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PubMed2006

Amygdala dysfunction in men with the fragile X premutation.

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are associated with autism spectrum disorder in childhood, premature ovarian failure, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS, and perhaps the other clinical presentations among carriers, are thought to be due to toxic gain-of-function of elevated levels of the expanded-repeat FMR1 mRNA. Previous structural MRI studies have implicated the amygdala as a potential site of dysfunction underlying social deficits and/or risk for FXTAS. As a preliminary investigation of this possible association, adult males with the premutation, and male controls matched for IQ, age and education, completed three protocols that probe amygdala and sympathetic function: (i) a functional MRI paradigm that measures brain response to fearful faces; (ii) a fear-potentiated startle paradigm that differentiates responses to fearful faces and fearful non-social images and (iii) measurement of skin conductance level during a brief social encounter. Compared with controls, men with the FMR1 premutation demonstrated diminished brain activation in the amygdala and several brain areas that mediate social cognition while viewing fearful faces. The reduced amygdala activation in the premutation group was significantly associated with self-report of psychological symptoms on the Symptom Checklist-90--Revised. These men also displayed a lack of startle potentiation while viewing fearful faces and showed reduced skin conductance response when greeting an unfamiliar experimenter in comparison with the control group. The current findings may be related to social cognition deficits reported previously in children and adults with the premutation. The aetiology for this dysfunction may be elevated FMR1 mRNA or reduced FMR1 protein that occurs in carriers with higher premutation CGG repeat alleles.

Adult↗

PubMed2002

Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications.

15q11- q13 contains many imprinted genes, and undergoes duplicon-mediated rearrangements, including deletions, duplications and triplications, and generation of marker chromosomes. Abnormal phenotypes, including language delays and autism spectrum disorders, are primarily observed with maternal 15q11- q13 duplication. To determine possible epigenetic effects on expression within duplicated 15q11- q13 regions, we utilized RNA-FISH to directly observe gene expression. RNA-FISH, unlike RT-PCR, is polymorphism-independent, and it also detects relative levels of expression at each allele. Unamplified, gene-specific RNA signals were detected using cDNA probes. Subsequent DNA-FISH confirmed RNA signals and assigned parental origin by colocalization of genomic probes. SNRPN and NDN expression was detected primarily from paternal alleles. Control Dystrobrevin transcripts were detected equally from both alleles; however, maternal-UBE3A signals were consistently larger than paternal signals in normal fibroblasts and in neural-precursor cells. Larger UBE3A signals were also observed on one or both maternal alleles in a cell line carrying a maternal interstitial duplication, on both alleles of a maternally derived marker(15) chromosome, and occasionally on a paternal allele in a cell line carrying a paternal interstitial duplication. Expression of NDNL2, just distal to the duplicated region, was not markedly altered but paralleled changes in UBE3A expression. Excess total maternal-UBE3A RNA was confirmed by Northern blot analysis of cell lines carrying 15q11- q13 duplications or triplications. These results demonstrate that: (1) UBE3A is imprinted in fibroblasts, lymphoblasts and neural-precursor cells; (2) allelic imprint status is maintained in the majority of cells upon duplication both in cis and in trans; and (3) alleles on specific types of duplications may exhibit an increase in expression levels/loss of expression constraints.

Autoantigens↗

PubMed2006

Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase.

