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PubMed2006

Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.

Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients. Studies of genetic variation in African-American autism families are rare. Analysis of 557 Caucasian and an independent population of 54 African-American families with 35 SNPs within GABRB1 and GABRA4 strengthened the evidence for involvement of GABRA4 in autism risk in Caucasians (rs17599165, p=0.0015; rs1912960, p=0.0073; and rs17599416, p=0.0040) and gave evidence of significant association in African-Americans (rs2280073, p=0.0287 and rs16859788, p=0.0253). The GABRA4 and GABRB1 interaction was also confirmed in the Caucasian dataset (most significant pair, rs1912960 and rs2351299; p=0.004). Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253). These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype.

Autistic Disorder↗

PubMed2026

Reversible exacerbation of parkinsonism during epirubicin-cyclophosphamide chemotherapy in a patient with PTEN hamartoma tumor syndrome and young-onset Parkinson's disease.

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS), caused by germline loss-of-function variants in PTEN, typically manifests as macrocephaly, neurodevelopmental disorders, and cancer susceptibility. Parkinson's disease has not been recognized as part of its known neurological spectrum. METHODS: We describe the clinical course of a patient with a germline PTEN nonsense variant (p.Arg130Ter) who developed young-onset Parkinson's disease before being diagnosed with bilateral breast cancer. RESULTS: The patient developed asymmetric, levodopa-responsive parkinsonism at 35 years of age, with reduced bilateral striatal dopamine transporter uptake. During two cycles of epirubicin-cyclophosphamide chemotherapy, her previously well-controlled parkinsonism showed reproducible and severe exacerbations. Symptoms began several days after chemotherapy, reached their maximum severity approximately one week after treatment, and resolved completely within approximately two weeks without modification of her antiparkinsonian medications. No dehydration, electrolyte disturbance, infection, or exposure to dopamine-receptor antagonists was identified. The chemotherapy regimen was discontinued after the second episode because of the reproducible temporal association. CONCLUSIONS: This case demonstrates reproducible, fully reversible exacerbations of parkinsonism during epirubicin-cyclophosphamide chemotherapy in a patient with PHTS and young-onset Parkinson's disease. These episodes may reflect transient vulnerability of dopaminergic neurons to chemotherapy-related systemic stress, although the causal role of PTEN haploinsufficiency remains uncertain.

Humans↗

PubMed2005

Orthotopic liver transplantation from a living-related donor in an infant with a peroxisome biogenesis defect of the infantile Refsum disease type.

Peroxisomal biogenesis defects include a number of severe neurodevelopmental disorders, among which infantile Refsum disease (IRD) occupies the mildest end of the spectrum. Although high docosahexaenoic acid (DHA) and low phytanic acid diets can correct some of the biochemical defects, they have not consistently altered the progressive course of the disease. We carried out orthotopic liver transplantation (OLT) in a mildly symptomatic 6-month-old infant who was a sibling of a severely neurologically impaired older sister. After transplantation the clinical course of this young child appeared much improved by comparison to her older sister. She walked alone at 4 years, had acceptable social interaction and had a noticeable recovery of audition. After transplantation her biochemical parameters were significantly improved: phytanic acid and very long-chain fatty acid (VLCFA) serum concentrations decreased. Abnormal bile acids disappeared from plasma. Although the OLT did not result in a cure of the disorder, the clinical and biochemical results suggest that OLT should be considered in mildly symptomatic patients.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2005

Brief report: non-random X chromosome inactivation in females with autism.

Autism is a heterogeneous neurodevelopmental disorder with a 3-4 times higher sex ratio in males than females. X chromosome genes may contribute to this higher sex ratio through unusual skewing of X chromosome inactivation. We studied X chromosome skewness in 30 females with classical autism and 35 similarly aged unaffected female siblings as controls using the polymorphic androgen receptor (AR) gene. Significantly, increased X chromosome skewness (e.g., >80:20%) was detected in our autism group (33%) compared to unaffected females (11%). X chromosome skewness was also seen in 50% of the mothers with autistic daughters. No mutation was seen in the promoter region of the XIST gene reported to be involved in X chromosome inactivation in our subjects. X chromosome skewness has been reported in female carriers of other neurological disorders such as X-linked mental retardation, adrenoleukodystrophy and Rett syndrome.

