Charlotte Modahl

Plasma oxytocin levels in autistic children.

BACKGROUND Social impairments are central to the syndrome of autism. The neuropeptide oxytocin (OT) has been implicated in the regulation of social behavior in animals but has not yet been examined in autistic subjects. METHODS To determine whether autistic children have abnormalities in OT, midday plasma samples from 29 autistic and 30 age-matched normal children, all prepubertal, were analyzed by radioimmunoassay for levels of OT. RESULTS Despite individual variability and overlapping group distributions, the autistic group had significantly lower plasma OT levels than the normal group. OT increased with age in the normal but not the autistic children. Elevated OT was associated with higher scores on social and developmental measures for the normal children, but was associated with lower scores for the autistic children. These relationships were strongest in a subset of autistic children identified as aloof. CONCLUSIONS Although making inferences to central OT functioning from peripheral measurement is difficult, the data suggest that OT abnormalities may exist in autism, and that more direct investigation of central nervous system OT function is warranted.

Oxytocin and autistic disorder: alterations in peptide forms

BACKGROUND Oxytocin (OT) is synthesized as a prohormone that is sequentially processed to peptides. These peptides are the bioactive amidated form (OT) and the C-terminal extended peptides, OT-Gly, OT-Gly-Lys and OT-Gly-Lys-Arg, which are designated together as OT-X. As an extension of our previous study finding decreased plasma OT in autism, studies were conducted to determine whether there were changes in OT peptide forms in autistic children. METHODS Twenty eight male subjects (97 +/- 20 months; range, 70-139 months), diagnosed with DSM-IV autistic disorder through observation and semi-structured interview, were compared with 31 age-matched nonpsychiatric control subjects (106 +/- 22 months; range, 74-140 months). Using OT antisera with different specificity for the peptide forms, we measured plasma OT and OT-X in each group. RESULTS T tests showed that there was a decrease in plasma OT (t = 4.4, p <.0001), an increase in OT-X (t = 2.3, p <.03) and an increase in the ratio of OT-X/OT (t = 4.5, p <.0001) in the autistic sample, compared with control subjects. CONCLUSIONS The results suggest that children with autistic disorder show alterations in the endocrine OT system. Deficits in OT peptide processing in children with autism may be important in the development of this syndrome.

Mitochondrial Dysfunction in Autistic Patients with 15q Inverted Duplication

Two autistic children with a chromosome 15q11‐q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function. Ann Neurol 2003;53:801–804

Multisite, double-blind, placebo-controlled trial of porcine secretin in autism.

OBJECTIVE To examine the efficacy of intravenous porcine secretin for the treatment of autistic disorder. METHOD Randomized, double-blind, placebo-controlled, crossover design. Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Observation Schedule (ADOS) and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects. RESULTS For the primary efficacy analysis, change of ADOS social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-0.8 +/- 2.9) and secretin groups (-0.6 +/- 1.4; t54 = 0.346, p < .73). The other measures showed no treatment effect for secretin compared with placebo. CONCLUSION There was no evidence for efficacy of secretin in this randomized, placebo-controlled, double-blind trial.

Association between amygdala volume and anxiety level : Magnetic resonance imaging (MRI) study in autistic children

Our objective was to evaluate brain-behavior relationships between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in a well-characterized population of autistic children. Volumes for the amygdala, hippocampus, and whole brain were obtained from three-dimensional magnetic resonance images (MRIs) captured from 42 children who met the criteria for autistic disorder. Anxious/depressed symptoms were assessed in these children by the Anxious/Depressed subscale of the Child Behavior Checklist. To investigate the association between anxious/depressed scores on the Child Behavior Checklist and amygdala volume, data were analyzed using linear regression methods with Pearson correlation coefficients. A multivariate model was used to adjust for potential covariates associated with amygdala volume, including age at MRI and total brain size. We found that anxious/depressed symptoms were significantly correlated with increased total amygdala volume (r = .386, P = .012) and right amygdala volume (r = .469, P = .002). The correlation between anxious/depressed symptoms and left amygdala volume did not reach statistical significance (r = .249, P = .112). Child Behavior Checklist anxious/depressed scores were found to be a significant predictor of amygdala total (P = .014) and right amygdala (P = .002) volumes. In conclusion, we have identified a significant brain-behavior relationship between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in our autistic cohort. This specific relationship has not been reported in autism. However, the existing literature on human psychiatry and behavior supports our reported evidence for a neurobiologic relationship between symptoms of anxiety and depression with amygdala structure and function. Our results highlight the importance of characterizing comorbid psychiatric symptomatology in autism. The abundance of inconsistent findings in the published literature on autism might reflect differences between study populations regarding age at MRI, level of impairment within autistic subjects, and underlying anxiety level in the selected study groups.