We applied genetic tools available in Drosophila to identify candidate substrates of the UBE3A ubiquitin ligase, the gene responsible for Angelman syndrome (AS). Human UBE3A was expressed in Drosophila heads to identify proteins differentially regulated in UBE3A-expressing versus wild-type extracts. Using two-dimensional gel and MALDI-TOF analysis, we detected 20 proteins that were differentially regulated by over-expression of human UBE3A in Drosophila heads. One protein responsive to UBE3A was the Rho-GEF pebble (pbl). Here, we present three lines of evidence suggesting that UBE3A regulates Pbl. First, we show genetic evidence that UBE3A and the Drosophila de-ubiquitinase fat facets (faf) exert opposing effects on Pbl function. Secondly, we find that both Pbl and ECT2, the mammalian orthologue of Pbl called epithelial cell transforming sequence 2 oncogene, physically interact with their respective ubiquitin E3 ligases. Finally, we show that Ect2 expression is regulated by Ube3a in mouse neurons as the pattern of Ect2 expression is dramatically altered in the hippocampus and cerebellum of Ube3a null mice. These results suggest that an orthologous UBE3A post-translational regulatory pathway regulates neuronal outgrowth in the mammalian brain and that dysregulation of this pathway may result in neurological phenotypes including AS and possibly other autism spectrum disorders.

Amino Acid Sequence↗

PubMed1994

Childhood-onset schizophrenia: an NIMH study in progress.

An ongoing study of the phenomenology, genetics, neuropsychology, physiology (eye tracking, autonomic responsivity), neuroimaging, biochemistry, and pharmacology of childhood-onset schizophrenia is described, and pilot data are presented for the first 22 subjects. Differentiation from autism "spectrum" disorders and other poorly defined, severe neurodevelopmental disorders is needed. Eye tracking and autonomic results are similar to patterns seen in later-onset schizophrenia and possibly more striking. Magnetic resonance imaging showed larger left frontal ventricular horn area for the schizophrenia subjects, larger left caudate, and lack of normal caudate asymmetry. Fluorodeoxyglucose positron emission tomography during an auditory continuous performance task revealed decreased right parietal/occipital glucose metabolic rate in the schizophrenia subjects, which may be secondary to poor attentional performance, and increased glucose metabolic rate in three left frontal regions, a left parietal region, and the right putamen. Clozapine has been effective and well tolerated in an open trial with 12 adolescents who responded poorly to typical neuroleptics; 16 subjects have been enrolled in a double-blind comparison of haloperidol and clozapine. Longitudinal study of this narrowly defined and possibly more homogeneous group of very early-onset schizophrenia subjects will be relevant to current neurodevelopmental theories addressing the role of puberty, progression of pathology, and continuity or discontinuity with later-onset schizophrenia.

Adolescent↗

PubMed2005

Magnetoencephalography identifies rapid temporal processing deficit in autism and language impairment.

Deficient rapid temporal processing may contribute to impaired language development by interfering with the processing of brief acoustic transitions crucial for speech perception. Using magnetoencephalography, evoked neural activity (M50, M100) to two 40 ms tones passively presented in rapid succession was recorded in 10 neurologically normal adults and 40 8-17-year-olds with autism, specific language impairment, Asperger syndrome or typical development. While 80% of study participants with intact language (Asperger syndrome, typical development, adults) showed identifiable responses to the second tone, which presented rapid temporal processing demands, 65% of study participants with impaired language (autism, specific language impairment) did not, despite having shown identifiable responses to the first tone. Rapid temporal processing impairments may be fundamentally associated with impairments in language rather than autism spectrum disorder.

Acoustic Stimulation↗

PubMed2006

Examination of the time between first evaluation and first autism spectrum diagnosis in a population-based sample.

Early identification of young children with an autism spectrum disorder (ASD) can lead to earlier entry into intervention programs that support improved developmental outcomes. The purpose of the present study was to examine identification and diagnostic patterns of children with ASD who live in a large metropolitan area. One hundred fifteen 8-year-old children diagnosed with ASD were identified from a population-based surveillance system at the Centers for Disease Control and Prevention. Primary variables of interest included earliest age of evaluation and earliest age of diagnosis identified from surveillance records, type of initial ASD diagnosis, evaluation sources that documented first ASD diagnosis, characteristics of professionals assigning first ASD diagnosis, and diagnostic tools used to aid the diagnostic process. We found that children with ASD identified by the surveillance system were initially evaluated at a mean of 48 months but were not diagnosed with ASD until a mean age of 61 months. There were no differences in timing of diagnosis based on sex or racial/ethnic classification, although degree of impairment associated with ASD predicted mean age at first evaluation and mean age at first ASD diagnosis. Most children were identified at non-school sources, such as hospitals and clinics; 24% of the sample did not receive a documented ASD diagnosis until entering school. Most practitioners (70%) did not use a diagnostic instrument when assigning the first ASD diagnosis. Implications for early identification of ASD are discussed.

