexia in the continuous performance task.

OBJECTIVE: To investigate whether attentional difficulties are a "core" feature of developmental Dyslexia. METHODS: Behavioural indices and event related potentials (ERPs) were recorded from 10 dyslexic participants (ages 15.5-17.4) and 10 control participants (ages 14.4-18.3) in the Continuous Performance Task (CPT), an established test of attentional performance. Participants were screened to ensure that none was diagnosable as attention deficit (ADHD). RESULTS: There were no significant differences in mean reaction time, error rate or sustained attention between the groups. By contrast, the P3 amplitude was significantly smaller and its latency significantly longer for the dyslexic group. This component was significantly lateralised in controls, whereas in dyslexics it was symmetrical. CONCLUSIONS: Under the relatively light workload conditions of the CPT, "pure" dyslexic participants showed no behavioural signs of attentional difficulties. The attenuated, delayed and symmetrical ERPs in our dyslexic group may reflect abnormal information processing in the right parietal lobe and abnormal interhemispheric asymmetry in Dyslexia. SIGNIFICANCE: The behavioural data suggest that abnormal attentional performance is not a "core" feature of developmental Dyslexia, and highlight the importance of distinguishing between dyslexic participants with and without ADHD symptoms. The presence of electrophysiological markers of Dyslexia in CPT revealed the atypical brain organisation that characterises "pure" Dyslexia.

Developmental dyslexia, learning and the cerebellum.

Theoretical frameworks for dyslexia must explain how the well-established phonological deficits and the literacy deficits arise. Our longstanding research programme has led to a distinctive 'twin level' framework that proposes, first, that the core deficits are well described in terms of poor skill automaticity. Second, these 'cognitive level' symptoms are attributed to abnormal cerebellar function--a 'brain-level' analysis. The evidence includes data from behavioural, imaging, neuroanatomical and learning studies. The frame-work leads to an 'ontogenetic' analysis that links cerebellar deficit at birth, via problems in articulation and working memory, to the known phonological, speed and literacy difficulties. Differences in locus of cerebellar impairment, experience and/or links to other brain regions may account for subtypes of dyslexia and possibly other developmental disorders. The automaticity/ cerebellar deficit framework provides an explicit demonstration that it is possible to explain motor, speed and phonological deficits within a unified account, integrating previously opposed approaches.

Brain structural mapping using a novel hybrid implicit/explicit framework based on the level-set method.

This paper presents a novel approach to feature-based brain image warping, by using a hybrid implicit/explicit framework, which unifies many prior approaches in a common framework. In the first step, we develop links between image warping and the level-set method, and we formulate the fundamental mathematics required for this hybrid implicit/explicit approach. In the second step, we incorporate the large-deformation models into these formulations, leading to a complete and elegant treatment of anatomical structure matching. In this latest approach, exact matching of anatomy is achieved by comparing the target to the warped source structure under the forward mapping and the source to the warped target structure under the backward mapping. Because anatomy is represented nonparametrically, a path is constructed linking the source to the target structure without prior knowledge of their point correspondence. The final point correspondence is constructed based on the linking path with the minimal energy. Intensity-similarity measures can be naturally incorporated in the same framework as landmark constraints by combining them in the gradient descent body forces. We illustrate the approach with two applications: (1) tensor-based morphometry of the corpus callosum in autistic children; and (2) matching cortical surfaces to measure the profile of cortical anatomic variation. In summary, the new mathematical techniques introduced here contribute fundamentally to the mapping of brain structure and its variation and provide a framework that unites feature and intensity-based image registration techniques.

Differentiating childhood-onset schizophrenia from psychotic mood disorders.

