Taina Nieminen-von Wendt

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 β-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.

Effectiveness of Melatonin in the Treatment of Sleep Disturbances in Children with Asperger Disorder

Sleep disturbances are common in patients with Asperger disorder. Although these sleep problems are often persistent and may significantly impair the childs daytime well-being, no treatment studies have been reported. In this open clinical trial, the effectiveness of melatonin was studied in a sample of 15 children with Asperger disorder (13 boys, 2 girls) aged 6-17 years using several questionnaires and actigraph measurements. They included assessments of sleep quality, tiredness, and behavior. Melatonin (3 mg/day) was used for 14 days. All the measurements were made three times: before the treatment period, during the treatment (days 12-14), and 3 weeks after the discontinuation of the treatment. The sleep patterns of all the children improved, and half of them displayed excellent responses to melatonin. In particular, actigraphically measured sleep latency decreased from 40.02 +/- 24.09 minutes to 21.82 +/- 9.64 minutes (p = 0.002), whereas sleep duration remained steady at 477.40 +/- 55.56 minutes and 480.48 +/- 50.71 minutes. Despite the short duration of the treatment, behavioral measures also displayed a significant improvement, and most of the effect disappeared after the discontinuation of the melatonin (p = 0.001). In conclusion, melatonin may provide an interesting new and well-tolerated treatment option for children with Asperger disorder suffering from chronic insomnia. However, these results must be confirmed in a controlled study.

Insomnia is a frequent finding in adults with Asperger syndrome

BackgroundAsperger syndrome (AS) is a neurodevelopmental disorder belonging to autism spectrum disorders with prevalence rate of 0,35% in school-age children. It has been most extensively studied in childhood while there is scarcity of reports concerning adulthood of AS subjects despite the lifelong nature of this syndrome. In children with Asperger syndrome the initiation and continuity of sleep is disturbed because of the neuropsychiatric deficits inherent of AS. It is probable that sleep difficulties are present in adulthood as well. Our hypothesis was that adults with AS suffer from difficulty in initiating and maintaining sleep and nonrestorative sleep (insomnia).Methods20 AS without medication were compared with 10 healthy controls devoid of neuropsychiatric anamnesis. Clinical examination, blood test battery and head MRI excluded confounding somatic illnesses. Structured psychiatric interview for axis-I and axis-II disorders were given to both groups as well as Beck Depression Inventory and Wechsler adult intelligence scale, revised version.Sleep quality was assessed with sleep questionnaire, sleep diary during 6 consecutive days and description of possible sleep problems by the participants own words was requested.Resultscompared with controls and with normative values of good sleep, AS adults had frequent insomnia. In sleep questionnaire 90% (18/20), in sleep diary 75% (15/20) and in free description 85% (17/20) displayed insomnia. There was a substantial psychiatric comorbidity with only 4 AS subject devoid of other axis-I or axis-II disorders besides AS. Also these persons displayed insomnia. It can be noted that the distribution of psychiatric diagnoses in AS subjects was virtually similar to that found among patient with chronic insomnia.Conclusionsthe neuropsychiatric deficits inherent of AS predispose both to insomnia and to anxiety and mood disorders. Therefore a careful assessment of sleep quality should be an integral part of the treatment plan in these individuals. Conversely, when assessing adults with chronic insomnia the possibility of autism spectrum disorders as one of the potential causes of this condition should be kept in mind.

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.

Sleep in Young Adults with Asperger Syndrome

Asperger syndrome (AS) is a neurodevelopmental disorder belonging to autism spectrum disorders. Both children and adults with AS have subjective impairment in the initiation and continuity of sleep, and studies using objective assessment are sparse. Twenty young AS adults with frequent complaints of low sleep quality were compared to 10 age-, gender- and education-matched controls without sleep complaints using polysomnography and spectral power analysis of slow-wave sleep. AS subjects displayed a similar polysomnographic profile as compared with controls. In spectral power analysis, a statistically nonsignificant trend towards decreased relative delta power and increased theta power in slow-wave sleep was found in the AS group. It seems that nonorganic insomnia, due to anxiety inherent in AS, is responsible for the low sleep quality in these subjects.

