Linkage and linkage disequilibrium scan for autism loci in an extended pedigree from Finland.

Population isolates, such as Finland, have proved beneficial in mapping rare causative genetic variants due to a limited number of founders resulting in reduced genetic heterogeneity and extensive linkage disequilibrium (LD). We have here used this special opportunity to identify rare alleles in autism by genealogically tracing 20 autism families into one extended pedigree with verified genealogical links reaching back to the 17th century. In this unique pedigree, we performed a dense microsatellite marker genome-wide scan of linkage and LD and followed initial findings with extensive fine-mapping. We identified a putative autism susceptibility locus at 19p13.3 and obtained further evidence for previously identified loci at 1q23 and 15q11-q13. Most promising candidate genes were TLE2 and TLE6 clustered at 19p13 and ATP1A2 at 1q23.

Epilepsy in the northern Finland birth cohort 1966 with special reference to fertility.

The aim of the study was to evaluate both the prevalence of epilepsy and the reproductive history of subjects with epilepsy in a population-based cohort study. The Northern Finland Birth Cohort 1966 (NFBC 1966) comprises 12,058 subjects with 39 years of follow-up. Of these subjects, 222 were identified as having epilepsy on the basis of information obtained from mailed questionnaires, hospital discharge registers, and records for reimbursed antiepileptic medications. The information on reproductive outcome was also updated. Both men and women with epilepsy did not differ from the reference group with respect to number of children. However, subjects with active epilepsy during adulthood had fewer children than those who achieved remission before adulthood. Subjects with epilepsy who achieved remission before adulthood did not differ from control subjects with respect to number of children.

Families' perceptions of given information in relation to their child's head injury.

UNLABELLED: Information and effective communication is an essential element in treating children in hospital. Researches have shown that parents who are well informed and well prepared were less anxious, a fact that was found to decrease the child's level of stress. Studies in the head injury population reveal that not only patients but their families need support such as general information about a head injury but also individual support, independent of the severity of the head injury. AIM: To describe the families' perceptions of information provided in relation to a head injury during their visit at the emergency department at Astrid Lindgren children's hospital. DESIGN: Retrospective, descriptive study. METHOD: Postal questionnaires at 3 months posthead injury. RESULTS: There were 96 families that participated, 51 families with children <5 years and 45 families with children >5 years. Eighty-five per cent of all families understood the information concerning head injury they had been given during the visit to the emergency department. However, only 69% received the information they needed about head injury in children before discharge from the emergency department. There were significant differences between the two age groups as to whether or not the information was addressed to the child or that the information was age appropriate. The results from our study should be interpreted with caution because of the relatively low number of respondents and the fact that the study was conducted using a questionnaire. Another limitation is the fact that we asked for the information 3 months posthead injury. CONCLUSIONS: Most families do understand the information that was provided and they also generally received the information they needed. However, they had not received information about common symptoms after a head injury. Strategies to improve information to families who experience a childhood head injury therefore seem necessary.

Allelic variants in HTR3C show association with autism.

Autism spectrum disorders (ASDs) are severe neurodevelopmental disorders with a strong genetic component. Only a few predisposing genes have been identified so far. We have previously performed a genome-wide linkage screen for ASDs in Finnish families where the most significant linkage peak was identified at 3q25-27. Here, 11 positional and functionally relevant candidate genes at 3q25-27 were tested for association with autistic disorder. Genotypes of 125 single nucleotide polymorphisms (SNPs) were determined in 97 families with at least one individual affected with autistic disorder. The most significant association was observed using two non-synonymous SNPs in HTR3C, rs6766410 and rs6807362, both resulting in P = 0.0012 in family-based association analysis. In addition, the haplotype C-C corresponding to amino acids N163-A405 was overtransmitted to affected individuals (P = 0.006). Sequencing revealed no other variants in the coding region or splice sites of HTR3C. Based on the association analysis results in a previously identified linkage region, we propose that HTR3C represents a novel candidate locus for ASDs and should be tested in other populations.