Autistic Disorder↗

PubMed2006

A two-year follow-up on risk status identified by the checklist for autism in toddlers.

We examined the characteristics of children at 4 to 5 years of age who were correctly and incorrectly classified as "at risk" for an autism spectrum diagnosis using the Checklist for Autism in Toddlers (CHAT) at age 2 to 3 years. Information is provided on the stability of risk/disorder status over a 2-year period of early development. Participants were 19 children with autism and 11 children with other developmental disabilities who had all been administered the CHAT between 2 and 3 years of age (Time 1) and received diagnostic and developmental re-evaluations between 4 and 6 years of age (Time 2). The risk status of children was discussed based on the original CHAT authors' criteria for risk of autism and the Denver modification for risk. High levels of stability in risk/diagnostic status from Time 1 assessments to Time 2 assessments were noted. Specifically, the original CHAT criteria for medium to high risk of autism applied at Time 1 predicted Time 2 diagnostic classification for 83% of the sample, and the Denver modification of the CHAT risk criteria predicted Time 2 diagnostic classification for 93% of the sample. Implications of the findings are discussed as they relate to early screening and identification of autism spectrum disorders.

Adaptation, Psychological↗

PubMed2006

Immunizations, neonatal jaundice and animal-induced injuries.

PURPOSE OF REVIEW: To review the literature published within the last year on three topics essential to clinical pediatrics: immunizations, neonatal jaundice, and animal-induced injuries. RECENT FINDINGS: New vaccines that protect against meningococcus, pertussis and rotavirus are safe, effective and recommended for routine immunization. Young children remain a high priority for influenza vaccination while the world awaits further developments of avian influenza. Pneumococcal and varicella vaccinations have benefited many. Debate exists on how to screen for hyperbilirubinemia in neonates and new strategies are emerging to prevent it. There seems to be no link between hyperbilirubinemia and autism spectrum disorders. We have learned that rabies can be transmitted by transplantation; it remains a global public health problem and its incidence is frequently underestimated in developing nations. Lastly, brown recluse spider bites are often misdiagnosed. SUMMARY: The face of pediatric infectious disease is changing as we incorporate new vaccines into our routine practice. Rotavirus vaccine has significant implications for the health of children across the globe. The management strategy for neonatal jaundice continues to focus on screening and prevention. We need to devote more energy to combating rabies in countries where it is endemic.

Animals↗

PubMed2026

Prenatal diagnosis and genetic counseling of a de novo 10q11.22q11.23 duplication associated with a normal development at 12 months of age.

BACKGROUND: Copy number variants are an important source of genomic variations, ranging from pathogenic to benign. The 10q11.22q11.23 region contains complex low-copy repeats that predispose to recurrent deletions and duplications via nonallelic homologous recombination. While some reports associate duplications of this region with developmental delay, intellectual disability, and autism spectrum disorders, emerging evidence suggests that such duplications may also be observed in phenotypically normal individuals, indicating incomplete penetrance and variable expressivity. CASE PRESENTATION: A 35-year-old pregnant woman with an unremarkable obstetric history underwent amniocentesis at 20 weeks of gestation. Conventional karyotyping and copy number variation sequencing (CNV-seq) were performed. CNV-seq revealed a de novo 4.56 Mb duplication at 10q11.22q11.23. The duplication was classified as a variant of uncertain significance. After extensive genetic counseling, the parents elected to continue the pregnancy. At 40 weeks of gestation, a female infant was delivered by cesarean section with normal birth parameters. A comprehensive physical examination at birth revealed no abnormalities. At the 12-month follow-up, the infant demonstrated normal growth parameters and age-appropriate neurodevelopmental milestones, with no evidence of dysmorphic features, developmental delay, or other clinical concerns. CONCLUSION: This report describes a prenatal case of a de novo 10q11.22q11.23 duplication with a normal development at 12 months of age. Our findings contribute to the growing body of literature suggesting that duplications in this pericentromeric region may exhibit incomplete penetrance and variable expressivity, and in some cases, may represent benign familial or de novo variants without apparent clinical consequences.