Autistic Disorder↗

PubMed2005

Subtle executive impairment in children with autism and children with ADHD.

BACKGROUND: The executive functions of inhibition, planning, flexible shifting of actions, and working memory are commonly reported to be impaired in neurodevelopmental disorders. METHOD: We compared these abilities in children (8-12 years) with high functioning autism (HFA, n = 17), attention deficit-hyperactivity disorder (ADHD, n = 21) and healthy controls (n = 32). Response inhibition was assessed using the Stroop Color and Word Test (Golden, 1978). Problem solving, set-shifting, and nonverbal memory were assessed using three tasks, respectively, from the CANTAB (Cambridge Cognition, 1996): the Stockings of Cambridge task; the Intra-Dimensional/Extra-Dimensional set-shifting task; and the Spatial Working Memory task (SWM) with tokens hidden behind 3, 4, 6, and 8 boxes. RESULTS: There were no group differences on the response inhibition, planning, or set-shifting tasks. On the SWM task, children with HFA made significantly more between-search errors compared with controls on both the most difficult problems (8-box) and on the mid-difficulty problems (6-box); however, children with ADHD made significantly more errors compared to controls on the most difficult (8-box) problems only. CONCLUSION: Our findings suggest that spatial working memory is impaired in both ADHD and HFA, and more severely in the latter. More detailed investigation is needed to examine the mechanisms that differentially impair spatial working memory, but on this set of tasks there appears to be sparing of other executive functions in these neuropsychiatric developmental disorders.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Psychopathology in children and adolescents with autism compared to young people with intellectual disability.

Autism is a neurodevelopmental disorder with a specific pattern of behavioural, communication and social problems. Additional mental health problems are often poorly understood and undetected. This study investigates the level and pattern of emotional and behavioural problems in young people with autism compared with children with intellectual disability (ID). Subjects were 381 young people with autism and a representative group of 581 Australian young people with ID aged 4-18 years. Parents/carers provided details of the emotional and behavioural problems of their child using the Developmental Behaviour Checklist (DBC-P). Young people with autism were found to suffer from significantly higher levels of psychopathology than young people with ID. The implications of this finding are discussed.

Adolescent↗

PubMed2006

Genetic program of neuronal differentiation and growth induced by specific activation of NMDA receptors.

Glutamate and its receptors are expressed very early during development and may play important roles in neurogenesis, synapse formation and brain wiring. The levels of glutamate and activity of its receptors can be influenced by exogenous factors, leading to neurodevelopmental disorders. To investigate the role of NMDA receptors on gene regulation in a neuronal model, we used primary neuronal cultures developed from embryonic rat cerebri in serum-free medium. Using Affymetrix Gene Arrays, we found that genes known to be involved in neuronal plasticity were differentially expressed 24 h after a brief activation of NMDA receptors. The upregulation of these genes was accompanied by a sustained induction of CREB phosphorylation, and an increase in synaptophysin immunoreactivity. We conclude that NMDA receptor activation elicits expression of genes whose downstream products are involved in the regulation of early phases of the process leading to synaptogenesis and its consolidation, at least in part through sustained CREB phosphorylation.

Animals↗

PubMed2000

What risk factors tell us about the causes of schizophrenia and related psychoses.