Variations in prenatal sociodemographic factors associated with intellectual disability: a study of the 20-year interval between two birth cohorts in northern Finland.

The authors followed two cohorts of children born in northern Finland in 1966 (n = 12,058) and 1985-1986 (n = 9,432) to examine whether associations between maternal sociodemographic factors assessed during pregnancy and intellectual disability in the offspring changed over a 20-year interval. Both of the cohorts were followed up to the age of 11.5 years using similar methods and definitions of intellectual disability. Data on sociodemographic factors were based on comparable questionnaires returned by the mothers during the 25th week of gestation. Despite an interval of 20 years between the cohorts, the main indicators of socioeconomic disadvantage and maternal multiparity remained as having the largest impact on the incidence of intellectual disability, while single factors such as older maternal age at delivery, being single, and living in a remote area lost their association with intellectual disability. Over 20 years, prepregnancy maternal obesity (body mass index > or =30) became a newly associated factor (adjusted odds ratio = 2.8, 95% confidence interval: 1.5, 5.3). A future challenge is to explore the mediating mechanisms between intellectual disability and its associated preventable intergenerational environmental or lifestyle factors.

Impaired recognition of facial emotions from low-spatial frequencies in Asperger syndrome.

The theory of 'weak central coherence' [Happe, F., & Frith, U. (2006). The weak coherence account: Detail-focused cognitive style in autism spectrum disorders. Journal of Autism and Developmental Disorders, 36(1), 5-25] implies that persons with autism spectrum disorders (ASDs) have a perceptual bias for local but not for global stimulus features. The recognition of emotional facial expressions representing various different levels of detail has not been studied previously in ASDs. We analyzed the recognition of four basic emotional facial expressions (anger, disgust, fear and happiness) from low-spatial frequencies (overall global shapes without local features) in adults with an ASD. A group of 20 participants with Asperger syndrome (AS) was compared to a group of non-autistic age- and sex-matched controls. Emotion recognition was tested from static and dynamic facial expressions whose spatial frequency contents had been manipulated by low-pass filtering at two levels. The two groups recognized emotions similarly from non-filtered faces and from dynamic vs. static facial expressions. In contrast, the participants with AS were less accurate than controls in recognizing facial emotions from very low-spatial frequencies. The results suggest intact recognition of basic facial emotions and dynamic facial information, but impaired visual processing of global features in ASDs.

Comparison of diagnostic methods for asperger syndrome.

Several different diagnostic sets of criteria exist for Asperger syndrome (AS), but there is no agreement on a gold standard. The aim of this study was to compare four diagnostic sets of criteria for AS: the ICD-10, the DSM-IV, the Gillberg & Gillberg, and the Szatmari criteria. The series consists of 36 children who had been referred to two centers with a tentative diagnosis of AS. The best agreement was between the ICD-10 and the DSM-IV criteria (Kappa coefficient 0.48), and the lowest between the Gillberg & Gillberg and Szatmari criteria (Kappa coefficient -0.21). The poor agreement between these sets of diagnostic criteria compromises the comparability of studies on AS.

Sleep in children with Asperger syndrome.

The prevalence of sleep disturbances in 52 children with Asperger syndrome (AS) as compared with 61 healthy controls (all subjects aged 5-17 years) was investigated. Problems with sleep onset and maintenance, sleep-related fears, negative attitudes toward sleeping, and daytime somnolence were more frequent among children with AS than among controls. Short sleep duration (<9 h) was almost twofold (59% vs. 32%), and the risk for sleep onset problems more than fivefold (53% vs. 10%) more common in the AS group than in the control group. Child-reported sleeping problems were also more prevalent in the AS group than in controls (58% vs. 7%). The results suggest that sleep disturbances should be routinely evaluated in children with AS.

Language abilities of children with Asperger syndrome.

