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▪ Cerebellar Volume Decreased and Brain Peripheral Cerebrospinal Fluid Increased in Groups With ASD Compared to Adult Controls [Hallahan et al., 2008]

  1. Top of page
  2. ▪ Cerebellar Volume Decreased and Brain Peripheral Cerebrospinal Fluid Increased in Groups With ASD Compared to Adult Controls [Hallahan et al., ]
  3. ▪ GABA-A Receptor Subunits in Brains of Those Who Had ASD [Fatemi, Reutiman, Folsom, & Thuras, ]
  4. ▪ Another Chromosomal Disorder Found in Autism and Other Developmental Disorders—Diagnosis by Genotype or Phenotype? [Mefford et al., ]

The authors conducted a structural neuroimaging study of 114 adults with ASD and 60 control individuals. The age range was 18–58 and age was matched by group. The full-scale IQ of the ASD group was 98 with a standard deviation of 18 and the full-scale IQ of the control group was 114 with a standard deviation of 12. The authors subdivided the ASD group into Asperger's syndrome (N=80), autism (N=28), and PDD NOS (N=6). The definition of Asperger's syndrome was an inclusive one in which there was an absence of language delay and absence of general cognitive delay, in an individual who would otherwise be classified as having autism.

The authors noted that previous studies had shown differences in brain size depending on the age of individuals being scanned, including data supporting a model for early overgrowth followed by a deceleration in growth curves of total brain volume. Because of the possibility of a course in which brain size was larger and then decreased, and because differential decrease in cortical gyrification with age has been reported in ASD, the authors hypothesized that there would be an increase in peripheral cerebrospinal fluid (CSF) in adults with ASD compared with controls.

The authors found a reduction in the size of the cerebellum in the adults with ASD compared with the control participants. There were no differences in cerebellar volume among ASD subgroups after correction for the IQ of the Asperger's syndrome subgroup being higher than the autism subgroup.

The authors also found an increase in brain peripheral CSF volume [brain peripheral CSF=total intracranial volume−(cerebral hemispheres+cerebellum+brainstem+ventricles)]. There was a small increase in peripheral CSF volume with age (r=0.23 in ASD). The correlation between peripheral CSF and age did not differ between ASD and controls and did not account for the difference between groups, which were age matched by group.

An additional analysis was conducted in which a subgroup of 51 controls was compared with a group of 69 individuals with Asperger's syndrome. This analysis confirmed both a reduction in cerebellar volume and an increase in brain peripheral CSF.

Lateral ventricular volume was larger in the ASD group compared with controls, but this difference was removed after correction for IQ. The authors did not find a difference in head size (intracranial volume), whole brain volume, or bulk lobar brain matter volume between the group with ASD and controls or among ASD subgroups. There was no difference in right–left asymmetry.

The authors' findings were consistent with their hypothesis of increased brain peripheral CSF. They note that a limitation of their study is that they did not measure cortical thickness or gyrification directly. Moreover, they acknowledge that the data are not longitudinal. Therefore, they are unable to determine when an increase in brain peripheral CSF developed. They consider the absence of a difference in head size to suggest that maximal brain volume was never higher in the group with ASD compared with controls.

In summary, the authors provide further evidence of cerebellar brain developmental differences in ASD in terms of their only cerebellar measure, which was total cerebellar volume. They also report increased brain peripheral CSF in ASD. Subsequent studies are necessary to determine whether the increase in brain peripheral CSF is due to a reduction in cortical thickness and/or gyrification over time. Nonetheless, the study is intriguing on the basis of using a large adult sample to test and confirm their hypothesis that there would be increased brain peripheral CSF. It is also important because in this large sample of high functioning adults with ASD that they did not find an overall increase in brain size. It contributes to a large body of neuroimaging studies in ASD by providing additional information about adults, including a group older and larger than many previous studies.