A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R

BackgroundAutism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes.Case presentationWe describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R.ConclusionsThe deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism.

Molecular genetic delineation of 2q37.3 deletion in autism and osteodystrophy: report of a case and of new markers for deletion screening by PCR

We recently studied a patient who meets criteria for autistic disorder and has a 2q37 deletion. Molecular cytogenetic studies were carried out using DNA isolated from 22 different 2q37 mapped BACs to more precisely define the extent of the chromosome deletion. We also analyzed 2q37 mapped polymorphic markers. In addition DNA sequences of BACs in the deletion region were scanned to identify microsatellite repeats. We describe four new polymorphic microsatellite repeat markers in the 2q37.3 region. These markers enabled us to determine the parental origin of the deletion in our patient. DNA from 8–13 unrelated individuals was used to determine heterozygosity estimates for these markers. We review four genes deleted in our patient – genes whose known functions and sites of expression in the brain and/or bone make them candidates for involvement in autism and/or the osteodystrophy observed in patients with 2q37.3 deletions.

Analysis of a 1-megabase deletion in 15q22-q23 in an autistic patient: identification of candidate genes for autism and of homologous DNA segments in 15q22-q23 and 15q11-q13.

We have identified a one megabase deletion in the 15q22-15q23 region in a patient with autism, developmental delay, and mild dysmorphism. Genes that map within the deletion region and genes that are interrupted or rearranged at the deletion breakpoints are candidate genes for autism. Fluroescence in situ hybridization studies in this patient revealed that part or all of the PML gene is absent from one chromosome 15 and a BAC clone containing the D15S124 gene locus hybridizes to only one chromosome 15. BAC clones containing the PTPN9, and SLP-1[hUNC24] genes showed markedly reduced hybridization in the 15q22-q23 region on one chromosome 15 in the patient. These BACs also hybridize to the 15q11-q13 region in close proximity to SNRPN and HERC2, and in this region there is equal intensity of signal on the normal and on the deleted chromosome. There are previous reports of deletions and duplications of the 15q11-q13 region in patients with autism. Our patient represents the first report of a 15q22-q23 deletion. Hybridization of the PTPN9 and Slp-1 Bac clones to the 15q11-q13 and the 15q22-q23 regions of chromosome 15 may be due to the presence of PTPN9 or SLP-1 gene sequences or to the presence of other gene sequences or to non-coding homologous DNA sequences. The PTPN9 gene encodes a non-receptor protein tyrosine phosphatase. The Slp-1 [hUNC24] gene is expressed mainly in the brain. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:765-770, 2000.

Molecular genetic delineation of a deletion of chromosome 13q12→q13 in a patient with autism and auditory processing deficits

In a sporadic case of autism and language deficit due to auditory processing defects, molecular genetic studies revealed that a chromosomal deletion occurred in the 13q12→q13 region. No chromosome abnormalities were detected in the parents. We determined that the deletion occurred on the paternally derived chromosome 13. There are two previous reports of chromosome 13 abnormalities in patients with autism. The deletion in the subject described in this paper maps between the two chromosome 13 linkage peaks described by Bradford et al. (2001) in studies of subjects with autism and language deficits. The 9-Mb region deleted in the patient described here contains at least four genes that are expressed in brain and that play a role in brain development. They are NBEA, MAB21L1, DCAMKL1 and MADH9. These genes therefore represent candidate genes for autism and specific language deficits.