Raija Vanhala

Speech–sound-selective auditory impairment in children with autism: They can perceive but do not attend

In autism, severe abnormalities in social behavior coexist with aberrant attention and deficient language. In the attentional domain, attention to people and socially relevant stimuli is impaired the most. Because socially meaningful stimulus events are physically complex, a deficiency in sensory processing of complex stimuli has been suggested to contribute to aberrant attention and language in autism. This study used event-related brain potentials (ERP) to examine the sensory and early attentional processing of sounds of different complexity in high-functioning children with autism. Acoustically matched simple tones, complex tones, and vowels were presented in separate oddball sequences, in which a repetitive “standard” sound was occasionally replaced by an infrequent “deviant” sound differing from the standard in frequency (by 10%). In addition to sensory responses, deviant sounds elicited an ERP index of automatic sound-change discrimination, the mismatch negativity, and an ERP index of attentional orienting, the P3a. The sensory sound processing was intact in the high-functioning children with autism and was not affected by sound complexity or “speechness.” In contrast, their involuntary orienting was affected by stimulus nature. It was normal to both simple- and complex-tone changes but was entirely abolished by vowel changes. These results demonstrate that, first, auditory orienting deficits in autism cannot be explained by sensory deficits and, second, that orienting deficit in autism might be speech–sound specific.

Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

A Genomewide Screen for Autism-Spectrum Disorders: Evidence for a Major Susceptibility Locus on Chromosome 3q25-27

To identify genetic loci for autism-spectrum disorders, we have performed a two-stage genomewide scan in 38 Finnish families. The detailed clinical examination of all family members revealed infantile autism, but also Asperger syndrome (AS) and developmental dysphasia, in the same set of families. The most significant evidence for linkage was found on chromosome 3q25-27, with a maximum two-point LOD score of 4.31 (Z(max )(dom)) for D3S3037, using infantile autism and AS as an affection status. Six markers flanking over a 5-cM region on 3q gave Z(max dom) >3, and a maximum parametric multipoint LOD score (MLS) of 4.81 was obtained in the vicinity of D3S3715 and D3S3037. Association, linkage disequilibrium, and haplotype analyses provided some evidence for shared ancestor alleles on this chromosomal region among affected individuals, especially in the regional subisolate. Additional potential susceptibility loci with two-point LOD scores >2 were observed on chromosomes 1q21-22 and 7q. The region on 1q21-22 overlaps with the previously reported candidate region for infantile autism and schizophrenia, whereas the region on chromosome 7q provided evidence for linkage 58 cM distally from the previously described autism susceptibility locus (AUTS1).

The discrimination of and orienting to speech and non-speech sounds in children with autism.

The present study aimed to find out how different stages of cortical auditory processing (sound encoding, discrimination, and orienting) are affected in children with autism. To this end, auditory event-related potentials (ERP) were studied in 15 children with autism and their controls. Their responses were recorded for pitch, duration, and vowel changes in speech stimuli, and for corresponding changes in the non-speech counterparts of the stimuli, while the children watched silent videos and ignored the stimuli. The responses to sound repetition were diminished in amplitude in the children with autism, reflecting impaired sound encoding. The mismatch negativity (MMN), an ERP indexing sound discrimination, was enhanced in the children with autism as far as pitch changes were concerned. This is consistent with earlier studies reporting auditory hypersensitivity and good pitch-processing abilities, as well as with theories proposing enhanced perception of local stimulus features in individuals with autism. The discrimination of duration changes was impaired in these children, however. Finally, involuntary orienting to sound changes, as reflected by the P3a ERP, was more impaired for speech than non-speech sounds in the children with autism, suggesting deficits particularly in social orienting. This has been proposed to be one of the earliest symptoms to emerge, with pervasive effects on later development.

Association of DISC1 with autism and Asperger syndrome

The DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders. Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, naffected=138) and Asperger syndrome (29 families, naffected=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1. These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.

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.

Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families

Several genome‐wide screens have been performed in autism spectrum disorders resulting in the identification of numerous putative susceptibility loci. Analyses of pooled primary data should result in an increased sample size and the different study samples have a potential to strengthen the evidence for some earlier identified loci, reveal novel loci, and even to provide information of the general significance of the locus. The objective of this study was to search for potential susceptibility loci for autism, which are supported by two independent samples.

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.

The perception of invariant speech features in children with autism.

We investigated whether the good pitch-discrimination abilities reported in individuals with autism have adverse effects on their speech perception by compromising their ability to extract invariant phonetic features from speech input. The MMN, a brain response reflecting sound-discrimination processes, was recorded from children with autism and their controls for phoneme-category and pitch changes in speech stimuli under two different conditions: (a) when all the other features of the standard and deviant stimuli were kept constant, and (b) when constant variation with respect to an irrelevant feature was introduced to the standard and deviant stimuli. Children with autism had enhanced MMNs for pitch changes in both conditions, as well as for phoneme-category changes in the constant-feature condition. However, when the phoneme-category changes occurred in phonemes having pitch variation, the MMN enhancement was abolished in autistic children. This suggests that children with autism lose their advantage in phoneme discrimination when the context of the stimuli is speech-like and requires abstracting invariant speech features from varying input.

MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features.

Objective: To discuss the diagnostic criteria for Rett syndrome based on mutational screening of the methyl-CpG-binding protein 2 gene ( MECP2 ) in patients with classic Rett syndrome and patients with Rett-like features. Methods: Thirty-nine patients with classical Rett syndrome, one with preserved speech variant (PSV), and 12 patients with developmental delay and some features of Rett syndrome were recruited for sequence analysis of the MECP2 gene coding region. The phenotype of the patients was correlated with the presence and type of the mutation as well as the X-chromosome inactivation (XCI) pattern. Results: found in 100% of the patients with classical Rett syndrome originating from Finland. One novel mutation, P127L, was detected in a patient with PSV. No mutations were found in other cases. The XCI status was found to be random in 72% of the patients with classical Rett syndrome, including the patient with PSV and all patients with developmental delay informative for the analysis. Conclusions: An MECP2 mutation can be found in almost every patient with classical Rett syndrome. More patients need to be analyzed in order to clarify the mutation prevalence in patients with atypical Rett syndrome and in patients with mental retardation.