The Genetics of Autism
Approximately 10% of the cases of autism are probably in some way
genetically derived. In other words they have taken place due to the
genes of the parents and, if neither of the parents are ASD affected, it would
be reasonable to expect that only 1 in 4 of further children would have the
conditions. However, this single gene idea is simply not reasonable in
that even if one of identical twins (i.e. with all their genes the same;
monozygotic) there is only a 93% that the other will be. The statistics
for non-identical twins shows that they also have a decent chance of having
autism if one has it (but this data is wide with 0% to 40% chances have been
reported). The excess of ASD in boys is quite clear in that approximately
3-4 cases are in boys rather than girls. This led a lot of the
researchers to look at the X-
chromosome
(of which there is only one in boys). These figures are simply inadequate for
denying that an environmental factor being involved as well: for instance the
increase that has taken place (see figure from US cases) cannot be explained
genetically. Also it has become clear that twins and second
children often do not have similar psychological symptoms of ASD to each
other. The work has been well reviewed but is still
showing further genetics that may be involved.
Some genetic changes seem to be reliably associated with ASD but some do not in that some of the genetic changes sometimes have it and in other cases this does not happen. This is known as non-specific association. For instance the autism is only part of the syndrome for Fragile X and even in that it is in only a percentage that have autism at all. The fact that some genetic modifications are closely associated with a likelihood of ASD has led some researchers to feel that all cases must have some kind of genetic aspect to them and, as we have found the genetic causes for them (e.g. tuberous sclerosis), then by looking at their gene changes it should be possible to get a good idea as to what might cause the condition but without the rest of that syndrome. You can see below a list of the non-specific associations with syndromes, associations with gene changes, and a long list of findings that we simply don’t know the significance of at this point.
The apparent increase in cases that we seem to have seen of autism over the last 15 years does suggest that either the genes are becoming modified faster than they were before or, because the ASD people might have many children, a specifically large gene is specifically involved. An example of this would be to look at cystic fibrosis, where again there is a range of different clinical severities, and about one person in 23 is thought to carry a modified specific gene. In CF it is because the gene is so large that it is commonly likely to be changed. In familial Alzheimer’s disease it is because many different genes are part of the same chain for the correct production of a specific protein. It also should be noted that the autism of some genetically associated cases are not psychologically the same as seen in other groups and as such some researchers wonder whether the genetic aspects are a misleading source of information. Currently the hypothesis is that there is an important protein factor that would make the developing child avoid autism, and this depends on the formation of a protein that causes the brain to work properly. Therefore, genes that decide if the protein is made, that decide how it is changed, how it is taken to the synapse of the nerve, how it interacts with other nerves….and so there are many factors that could cause the illness and that is why when we look for specific genes we are having such difficulty in nailing it down.
Some elements and genes associated with ASD:
· Non
Specific Associations
· Angelman Syndrome (associated with a deletion in the 15q-q13 region)
· Prader-Willi syndrome (associated with a deletion in the 15q-q13 region)
·
Late onset Lennox Gestaut Syndrome (associated with a
deletion in the 15q-q13 region)
·
Neurofibromatosis
type 1
Many
individual genetic modifications, particularly of chromosome 6 (these are not
reviewed here but see Muhle et al below). See non-specific range
·
Specific genetic
changes that seem to be involved
· Neuroligin and Neurexin
(X-linked)
· Oxytocin and vasopressin receptor proteins
· Advanced glycation end product changes
·
SHANK3
·
Creatine
Transporter Protein
·
Serotonin: many genes associated with manufacture,
release and reception
·
MET
Multiple de novo chromosomal deletions and
duplications
Genetics that are NOT apparently associated with autism
Animal models of autism: as created using genetic
techniques.
Excellent Scientific Reviews:
This can be looked on in a way as autism being associated with known genetic conditions (e.g. Alpert’s syndrome) or with specific genes and these separate directions gradually meet up (but not yet!). The major problem at this point is that there are so many permutations and oddities that it is just impossible to be sure of the genetic abnormality that might have taken place in any child.
Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004 May;113(5):e472-86.. Major Review in 2004. They make it clear that there is no specific gene that will produce the disease reliably but they explain which specific parts are aimed at being involved. They also are not that impressed that all the ASDs are in fact the same condition (e.g. fragile X ASD is in fact often associated with other changes in the body like hyperorchidism). They explain that the association between monozygotic twins is not perfect (93%) and familial changes are difficult to be sure of in that they depend on the way in which the diagnosis is made. The reason for this is that there is almost certainly an environmental factor as well on which the genetic factor depends to produce the ASD. There are many genetic syndromes associated with autism but only a limited range appear to have useful that may indicate more about autism itself. The full list of syndromes is here but more useful ones are discussed to a greater extent further on: Angelman syndrome, Prader-Willi syndrome, 15q11-q13 duplication, fragile X syndrome, fragile X premutation, deletion of chromosome 2q, XYY syndrome, Smith-Lemli-Opitz syndrome, Apert syndrome, mutations in the ARX gene, De Lange syndrome, Smith-Magenis syndrome, Williams syndrome, Rett syndrome, Noonan syndrome, Down syndrome, velo-cardio-facial syndrome, myotonic dystrophy, Steinert disease, tuberous sclerosis, Duchenne's disease, Timothy syndrome, 10p terminal deletion, Cowden syndrome, 45,X/46,XY mosaicism, Myhre syndrome, Sotos syndrome, Cohen syndrome, Goldenhar syndrome, Joubert syndrome, Lujan-Fryns syndrome, Moebius syndrome, hypomelanosis of Ito, neurofibromatosis type 1, CHARGE syndrome and HEADD syndrome. (see this article to look up a lot of the specific syndromes that may, or may not have autism as part of them).
Szatmari P, Paterson AD et al . Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007 Mar;39(3):319-28. Epub 2007 Feb 18. This has a very large number of authors and is particularly interested to implicate chromosome 11p12-p13 and neurexins.
Grice DE, Buxbaum JD. The genetics of autism spectrum disorders. Neuromolecular Med. 2006;8(4):451-60. Review (this article looks very much into the genetic DNA direction rather than the syndrome association of autism.
Burmeister M, McInnis MG, Zöllner S. Psychiatric genetics: progress amid controversy. Nat Rev Genet. 2008 Jul;9(7):527-40. Review.
Mendelsohn NJ, Schaefer GB. Genetic evaluation of autism. Semin Pediatr Neurol. 2008 Mar;15(1):27-31. Review. (They go into the ways in which this is being investigated)
Liu XQ, Paterson AD, Szatmari P; The Autism Genome Project Consortium. Genome-wide Linkage Analyses of Quantitative and Categorical Autism Subphenotypes. Biol Psychiatry. 2008 Jul 15. [Epub ahead of print) They basically found that it was difficult to be sure of any specific genetic change that was certain for the illness but that there might be subphenotypes that were more obvious.
Genetics of autism spectrum disorders. Kumar
RA, Christian SL. Curr Neurol Neurosci Rep. 2009 May;9(3):188-97. Many techniques have been used to
characterize the genetic bases of ASDs. Linkage studies have identified several
replicated susceptibility loci, including 2q24-2q31, 7q, and 17q11-17q21.
Association studies and mutation analysis of candidate genes have implicated
the synaptic genes NRXN1, NLGN3, NLGN4, SHANK3, and CNTNAP2 in ASDs.
Traditional cytogenetic approaches highlight the high frequency of large
chromosomal abnormalities (3%-7% of patients), including the most frequently
observed maternal 15q11-13 duplications (1%-3% of patients). They then go on to
discuss the microarray system for looking for small changes in individual genes
or wide arrangements and how many groups have found various changes including
some of the ones mentioned above. They
admit in the end, however, that any specific genetic cause of autism, even in
familial cases remains unclear.
Nuclear and mitochondrial genome defects in autisms.
Smith M, Spence MA, Flodman P. Ann N Y Acad Sci. 2009 Jan;1151:102-32.
Collectively these data provide additional evidence of nuclear and mitochondrial
genome imbalance in autism and evidence of specific candidate genes in autism.
We present data on dosage changes in genes that map on the X chromosomes and
the Y chromosome. Precise analyses of Y located genes are often difficult
because of the high degree of homology of X- and Y-related genes.
AutDB: a gene reference resource for autism research. Basu SN, Kollu R, Banerjee-Basu S. Nucleic Acids Res. 2009 Jan;37(Database issue):D832-6. This contains the web site addresses to show the genetic information that is already available in autism. The difficulty has always been the different methods used by different researchers to demonstrate findings. Try http://www.mindspec.org/autdb.html . What you find is that a huge number of potential genes are put forward as being involved.
Current developments in the genetics of autism: from
phenome to genome. Losh M, Sullivan PF, Trembath D, Piven J. J Neuropathol Exp Neurol. 2008 Sep;67(9):829-37.
Copy-number variations associated with autism spectrum
disorder. Kakinuma H, Sato H. Pharmacogenomics.
2008 Aug;9(8):1143-54.
Genome-wide linkage analyses of quantitative and
categorical autism subphenotypes. Liu XQ, Paterson AD, Szatmari P;
Autism Genome Project Consortium. Biol Psychiatry.
2008 Oct 1;64(7):561-70. The search for
susceptibility genes in autism and autism spectrum disorders (ASD) has been
hindered by the possible small effects of individual genes and by genetic
(locus) heterogeneity. To overcome these obstacles, one method is to use
autism-related subphenotypes instead of the categorical diagnosis of autism
since they may be more directly related to the underlying susceptibility
loci. What they then did was to divide
the cases into those with extreme phenotypes from those with those with lesser
forms. They then looked for genetics
that might follow the effects. When the
ASD families with IQ > or = 70 were used, a logarithm of odds (LOD) score of
4.01 was obtained on chromosome 15q13.3-q14, which was previously linked to
schizophrenia. We also obtained a LOD score of 3.40 on chromosome 11p15.4-p15.3
using the ASD families. They claimed
that it was probably a very useful system.