Genetic, epidemiologic, and molecular studies concur that liability to schizophrenia is transmitted through the inheritance of a number of genes of relatively small effect, some of which are shared with other psychoses. Each of these susceptibility genes causes minor deviations that are relatively innocent in themselves, for example, increased lateral ventricular volume, schizotypal personality, or subtle cognitive difficulties. However, when an individual is unlucky enough to inherit several of these traits, their cumulative effect, often compounded by environmental hazards, propels that person over a threshold for the expression of frank psychosis. Early environmental risk factors for schizophrenia include urban and winter birth, fetal malnutrition and hypoxia, and possibly prenatal viral infections; these early hazards have only a modest risk-increasing effect, and operate in the context of genetic risk. Preschizophrenic children are more likely to have minor psychomotor and cognitive problems; low IQ has a linear relationship with risk for schizophrenia. However, schizophrenia is not simply a neurodevelopmental disorder, because risk factors have been identified that have their effects proximal to the onset of psychosis: drug abuse, immigrant status, and social adversity and isolation. Both genetic and environmental risk factors appear to operate across diagnostic categories and therefore support a dimensional model of psychosis.

Brain↗

PubMed2000

The molecular genetics of autism.

Autism is a severe neurodevelopmental disorder characterized by communication and social deficits and by stereotyped, repetitive behaviors. The syndrome of autism is highly heritable, is considered to be etiologically heterogeneous and is thought to be the result of multiple, interacting genes. It is more common than previously thought, and has a complex pattern of genetic transmission. From four recently completed genome-wide linkage screens of autism, distal 7q has emerged as the most prominent chromosomal region of interest. Additional support for 7q comes from autistic individuals with gross 7q cytologic abnormalities, and from linkage and association data in families with language and speech disorders. Chromosome 15q11-13 is also of interest because of numerous reports of macroscopic and molecular abnormalities in the region associated with Prader-Willi and Angelman syndromes. In this review, molecular aspects of these data, as well as future avenues of investigation, are discussed.

Autistic Disorder↗

PubMed1992

Domain specificity in conceptual development: neuropsychological evidence from autism.

To understand some aspects of conceptual development it is necessary to take cognitive architecture into account. For this purpose, the study of normal development is often not sufficient. Fortunately, one can also study neurodevelopmental disorders. For example, autistic children have severe difficulties developing certain kinds of concepts but not others. We find that whereas autistic children perform very poorly on tests of the concept, believes, they are at or near ceiling on comparable tasks that test understanding of pictorial representation. A similar pattern was found in a second study which looked at understanding of a false map or diagram: normal 4-year-olds showed a marked advantage in understanding a false belief over a false map, while the autistic subjects performed better on the map. These findings suggest that the concept, believes, develops as a domain-specific notion that is not equatable with "having a picture (map or diagram) in the head." This result supports the existence of a specialized cognitive mechanism, which subserves the development of folk psychological notions, and which is dissociably damaged in autism. We extend these ideas to outline a new model of the development of false belief performance.

Autistic Disorder↗

PubMedDate not supplied

Electroencephalographic sleep in schizophrenia: a critical review.

Several polysomnographic abnormalities seem to occur consistently in schizophrenic patients: impaired sleep continuity and reduced total sleep, reduced amounts of slow wave sleep, and reduced rapid eye movement (REM) sleep latency and defective REM rebound following REM deprivation. None of these findings is specific for schizophrenia, and only a subgroup of schizophrenic patients seem to have these abnormalities. It appears that reduced slow wave sleep may be related to a neurodevelopmental disorder related to the defect state in schizophrenia. The pathophysiological significance of the defective REM rebound and the REM sleep abnormalities in schizophrenia remain uncertain. Carefully designed studies are needed to further characterize the sleep disturbance in schizophrenia and to study them in relation to other, known pathophysiological changes in this disorder.

Cerebral Cortex↗

PubMed1996

Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism.

Immune factors such as autoimmunity have been implicated in the genesis of autism, a neurodevelopmental disorder. Since autoimmune response involves immune activation, the plasma levels of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), interleukin-12 (IL-12), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble intercellular adhesion molecule-1 (sICAM-1) were measured in autistic patients and age-matched normal controls. The levels of IL-12 and IFN-gamma were significantly (P < or = 0.05) higher in patients as compared to controls. However, IFN-alpha, IL-6, TNF-alpha, and sICAM-1 levels did not significantly differ between the two groups. Because macrophage-derived IL-12 is known to selectively induce IFN-gamma in T helper type-1 (Th-1) cells, it is suggested that IL-12 and IFN-gamma increases may indicate antigenic stimulation of Th-1 cells pathogenetically linked to autoimmunity in autism.