OBJECTIVE: The authors systematically examined a sample of patients who were referred to an ongoing National Institute of Mental Health (NIMH) study of childhood-onset schizophrenia (COS), but who received diagnoses of mood disorders at the NIMH, to analyze the reliability of these research-setting diagnoses and to characterize the patients clinically. Pilot data regarding the clinical course of these patients over a 2- to 7-year follow-up period were also obtained. METHOD: Thirty-three cases were selected from the 215 pediatric patients who had been screened in person from 1991 to 1999 for admission to the COS study. These 33 patients had been excluded from the COS study on the basis of a day-long evaluation, including a structured diagnostic interview, which yielded a diagnosis of a mood disorder rather than schizophrenia. This subgroup, together with six COS subjects (for a total N= 39), were included in a diagnostic reliability study in which they were reevaluated by three psychiatrists who were blind to the initial research diagnosis. In addition, pilot follow-up data regarding current function and treatment status were obtained for 25 of the 33 patients with mood disorders. RESULTS: Overall, the interrater reliability of the three raters was excellent (kappa = 0.90). Global reliability between these raters and the NIMH research diagnoses was good (average kappa across diagnoses = 0.61), and agreement for those patients who had mood disorders was good (86% agreement; kappa = 0.60). Pilot follow-up data indicate that none of the subjects with a diagnosed mood disorder developed a clinical course resembling schizophrenia. CONCLUSIONS: Many of the patients referred to the NIMH COS study with clinical diagnoses of schizophrenia had psychotic mood disorders diagnosed on the basis of a comprehensive research evaluation including structured diagnostic interviews, and these research diagnoses were reliable. The diagnosis of COS is difficult and requires a time-consuming evaluation process.

Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.

Neurodevelopmental models for the pathology of schizophrenia propose both polygenetic and environmental risks, as well as early (pre/perinatal) and late (usually adolescent) developmental brain abnormalities. With the use of brain mapping algorithms, we detected striking anatomical profiles of accelerated gray matter loss in very early-onset schizophrenia; surprisingly, deficits moved in a dynamic pattern, enveloping increasing amounts of cortex throughout adolescence. Early-onset patients were rescanned prospectively with MRI, at 2-year intervals at three time points, to uncover the dynamics and timing of disease progression during adolescence. The earliest deficits were found in parietal brain regions, supporting visuospatial and associative thinking, where adult deficits are known to be mediated by environmental (nongenetic) factors. Over 5 years, these deficits progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral prefrontal cortices, and frontal eye fields. These emerging patterns correlated with psychotic symptom severity and mirrored the neuromotor, auditory, visual search, and frontal executive impairments in the disease. In temporal regions, gray matter loss was completely absent early in the disease but became pervasive later. Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies. These emerging dynamic patterns were (i) controlled for medication and IQ effects, (ii) replicated in independent groups of males and females, and (iii) charted in individuals and groups. The resulting mapping strategy reveals a shifting pattern of tissue loss in schizophrenia. Aspects of the anatomy and dynamics of disease are uncovered, in a changing profile that implicates genetic and nongenetic patterns of deficits.

Developmental dyslexia: the cerebellar deficit hypothesis.

Surprisingly, the problems faced by many dyslexic children are by no means confined to reading and spelling. There appears to be a general impairment in the ability to perform skills automatically, an ability thought to be dependent upon the cerebellum. Specific behavioural and neuroimaging tests reviewed here indicate that dyslexia is indeed associated with cerebellar impairment in about 80% of cases. We propose that disorders of cerebellar development can in fact cause the impairments in reading and writing characteristic of dyslexia, a view consistent with the recently appreciated role of the cerebellum in language-related skills. This proposal has implications for early remedial treatment.

Smooth pursuit eye-tracking impairment in childhood-onset psychotic disorders.

OBJECTIVE: Although childhood-onset schizophrenia is relatively rare, a sizable group of children with severe emotional disturbances have transient psychotic symptoms that fall outside of current syndrome boundaries. The relationship of this group of children to those with childhood-onset schizophrenia and other childhood psychiatric disorders is unclear. In this study, the authors compared smooth pursuit eye tracking, a biological trait marker associated with schizophrenia, of children and adolescents with psychotic disorder not otherwise specified to that of children with childhood-onset schizophrenia and healthy comparison subjects. METHOD: By means of infrared oculography, smooth pursuit eye movements during a 17 degrees /second visual pursuit task were quantitatively and qualitatively compared in 55 young adolescents (29 with childhood-onset schizophrenia and 26 with psychotic disorder not otherwise specified) and their respective independent healthy comparison groups (a total of 38 healthy subjects). RESULTS: Subjects with childhood-onset schizophrenia had qualitatively poorer eye tracking, higher root mean square error, lower gain, and a greater frequency of catch-up saccades than healthy children. Subjects with psychotic disorder not otherwise specified also had qualitatively poorer eye tracking, higher root mean square error, and lower gain than healthy children, but saccade frequency did not differ significantly. CONCLUSIONS: Children with childhood-onset schizophrenia exhibit a pattern of eye-tracking dysfunction similar to that reported for adult patients. Similar abnormalities were seen in the subjects with psychotic disorder not otherwise specified except that they did not exhibit a greater frequency of catch-up saccades. Prospective longitudinal neurobiological and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders. Also, family studies are planned to establish whether eye-tracking dysfunction represents a trait- or state-related phenomenon in subjects with psychotic disorder not otherwise specified.