Heterogeneous dysregulation of microRNAs across the
autism spectrum. Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y,
Wall DP, Geschwind DH, Lao K,
A synaptic trek to autism. Bourgeron T. Curr Opin Neurobiol. 2009 Apr;19(2):231-4. This explains how several of the genetic
changes that we have seen seem to be
specifically involved in synaptic abnormalities. Mutations in TSC1/TSC2, NF1, or PTEN activate
the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis,
neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1
alter synaptic function and lead to mental retardation, typical autism, or
Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal
cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is
associated with synaptogenesis and imbalance between excitatory and inhibitory
currents. Taken together, these data strongly suggest that abnormal synaptic
homeostasis represent a risk factor to ASD.
In a way this reminds me of the research that went into Alzheimer’s
disease, where certain forms were genetically caused but they seemed to be
completely unrelated…until it was found exactly what they did and they all
connected up.
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MET gene
This is known as an onchogene involved in tumour
development. However it is also involved
in signalling in the formation of the immune system, embryogenesis and
peripheral organ development and repair.
One thing that may be important is that it is involved in the developing
nervious system and have been implicated in neuronal development.
MET and autism susceptibility: family and case-control
studies. Sousa I, Clark TG, Toma C, Kobayashi K, Choma M, Holt R,
Sykes NH, Lamb JA, Bailey AJ, Battaglia A, Maestrini E, Monaco AP;
International Molecular Genetic Study of Autism Consortium (IMGSAC). Eur J Hum Genet. 2009 Jun;17(6):749-58. The MET gene is associated with the 7q site
that has been shown to be associated with ASD.
The MET is in fact an oncogene. Here they present a family-based
association analysis covering the entire MET locus. Significant results were
obtained in both single locus and haplotype approaches with a single nucleotide
polymorphism in intron 1 (rs38845, P<0.004) and with one intronic haplotype
(AAGTG, P<0.009) in 325 multiplex IMGSAC families and 10 IMGSAC trios.
Although these results failed to replicate in an independent sample of 82
Italian trios, the association itself was confirmed by a case-control analysis
performed using the Italian cohort (P<0.02).
Association of MET with social and communication
phenotypes in individuals with autism spectrum disorder.
Genetic evidence implicating multiple genes in the MET
receptor tyrosine kinase pathway in autism spectrum disorder.
Dynamic gene and protein expression patterns of the
autism-associated met receptor tyrosine kinase in the developing mouse
forebrain. Judson MC, Bergman MY,
Distinct genetic risk based on association of MET in
families with co-occurring autism and gastrointestinal conditions.
When linkage signal for autism MET candidate gene.
Disruption of cerebral cortex MET signaling in autism
spectrum disorder. Campbell DB, D'Oronzio R, Garbett K, Ebert PJ,
Mirnics K, Levitt P, Persico AM. Ann Neurol.
2007 Sep;62(3):243-50.
A genetic variant that disrupts MET transcription is associated with autism. Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16834-9
This site has been found to be
involved in some way by several groups.
With duplications in it, modifications of the site itself, and within
short distances of it on the chromosome.
Exactly how it would be involved is unclear. The Angelman syndrome, Prader-Willi syndrome
and a single report of a late onset Lennox-Gestaut syndrome are modified and
are associated with a high proportion to have ASD. Changes in the 15q chromosome are often
associated with other changes such as prominent mental retardation.
Simon EW, Haas-Givler B, Finucane B. A longitudinal follow-up study of autistic symptoms in
children and adults with duplications of 15q11-13. Am J Med Genet B
Neuropsychiatr Genet. 2009 Jun 22.
They were quite happy that the duplication was closely associated with
the syndrome in some way (although why they were not sure). Investigation of 29 individuals, tentative
conclusions were drawn based on cross-sectional data suggesting that autistic
symptoms increased with age, most specifically in the area of social interaction
Kato
C, Tochigi M, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto O, Kim
SY, Watanabe K, Kano Y, Nanba E, Kato N, Sasaki T. Association study of the
commonly recognized breakpoints in chromosome 15q11-q13 in Japanese autistic
patients. Psychiatr Genet. 2008 Jun;18(3):133-6.
Kim
SJ, Brune CW, Kistner EO, Christian SL, Courchesne EH, Cox NJ, Cook EH.
Transmission disequilibrium testing of the chromosome 15q11-q13 region in
autism. Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 24.
Dykens
EM, Sutcliffe JS, Levitt P. Autism and 15q11-q13 disorders: behavioral, genetic,
and pathophysiological issues. Ment Retard Dev Disabil Res Rev. 2004;10(4):284-91.
Nurmi
EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS.
Exploratory subsetting of autism families based on savant skills improves
evidence of genetic linkage to 15q11-q13. J Am Acad Child Adolesc Psychiatry.
2003 Jul;42(7):856-63
Ma
DQ, Jaworski J, Menold MM, Donnelly S, Abramson RK, Wright HH, Delong GR,
Gilbert JR, Pericak-Vance MA, Cuccaro ML. Ordered-subset analysis of savant
skills in autism for 15q11-q13. Am J Med Genet B Neuropsychiatr Genet. 2005 May
5;135B(1):38-41.
Genome-wide linkage in Utah autism pedigrees. Allen-Brady K, Robison R, Cannon D, Varvil T,
Villalobos M, Pingree C, Leppert MF, Miller J, McMahon WM, Coon H. Mol Psychiatry. 2009 May 19 This genome-wide screen of 70 families
includes 20 large extended pedigrees of 6-9 generations, 6 moderate-sized
families of 4-5 generations and 44 smaller families of 2-3 generations. The
Center for Inherited Disease Research (CIDR) provided genotyping using the Illumina
Linkage Panel 12, a 6K single-nucleotide polymorphism (SNP) platform. Results
from 192 subjects with an autism spectrum disorder (ASD) and 461 of their
relatives revealed genome-wide significance on chromosome 15q, with three
possibly distinct peaks: 15q13.1-q14 (heterogeneity LOD (HLOD)=4.09 at 29 459
872 bp); 15q14-q21.1 (HLOD=3.59 at 36 837 208 bp); and 15q21.1-q22.2 (HLOD=5.31
at 55 629 733 bp). Two of these peaks replicate earlier findings. Additional suggestive results on chromosomes
2p25.3-p24.1 (HLOD=1.87), 7q31.31-q32.3 (HLOD=1.97) and 13q12.11-q12.3
(HLOD=1.93). Affected subjects in families supporting the linkage peaks found
in this study did not reveal strong evidence for distinct phenotypic subgroups.
Linkage and linkage disequilibrium scan for autism loci
in an extended pedigree from Finland. Kilpinen H, Ylisaukko-oja T, Rehnström
K, Gaál E, Turunen JA, Kempas E, von Wendt L, Varilo T, Peltonen L. Hum Mol Genet. 2009 Aug 1;18(15):2912-21. We have here used this special opportunity to
identify rare alleles in autism by genealogically tracing 20 autism families
into one extended pedigree with verified genealogical links reaching back to
the 17th century. In this unique pedigree, we performed a dense microsatellite
marker genome-wide scan of linkage and LD and followed initial findings with
extensive fine-mapping. We identified a putative autism susceptibility locus at
19p13.3 and obtained further evidence for previously identified loci at 1q23
and 15q11-q13. Most promising candidate genes were TLE2 and TLE6 clustered at
19p13 and ATP1A2 at 1q23.
Late-onset Lennox-Gastaut syndrome in a patient with
15q11.2-q13.1 duplication. Orrico A, Zollino M, Galli L, Buoni S,
Marangi G, Sorrentino V. Am J Med Genet A. 2009
May;149A(5):1033-5. This simply
contained an autistic patient and was found to have the microduplication.
Chipping away at the common epilepsies with complex
genetics: the 15q13.3 microdeletion shows the way. Mulley JC,
Dibbens LM.
Genome
Med. 2009 Mar 25;1(3):33. They merely
include autism as being part of their study and how microdeletion is not
generally what is found in ASD but can be.
This is, however, quite a good review of the various other factors
associated with the region of the chromosome.
15q13.3 microdeletions increase risk of idiopathic
generalized epilepsy. Helbig I, Mefford HC, Sharp AJ, Guipponi M,
Fichera M, Franke A, Muhle H, de Kovel C, Baker C, von Spiczak S, Kron KL,
Steinich I, Kleefuss-Lie AA, Leu C, Gaus V, Schmitz B, Klein KM, Reif PS,
Rosenow F, Weber Y, Lerche H, Zimprich F, Urak L, Fuchs K, Feucht M, Genton P,
Thomas P, Visscher F, de Haan GJ, Møller RS, Hjalgrim H, Luciano D, Wittig M,
Nothnagel M, Elger CE, Nürnberg P, Romano C, Malafosse A, Koeleman BP, Lindhout
D, Stephani U, Schreiber S, Eichler EE, Sander T. Nat Genet. 2009
Feb;41(2):160-2. identified 15q13.3
microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with
idiopathic generalized epilepsy (IGE), which were not detected in 3,699
controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE
syndromes without other features previously associated with 15q13.3
microdeletions, such as intellectual disability, autism or schizophrenia.
A 15q13.3 microdeletion segregating with autism.
Pagnamenta AT, Wing K, Akha ES, Knight SJ, Bölte S, Schmötzer G, Duketis E,
Poustka F, Klauck SM, Poustka A, Ragoussis J, Bailey AJ, Monaco AP;
International Molecular Genetic Study of Autism Consortium. Eur J Hum Genet. 2009 May;17(5):687-92. In this study,
a rare approximately 2 Mb microdeletion involving chromosome band 15q13.3 was
detected in a multiplex autism family. This genomic loss lies between distal
break points of the Prader-Willi/Angelman syndrome locus and was first
described in association with MR and epilepsy.
Chromosome 15q11-13 duplication syndrome brain reveals
epigenetic alterations in gene expression not predicted from copy number.
Hogart A, Leung KN, Wang NJ, Wu DJ, Driscoll J, Vallero RO, Schanen NC, LaSalle
JM. J Med Genet. 2009 Feb;46(2):86-93. findings suggest that genetic copy number
changes combined with additional genetic or environmental influences on
epigenetic mechanisms impact outcome and clinical heterogeneity of 15q11-13
duplication syndromes. They looked for
many of the individual genes within the region and tried to find out if any
were specifically associated with the condition.
Microdeletion/duplication at 15q13.2q13.3 among
individuals with features of autism and other neuropsychiatric disorders.
Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson
H, Gentile J, Harris DJ, Hegde V, Hundley R, Khwaja O, Kothare S, Luedke C,
Nasir R, Poduri A, Prasad K, Raffalli P, Reinhard A, Smith SE, Sobeih MM, Soul
JS, Stoler J, Takeoka M, Tan WH, Thakuria J, Wolff R, Yusupov R, Gusella JF,
Daly MJ, Wu BL. J Med Genet. 2009 Apr;46(4):242-8.
The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication
syndrome may include features of autism spectrum disorder, a variety of
neuropsychiatric disorders, and cognitive impairment. Recognition of this
broader phenotype has implications for clinical diagnostic testing and efforts
to understand the underlying aetiology of this syndrome.
Familial and sporadic 15q13.3 microdeletions in Idiopathic Generalized Epilepsy: Precedent for Disorders with Complex Inheritance. Dibbens LM, Mullen S, Helbig I, Mefford HC, Bayly MA, Bellows S, Leu C, Trucks H, Obermeier T, Wittig M, Franke A, Caglayan H, Yapici Z; EPICURE Consortium, Sander T, Eichler EE, Scheffer IE, Mulley JC, Berkovic SF. Hum Mol Genet. 2009 Jul 10.
Cohen IL, Liu X, Schutz C, White BN, Jenkins EC, Brown WT, Holden JJ Association of autism severity with a monoamine oxidase A functional polymorphism.Clin Genet. 2003 Sep;64(3):190-7.
Huang YY, Cate SP, Battistuzzi C, Oquendo MA, Brent D, Mann JJ An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences Neuropsychopharmacology. 2004 Aug;29(8):1498-505.
Davis LK, Hazlett HC, Librant AL, Nopoulos P, Sheffield VC, Piven J, Wassink TH. Cortical enlargement in autism is associated with a functional VNTR in the monoamine oxidase A gene. Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 24. (see MRI scanning concerning brain enlargement. A polymorphism exists within the promoter region of the MAOA gene that influences MAOA expression levels so that "low activity" alleles are associated with increased neurotransmitter levels in the brain. Individuals with autism often exhibit elevated serotonin levels. A consistent association between the "low activity" allele and larger brain volumes for regions of the cortex in children with autism but not in controls. They did not find evidence for over-transmission of the "low activity" allele in a separate sample of 114 affected sib pair families.)
Roohi J, Devincent CJ, Hatchwell E, Gadow KD. Association of a Monoamine Oxidase-A Gene Promoter Polymorphism With ADHD and Anxiety in Boys With Autism Spectrum Disorder. J Autism Dev Disord. 2008 Jun 20.
Hranilović
D, Novak R, Babić M, Novokmet M, Bujas-Petković Z, Jernej B.
Hyperserotonemia in autism: the potential role of 5HT-related gene variants.
Coll Antropol. 2008 Jan;32 Suppl 1:75-80.
(they looked at the effect of the MAOA gene and others in increasing the serotonin
levels of the platelets).
Family- and population-based association studies of
monoamine oxidase A and autism spectrum disorders in Korean. Yoo HJ,
Lee SK, Park M, Cho IH, Hyun SH, Lee JC, Yang SY, Kim SA. Neurosci Res. 2009 Mar;63(3):172-6. This study evaluates the relationship between
ASDs and MAOA markers (i.e., uVNTR and four single nucleotide polymorphisms
(SNPs)) in 151 Korean family trios with children diagnosed with ASDs, and 193
unrelated Korean controls. In a
family-based association test (FBAT) analysis, it was observed that, in the
dominant model, a three-repeat allele of a MAOA-uVNTR marker was preferentially
transmitted in ASDs (Z=2.213, p=0.027). Moreover, in the global haplotype
analysis, the statistically significant evidence of associations with ASD were
demonstrated in additive and dominant models (additive chi(2)=11.349, d.f.=2,
p=0.003; dominant chi(2)=6.198, d.f.=2, p=0.045).
Association of a monoamine oxidase-a gene promoter
polymorphism with ADHD and anxiety in boys with autism spectrum disorder. Roohi J, DeVincent CJ, Hatchwell E, Gadow
KD. J Autism Dev
Disord. 2009 Jan;39(1):67-74. Parents and teachers completed a
DSM-IV-referenced rating scale for 5- to 14-year-old boys with ASD (n = 43).
Planned comparisons indicated that children with the 4- versus 3-repeat allele
had significantly (p < 05) more severe parent-rated ADHD inattention and
impulsivity, and more severe teacher-rated symptoms of generalized anxiety. Our
results support a growing body of research indicating that concomitant
behavioral disturbances in children with ASD warrant consideration as clinical
phenotypes, but replication with independent samples is necessary to confirm
this preliminary finding.
Regulation of monoamine oxidase A by the SRY gene on the
Y chromosome. Wu JB, Chen K,
Li Y, Lau YF, Shih JC. FASEB J. 2009 Aug
6.
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GABA receptor and production
Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R. Association between a GABRB3 polymorphism and autism. Mol Psychiatry. 2002;7(3):311-6. (gamma-aminobutyric acid type-A receptor beta3 subunit gene (GABRB3) has been associated in one study(2) but not others.(3-5) We completed an association analysis with 155CA-2 using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). We also used four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) localized within 150 kb of 155CA-2. The use of multi-allelic TDT (MTDT) (P < 0.002), as well as the TDT (P < 0.004), demonstrated an association between autistic disorder and 155CA-2 in these families. Meiotic segregation distortion could be excluded as a possible cause for these results since no disequilibrium was observed in unaffected siblings. These findings support a role for genetic variants within the GABA receptor gene complex in 15q11-13 in autistic disorder.)
McCauley
JL, Olson
LM, Delahanty
R, Amin
T, Nurmi
EL, Organ
EL, Jacobs
MM, Folstein
SE, Haines
JL, Sutcliffe
JS. A linkage disequilibrium map of the 1-Mb
15q12 GABA(A) receptor subunit cluster and association to autism
Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131B(1):51-9 (looked
into because of the association with the Prader-Willi/Agelmann syndrome)
Expression of GABA(B) receptors is altered in brains of
subjects with autism.
GABA(A) receptor downregulation in brains of subjects
with autism. Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD. J Autism Dev Disord. 2009 Feb;39(2):223-30. Gamma-aminobutyric acid A (GABA(A)) receptors
are ligand-gated ion channels responsible for mediation of fast inhibitory
action of GABA in the brain. Preliminary reports have demonstrated altered
expression of GABA receptors in the brains of subjects with autism suggesting
GABA/glutamate system dysregulation. We investigated the expression of four
GABA(A) receptor subunits and observed significant reductions in GABRA1,
GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann's Area 40 (BA40)),
while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1
was significantly altered in superior frontal cortex (BA9). The presence of
seizure disorder did not have a significant impact on GABA(A) receptor subunit
expression in the three brain areas. Our results demonstrate that GABA(A)
receptors are reduced in three brain regions that have previously been
implicated in the pathogenesis of autism, suggesting widespread GABAergic
dysfunction in the brains of subjects with autism. This seems a sort of re-publication of the
article above.
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Tuberous sclerosis (assn)
This is a specific uncommon
condition that is found to have an excess of autism. Its help in
indicating the background to the disease in the brain is not good. Click
on the Marcotte paper and get some more information on the illness. Tuberous sclerosis complex (TSC) is an
inherited genetic disorder commonly associated with neuropsychiatric
complications like epilepsy, mental retardation, autism and other behavioral
problems and constitutes about 1-4% of the autistic population. It is associated with alterations in the
TSC1 and TSC2 genes.
Marcotte L, Crino PB. The neurobiology of the tuberous sclerosis complex. Neuromolecular Med. 2006;8(4):531-46.
Wiznitzer M. Autism and tuberous sclerosis. J Child Neurol. 2004 Sep;19(9):675-9. Review
Humphrey A, Neville BG, Clarke A, Bolton PF. Autistic regression associated with seizure onset in an infant with tuberous sclerosis. Dev Med Child Neurol. 2006 Jul;48(7):609-11.
Asano
E, Chugani DC, Muzik O, Behen M, Janisse J, Rothermel R, Mangner TJ,
Chakraborty PK, Chugani HT. Autism in tuberous sclerosis complex is related
to both cortical and subcortical dysfunction. Neurology. 2001 Oct 9;57(7):1269-77.
Tuberous sclerosis complex activity is required to
control neuronal stress responses in an mTOR-dependent manner. Di
Nardo A, Kramvis I, Cho N, Sadowski A, Meikle L, Kwiatkowski DJ, Sahin M. J Neurosci. 2009 May 6;29(18):5926-37. The tuberous sclerosis complex is a
neurogenetic disorder caused by loss-of-function mutations in either the TSC1
or TSC2 genes. The TSC1/TSC2 protein complex plays a major role in controlling
the Ser/Thr kinase mammalian target of rapamycin (mTOR), which is a master
regulator of protein synthesis and cell growth. In this study, we show that
endoplasmic reticulum (ER) stress regulates TSC1/TSC2 complex to limit mTOR
activity. Exactly why this should be
associated with autism in the patient is not clear.
Correlation of autism with temporal tubers in tuberous
sclerosis complex. Kothur K, Ray M, Malhi P. Neurol
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Phenylketonurea (assn)
Baieli S, Pavone L, Meli C, Fiumara A, Coleman M. Autism and phenylketonurea. J Autism Dev Disord. 2003 Apr;33(2):201-4.
Smith-Lemli-Opitz syndrome:
a genetic abnormality of the cholesterol manufacturing path (NB all normal steroid hormones like androgens and oestrogens are made from cholesterol in the body. This is one of the groups where the syndrome of autism is noticeably different from the wide range of ASD as seen in other cases)
Bukelis I, Porter FD, Zimmerman AW, Tierney E. Smith-Lemli-Opitz syndrome and autism spectrum disorder. Am J Psychiatry. 2007 Nov;164(11):1655-61.
Sikora
DM, Pettit-Kekel K, Penfield J, Merkens LS, Steiner RD. The near universal
presence of autism spectrum disorders in children with Smith-Lemli-Opitz
syndrome. Am J Med Genet A. 2006 Jul 15;140(14):1511-8.