Current diagnostic taxonomies (ICD-10, DSM-IV) emphasize normal acquisition of language in Asperger syndrome (AS). Although many linguistic sub-skills may be fairly normal in AS there are also contradictory findings. There are only few studies examining language skills of children with AS in detail. The aim of this study was to study language performance in children with AS and their age, sex and IQ matched controls. Children with AS had significantly lower scores in the subtest of Comprehension of Instructions. Results showed that although many linguistic skills may develop normally, comprehension of language may be affected in children with AS. The results suggest that receptive language processes should be studied in detail in children with AS.

Informational needs in families after their child's mild head injury.

OBJECTIVE: When a child is hospitalized due to an illness or injury, the entire family may experience stress and/or anxiety. According to parents who have been in such a situation, providing adequate information is one of the most valuable ways to help the family deal with such feelings. Most mild head injuries suffered by children do not require hospitalisation and in such cases, their families should be provided with appropriate information in connection with their visit to the emergency ward. In the present study, family informational needs are characterized. METHODS: The families of 57 children who had suffered a mild head injury at 0-15 years of age answered one open-ended question. The analysis was carried out using content analysis. RESULTS: This analysis revealed two types of needs, i.e., a need for information concerning the head injury itself and how to provide care, as well as a need for reassurance and support in sharing and coping with the emotional burden. CONCLUSION: Despite differences in the severity of the child's head injury and requirement for hospitalisation, all the families expressed the same informational needs but also the need for emotional support. PRACTICE IMPLICATIONS: In connection with the treatment of children with head injuries, health-care personnel should provide the parents both with information concerning the injury and its treatment and with emotional support.

No association between common variants in glyoxalase 1 and autism spectrum disorders.

The autism spectrum disorders (ASDs) are complex diseases with a strong genetic component. Numerous candidate gene studies have tested association between various functional and positional candidate genes and autism, but no common variation predisposing for autism has been identified to date. It has been previously proposed, that glyoxalase 1 (GLO1) might be involved in the pathogenesis of autism as GLO1 protein polarity was significantly changed in the brains of autism patients compared to controls. GLO1 harbors a functional polymorphism that affects the polarity and the enzymatic activity of the protein. In the same study, this polymorphism showed a suggestive association to autism. To investigate whether common variants in GLO1 predispose to autism in the Finnish population, we have genotyped six polymorphisms in GLO1 in families with more than 230 individuals affected with ASDs and carried out both linkage and association analyses. We did not observe significant linkage or association between any SNP and ASDs. Therefore, we suggest that common variants in GLO1 are not significant susceptibility factors for ASDs in the Finnish population.

Auditory cortical change detection in adults with Asperger syndrome.

The present study investigated whether auditory deficits reported in children with Asperger syndrome (AS) are also present in adulthood. To this end, event-related potentials (ERPs) were recorded from adults with AS for duration, pitch, and phonetic changes in vowels, and for acoustically matched non-speech stimuli. These subjects had enhanced mismatch negativity (MMN) amplitudes particularly for pitch and duration deviants, indicating enhanced sound-discrimination abilities. Furthermore, as reflected by the P3a, their involuntary orienting was enhanced for changes in non-speech sounds, but tended to be deficient for changes in speech sounds. The results are consistent with those reported earlier in children with AS, except for the duration-MMN, which was diminished in children and enhanced in adults.

Sustained favorable effects of cognitive training in children with acquired brain injuries.

The overall aim of the present study was to assess in greater detail the sustained effects of a broad-based cognitive training programme on the neuropsychological performance of children with acquired brain injury. In particular, the long term (6 months) effects on cognitive functions, as well as how various moderators (gender, age at the time of injury/diagnosis, time since injury/diagnosis, age at the training) might influence outcome were investigated. A group of 38 children, 9-16 years of age, with various types of acquired brain injury had earlier been randomly assigned into treatment and control groups. These two groups had first been assessed directly after completion of the training and were now reassessed 6 months later. The treatment group exhibited significantly more persistent improvements with respect to complex tasks of attention and memory in comparison to the control group. In contrast there were no differences on simple reaction time tests. We conclude that the long term effects on cognitive functions of this broad-based neuro-cognitive training is encouraging. These positive results should be further investigated in larger more specific diagnostic groups and in different settings.