Asperger Syndrome, Alexithymia and Perception of Sleep

Two research traditions, the one on Asperger syndrome (AS) and the other on alexithymia, have produced similar findings independently of each other indicating a possible association between these two phenomena. Both conditions are also associated with impaired initiation and continuity of sleep. Twenty AS adults were compared with 10 healthy controls using the Toronto Alexithymia Scale and the Basic Nordic Sleep Questionnaire. AS subjects were significantly more alexithymic and reported lower sleep quality as compared with controls. AS and alexithymia are associated although the mediating factors are unknown. It is possible that alexithymic traits predispose to anxiety, which in turn lowers the sleep quality in AS adults. Alternatively, low sleep quality might be due to AS itself.

Reorganization of functionally connected brain subnetworks in high-functioning autism

Previous functional connectivity studies have found both hypo‐ and hyper‐connectivity in brains of individuals having autism spectrum disorder (ASD). Here we studied abnormalities in functional brain subnetworks in high‐functioning individuals with ASD during free viewing of a movie containing social cues and interactions. Twenty‐six subjects (13 with ASD) watched a 68‐min movie during functional magnetic resonance imaging. For each subject, we computed Pearsons correlation between haemodynamic time‐courses of each pair of 6‐mm isotropic voxels. From the whole‐brain functional networks, we derived individual and group‐level subnetworks using graph theory. Scaled inclusivity was then calculated between all subject pairs to estimate intersubject similarity of connectivity structure of each subnetwork. Additional 54 individuals (27 with ASD) from the ABIDE resting‐state database were included to test the reproducibility of the results. Between‐group differences were observed in the composition of default‐mode and ventro‐temporal‐limbic (VTL) subnetworks. The VTL subnetwork included amygdala, striatum, thalamus, parahippocampal, fusiform, and inferior temporal gyri. Further, VTL subnetwork similarity between subject pairs correlated significantly with similarity of symptom gravity measured with autism quotient. This correlation was observed also within the controls, and in the reproducibility dataset with ADI‐R and ADOS scores. Our results highlight how the reorganization of functional subnetworks in individuals with ASD clarifies the mixture of hypo‐ and hyper‐connectivity findings. Importantly, only the functional organization of the VTL subnetwork emerges as a marker of inter‐individual similarities that co‐vary with behavioral measures across all participants. These findings suggest a pivotal role of ventro‐temporal and limbic systems in autism. Hum Brain Mapp 37:1066–1079, 2016.

Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample.

Objective Autism spectrum disorders (ASD) often show obsessive repetitive symptoms that are characteristic to obsessive-compulsive disorder (OCD). Aberrant glutamate function has been suggested to a risk for both ASDs and OCD. Considering the common metabolic pathway and recent results from association studies both in OCD and ASDs, a question, whether there is common molecular background in ASDs and OCD, was raised. Methods Ten single nucleotide polymorphisms (SNPs) at 9p24 and 11p12-p13 containing glutamate transporter genes SLC1A1 and SLC1A2 and their neighboring regions in 175 patients with ASDs and 216 controls of Finnish origin were analyzed using real-time-PCR or direct sequencing. Results The strongest association was detected with rs1340513 in the JMJD2C gene at 9p24.1 (P=0.007; corrected P=0.011) that is the same SNP associated with infantile autism (P=0.0007) in the autism genome project consortium (2007). No association was detected at 11p12-p13 with ASD. Interestingly, the strongest association in OCD has been found at rs301443 (P=0.000067) residing between SLC1A1 and JMJD2C at 9p24. Conclusion In summary, our results give evidence for a possible common locus for OCD and ASDs at 9p24. We speculate that the area may represent a special candidate region for obsessive repetitive symptoms in ASDs.

Clinical neurological abnormalities in young adults with Asperger syndrome

Abstract  Children with Asperger syndrome (AS), a neurodevelopmental disorder falling in the autism spectrum disorders, have an increased rate of neurological abnormalities, especially in motor coordination. While AS is a lifelong condition, little is known about the persistence of neurological abnormalities in adulthood. Twenty young adults with AS were compared with 10 healthy controls using a structured clinical neurological rating scale. The score for neurological abnormalities was higher in the AS group. In addition, a subscore for neurological soft signs indicating defective functioning of the central nervous system with a non‐localizing value was significantly higher in the AS subjects. This preliminary study indicates that neurological abnormalities, soft signs in particular, represent a non‐specific vulnerability factor for AS. Consistent with other features of AS, neurological abnormalities seem to persist into adulthood.

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

BackgroundThe 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.MethodsTen 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.ResultsThe 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.ConclusionAn 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.