Immunohistochemical and microarray analyses of a mouse
model for the smith-lemli-opitz syndrome. Waage-Baudet H, Dunty WC
Jr, Dehart DB, Hiller S, Sulik KK. Dev Neurosci.
2005;27(6):378-96. This is an attempt to
assess mouse models in autism.
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Association with Neuroligin and Neurexin (also Neuropilin, neuroligin1 and Sepaporin data)
(X-linked, and currently being chased). These are represented by the genes NLGN3 and NLGN4. The proteins connect between synapses such that one goes from one side and the other from the other side…all very reasonable. Unfortunately it is not completely clear what they do. I could not find any examples of null mice (ones where the gene had been removed) for instance.
Feng J, Schroer R, Yan J, Song W, Yang C, Bockholt A, Cook EH Jr, Skinner C, Schwartz CE, Sommer SS. High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett. 2006 Nov 27;409(1):10-3.
Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007 Oct 5;318(5847):71-6
Levinson JN, El-Husseini A. A crystal-clear interaction: relating neuroligin/neurexin complex structure to function at the synapse. Neuron. 2007 Dec 20;56(6):937-9.
Yamakawa H, Oyama S, Mitsuhashi H, Sasagawa N, Uchino S, Kohsaka S, Ishiura S. Neuroligins 3 and 4X interact with syntrophin-gamma2, and the interactions are affected by autism-related mutations. Biochem Biophys Res Commun. 2007 Mar 30;355(1):41-6.
Talebizadeh Z, Lam DY, Theodoro MF, Bittel DC, Lushington GH, Butler MG. Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J Med Genet. 2006 May;43(5):e21.
This attempts to show at which point during the development we see the activity of specific genes
during hard line period leading up to the box with the gene’s name in it. However it may continue past this (dotted line)
to have a period of influence (Pardo and Eberhart 2007)
Chen X, Liu H, Shim AH, Focia PJ, He X. Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions. Nat Struct Mol Biol. 2008 Jan;15(1):50-6. Epub 2007 Dec 16.
De Jaco A, Comoletti D, King CC, Taylor P. Trafficking of cholinesterases and neuroligins mutant proteins An association with autism. Chem Biol Interact. 2008 Apr 29. Recent studies reported that sequence polymorphisms in neuroligin-3 (NLGN3) and neuroligin-4 (NLGN4) genes have been linked to autism spectrum disorders indicating neuroligin genes as candidate targets in brain disorders. They have characterized a single mutation found in two affected brothers that substituted Arg451 to Cys in NL3. Data show that the exposed Cys causes retention of the protein in the endoplasmic reticulum (ER) when expressed in HEK-293 cells. Mutations in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and found a similar processing deficiency and intracellular retention (De Jaco et al., J Biol Chem. 2006, 281:9667-76). NL3, AChE and BChE mutant proteins are recognized as misfolded in the ER, and degraded via the proteasome pathway. A 2D electrophoresis coupled with mass spectrometry based approach was used to analyze proteins co-immunoprecipitating with NL3 and show differential expression of factors interacting with wild type and mutant NL3. We identified several proteins belonging to distinct ER resident chaperones families, including calnexin, responsible for playing a role in the folding steps of the AChE and NLs. The wonder is whether we are looking at changes in protein modification within the ER.
Yan J, Noltner K, Feng J, Li W, Schroer R, Skinner C, Zeng W, Schwartz CE, Sommer SS. Neurexin 1alpha structural variants associated with autism. Neurosci Lett. 2008 Jun 27;438(3):368-70. Epub 2008 Apr 25. (Neurexins are presynaptic membrane cell-adhesion molecules which bind to neuroligins, a family of proteins that are associated with autism. To explore the possibility that structural variants in the neurexin alpha genes predispose to autism, the coding regions and associated splice junctions of the neurexin 1alpha gene were sequenced in 116 Caucasian patients with autism and 192 Caucasian controls. Five ultra-rare structural variants including a predicted splicing mutation were found in patients with autism and absent in 10,000 control alleles. However one ultra-rare one was found in a control. Always the difficulty with ultra-rare ones is that you don’t know which ones matter in the body all that much and the one found in the control may have less significance than those in the autistics)
Bolliger MF, Pei J, Maxeiner S, Boucard AA, Grishin NV, Südhof TC. Unusually rapid evolution of Neuroligin-4 in mice. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6421-6. Epub 2008 Apr 23 (the aim being to look for a genetic model)
Gant JC, Thibault O, Blalock EM, Yang J, Bachstetter A, Kotick J, Schauwecker PE, Hauser KF, Smith GM, Mervis R, Li Y, Barnes GN. Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: Implications for autism and epilepsy. Epilepsia. 2008 Jul 24. [Epub ahead of print] (The semaphorin 3F (Sema3F) ligand and its receptor, neuropilin 2 (NPN2) are highly expressed within limbic areas. They actually removed the gene for NPN2 and looked at the neurological changes that might be seen…of course in mice it was difficult to interpret as a cause of something in humans but it was suggested as being involved) This is difficult to interpret but should be used as a key to look for further neurological data from PubMed.
Yan
J, Feng J, Schroer R, Li W, Skinner C, Schwartz CE, Cook EH Jr, Sommer SS.
Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr Genet.
2008 Aug;18(4):204-7. (The absence of p.I679V in 2986 control Y
chromosomes and the high similarity of NLGN4 and NLGN4Y are consistent with the
hypothesis that p.I679V contributes to the etiology of autism. The presence of
only one structural variant in our population of 335 males with autism/mental
retardation, the unavailability of significant family cosegregation and an
absence of functional assays are, however, important limitations of this
study. As a result the significance must be questioned)
Neuroligin-3-deficient mice: model of a monogenic
heritable form of autism with an olfactory deficit. Radyushkin K,
Hammerschmidt K, Boretius S, Varoqueaux F, El-Kordi A, Ronnenberg A, Winter D,
Frahm J, Fischer J, Brose N, Ehrenreich H. Genes Brain Behav. 2009
Jun;8(4):416-25. mutations in the postsynaptic cell adhesion protein
neuroligin-4 and point mutations in its homologue neuroligin-3 (NL-3) that were
found to cause certain forms of monogenic heritable ASD in humans. Here, we
show that NL-3-deficient mice display a behavioral phenotype reminiscent of the
lead symptoms of ASD: reduced ultrasound vocalization and a lack of social
novelty preference. The latter may be related to an olfactory deficiency
observed in the NL-3 mutants.
Bridging the synaptic gap: neuroligins and neurexin I in
Apis mellifera. Biswas S, Russell RJ, Jackson CJ, Vidovic M,
Ganeshina O, Oakeshott JG, Claudianos C. PLoS One.
2008;3(10):e3542. This effect was being
looked for in the nerves of the honey bee.
A Substitution Involving the NLGN4 Gene Associated with Autistic Behavior in the Greek Population. Pampanos A, Volaki K, Kanavakis E, Papandreou O, Youroukos S, Thomaidis L, Karkelis S, Tzetis M, Kitsiou-Tzeli S. Genet Test Mol Biomarkers. 2009 Aug 2
Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Kolozsi E, Mackenzie RN, Roullet FI, Decatanzaro D, Foster JA. Neuroscience. 2009 Jul 13. That is indeed interesting in that valproate given to the pregnant mother is statistically associated with autism in the offspring. The idea being that valproate would cause its effect through neuroligin. However, at this moment there is a good model in rats of autism as a result of the valproate.
Trafficking of cholinesterases and neuroligins mutant proteins. An association with autism. De Jaco A, Comoletti D, King CC, Taylor P. Chem Biol Interact. 2008 Sep 25;175(1-3):349-51.
No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level. Wermter AK, Kamp-Becker I, Strauch K, Schulte-Körne G, Remschmidt H. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):535-7
Disruption of neurexin 1 associated with autism spectrum
disorder. Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ,
Shen Y, Lally E, Weiss LA, Najm J, Kutsche K, Descartes M, Holt L, Braddock S,
Troxell R, Kaplan L, Volkmar F, Klin A, Tsatsanis K, Harris DJ, Noens I, Pauls
DL, Daly MJ, MacDonald ME, Morton CC, Quade BJ, Gusella JF. Am J Hum Genet. 2008 Jan;82(1):199-207. Their findings were in humans and also that
there were other changes near to the genetic changes.
Altered synchrony and connectivity in neuronal networks
expressing an autism-related mutation of neuroligin 3. Gutierrez RC,
Hung J, Zhang Y, Kertesz AC, Espina FJ, Colicos MA. Neuroscience.
2009 Aug 4;162(1):208-21. The neuroligin (NL) gene family codes for brain
specific cell adhesion molecules that play an important role in synaptic
connectivity. Recent studies have identified NL mutations linked to patients
with autism spectrum disorders (ASD). Cognitive deficits seen in autistic
patients are hypothesized to arise from altered synchronicity both within and between
brain regions. They use a rat model and show how the expression of
autism-associated neuroligin mutation R471C-NL3 affects synchrony in
dissociated cultures of rat hippocampal neurons. The useful aspect of all this is to show how
the ability of nerves to interact and do things in a synchronous way is lost.
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Glutamate
genetic association (also see the mitochondrial changes below with SCL25A12 gene )
Note that the various genes that are needed for glutamate to be used as a transmitter may be involved. For instance, the glutamic acid decarboxylase (GAD), the receptor gene and any of the genes involved in its creation.
Serajee
FJ, Zhong H, Nabi R, Huq AH. The metabotropic glutamate receptor 8 gene at
7q31: partial duplication and possible association with autism. J Med Genet.
2003 Apr;40(4):e42.
Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia. Bah J, Quach H, Ebstein RP, Segman RH, Melke J, Jamain S, Rietschel M, Modai I, Kanas K, Karni O, Lerer B, Gourion D, Krebs MO, Etain B, Schürhoff F, Szöke A, Leboyer M, Bourgeron T. Neuroreport. 2004 Aug 26;15(12):1987-91. a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05).
Frequency and transmission of glutamate receptors GRIK2
and GRIK3 polymorphisms in patients with obsessive compulsive disorder.
Delorme R, Krebs MO, Chabane N, Roy I, Millet B, Mouren-Simeoni MC, Maier W,
Bourgeron T, Leboyer M. Neuroreport. 2004 Mar 22;15(4):699-702.
Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Nanba E, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N, Sasaki T. Tachykinin 1 (TAC1) gene SNPs and haplotypes with autism: a case-control study. Brain Dev. 2007 Sep;29(8):510-3. Epub 2007 Mar 21. (To elucidate the genetic background of autism, we analyzed the relationship between three single nucleotide polymorphisms (SNPs) of the Tachykinin 1 gene (TAC1) and autism, because TAC1 is located in the candidate region for autism and produces substance P and neurokinins. These products modulate glutamatergic excitatory synaptic transmission and are also involved in inflammation. They found that Thus, the TAC1 locus is not likely to play a major role in the development of autism.)
Autism-specific copy number variants further implicate
the phosphatidylinositol signaling pathway and the glutamatergic synapse in the
etiology of the disorder.Cuscó I, Medrano A, Gener B, Vilardell M,
Gallastegui F, Villa O, González E, Rodríguez-Santiago B, Vilella E, Del Campo
M, Pérez-Jurado LA. Hum Mol Genet. 2009 May 15;18(10):1795-804. Epub 2009 Feb
26. Only 13 of the 238 detected copy
number alterations, ranging in size from 89 kb to 2.4 Mb, were present
specifically in the autistic population (12 out of 96 individuals, 12.5%).
Following validation by additional molecular techniques, we have characterized
these novel candidate regions containing 24 different genes including
alterations in two previously reported regions of chromosome 7 associated with
the ASD phenotype.
Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T; Paris Autism Research International Sibpair (PARIS) Study. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry. 2002;7(3):302-10. (they have been finding out that certain mice with autistic type symptoms have altered glutamate receptors and so it was worth looking for this in the human cases)
Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J.Postmortem brain abnormalities of the glutamate neurotransmitter system in autism.Neurology. 2001 Nov 13;57(9):1618-28.
Correia C, Coutinho AM, Diogo L, Grazina M, Marques C, Miguel T, Ataíde A, Almeida J, Borges L, Oliveira C, Oliveira G, Vicente AM. Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene. J Autism Dev Disord. 2006 Nov;36(8):1137-40.
Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, Hager J, Rousseau F, Curatolo P, Manzi B, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Lenti C, Saccani M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM. Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1.
Mol Psychiatry. 2008 Jul 8.
[Epub ahead of print]
Purkinje cell loss in autism may involve epigenetic
changes in the gene encoding GAD. Peedicayil J, Thangavelu P. Med Hypotheses. 2008 Dec;71(6):978. Epub 2008 Sep 9.
A population-based association study of glutamate decarboxylase 1 as a candidate gene for autism. Buttenschøn HN, Lauritsen MB, El Daoud A, Hollegaard M, Jorgensen M, Tvedegaard K, Hougaard D, Børglum A, Thorsen P, Mors O. J Neural Transm. 2009 Mar;116(3):381-8. The glutamate decarboxylase gene 1 (GAD1) located within chromosome 2q31 encodes the enzyme, GAD67, catalyzing the production of gamma-aminobutyric acid (GABA) from glutamate. Numerous independent findings have suggested the GABAergic system to be involved in autism. The present study investigates a Danish population-based, case-control sample of 444 subjects with childhood autism and 444 controls. Nine single nucleotide polymorphisms (SNPs) comprising the GAD1 gene and the microsatellite marker D2S2381 were examined for association with autism. We found no association between childhood autism and any single marker or 2-5 marker haplotypes. However, a rare nine-marker haplotype was associated with childhood autism. We cannot exclude neither GAD1 as a susceptibility gene nor the possibility of another susceptibility gene for autism to be located on chromosome 2q31.
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Fragile X.
This
is generally not referred to as autism per se as it includes other factors such
as developmental delays in walking or language, somatic dysmorphology (e.g.
large ears, large head). The cases are
generally male.
(this is well investigated and you should look this up separately)
Farzin F, Perry H, Hessl D, Loesch D, Cohen J, Bacalman S, Gane L, Tassone F, Hagerman P, Hagerman R. Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X permutation. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S137-44. (a good review)
Jinorose
U, Vasiknanonte P, Limprasert P, Brown WT, Panich V. The frequency of
fragile X syndrome among selected patients at
Kelley DJ, Davidson RJ, Elliott JL, Lahvis GP, Yin JC, Bhattacharyya A. The Cyclic AMP Cascade Is Altered in the Fragile X Nervous System. PLoS ONE. 2007 Sep 26;2(9):e931. (increased cyclic AMP is produced by platelets, and other blood cells. This research was carried out to attempt to find the reason for the increase. Note that cAMP rise has been found in other forms of autism.
Gothelf D, Furfaro JA, Hoeft F, Eckert MA, Hall SS, O'Hara R, Erba HW, Ringel J, Hayashi KM, Patnaik S, Golianu B, Kraemer HC, Thompson PM, Piven J, Reiss AL. Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP). Ann Neurol. 2008 Jan;63(1):40-51.
Hay DA. Fragile X - A challenge to models of the mind and to best clinical practice. Cortex. 2008 Jun;44(6):626-7. Epub 2007 Dec 23.
Brodkin ES. Social behavior phenotypes in fragile X syndrome, autism, and the Fmr1 knockout mouse: theoretical comment on McNaughton et al. (2008). Behav Neurosci. 2008 Apr;122(2):483-9. Review.
McNaughton CH, Moon J, Strawderman MS, Maclean KN, Evans J, Strupp BJ. Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome. Behav Neurosci. 2008 Apr;122(2):293-300.
Garber KB, Visootsak J, Warren ST. Fragile X syndrome. Eur J Hum Genet. 2008 Jun;16(6):666-72. Epub 2008 Apr 9
Gong X, Bacchelli E, Blasi F, Toma C, Betancur C, Chaste P, Delorme R, Durand CM, Fauchereau F, Botros HG, Leboyer M, Mouren-Simeoni MC, Nygren G, Anckarsäter H, Rastam M, Gillberg IC, Gillberg C, Moreno-De-Luca D, Carone S, Nummela I, Rossi M, Battaglia A, Jarvela I, Maestrini E, Bourgeron T; The International Molecular Genetic Study of Autism Consortium (IMGSAC)http://www.well.ox.ac.uk/∼maestrin/iat.html.. Analysis of X chromosome inactivation in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 24. (this goes into much more than the fragile X but gives a good indication as to how they fit together)
García-Nonell C, Ratera ER, Harris S, Hessl D, Ono MY, Tartaglia N, Marvin E, Tassone F, Hagerman RJ. Secondary medical diagnosis in fragile X syndrome with and without autism spectrum disorder. Am J Med Genet A. 2008 Aug 1;146A(15):1911-6.
Kelley DJ, Bhattacharyya A, Lahvis GP, Yin JC, Malter J, Davidson RJ. The cyclic AMP phenotype of fragile X and autism. Neurosci Biobehav Rev. 2008 Jun 17. (they use the cyclic AMP phenotype to tell in some way assess the fragile X syndrome)
Gatto
CL, Broadie K. Temporal
requirements of the fragile X mental retardation protein in the regulation of
synaptic structure.
Development. 2008 Aug;135(15):2637-48.
Epub 2008 Jun 25.
The State of Synapses in Fragile X Syndrome.
Pfeiffer BE, Huber KM. Neuroscientist. 2009 Mar 26 FXS is caused by loss of function of the Fmr1
gene, which encodes the RNA binding protein, fragile X mental retardation
protein (FMRP). Therefore, FXS is a tractable model to understand synaptic
dysfunction in cognitive disorders. FMRP is present at synapses where it
associates with mRNA and polyribosomes.
The most interesting factor of all this is that it is
A rapid polymerase chain reaction-based screening method
for identification of all expanded alleles of the fragile X (FMR1) gene in
newborn and high-risk populations.
Tassone F, Pan R, Amiri K,
Association between the oxytocin receptor (OXTR) gene and
autism: relationship to Vineland Adaptive Behavior Scales and cognition.
Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP. Mol Psychiatry. 2008 Oct;13(10):980-8. Evidence both from animal and human studies
suggests that common polymorphisms in the oxytocin receptor (OXTR) gene are
likely candidates to confer risk for autism spectrum disorders (ASD). In lower
mammals, oxytocin is important in a wide range of social behaviors, and recent
human studies have shown that administration of oxytocin modulates behavior in
both clinical and non-clinical groups. Additionally, two linkage studies and
two recent association investigations also underscore a possible role for the
OXTR gene in predisposing to ASD.
Significant association with single SNPs and haplotypes (global P-values
<0.05, following permutation test adjustment) were observed with ASD.
Association was also observed with IQ and the Vineland Adaptive Behavior Scales
(VABS). In particular, a five-locus haplotype block
(rs237897-rs13316193-rs237889-rs2254298-rs2268494) was significantly associated
with ASD (nominal global P=0.000019; adjusted global P=0.009) and a single
haplotype (carried by 7% of the population) within that block showed highly
significant association (P=0.00005).
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Mitochondrial problems
(NB the decreased levels of carnotine) both genetic and apparently a dysfunction of the mitochondria that appear normal under electron microscropy. Some of the work indicates genetic changes in the DNA that is found in mitochondria..but some researchers simply show the mitochondria not working adequately, the reason for which is unclear. The recent review seems to explain how the mitochondrial modifications may give the changes that we see. However, this type of explanation has been seen through many other causes of ASD. See also see the SCL25A12 gene below.
Filipek PA, Juranek J, Smith M, Mays LZ, Ramos ER, Bocian M, Masser-Frye D, Laulhere TM, Modahl C, Spence MA, Gargus JJ. Mitochondrial dysfunction in autistic patients with 15q inverted duplication. Ann Neurol. 2003 Jun;53(6):801-4.
Tsao CY, Mendell JR. Autistic disorder in 2 children with mitochondrial disorders. J Child Neurol. 2007 Sep;22(9):1121-3
Correia C, Coutinho AM, Diogo L, Grazina M, Marques C, Miguel T, Ataíde A, Almeida J, Borges L, Oliveira C, Oliveira G, Vicente AM. Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene. J Autism Dev Disord. 2006 Nov;36(8):1137-40.