Analysis of four neuroligin genes as candidates for autism.

Neuroligins are cell-adhesion molecules located at the postsynaptic side of the synapse. Neuroligins interact with beta-neurexins and this interaction is involved in the formation of functional synapses. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have recently been implicated in pathogenesis of autism. The neuroligin gene family consists of five members (NLGN1 at 3q26, NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11), of which NLGN1 and NLGN3 are located within the best loci observed in our previous genome-wide scan for autism in the Finnish sample. Here, we report a detailed molecular genetic analysis of NLGN1, NLGN3, NLGN4, and NLNG4Y in the Finnish autism sample. Mutation analysis of 30 probands selected from families producing linkage evidence for Xq13 and/or 3q26 loci revealed several polymorphisms, but none of these seemed to be functional. Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P=0.002), NLGN3 (DXS7132, P=0.014), and NLGN4 (DXS996, P=0.031). We conclude that neuroligin mutations most probably represent rare causes of autism and that it is unlikely that the allelic variants in these genes would be major risk factors for autism.

Higher plasma ACTH levels in adults with Asperger syndrome.

OBJECTIVE: The aim of this preliminary study was to characterize the levels of plasma adrenocorticotropic hormone (ACTH) and cortisol in adult patients with Asperger syndrome (AS). METHODS: Twenty medication-free individuals with high-functioning AS were recruited from a clinic specialized in autism spectrum disorders. Ten age-matched healthy persons (hospital staff or students) with no neuropsychiatric disorders served as controls. Blood samples for the assessment were collected at 8:00 a.m. RESULTS: The patients with AS had significantly higher plasma-ACTH values than did the healthy controls. Plasma-cortisol levels were similar in both groups. CONCLUSION: Increased plasma-ACTH levels are associated with AS. Future studies are needed to clarify whether this finding is a biological consequence of chronic anxiety and elevated stress, or a sign of facilitated response to an acute novel stressor.

Subjective face recognition difficulties, aberrant sensibility, sleeping disturbances and aberrant eating habits in families with Asperger syndrome.

BACKGROUND: The present study was undertaken in order to determine whether a set of clinical features, which are not included in the DSM-IV or ICD-10 for Asperger Syndrome (AS), are associated with AS in particular or whether they are merely a familial trait that is not related to the diagnosis. METHODS: Ten large families, a total of 138 persons, of whom 58 individuals fulfilled the diagnostic criteria for AS and another 56 did not to fulfill these criteria, were studied using a structured interview focusing on the possible presence of face recognition difficulties, aberrant sensibility and eating habits and sleeping disturbances. RESULTS: The prevalence for face recognition difficulties was 46.6% in individuals with AS compared with 10.7% in the control group. The corresponding figures for subjectively reported presence of aberrant sensibilities were 91.4% and 46.6%, for sleeping disturbances 48.3% and 23.2% and for aberrant eating habits 60.3% and 14.3%, respectively. CONCLUSION: An aberrant processing of sensory information appears to be a common feature in AS. The impact of these and other clinical features that are not incorporated in the ICD-10 and DSM-IV on our understanding of AS may hitherto have been underestimated. These associated clinical traits may well be reflected by the behavioural characteristics of these individuals.

Health-related quality of life of adolescents and young adults 10 years after serious traumatic brain injury.