Children and adolescents with psychotic disorder not otherwise specified: a 2- to 8-year follow-up study.

Although psychotic phenomena in children with disruptive behavior disorders are more common than expected, their prognostic significance is unknown. To examine the outcome of pediatric patients with atypical psychoses, a group of 26 patients with transient psychotic symptoms were evaluated with clinical and structured interviews at the time of initial contact (mean age, 11.6 +/- 2.7 years) and at follow-up 2 to 8 years later. Measures of functioning and psychopathology were also completed at their initial assessment. Risk factors associated with adult psychotic disorders (familial psychopathology, eyetracking dysfunction in patients and their relatives, obstetrical complications, and premorbid developmental course in the proband) had been obtained at study entry. On follow-up examination (mean age, 15.7 +/- 3.4 years), 13 patients (50%) met diagnostic criteria for a major axis I disorder: three for schizoaffective disorder, four for bipolar disorder, and six for major depressive disorder. The remaining 13 patients again received a diagnosis of psychotic disorder not otherwise specified (NOS), with most being in remission from their psychotic symptoms. Among this group who had not developed a mood or psychotic disorder, disruptive behavior disorders were exceedingly common at follow-up and were the focus of their treatment. Higher initial levels of psychopathology, lower cognitive abilities, and more developmental motor abnormalities were found in patients with a poor outcome. Obstetrical, educational, and family histories did not differ significantly between the groups. Through systematic diagnostic evaluation, children and adolescents with atypical psychotic disorders can be distinguished from those with schizophrenia, a difference with important treatment and prognostic implications. Further research is needed to delineate the course and outcome of childhood-onset atypical psychoses, but preliminary data indicate improvement in psychotic symptoms in the majority of patients and the development of chronic mood disorders in a substantial subgroup.

Cerebellar tests differentiate between groups of poor readers with and without IQ discrepancy.

A comprehensive test battery, including phonological, speed, motor and cerebellar tasks, was administered to the entire cohort of two schools for children with learning disabilities. Testing was undertaken blind without accessing the psychometric data on the children. Children were then allocated to a discrepancy group on the basis of their IQ, with the majority (n = 29) classified as nondiscrepant (IQ < 90) and a smaller set (n = 7), with IQ of at least 90, classified as discrepant (with dyslexia). Both groups showed significant deficits relative to age-matched controls on almost all the tests. On phonological, speed, and motor tasks, the nondiscrepant group were at least as severely impaired as the discrepant group. By contrast, on the cerebellar tests of postural stability and muscle tone, the nondiscrepant group performed significantly better than the children with dyslexia and close to the level of the controls. The findings indicate that cerebellar tests may prove a valuable method of differentiating between poor readers with and without IQ discrepancy. The findings are interpreted in terms of the cerebellar deficit hypothesis for dyslexia.

Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21.

Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:749-753, 2000. Published 2000 Wiley-Liss, Inc.

An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without poststreptococcal exacerbations.

Patients with childhood-onset obsessive-compulsive disorder (OCD) with symptom exacerbations following streptococcal infections benefit from treatment with plasma exchange. In this study, 5 patients with treatment-refractory OCD without a history of streptococcus-related exacerbations underwent an open 2-week course of therapeutic plasma exchange. Behavioral ratings, completed at baseline and 4 weeks after the initial treatment, included the Clinical Global Impressions Scale and the Yale-Brown Obsessive Compulsive Scale. All 5 patients completed the trial with few side effects, but none showed significant improvement. Plasma exchange does not benefit children and adolescents with OCD who do not have streptococcus-related exacerbations.