▪ GABA-A Receptor Subunits in Brains of Those Who Had ASD [Fatemi, Reutiman, Folsom, & Thuras, 2008]

  1. Top of page
  2. ▪ Cerebellar Volume Decreased and Brain Peripheral Cerebrospinal Fluid Increased in Groups With ASD Compared to Adult Controls [Hallahan et al., ]
  3. ▪ GABA-A Receptor Subunits in Brains of Those Who Had ASD [Fatemi, Reutiman, Folsom, & Thuras, ]
  4. ▪ Another Chromosomal Disorder Found in Autism and Other Developmental Disorders—Diagnosis by Genotype or Phenotype? [Mefford et al., ]

The authors followed up on earlier studies demonstrating reduced postmortem GABA-A receptor radioligand binding in samples from individuals with ASD compared with controls by studying the amount of protein of several of the GABA-A receptor subunits. Most GABA-A receptors are composed of multiple subunits (multimeric) with the most common composition being a protein complex with two α subunits, two β subunits, and one γ subunit. (It may be helpful to the reader less familiar with naming of similar receptors to remember that α, β, and γ are the first three letters of the Greek alphabet, with α often given to the highest level of the subdivision of related proteins.) There are six α subunits, three β subunits, and three γ subunits. The authors studied the amount of protein using the classic technique of labeling specific proteins with antibody. In contrast to studies of mRNA expression that allow near genome-wide coverage of gene expression, proteins are not yet able to be studied with such high throughput and the study of GABA-A α1,2,3 and GABA-A β 3 represents a relatively large number of proteins studied in this field. The authors refer to the subunits by their genetic symbols, in which the GABA-A is shortened to GAB, followed by R for receptor and α 1 designated as A1, so that GABA-A receptor α 1 subunit is GABRA1. It is important to note that GABRB3 is a GABA-A receptor β subunit and not a GABA-B receptor. This nomenclature has confused many more researchers than readers of this review.

Three brain regions were logically chosen. One may note that subregions of the amygdala and hippocampus are logical to study, but tissue access committees are reasonably protective of this very limited resource. One may also find the sample size relatively small in comparison to studies not involving brain tissue. However, the study has the distinct advantage of studying the brain, the organ of interest.

The authors found a reduction in the subunits, GABRA1, GABRA2, GABRA3, and GABRB3 in Brodmann's area 40 (BA40) (in parietal cortex), GABRA1 and GABRB3 in cerebellum, and GABRA1 in BA9 (superior frontal cortex). The authors did not find an impact of seizure history on the findings. The authors discuss the possible relationship of these findings to genetic syndromes, such as 15q11-q13 duplication syndromes, which include the GABRB3 gene (as well as GABRA5 and GABRG3 not studied in this article and many other genes in the region). The findings are consistent with previous studies showing a reduction in GABRB3 mRNA in brains from an overlapping but not identical sample [Samaco, Hogart, & LaSalle, 2005]. The authors also discuss that several groups, but certainly not all, who have studied the region have reported genetic association to GABRB3 polymorphisms or linkage to the region. It is notable that to date, there has been no connection between the genetic studies and the gene expression or protein quantitation studies. Possibly connecting these related fields is one of many logical next steps.

The other question is whether the changes in the GABA-A receptor subunits account for the reduction in flunitrazepam-labeled GABA-A receptor maximal binding previously reported. This is an area where several postmortem findings are converging to suggest a reduction in GABA-A receptor binding in at least a subset of individuals with ASD.