The aim of this study was to investigate health-related quality of life (HRQoL) in a population-based group of young adults with serious traumatic brain injury (TBI) acquired 10 years earlier. In the time period 1987--1991, all 165 residents (<18 years of age) in the south-western health care region of Sweden who had suffered a serious TBI were followed up. Of these, 109 (67%) participated in this follow-up study, which was conducted using the 15-dimension (15D) HRQoL instrument. Their HRQoL was compared with that of 1,039 individuals drawn randomly from the National Population Register for the Finnish Health Care Survey 1995/1996 and matched for age and sex. Nine (mobility, vision, hearing, eating, speech, mental status, depression, distress and usual activities) of the 15 dimensions were significantly aberrant in the TBI group. This TBI group differed markedly from children with organ transplantation, as the transplantation children did not differ from a control group in terms of HRQoL. Compared with other groups of children with congenital or long-lasting conditions, the TBI group had more medical and mental problems.

Genomic screen and follow-up analysis for autistic disorder.

Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant impairment in social, communicative, and behavioral functioning. A genetic basis for AutD is well established with as many as 10 genes postulated to contribute to its underlying etiology. We have completed a genomic screen and follow-up analysis to identify potential AutD susceptibility loci. In stage one of the genome screen, 52 multiplex families (two or more AutD affected individuals/family) were genotyped with 352 genetic markers to yield an approximately 10 centimorgan (cM) grid, inclusive of the X chromosome. The selection criterion for follow-up of interesting regions was a maximum heterogeneity lod score (MLOD) or a maximum nonparametric sib pair lod score (MLS) of at least 1.0. Eight promising regions were identified on chromosomes 2, 3, 7, 15, 18, 19, and X. In the stage two follow-up study we analyzed an additional 47 multiplex families (total=99 families). Regions on chromosomes 2, 3, 7, 15, 19, and X remained interesting (MLOD> or =1.0) in stage two analysis. The peak lod score regions on chromosomes 2, 7, 15, 19, and X overlap previously reported peak linkage areas. The region on chromosome 3 is unique.

Increased presynaptic dopamine function in Asperger syndrome.

The etiology of Asperger syndrome is essentially unknown, but abnormality of the dopamine system has been shown in clinically overlapping disorders. The present study was designed to investigate the presynaptic dopamine function in Asperger syndrome. Eight healthy, drug-free males with Asperger syndrome and five healthy male controls were examined with positron emission tomography using 6-[18F]fluoro-L-DOPA ([18F]FDOPA) as a tracer. In the Asperger syndrome group, the [18F]FDOPA influx (Ki) values were increased in the striatum, i.e. in the putamen and caudate nucleus and in the frontal cortex. The results indicate that the dopamine system is affected in subjects with Asperger syndrome. Partially similar results have also been obtained in schizophrenia, suggesting an overlap not only of the clinical features but also of pathogenesis.

The association of preceding traumatic brain injury with mental disorders, alcoholism and criminality: the Northern Finland 1966 Birth Cohort Study.

The purpose of this study was to test the hypothesis that traumatic brain injury (TBI) during childhood and adolescence is associated with psychiatric disorders, heavy alcohol use and criminal offenses in adulthood. We made use of an unselected, general population birth cohort (n=12058) in Northern Finland, which was followed up prospectively up to the age of 31. The data on TBIs of the cohort members were collected from the hospital case notes of the outpatient clinics of the hospitals in the region and from the Finnish Hospital Discharge Registers (FHDR). The data on mental disorders including alcohol diagnoses were also collected from the FHDR after a careful validation process. The Ministry of Justice provided information on criminal offenses for all subjects. The final number of subjects in our study was 5589 males and 5345 females. We found that after controlling for confounders, TBI during childhood or adolescence increased the risk of developing mental disorders two-fold (OR 2.1, 95% CI 1.1-3.6) and TBI was significantly related to later mental disorder with coexisting criminality in male cohort members (OR 4.1, 95% CI 1.2-13.6). The results support the TBI's association with psychiatric morbidity, which should not be overlooked when treating psychiatric patients, especially those with comorbid criminality.