Poling JS, Frye RE, Shoffner J, Zimmerman AW. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2. (Suble changes in chemistry, bicarbonate level, reduced cytochrome c in muscle biopsy. They noticed that the serum creatin kinase level also was abnormally elevated in 47% of 47 autistic patients not known to have mitochondrial problems)
Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD. Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry. 2004 Apr;161(4):662-9
Fillano JJ, Goldenthal MJ, Rhodes CH, Marin-Garcia J. Mitrochondrial dysfunction in patients with hypotonia, epilepsy autism and developmental delay: HEADD syndrome. J Child Neurol. 2002;17:435-9. (They could see modifications under EM of the mitochondria, enzyme alterations, and DNA deletions in mitochondria DNA).
Rossignol DA, Bradstreet JJ. Evidence of mitochondrial dysfunction in autism and implications for treatment. Biochem and Biotech 2008;4:2008-17. (Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning. Exposure to environmental toxins is the likely etiology for MtD in autism. This demonstrates that although there is a very low prevalence of mitochondrial disease in autism, and hence none out of 20 were seen to have any alterations of mitochondria under EM on muscle biopsy, there were good reasons why the normal looking mitochondria of autism may actually not be working correctly. This would be expected to show decreased energy metabolism in the brain using ATP but more using phosphocreatinine, depleted glutathione levels, chronic gastrointestinal problems, seizures, hypotonia, abnormalities in fatty acid oxidation, impairment in beta-oxidation and various other obscure chemical alterations e.g. elevated lactate, ammonia, aspartate, aminotransferase, pyruvate, creatine kinase and lowered carnitine levels).
Chugani DC, Sundram BS, Behen M, Lee ML, Moore GJ. Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry. 1999 May;23(4):635-41. (Plasma lactate levels were measured in 15 autistic children compared to 15 children with epilepsy. Preliminary results show lower levels of n-acetyl acetic acid cerebellum in autistic children (p = 0.043). Lactate was detected in the frontal lobe in one autistic boy, but was not detected any of the other autistic subjects or siblings. 4. Plasma lactate levels were higher in the 15 autistic children compared to 15 children with epilepsy (p = 0.0003). 5. Higher plasma lactate in the autistic group is consistent with metabolic changes in some autistic children. They admit that they simply don’t know what this means except the possibility that it may be due to a change in the metabolic factors and activity of perhaps mitochondria)
This is a very specific gene from chromosome 2. The protein that it is involved with is the aspartate glutamate carrier express in the brain. The problems with finding such a precise gene as this means that unless quite large numbers of cases are studied it is not all that likely that a certainly of statistical significance will be found. What is needed is evidence that the carrier is important at this point. It is important to involve this with potential mitochondrial changes.
Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L. Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31. Am J Psychiatry. 2005 Nov;162(11):2182-4 (this was not agreed by another group)…..
Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Pericak-Vance MA. Lack of association between autism and SLC25A12. Am J Psychiatry. 2006 May;163(5):929-31. (so its not so clear!)
Ramoz N, Cai G, Reichert JG, Silverman JM, Buxbaum JD. An analysis of candidate autism loci on chromosome 2q24-q33: Evidence for association to the STK39 gene. Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 17.
Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A, Iwayama Y, Delezoide AL, Moalic JM, Muller D, Dean B, Yoshikawa T, Gorwood P, Buxbaum JD, Ramoz N, Simonneau M. SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Mol Psychiatry. 2008 Apr;13(4):385-97. Epub 2008 Jan 8.
Silverman JM, Buxbaum JD, Ramoz N, Schmeidler J, Reichenberg A, Hollander E, Angelo G, Smith CJ, Kryzak LA. Autism-related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2008 Apr 5;147(3):408-10.
Hong CJ, Liou YJ, Liao DL, Hou SJ, Yen FC, Tsai SJ. Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Oct 1;31(7):1510-3. Epub 2007 Jul 17.
Correia C, Coutinho AM, Diogo L, Grazina M, Marques C, Miguel T, Ataíde A, Almeida J, Borges L, Oliveira C, Oliveira G, Vicente AM. Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene. J Autism Dev Disord. 2006 Nov;36(8):1137-40.
Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Pericak-Vance MA. Lack of association between autism and SLC25A12.
Am J Psychiatry. 2006 May;163(5):929-31.
Blasi F, Bacchelli E, Carone S, Toma C, Monaco AP, Bailey AJ, Maestrini E; International Molecular Genetic Study of Autism Consortium (IMGSAC). SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample. Eur J Hum Genet. 2006 Jan;14(1):123-6.
Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD. Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry. 2004 Apr;161(4):662-9.
Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A,
Iwayama Y, Delezoide AL, Moalic JM, Muller D, Dean B, Yoshikawa T, Gorwood P,
Buxbaum JD, Ramoz N, Simonneau M. SLC25A12 expression is associated with neurite outgrowth and is
upregulated in the prefrontal cortex of autistic subjects. Mol Psychiatry. 2008
Apr;13(4):385-97.
Epub 2008 Jan 8.
Mitochondrial aspartate/glutamate carrier SLC25A12 gene
is associated with autism. Turunen JA, Rehnström K, Kilpinen H,
Kuokkanen M, Kempas E, Ylisaukko-Oja T. Autism Res.
2008 Jun;1(3):189-92. They failed to
find any evidence for this gene to be involved in a major group in
Functional analysis of a potassium-chloride
co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA
methylation site. Moser D, Ekawardhani S, Kumsta R, Palmason H, Bock
C, Athanassiadou Z, Lesch KP, Meyer J. Neuropsychopharmacology.
2009 Jan;34(2):458-67. (this may have
nothing to do with it)
Joubert’s
syndrome
Association of common variants in the Joubert syndrome
gene (AHI1) with autism. Alvarez Retuerto AI, Cantor RM, Gleeson JG,
Ustaszewska A, Schackwitz WS, Pennacchio LA, Geschwind DH. Hum Mol Genet. 2008 Dec 15;17(24):3887-96. Joubert
syndrome (JS) is a rare recessively inherited disorder, with mutations reported
at several loci including the gene Abelson's Helper Integration 1 (AHI1). A
significant proportion of patients with JS, in some studies up to 40%, have
been diagnosed with autism spectrum disorder (ASD) and several linkage studies
in ASD have nominally implicated the region on 6q where AHI1 resides. To
evaluate AHI1 in ASD, we performed a three-stage analysis of AHI1 as an a
priori candidate gene for autism. Re-sequencing was first used to screen AHI1,
followed by two subsequent association studies, one limited and one covering the
gene more completely, in Autism Genetic Resource Exchange (AGRE) families. In
stage 3, we found evidence of an associated haplotype in AHI1 with ASD after
correction for multiple comparisons, in a region of the gene that had been
previously associated with schizophrenia. These data suggest a role for AHI1 in
common disorders affecting human cognition and behavior
Hyperlexia often part of Savant syndrome
An odd condition in which the child has a precocious ability to read words, far above what would be expected at their chronological age or an intense fascination with letters or numbers, significant difficulty in understanding verbal language and abnormal social skills, difficulty in socializing and interacting appropriately with people. A proportion of them are autistic but no specific genetic background is understood currently. It is probably not a single condition and some children with autism caused by some other factor might have hyperlexia as a result. Similarly Savant syndrome is a person that shows remarkable islands of ability, generally musical talent amongst many other mental losses, often social aspects. Again genetically it is difficult to point directly at specific genes that are involved although attempts have been made.
Newman TM, Macomber D, Naples AJ, Babitz T, Volkmar F, Grigorenko EL. Hyperlexia in children with autism spectrum disorders. J Autism Dev Disord. 2007 Apr;37(4):760-74.
Turkeltaub PE, Flowers DL, Verbalis A, Miranda M, Gareau L, Eden GF. The neural basis of hyperlexic reading: an FMRI case study. Neuron. 2004 Jan 8;41(1):11-25.
Tirosh E, Canby J. Autism with hyperlexia: a distinct syndrome? Am J Ment Retard. 1993 Jul;98(1):84-92.
MecP2 Changes
Rett Syndrome, an X-linked
dominant neurodevelopmental disorder characterized by regression, after the age
of 1 or 2 years, of language and hand use, is primarily caused by mutations in
methyl-CpG-binding protein 2 (MECP2). Loss of function mutations in MECP2 are
also found in other neurodevelopmental disorders such as autism, Angelman-like
syndrome and non-specific mental retardation. Furthermore, duplication of the
MECP2 genomic region results in mental retardation with speech and social
problems. The common features of human neurodevelopmental disorders caused by
the loss or increase of MeCP2 function suggest that even modest alterations of
MeCP2 protein levels result in neurodevelopmental problems. One of the interesting and useful factors
about this is that there is a mouse model of the gene changes (see below). The MECP2 gene encodes the methyl-cytosine
binding protein, almost entirely found as a problem in girls because it is was
found as a homozygous problem in boys it would be fatal. We are now seeing minor changes in the MecP2
genes giving rise to lesser symptomatic changes occasionally without the
broader spectrum of the condition.
MeCP2 mutations in mice also appear to alter the regulation of
excitation of nervous tissue through effecting the synapse.
Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, McGill BE, Goulding EH, Sullivan E, Tecott LH, Zoghbi HY. Neuron. 2008 Sep 25;59(6):947-58.
Santos M, Temudo T, Kay T, Carrilho I, Medeira A,
Cabral H, Gomes R, Lourenço MT, Venâncio M, Calado E, Moreira A, Oliveira G,
Maciel P. J Child Neurol. 2009 Jan;24(1):49-55
Loat
C, Curran S, Lewis C, Abrahams B, Duvall J, Geschwind D, Bolton P, Craig I.
Methyl - CpG - binding protein (MECP2) polymorphisms and vulnerability to
autism. Genes Brain Behav. 2008 Jun 2.
MECP2 promoter methylation and X chromosome inactivation
in autism. Nagarajan RP, Patzel KA, Martin M, Yasui DH, Swanberg SE,
Hertz-Picciotto I, Hansen RL, Van de Water J, Pessah IN, Jiang R, Robinson WP,
LaSalle JM. Autism Res. 2008 Jun;1(3):169-78.
This followed the discovery of increased MECP2 promoter methylation
associated with decreased MeCP2 protein expression in autism male brain. They looked to see if quite a wide range of
genes in the X chromosome were methylated and found that this was not the case
and that in the autistic patients it appeared to be relatively specific in its
gene.
