Impaired neural discrimination of emotional speech prosody in children with autism spectrum disorder and language impairment.

Autism spectrum disorders (ASD) are characterized by deficient social and communication skills, including difficulties in perceiving speech prosody. The present study addressed processing of emotional prosodic changes (sad, scornful and commanding) in natural word stimuli in typically developed school-aged children and in children with ASD and language impairment. We found that the responses to a repetitive word were diminished in amplitude in the children with ASD, reflecting impaired speech encoding. Furthermore, the amplitude of the MMN/LDN component, reflecting cortical discrimination of sound changes, was diminished in the children with ASD for the scornful deviant. In addition, the amplitude of the P3a, reflecting involuntary orienting to attention-catching changes, was diminished in the children with ASD for the scornful deviant and tended to be smaller for the sad deviant. These results suggest that prosody processing in ASD is impaired at various levels of neural processing, including deficient pre-attentive discrimination and involuntary orientation to speech prosody.

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.

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, n(affected)=138) and Asperger syndrome (29 families, n(affected)=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.

Evidence for allelic association on chromosome 3q25-27 in families with autism spectrum disorders originating from a subisolate of Finland.

Recent molecular studies on autism and related disorders have supported a multilocus etiology for the disease spectrum. To maximize genetic and cultural homogeneity, we have focused our molecular studies to families originating from a subisolate of Central Finland. Genealogical studies enabled the identification of a megapedigree comprising of 12 core families with autism and Asperger syndrome (AS). We analyzed two chromosomal regions on Iq and 3q showing highest lod scores in our genome-wide scan, as well as the AUTS1 locus on chromosome 7q. For markers on 3q25-27, more significant association was observed in families from subisolate compared to families from the rest of Finland. In contrast, no clear evidence for association on AUTS1 locus was obtained. The wide interval showing association, in particular, on chromosome 3q suggests a locus for autism spectrum of disorders on this chromosomal region.

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.

A quantitative controlled MRI study of the brain in 28 persons with Asperger syndrome.

BACKGROUND: As structural brain abnormalities have been reported in infantile autism, the aim of this study was to determine whether such findings also exist in Asperger Syndrome (AS). METHODS: The diagnosis of Asperger Syndrome was based on the criteria in ICD-10 and DSM-IV. Brain magnetic resonance imaging (MRI) was performed with a 1.5 T imager. T2-weighted axial and coronal slices and T1-weighted three dimensional sagittal slices were obtained and visual and quantitative analysis were performed. SUBJECTS: There were 28 Asperger individuals, 17 children and adolescents (age 6-19 years, mean 12.4 years), 11 adults (age 20-60 years, mean 37. 9 years) and 28 healthy age and gender matched controls. RESULTS: Mild inconsistent alterations were detected in 13/28 of the individuals with Asperger Syndrome compared to 6/23 in the comparable controls. There were no differences between the right and left hemispheres, nor was there any abnormality in terms of myelination or migration. The anterior-posterior diameters of the mesencephalon were statistically significantly shorter in the Asperger syndrome individuals than in the controls. CONCLUSIONS: No consistent focal brain abnormalities for Asperger Syndrome were detected. The reduced diameters of the mesencephalon in the Asperger group support the hypothesis that the mesencephalon may be involved in the pathogenesis of Asperger Syndrome.

Low levels of insulin-like growth factor-I in cerebrospinal fluid in children with autism.

Autism is a behaviourally defined syndrome characterized by disturbances of social interaction and communication and restrictions of behaviour patterns and imagination. The pathogenesis of autism is unknown but it is suspected that a number of genetic factors may be involved. Neurotrophic factors such as insulin-like growth factor-I (IGF-I) play a role in early brain development. The aim of this study was to determine whether IGF-I levels might be associated with the development of autism. IGF-I levels were measured in the CSF of 11 children with autism (4 females, 7 males; mean age 3.8 years, SD 1.1) using a sensitive radioimmunoassay method and compared with levels in 11 control participants (6 females, 5 males; mean age 3.8 years). Levels of IGF-I in the CSF were statistically significantly lower in the children with autism than in the control children (p=0.03). IGF-I may play a role in pathogenetic mechanisms of autism and the role of neurotrophic factors in autism and other neurodevelopmental diseases should be studied further.

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.

Analysis of autism susceptibility gene loci on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q in Finnish multiplex families.

The role of genetic factors in the etiology of the autistic spectrum of disorders has clearly been demonstrated. Ten chromosomal regions, on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q have potentially been linked to autism.1-8 We have analyzed these chromosomal regions in a total of 17 multiplex families with autism originating from the isolated Finnish population by pairwise linkage analysis and sib-pair analysis. Mild evidence for putative contribution was found only with the 1p chromosomal region in the susceptibility to autism. Our data suggest that additional gene loci exist for autism which will be detectable in and even restricted to the isolated Finnish population.