Autistic Disorder↗

PubMedDate not supplied

A study and review of developmental dysgraphia in relation to acquired dysgraphia.

A survey of developmental dysgraphia in a population of 259 normal 13- and 14-year-old schoolchildren has been carried out. The neurological characteristics of handwriting impairments in the 25 children with the poorest handwriting skills are described. These data form the basis of a clinical classification of developmental dysgraphia. A group of simple clinical tests of handwriting and associated functions are offered for routine use. Because they are based on neurological principles relating to acquired dysgraphia, the classification and testing format may be used for correlation with neuro-imaging in research studies. More importantly, they may also facilitate both counselling and remediation for a particular child. The test battery could be modified for use in epidemiological surveys of neurodevelopmental disorders.

Adolescent↗

PubMed1996

Wakefulness and arousal in neonates born to women with schizophrenia: diminished arousal and its association with neurological deviations.

Arousal at 3-4 days of age was blindly assessed during the course of a standardized neurological examination of offspring born to index women with schizophrenic (n = 20), schizo-affective (n = 12), affective (n = 19) and unspecified functional (n = 4) psychoses, as well as 70 offspring born to control women with no history of psychosis. The offspring of women with schizophrenia was the only index group to differ from controls in showing significantly reduced arousal. Among the offspring of schizophrenics, reduced arousal was associated with neurological abnormality and deviant sensitivity to stimulation but not with obstetric complications. Only a subgroup of schizophrenics' offspring showed these characteristics. Deviations in arousal, neurological status and sensitivity may be part of a more generalized pattern representing a possibly genetically based neurodevelopmental disorder evident within this particular group at heightened risk for schizophrenia.

Adult↗

PubMed1996

Congenital anomalies in relatives of schizophrenic probands may indicate a retinoid pathology.

Retinoic acid, the morphogenic derivative of vitamin A, has been shown to alter patterns of neurulation and to regulate the expression of many genes involved in central nervous system development. Retinoid toxicity can result in craniofacial, limb, digit, heart and urogenital abnormalities. Hydrocephalus, due to increased ventricular size and/or decreased size of the hind- or forebrain, occurs frequently. Comparison of the frequency and type of congenital anomalies in extended pedigrees of 12 Ashkenazi probands with schizophrenia and seven normal Ashkenazi control probands indicates that relatives of the schizophrenic probands present a gamut of both minor and major congenital anomalies similar to, but less severe than, those caused by retinoid excess or deficiency, and at a frequency significantly greater than in control pedigrees. Within schizophrenic pedigrees, those diagnosed with schizophrenia spectrum illnesses are more likely to present such anomalies than are non-spectrum members. Retinoic acid receptors are present in all parts of the cranial region and delivery of retinoids is exquisitely controlled throughout embryonic and fetal development. Alterations in the functioning of the retinoid cascade may have profound implications for neurodevelopmental disorders like schizophrenia.

Abnormalities, Multiple↗

PubMedDate not supplied

Frontal lobe dysfunction and everyday problem-solving: social and non-social contributions.

Everyday problem-solving involves both non-social executive processes, social and emotional processes, and draws upon social and practical knowledge. A series of studies including both adult-acquired lesions and neurodevelopmental disorders is reviewed examining problem-solving on a real-life-type task that involves generating a range of solutions to brief problem scenarios and selecting preferred solutions to solve the problems. Impairments in problem-solving are described in groups of participants with left anterior frontal lobe lesions, Tourette's syndrome and Asperger's syndrome. By contrast, healthy older people did not show problem-solving deficits on the same task. The possible contributions of non-social executive skills, social and emotional skills, and knowledge acquired from experience are each considered in relation to everyday performance. Multiple cognitive/emotional routes to the development of everyday life difficulties pose a complex challenge both in understanding the nature of the relevant processes and in developing adequate methods for management and rehabilitation.