Psychiatric disorders in first-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

OBJECTIVE: To determine the rates of psychiatric disorders in the first-degree relatives of children with infection-triggered obsessive-compulsive disorder (OCD) and/or tics (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; PANDAS). METHOD: The probands of this study were 54 children with PANDAS (n = 24 with a primary diagnosis of OCD; n = 30 with a primary diagnosis of a tic disorder). One hundred fifty-seven first-degree relatives (100 parents [93%] and 57 siblings [100%]) were evaluated for the presence of a tic disorder. One hundred thirty-nine first-degree relatives (100 parents [93%] and 39 of 41 siblings over the age of 6 [95%]) were evaluated with clinical and structured psychiatric interviews to determine the presence of subclinical OCD, OCD, and other DSM-IV Axis I disorders. RESULTS: Twenty-one probands (39%) had at least one first-degree relative with a history of a motor or vocal tic; 6 mothers (11%), 9 fathers (19%), and 8 siblings (16%) received this diagnosis. Fourteen probands (26%) had at least one first-degree relative with OCD; 10 mothers (19%), 5 fathers (11%), and 2 siblings (5%), received this diagnosis. An additional 8 parents (8%) and 3 siblings (8%) met criteria for subclinical OCD. Eleven parents (11%) had obsessive-compulsive personality disorder. CONCLUSIONS: The rates of tic disorders and OCD in first-degree relatives of pediatric probands with PANDAS are higher than those reported in the general population and are similar to those reported previously for tic disorders and OCD. Further study is warranted to determine the nature of the relationship between genetic and environmental factors in PANDAS.

Premorbid speech and language impairments in childhood-onset schizophrenia: association with risk factors.

OBJECTIVE: As both premorbid neurodevelopmental impairments and familial risk factors for schizophrenia are prominent in childhood-onset cases (with onset of psychosis by age 12), their relationship was examined. METHOD: Premorbid language, motor, and social impairments were assessed in a cohort of 49 patients with childhood-onset schizophrenia. Familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications were assessed without knowledge of premorbid abnormalities and were compared in the patients with and without developmental impairments. RESULTS: Over one-half of the patients in this group had developmental dysfunction in each domain assessed. The patients with premorbid speech and language impairments had higher familial loading scores for schizophrenia spectrum disorders and more obstetrical complications, and their relatives had worse smooth-pursuit eye movements. The boys had more premorbid motor abnormalities, but early language and social impairments did not differ significantly between genders. There were no other significant relationships between premorbid social or motor abnormalities and the risk factors assessed here. CONCLUSIONS: Premorbid developmental impairments are common in childhood-onset schizophrenia. The rates of three risk factors for schizophrenia (familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications) were increased for the probands with premorbid speech and language impairments, suggesting that the pathophysiology of schizophrenia involves the abnormal development of language-related brain regions.

Evaluating frequency proximity in stream segregation.

Consecutive sounds of similar structure that are close in frequency or pitch are more likely to be perceived as part of the same sequence than those at greater frequency separations. The principle of grouping into such perceptual sequences, or auditory streams, is known as frequency proximity. However, the metric by which one frequency difference is judged to be greater or less than another in complex auditory scenes is not yet known. Two experiments explored the metric for frequency proximity. We presented repeating three-tone stimulus patterns at a rate where they are normally heard as two streams, one containing the highest tone and one containing the lowest. The middle tone joined one stream or the other depending on its frequency. Subjects reported the perceived allocation of the variable tone by responding on a 5-point scale. The frequency at which either of these two percepts was equally probable was found to be lower than a logarithmic midpoint or the midpoints on a cochlear map or the Mel scale; that is, it was unlike metrics arrived at by direct comparisons of tones. Further, the midpoint for high and low tones presented synchronously was lower than that for the same tones presented sequentially, demonstrating that in addition to a proximity factor, some additional factor or factors must operate differently when the lower and upper fixed tones are, or are not, presented simultaneously.