Methyl-CpG-binding protein 2 polymorphisms and
vulnerability to autism. Loat CS, Curran S, Lewis CM, Duvall J,
Geschwind D,
Reciprocal co-regulation of EGR2 and MECP2 is disrupted
in Rett syndrome and autism. Swanberg SE, Nagarajan RP, Peddada S,
Yasui DH, LaSalle JM. Hum Mol Genet. 2009 Feb
1;18(3):525-34. Reduction in EGR2 and
MeCP2 levels in cultured human neuroblastoma cells by RNA interference
reciprocally reduced expression of both EGR2 and MECP2 and their protein
products. Consistent with a role of MeCP2 in enhancing EGR2, Mecp2-deficient
mouse cortex samples showed significantly reduced EGR2 by quantitative
immunofluorescence. Furthermore, MeCP2 and EGR2 show coordinately increased
levels during postnatal development of both mouse and human cortex. In contrast to age-matched Controls, RTT and
autism postmortem cortex samples showed significant reduction in EGR2.
Together, these data support a role of dysregulation of an activity-dependent
EGR2/MeCP2 pathway in RTT and autism.
A partial loss of function allele of methyl-CpG-binding
protein 2 predicts a human neurodevelopmental syndrome. Samaco RC,
Fryer JD, Ren J, Fyffe S, Chao HT, Sun Y, Greer JJ, Zoghbi HY, Neul JL. Hum Mol Genet. 2008 Jun 15;17(12):1718-27. They tried making even slight changes in the
gene and found that it could make quite a major change in the neurogeneration in
the mouse model.
Novel exon 1 mutations in MECP2 implicate isoform
MeCP2_e1 in classical Rett syndrome.
MECP2 promoter methylation and X chromosome inactivation
in autism. Nagarajan RP,
Patzel KA, Martin M, Yasui DH, Swanberg SE, Hertz-Picciotto I, Hansen RL, Van
de Water J, Pessah IN, Jiang R, Robinson WP, LaSalle JM. Autism Res.
2008 Jun;1(3):169-78.
Creatine Transporter Protein Deficiency
Creatine transporter deficiency: prevalence among patients with mental retardation and pitfalls in metabolite screening. Arias A, Corbella M, Fons C, Sempere A, García-Villoria J, Ormazabal A, Poo P, Pineda M, Vilaseca MA, Campistol J, Briones P, Pàmpols T, Salomons GS, Ribes A, Artuch R. Clin Biochem. 2007 Nov;40(16-17):1328-31. (but the testing for it cannot be simply by creatinine/urea ratios).
X-linked creatine transporter defect: an overview. Salomons GS, van Dooren SJ, Verhoeven NM, Marsden D, Schwartz C, Cecil KM, DeGrauw TJ, Jakobs C. J Inherit Metab Dis. 2003;26(2-3):309-18.
Cerebral creatine transporter deficiency: an infradiagnosed neurometabolic disease] Campistol J, Arias-Dimas A, Poo P, Pineda M, Hoffman M, Vilaseca MA, Artuch R, Ribes A. Rev Neurol. 2007 Mar 16-31;44(6):343-7.
Newmeyer
A, deGrauw T, Clark J, Chuck G, Salomons G. Screening of male patients with
autism spectrum disorder for creatine transporter deficiency. Neuropediatrics.
2007 Dec;38(6):310-2.
1H MR spectroscopy as a diagnostic tool for cerebral
creatine deficiency.
Dezortova M, Jiru F, Petrasek J, Malinova V, Zeman J,
Jirsa M, Hajek M. MAGMA. 2008
Sep;21(5):327-32. Total creatine (tCr)
constitutes one of the most prominent signals in human brain MR spectra. A
significant decrease in the tCr signal indicates a severe disorder of creatine
metabolism. We describe the potential of 1H MR spectroscopy in differential
diagnosis of creatine transporter (SLC6A8) deficiency syndrome. Metabolic images of N-acetylaspartate, tCr
and choline concentrations showed a very low tCr signal in the male, which was
approximately three times lower than in his sister (male/female/controls:
tCr=1.6/4.6/7.5 mM). Despite creatine supplementation, no improvement in
clinical status and tCr concentration in the MR spectra of the male was
observed and diagnosis of SLC6A8 deficiency was proposed. Sequence analysis of
the SLC6A8 gene revealed a novel pathogenic frameshift mutation c.219delC;
p.Asn74ThrfsX23, hemizygous in the male and heterozygous in the female.
CONCLUSIONS: The diagnosis of X-linked mental retardation caused by the SLC6A8
deficiency can be independently established by 1H MR spectroscopy.
The DLX1and DLX2 genes and susceptibility to autism
spectrum disorders. Liu X, Novosedlik N, Wang A, Hudson ML, Cohen
IL, Chudley AE, Forster-Gibson CJ, Lewis SM, Holden JJ. Eur J Hum Genet. 2009 Feb;17(2):228-35. The DLX genes encode homeodomain-containing
transcription factors controlling the generation of GABAergic cortical interneurons.
The DLX1 and DLX2 genes lie head-to-head in 2q32, a region associated with
autism susceptibility. Further testing
in 306 SPX families replicated the association at rs4519482 (P=0.033) and the
over transmission of the haplotype GGGTG (P=0.012) although P-values were not
significant after correction for multiple testing. The findings support the
presence of two functional polymorphisms, one in or near each of the DLX genes
that increase susceptibility to, or cause, autism in MPX families where there
is a greater genetic component for these conditions.
SHANK3 (SH3 and multiple
ankyrin repeat domains protein) gene encodes a master synaptic scaffolding
protein at postsynaptic density (PSD) of excitatory synapse. This encodes a a cytoplasmic binding partner
of the neuroligins was also identified
to be resulting from a chromosomal deletion. It was identified as being possibly involved
in autism through a chromosomal deletion.
Novel de novo SHANK3 mutation in autistic patients.
Gauthier J, Spiegelman D, Piton A, Lafrenière RG, Laurent S, St-Onge J,
Lapointe L, Hamdan FF, Cossette P, Mottron L, Fombonne E, Joober R, Marineau C,
Drapeau P, Rouleau GA. Am J Med Genet B Neuropsychiatr
Genet. 2009 Apr 5;150B(3):421-4.
More recently de novo mutations in the SHANK3 gene, a synaptic
scaffolding protein, have been associated with the ASD phenotype. As part of
our gene discovery strategy, we sequenced the SHANK3 gene in a cohort of 427
ASD subjects and 190 controls. Here, we report the identification of two
putative causative mutations: one being a de novo deletion at an intronic donor
splice site and one missense transmitted from an epileptic father.
Association study of SHANK3 gene polymorphisms with
autism in Chinese Han population. Qin J, Jia M, Wang L, Lu T, Ruan
Y, Liu J, Guo Y, Zhang J, Yang X, Yue W, Zhang D. BMC
Med Genet. 2009 Jun 30;10(1):61.
They did NOT find any association with the Han population.
Copy number variation and association analysis of SHANK3
as a candidate gene for autism in the IMGSAC collection. Sykes NH,
Toma C, Wilson N, Volpi EV, Sousa I, Pagnamenta AT, Tancredi R, Battaglia A,
Maestrini E, Bailey AJ, Monaco AP. Eur J Hum Genet.
2009 Apr 22
Novel de novo SHANK3 mutation in autistic patients.
Gauthier J, Spiegelman D, Piton A, Lafrenière RG, Laurent S, St-Onge J,
Lapointe L, Hamdan FF, Cossette P, Mottron L, Fombonne E, Joober R, Marineau C,
Drapeau P, Rouleau GA. Am J Med Genet B Neuropsychiatr
Genet. 2009 Apr 5;150B(3):421-4.
Contribution of SHANK3 mutations to autism spectrum
disorder. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D,
Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW. Am J Hum Genet. 2007 Dec;81(6):1289-97. To assess the quantitative contribution of
SHANK3 to the pathogenesis of autism, we determined the frequency of DNA
sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained
in
Mutations in the gene encoding the synaptic scaffolding
protein SHANK3 are associated with autism spectrum disorders.Durand
CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G,
Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R,
Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L,
Gillberg C, Leboyer M, Bourgeron T. Nat Genet.
2007 Jan;39(1):25-7.
22q11
This gene is associated with
velo-cardiofacial syndromes are seen in about 1% of of autistic syndromes but
are generally found with other features such as cleft palate and congenital
heart disease. It is now often found
without a typical broad spectrum of disease when minor changes in the gene
rather than its deletion are found. The
22q13.3 deletion syndrome is a recognizable malformation syndrome associated
with developmental delay, hypotonia, delayed or absent speech, autistic-like
behavior, normal to accelerated growth and dysmorphic facies. The prevalence of
this disorder is unknown, but it is likely under-diagnosed. Age at diagnosis
has varied widely, from cases diagnosed prenatally to 46 years. Males and
females are equally affected.
Over-expression of a human chromosome 22q11.2 segment
including TXNRD2, COMT, and ARVCF developmentally affects incentive learning
and working memory in mice. Suzuki G, Harper KM, Hiramoto T, Funke
B, Lee M, Kang G, Buell M, Geyer MA, Kucherlapati R, Morrow B, Männistö PT,
Agatsuma S, Hiroi N. Hum Mol Genet. 2009
Performance on the Modified Card Sorting Test and its
relation to psychopathology in adolescents and young adults with 22q11.2
deletion syndrome. Rockers K, Ousley O, Sutton T, Schoenberg E,
Coleman K, Walker E, Cubells JF. J Intellect Disabil
Res. 2009 Jul;53(7):665-76.
Autism, ADHD, mental retardation and behavior problems in
100 individuals with 22q11 deletion syndrome. Niklasson L, Rasmussen
P, Oskarsdóttir S, Gillberg C. Res Dev Disabil.
2009 Jul-Aug;30(4):763-73.
Microduplication 22q11.2 in a child with autism spectrum
disorder: clinical and genetic study. Ramelli GP, Silacci C,
Ferrarini A, Cattaneo C, Visconti P, Pescia G. Dev Med
Child Neurol. 2008 Dec;50(12):953-5.
22q11.2 deletion syndrome: behaviour problems of children
and adolescents and parental stress. Briegel W, Schneider M, Schwab
KO. Child Care Health Dev. 2008
Nov;34(6):795-800.