10q11.22q11.23 duplication↗

PubMed2005

Adults with autism living at home or in non-family settings: positive and negative aspects of residential status.

BACKGROUND: Very little is known about the context of caregiving by parents of adults with autism or about the perceived impacts of continued patterns of co-residence vs. out-of-family living. In the present study, maternal assessments of residential status, involvement with adult children living in a non-family setting, and the impacts on mothers of their residential arrangements were examined. METHODS: Mothers from 133 families of adults (aged 22 years and older) with autism spectrum disorder (ASD) completed questionnaires as part of a longitudinal study on family caregiving. Mothers completed open-ended questions regarding the positive and negative aspects of their child's residential arrangement. Mothers also completed scaled questions regarding their satisfaction with their child's residential arrangement, the different ways in which people's lives change after a relative moves from the home, and the frequency of contact with their son or daughter. RESULTS: Mothers found co-residing with their adult child to be of greatest positive benefit to the family while those living apart found this residential arrangement of greatest benefit to the son or daughter with ASD. The greatest negative consequences for co-residing mothers were understood to fall on families, while mothers felt the majority of negative consequences for those that lived apart. There was a high level of contact and maternal involvement between the mother and adult child with ASD even after out-of-home placement. CONCLUSIONS: Residential status, as appraised by mothers, has varying impacts on the individual with ASD, on the family, and on mothers as individuals and caregivers. The present analysis suggests the multifaceted and highly contingent maternal experience associated with where her child with ASD lives. Among families whose children live elsewhere, there is an impressive amount of continued contact between these families and their son/daughter.

Adolescent↗

PubMed2005

Links between social and linguistic processing of speech in preschool children with autism: behavioral and electrophysiological measures.

Data on typically developing children suggest a link between social interaction and language learning, a finding of interest both to theories of language and theories of autism. In this study, we examined social and linguistic processing of speech in preschool children with autism spectrum disorder (ASD) and typically developing chronologically matched (TDCA) and mental age matched (TDMA) children. The social measure was an auditory preference test that pitted 'motherese' speech samples against non-speech analogs of the same signals. The linguistic measure was phonetic discrimination assessed with mismatch negativity (MMN), an event-related potential (ERP). As a group, children with ASD differed from controls by: (a) demonstrating a preference for the non-speech analog signals, and (b) failing to show a significant MMN in response to a syllable change. When ASD children were divided into subgroups based on auditory preference, and the ERP data reanalyzed, ASD children who preferred non-speech still failed to show an MMN, whereas ASD children who preferred motherese did not differ from the controls. The data support the hypothesis of an association between social and linguistic processing in children with ASD.

Autistic Disorder↗

PubMed2005

The genetic relationship between individual differences in social and nonsocial behaviours characteristic of autism.

Two types of behaviours shown in children - those reflecting social impairment and nonsocial obsessive repetitive behaviours - are central to defining and diagnosing autism spectrum disorders (ASDs). Parent and teacher data on social and nonsocial behaviours were obtained from a community sample of >3000 7-year-old twin pairs. Social and nonsocial behaviours were only modestly correlated, and it was found that some individuals had extreme scores on either social or nonsocial scales but not both. Genetic model-fitting showed that social and nonsocial behaviours are both highly heritable, but their genetic overlap is modest, with most of the genetic influence being specific to either social or nonsocial behaviours. Considering these behaviours separately might help clarify gene-brain-behaviour pathways in future research.