Adolescent↗

PubMed2005

N-methyl-D-aspartate subunit expression during mouse development altered by in utero alcohol exposure.

OBJECTIVE: Alcohol-related neurodevelopmental disorders are contributors to long-term learning disabilities. By using a model for fetal alcohol syndrome, we have shown that prenatal alcohol exposure results in adult learning deficits of unknown mechanisms. In the developing hippocampus, the N-methyl-D-aspartate (NMDA) receptor subunit NR2B triggers long-term potentiation, fundamental to learning and memory; this is supplemented by the less plastic NR2A subunit in the adult. To understand the mechanism of learning deficits in FAS, we evaluated NR2B and NR2A expression in embryonic and adult mice. STUDY DESIGN: Pregnant C57Bl6/J mice were treated on gestational day 8 with alcohol or control (saline solution). Embryos were harvested at 6 hours, 24 hours, and 10 days, and brains from adult offspring were collected at 3 months (after evaluation for learning deficit). Calibrator-normalized relative real-time polymerase chain reaction was performed for NR2B and NR2A with glyceraldehyde-3-phosphate dehydrogenase standardization. Statistical analysis included analysis of variance. RESULTS: At 6 hours, NR2B expression in the alcohol-exposed embryos was higher than in controls (P < .01). NR2A was not expressed in either group. By 24 hours there was no difference in NR2B (P = .3). However, at 10 days NR2B was lower in alcohol-exposed animals (P = .02). In the adult brains there was a relative decrease in NR2B (P = .03) and an increase in NR2A (P < .01). CONCLUSION: Prenatal alcohol exposure during development induces NR2B expression deregulation in the embryos that persists until adulthood, when a relative increase in the less modifiable subunit NR2A occurs. This alteration in NMDA receptor subunits may underlie the learning abnormalities in fetal alcohol syndrome.

Animals↗

PubMed2006

Binge alcohol exposure during all three trimesters alters bone strength and growth in fetal sheep.

Women who drink while pregnant are at a high risk of giving birth to children with neurodevelopmental disorders. Heavy consumption of alcohol during pregnancy is also known to be deleterious to fetal bone growth in both humans and laboratory animals. However, nothing is known regarding the effect of maternal moderate and heavy alcohol binging on fetal and maternal bone strength. The purpose of this study was to determine the effects of moderate and heavy alcohol binging throughout gestation on fetal and maternal bone growth and strength. The study was conducted using an ovine model system. The large body mass of the ovine fetus, the longer gestation that is more similar to that of humans, and the fact that all three trimester equivalents occur in utero, make the sheep an excellent model for studying Fetal Alcohol Spectrum Disorder. Suffolk ewes were mated and, beginning on gestational day 4, received intravenous infusions over 1 h on 3 consecutive days per week followed by 4 days without treatment concluding on day 132 of pregnancy. Pregnant ewes were divided into four groups: two alcohol treatment groups (0.75 and 1.75 g/kg of body weight), one pair-fed saline control group, and an untreated normal control group. The fetuses were harvested on gestational day 133. Maternal and fetal femoral and tibial dimensions were measured and the maximum strength (MPa) carried by the bone tissue was determined using a three-point bending procedure. Maternal bones were not different among groups. The higher alcohol dose resulted in reduced fetal femoral bone strength, whereas the tibial bone strength was lower when compared with the normal control subjects. In contrast, the lower alcohol dose increased fetal femoral strength compared to the normal control subjects. The alcohol-exposed fetal bones also tended to exhibit reduced lengths. We conclude that binge alcohol exposure throughout gestation resulted in dose-dependent differences in the maximum stress absorbed by the fetal bones.

Alcohol Drinking↗