Insulin-like growth factor-I in cerebrospinal fluid and serum in Rett syndrome.

Rett syndrome is a neurodevelopmental disease characterized by failure of somatic and brain growth. The insulin-like growth factor system mediates most actions of growth hormone. Evidence that it plays an important role in early development of the brain is increasing. The aim of the study reported was to assess the role of the insulin-like growth factor system in the pathogenesis of Rett syndrome. We measured insulin-like growth factor-I levels in serum (8 patients, mean age 9.1 years) and cerebrospinal fluid (13 patients, mean age 7 years) using a sensitive radioimmunoassay method and compared them with those in age-matched controls (13 and 26 patients, respectively). Neither serum nor cerebrospinal fluid insulin-like growth factor-I levels differed from those in controls. We also measured insulin-like growth factor binding protein-3 levels in serum (in 9 patients and 8 controls) and in cerebrospinal fluid (in 12 patients and 11 controls) and serum growth hormone levels (in 8 patients and 11 controls); the levels in patients did not differ from those in controls. We found no significant correlation between serum and cerebrospinal fluid insulin-like growth factor-I in Rett syndrome. This may indicate an independent role of insulin-like growth factor system in the central nervous system, making serum insulin-like growth factor-I measurement unreliable as an indicator of disturbed function in the central nervous system. Our results did not support the notion that a defective insulin-like growth factor-I system explains the lack of somatic and brain growth in Rett syndrome.

Levels of cerebrospinal fluid nerve-growth factor differ in infantile autism and Rett syndrome.

Autism and Rett syndrome (RS) are both developmental disorders of unknown origin. Autism is a behaviourally defined syndrome. RS, which affects girls only, is characterized by a profound learning disability following early normal development, with a consistent cluster of clinical features. Differentiation of RS from infantile autism in the very early stages of the disorders is not always easy. Both syndromes still lack discriminative laboratory markers for accurate diagnosis and differentiation. We decided to compare the CSF nerve-growth factor (NGF) levels of children with infantile autism and children with RS using enzyme-linked immunosorbent assay (ELISA). Our findings of mainly normal CSF NGF in autism and low to negligible values in RS are in agreement with the different morphological and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. CSF NGF could be used as a biochemical marker for differentiation of patients with autism from those with RS.

Neurotrophic factors in cerebrospinal fluid and serum of patients with Rett syndrome.

Rett syndrome is now considered to be a neurodevelopmental disease. Its cause is unknown, but it has been suggested that neuronal growth factors and neurotransmitters play important roles. We measured levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid, and nerve growth factor and brain-derived neurotrophic factor in serum in child and adolescent patients with Rett syndrome. Levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid were below the limit of sensitivity of the methods used. Serum levels of nerve growth factor and brain-derived neurotrophic factor did not differ from control values. In Rett syndrome, the normal serum levels of nerve growth factor together and previously reported low levels of the factor in cerebrospinal fluid indicate that the latter may reflect low levels of nerve growth factor in the central nervous system.

Pons tumour behind a phenotypic Rett syndrome presentation.

We describe a girl with a brain-stem tumour and symptoms very similar to those of Rett syndrome (RS). Her early history was uneventful and development was normal (except for hypotonia). At the age of 6 months her development slowed. Subsequently, deterioration occurred and the features characteristic of RS were seen: loss of purposeful hand use, stereotypic hand movements, impaired social contact, decelerated head growth, and ataxia. Cerebral CT at the age of 3 years and 4 months revealed a tumour in the region of the pons and hydrocephalus. We suggest that a pons/midbrain tumour appearing at an early age may affect the developing CNS and cause symptoms similar to those of RS. A possible causal connection between midbrain pathology and RS is supported by this case.

West syndrome: cerebrospinal fluid nerve growth factor and effect of ACTH.

West syndrome is a strictly age-limited encephalopathy of early infancy with unknown pathogenesis. It is often progressive, leading to mental retardation. Neurotrophic factors are important for the regulation of neuronal survival and differentiation, and their expression is influenced by hormones. Levels of beta-nerve growth factor in the cerebrospinal fluid were examined by two-site enzyme-linked immunosorbent assay method. Human antigen was used as a standard. We present data on largely normal levels of nerve growth factor in the cerebrospinal fluid of infants with cryptogenic etiology, but low or negligible levels in infants with symptomatic etiology, and very high levels in infants with symptomatic postinfectious etiology. Treatment with ACTH led to a greater increase in patients with a good response than in those with a poor response. Low nerve growth factor in patients with symptomatic infantile spasms possibly reflects massive neuronal death. The regression seen in these infants and their poor response to ACTH therapy may be due in part to lack of growth factors supporting neuron survival. This study, previously only demonstrated in animal models, is the first to depict nerve growth factor gene activity in humans as modulated by steroids.