Autistic Disorder↗

PubMed2005

No effect of MMR withdrawal on the incidence of autism: a total population study.

BACKGROUND: A causal relationship between the measles, mumps, and rubella (MMR) vaccine and occurrence of autism spectrum disorders (ASD) has been claimed, based on an increase in ASD in the USA and the UK after introduction of the MMR vaccine. However, the possibility that this increase is coincidental has not been eliminated. The unique circumstances of a Japanese MMR vaccination program provide an opportunity for comparison of ASD incidence before and after termination of the program. METHODS: This study examined cumulative incidence of ASD up to age seven for children born from 1988 to 1996 in Kohoku Ward (population approximately 300,000), Yokohama, Japan. ASD cases included all cases of pervasive developmental disorders according to ICD-10 guidelines. RESULTS: The MMR vaccination rate in the city of Yokohama declined significantly in the birth cohorts of years 1988 through 1992, and not a single vaccination was administered in 1993 or thereafter. In contrast, cumulative incidence of ASD up to age seven increased significantly in the birth cohorts of years 1988 through 1996 and most notably rose dramatically beginning with the birth cohort of 1993. CONCLUSIONS: The significance of this finding is that MMR vaccination is most unlikely to be a main cause of ASD, that it cannot explain the rise over time in the incidence of ASD, and that withdrawal of MMR in countries where it is still being used cannot be expected to lead to a reduction in the incidence of ASD.

Autistic Disorder↗

PubMed2006

Autistic features in a total population of 7-9-year-old children assessed by the ASSQ (Autism Spectrum Screening Questionnaire).

BACKGROUND: The prevalence of autism is reported to be on the rise worldwide. Change of diagnostic criteria and a broadening of the concept of autism have been mentioned as contributing factors. Further studies of general populations are needed. The present study assessed the distribution of autistic features in a total population of children 7-9 years of age, and explored the impact of age, gender, informant, and participation bias on symptom report. METHODS: Teacher and parent forms of the Autism Spectrum Screening Questionnaire (ASSQ) were used in the "Bergen Child Study", a total population study of 9430 children aged 7-9 years. Completed teacher forms were returned for 97% and parent forms for 71% of the children. High-scorers were defined according to the ASSQ validation study by Ehlers, Gillberg, and Wing (1999). RESULTS: The distribution of ASSQ scores was found to be almost continuous. Of the children with both a teacher and a parent form, 2.1% were defined as high-scorers. Children without parent informed consent (i.e., anonymous children) obtained significantly higher teacher scores than those who had questionnaires completed by both parent and teacher. Adjusting prevalence for the anonymous children, the prevalence of high-scorers was 2.7% of the total population. Age did not affect symptom scores. Boys scored higher and parents reported more symptoms, particularly in girls. Agreement between informants was low to moderate. CONCLUSIONS: Autism symptoms are not uncommon in the general population of children. Our findings are consistent with the concept of autism as a spectrum. Non-responders had a higher load of autism symptoms than identified children, indicating that reports on the prevalence of autism in a responder group underestimate true prevalence. Large differences across informants suggested the need to gather information both from families and from schools when screening for autism spectrum disorders.

Age Factors↗

PubMed1994

Developmental prosopagnosia in Asperger syndrome: presentation and discussion of an individual case.

The case of a young man is presented who initially appeared to be quite normal and very intelligent, if somewhat immature. Profound prosopagnosia was discovered in the course of a psychological assessment. Closer investigation revealed definite autistic features of the Asperger type, and both conditions ran in the family in a milder form. Questions arising from observations and experiments as well as from the case history are discussed, and an attempt is made to elucidate some problems in the light of the original theories about these conditions. It is suggested that prosopagnosia may be an essential symptom in one of the autism spectrum disorders, perhaps of a specific subgroup of Asperger syndrome. Visual hypo-emotionality is suggested as a possible common denominator of the two conditions.