▪ Another Chromosomal Disorder Found in Autism and Other Developmental Disorders—Diagnosis by Genotype or Phenotype? [Mefford et al., 2008]

  1. Top of page
  2. ▪ Cerebellar Volume Decreased and Brain Peripheral Cerebrospinal Fluid Increased in Groups With ASD Compared to Adult Controls [Hallahan et al., ]
  3. ▪ GABA-A Receptor Subunits in Brains of Those Who Had ASD [Fatemi, Reutiman, Folsom, & Thuras, ]
  4. ▪ Another Chromosomal Disorder Found in Autism and Other Developmental Disorders—Diagnosis by Genotype or Phenotype? [Mefford et al., ]

The authors report both microdeletion and microduplication of 1q21.1. The reviews of reports of chromosomal deletions and duplications in this journal has not yet included a description of the cytogenetic nomenclature. 1q21.1 is read “one q two one point one” instead of “one q twenty-one point one” because it refers to the first sub-band of what was originally the second band when the resolution of chromosomes was much lower, instead of it being on the first subdivision (point 1) of the twenty-first band. This clarification may help the reader understand that band 11 is the band closest to the centromere on each arm and not the eleventh band on the arm of a chromosome. It may also be useful to know that the p arm refers to the small (petite) arm and the q arm to the long arm (because q follows p).

The 1q21.1 microduplication syndrome was found in patients with intellectual disability or ASD with other clinical manifestations such as macrocephaly. The 1q21.1 microdeletion syndrome was found in subjects with variable clinical manifestations including schizophrenia, mild to moderate intellectual disability, microcephaly, cataracts, and cardiac abnormalities. Both syndromes were found more commonly in affected subjects (defined more broadly than ASD) compared with controls.

This is another in a series of syndromes identified in association with intellectual disability and/or ASD owing to recent rapid advances in the resolution of chromosomal analysis. The variable expression of clinical signs and symptoms with the same deletion or duplication is of interest. It is likely that other variation in the genome and environmental factors (recognizing that a strong “environmental” factor may include the differential environment that is genetically determined by male or female sex) may contribute to this phenotypic variability.

Because of the absence of perfect correlation between phenotype and genotype, the authors recommend that diagnosis be genotype-driven. This is an interesting perspective that makes sense from a laboratory perspective. However, the relevance of the laboratory test is to genetic recurrence risk and prediction of phenotypic characteristics. For example, if the course or interventions (both in terms of benefits and risk for adverse events) is different, then the knowledge that a patient has this genotypic diagnosis is important beyond the very important relevance to diagnosis (depending on the finding). However, if one is considering diagnosis in the sense of determining the most appropriate educational placement and therapeutic planning, the clinical diagnosis of an ASD or the more important full assessment of strengths and weaknesses of the individual become much more relevant than the genotypic diagnosis. Diagnostic systems should be able to take into account both clinical (phenotypic) and genotypic diagnoses/descriptions.

One may ask the question what the deletions and duplications may tell us about the impact of the genetic change to the development of the brain. One of the first obstacles is that the recurrent genomic disorders, such as 1q21.1 deletions/duplications occur at low copy repeats in the genome. These are regions that have large stretches of almost identical sequence where deletions or duplications are more likely to occur than at other places in the genome. This occurs by misalignment during creation of the egg or sperm at a low rate (often about 1:5000 births). The nonrandom location of such deletions and duplications decreases the likelihood of overlapping deletions and duplications that would allow fine mapping of the relevant genes in the interval. One or more of the genes in the 1q21.1 region may contribute to the clinical disorder through a dose-dependent effect on gene expression in the developing nervous system.

  • Fatemi, S.H., Reutiman, T.J., Folsom, T.D., & Thuras, P.D. (2008). GABA(A) receptor downregulation in brains of subjects with autism. Journal of Autism and Devlopmental Disorders, online in advance of print.
  • Hallahan, B., Daly, E.M., McAlonan, G., Loth, E., Toal, F., et al. (2008). Brain morphometry volume in autistic spectrum disorder: a magnetic resonance imaging study of adults. Psychological Medicine, online in advance of print.
  • Mefford, H.C., Sharp, A.J., Baker, C., Itsara, A., Jiang, Z., et al. (2008). Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. The New England Journal of Medicine, 359, 16851699.
  • Samaco, R.C., Hogart, A., LaSalle, J.M. (2005). Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Human Molecular Genetics, 14, 483492.