Adaptation, Psychological↗

PubMed2005

Cognitive and behavioural characteristics in blind children with bilateral optic nerve hypoplasia.

AIM: To describe cognitive and behavioural characteristics in a group of blind children with bilateral optic nerve hypoplasia (ONH). METHODS: Data from records, parents, teachers, and repeated developmental assessments of 13 blind children with ONH born in 1988-1998 were analysed. All children had neuroimaging and/or hormonal evidence of midline malformations. They were all blind and able to communicate with speech. RESULTS: Severe mood swings and temper tantrums were common, especially during the first years of life. Later in life, sluggish tempo, low frustration tolerance and a narrow range of interests were common. Autism had been diagnosed in 6/13 children, autistic-like condition (ALC) was found in another three. The behaviour of the remaining four children was not within the autism spectrum. Eight children had cognitive capacities within the normal or near-normal range; five had mental retardation. Autism/ALC was found in all cognitive subgroups. All children exhibited fluent speech and, of these, 12 had started to talk at the expected age, but had clear deficiencies in communicative ability. CONCLUSION: These children had a common pattern of behavioural characteristics including autism spectrum disorders independent of intellectual capacities.

Abnormalities, Multiple↗

PubMed2005

Hospitalisations from birth to 5 years in a population cohort of Western Australian children with intellectual disability.

AIMS: To describe the hospitalisation history in the first five years of life for all children born in Western Australia (WA) between 1983 and 1992 and diagnosed with intellectual disability (ID). METHODS: Unit record linkage of the WA Midwives Collection, WA Intellectual Disability Database, and the WA Hospital Morbidity Dataset provided the population database of WA born children with and without ID. Affected children were divided into those co-affected with autism spectrum disorders (ASD), and those whose ID had or had no known biomedical cause. Those without a biomedical cause were further subdivided into mild-moderate and severe categories. RESULTS: On average, ID affected children were more likely than non-affected children to be admitted to hospital (RR: 1.64; 95% CI 1.6 to 1.7), on more occasions (5.3 versus 2.2 admissions), for longer (29.6 versus 8.3 days), and for a larger range of clinical diagnoses. The only exception was the group of children co-diagnosed with ASD whose hospitalisation profile resembled more that of non-affected children. CONCLUSIONS: This total population study is unique because of the availability of the system of linkable population registers and administrative health databases in WA. The results indicated that this vulnerable population of children with ID has substantial medical needs. This paper points to the need for authorities to develop supportive programmes for this population especially in the current climate of de-medicalisation of ID. More research is not only needed on the welfare of the affected children but also on the impact of the substantial medical and other needs of affected children on the rest of their immediate and extended families.

Autistic Disorder↗

PubMed2006

Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism.

OBJECTIVE: To screen cDNA for NLGN3 and NLGN4 from lymphoblastoid cells from autistic subjects. METHODS AND RESULTS: 10 young autistic females and 30 non-autistic subjects were studied for alterations in two X linked genes, NLGN3 and NLGN4. A novel NLGN4 isoform lacking exon 4, which occurred de novo on the paternal allele, was identified in one of the autistic females. Monoallelic expression of NLGN4 was seen in this subject and in 11 of 14 informative autistic and non-autistic females using a single nucleotide polymorphism found at 3' UTR. Additionally, the NLGN3 transcript was present in two isoforms (with and without exon 7) in nine of 10 autistic females and in 30 non-autistic subjects, including parents of the autistic female having only the complete transcript with exon 7, and from the whole brain of a control. The novel truncated NLGN3 product may have a regulatory role, as reported in other proteins (for example, vasopressin receptor) by attenuating the function of the full length isoform, resulting in a reduction of the mature protein. Three dimensional protein structures were characterised using comparative modelling, and significant changes were suggested in the protein cores for these two neuroligin isoforms. CONCLUSIONS: Splice variants may lead to potentially abnormal neuroligins in the causation of autism spectrum disorders.

Alleles↗