Comparing phenotypes in patients with idiopathic autism
to patients with velocardiofacial syndrome (22q11 DS) with and without autism.
Kates WR, Antshel KM, Fremont WP, Shprintzen RJ, Strunge LA, Burnette CP,
Higgins AM. Am J Med Genet A. 2007 Nov
15;143A(22):2642-50.
22q13.3 deletion syndrome: a recognizable malformation
syndrome associated with marked speech and language delay.
Cusmano-Ozog K, Manning MA, Hoyme HE. Am J Med Genet C
Semin Med Genet. 2007 Nov 15;145C(4):393-8. Review
The 22q11.2 deletion in children: high rate of autistic
disorders and early onset of psychotic symptoms. Vorstman JA, Morcus
ME, Duijff SN, Klaassen PW, Heineman-de Boer JA, Beemer FA, Swaab H, Kahn RS,
van Engeland H. J Am Acad Child Adolesc Psychiatry.
2006 Sep;45(9):1104-13.
Deletion 22q13.3 syndrome. Phelan MC. Orphanet J Rare Dis. 2008 May 27;3:14.
CNTNAP2 and Contactin
The CNTNAP2 is the gene that encodes for the contactin
protein-2, which is a member ofte neurexin superfamily). Changes in them are associated in the
presence of autism in the case but not frequently. Mutations in the gene which can affect the
neuronal synapse, tend nt to be highly specific for autism but rather cause a
broader mental retardation phenotype in some patients and pure autism in
others.
Disruption of CNTNAP2 and additional structural genome
changes in a boy with speech delay and autism spectrum disorder.
Poot M, Beyer V, Schwaab I, Damatova N, Van't Slot R, Prothero J, Holder SE,
Haaf T. Neurogenetics. 2009 Jul 7
A functional genetic link between distinct developmental
language disorders. Vernes SC, Newbury DF, Abrahams BS, Winchester
L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH, Monaco
AP, Fisher SE. N Engl J Med. 2008 Nov
27;359(22):2337-45.
Molecular cytogenetic analysis and resequencing of
contactin associated protein-like 2 in autism spectrum disorders.
Bakkaloglu B, O'Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, Chawarska K,
Klin A, Ercan-Sencicek AG, Stillman AA, Tanriover G, Abrahams BS, Duvall JA,
Robbins EM, Geschwind DH, Biederer T, Gunel M, Lifton RP, State MW. Am J Hum Genet. 2008 Jan;82(1):165-73.
A common genetic variant in the neurexin superfamily
member CNTNAP2 increases familial risk of autism. Arking DE, Cutler
DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH,
Chakravarti A. Am J Hum Genet. 2008
Jan;82(1):160-4.
Linkage, association, and gene-expression analyses
identify CNTNAP2 as an autism-susceptibility gene. Alarcón M,
Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M,
Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH. Am J Hum Genet. 2008 Jan;82(1):150-9.
Disruption of contactin 4 in three subjects with autism
spectrum disorder. Roohi J, Montagna C, Tegay DH, Palmer LE,
DeVincent C, Pomeroy JC, Christian SL, Nowak N, Hatchwell E. J Med Genet. 2009 Mar;46(3):176-82. Array based comparative genomic hybridisation
identified a paternally inherited chromosome 3 copy number variation (CNV) in
three SUBJECTS: a deletion in two siblings and a duplication in a third,
unrelated individual. These variations were fluorescence in situ hybridisation
(FISH) validated and the end points further delineated using a custom fine
tiling oligonucleotide array. CNTN4 plays an essential role in the formation,
maintenance, and plasticity of neuronal networks. Disruption of this gene is
known to cause developmental delay and mental retardation. This report suggests
that mutations affecting CNTN4 function may be relevant to ASD pathogenesis.
Multiple deletions and
duplications of genes found in autistic patients
This has been found
basically because of the new systems that have become available since around
2005. As such you may need to look up
individual changes seen that are not particularly common as the researchers
have found strange findings in their specific group that have not been reported
prior to them. However some have been
found to be relatively often (e.g. the 15q changes). Up to 7-10% of the autistic cases were found
to have the deletions or duplications in excess of the control population.
Strong association of de novo copy number mutations with
autism. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C,
Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee
YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen
PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse
D, Geschwind DH, Gilliam TC, Ye K, Wigler M. Science.
2007 Apr 20;316(5823):445-9.
Identifying autism loci and genes by tracing recent shared ancestry. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA. Science. 2008 Jul 11;321(5886):218-23.
Association and mutation analyses of 16p11.2 autism candidate genes. Kumar RA, Marshall CR, Badner JA, Babatz TD, Mukamel Z, Aldinger KA, Sudi J, Brune CW, Goh G, Karamohamed S, Sutcliffe JS, Cook EH, Geschwind DH, Dobyns WB, Scherer SW, Christian SL. PLoS One. 2009;4(2):e4582. They go through a number of possibilities and show that there is quite a lot that are deleted or duplicated in these patients.
Disruption of neurexin 1 associated with autism spectrum
disorder. Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen
Y, Lally E, Weiss LA, Najm J, Kutsche K, Descartes M, Holt L, Braddock S,
Troxell R, Kaplan L, Volkmar F, Klin A, Tsatsanis K, Harris DJ, Noens I, Pauls
DL, Daly MJ, MacDonald ME, Morton CC, Quade BJ, Gusella JF. Am J Hum Genet. 2008 Jan;82(1):199-207. Their findings were in humans and also that
there were other changes near to the genetic changes.
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Kleine-Levin syndrome
Mukaddes NM, Fateh R, Kilincaslan A. Kleine-Levin syndrome in two subjects with diagnosis of autistic disorder. World J Biol Psychiatry. 2008 Feb 6:1-4.
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Familial Clustering
This is the finding that there is an excess number of cases of autism in specific families and is used to show that there is a tendency to either a genetic cause or a genetic factor that is involved.
Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999 Jun;14(6):388-94. (this article is mainly about the autoimmune excess in the familial group but goes over the familial clusters seen)
Molloy CA, Morrow AL, Meinzen-Derr J, Dawson G, Bernier R, Dunn M, Hyman SL, McMahon WM, Goudie-Nice J, Hepburn S, Minshew N, Rogers S, Sigman M, Spence MA, Tager-Flusberg H, Volkmar FR, Lord C. Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):317-24. The only specific autoimmune disorder found to be associated with regression was autoimmune thyroid disease (adjusted OR=2.09; 95% CI: 1.28, 3.41).
Yoo HJ, Cho IH, Park M, Cho E, Cho SC, Kim BN, Kim JW, Kim SA. Association between PTGS2 polymorphism and autism spectrum disorders in Korean trios. Neurosci Res. 2008 Jun 5. Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in neuroplasticity and the neuropathology of the central nervous system. Polymorphisms of PTGS2 (the gene encoding Cox-2) with 151 Korean family trios including children with ASDs. Specific symptom domain scores of ADOS and ADI-R, including communication, qualitative abnormalities in reciprocal social interaction, and overactivity/agitation. Also see: Kim HW, Cho SC, Kim JW, Cho IH, Kim SA, Park M, Cho EJ, Yoo HJ. Family-based association study between NOS-I and -IIA polymorphisms and autism spectrum disorders in Korean trios. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 18. (much of the same authors on this group).
Didden
R, Sigafoos J, Green VA, Korzilius H, Mouws C, Lancioni GE, O'Reilly MF, Curfs
LM. Behavioural flexibility in individuals with Angelman syndrome, Down
syndrome, non-specific intellectual disability and Autism spectrum disorder. J
Intellect Disabil Res. 2008 Jun;52(Pt
6):503-9. Epub 2007 Apr 2.
Late-onset Lennox-Gastaut syndrome in a patient with
15q11.2-q13.1 duplication. Orrico A, Zollino M, Galli L, Buoni S,
Marangi G, Sorrentino V. Am J Med Genet A. 2009
May;149A(5):1033-5. This simply
contained an autistic patient and was found to have the microduplication.
Genetics that are NOT associated with autism syndromes
Always a problem is that the authors have put large amounts of work into a subject and to find that their chosen gene has nothing to do with it must be difficult for them. As a result there is a tendency to give titles to the article that tends to make you think that there is a connection….but when you read it you find that they found nothing.
Anderson
BM, Schnetz-Boutaud
N, Bartlett
J, Wright
HH, Abramson
RK, Cuccaro
ML, Gilbert
JR, Pericak-Vance
MA, Haines
JL. Examination of association to autism of common genetic variation in
genes related to dopamine. Autism Res.
2008 Dec;1(6):364-9. In fact no association between the dopamine
pathway genetics and autism was found.
Examination of association to autism of common genetic
variationin genes related to dopamine. Anderson BM, Schnetz-Boutaud
N, Bartlett J, Wright HH, Abramson RK, Cuccaro ML, Gilbert JR, Pericak-Vance
MA, Haines JL. Autism Res. 2008
Dec;1(6):364-9. although widespread
searches for genes associated to autism have taken place and suggested the
dopamine pathway they failed to find any specific gene abnormalities that were
involved.
The screening of SLC6A8 deficiency among Estonian
families with X-linked mental retardation.Puusepp H, Kall K,
Salomons GS, Talvik I, Männamaa M, Rein R, Jakobs C, Ounap K. J Inherit Metab Dis. 2009 Jan 10. It seemed to be much more associated with a
simple family phenomenon. Results
indicated positive associations with ASD for D6S265*220 (p < 0.01) and
MOGc*131 (p < 0.05) and negative associations for MOGc*117 and MIB*346
alleles (p < 0.01) in ASD children. Polymorphism haplotype analysis
indicated that D6S265 allele *220 and MOGc allele *131 were significantly more
likely to be transmitted together, as a whole haplotype, to ASD children (p
< 0.05). Conversely, the D6S265*224-MOGc*117-rs2857766(G) haplotype was
significantly less frequently transmitted to ASD children (p < 0.01). The
results present novel gene markers, reinforcing the hypothesis that genetic
factors play a pivotal role in the pathogenesis of ASD. The problem with all this is that
researchers can carry out so many tests that simply by luck there is a chance
that many of the ASD patients will be positive and the normal controls will be
negative. In general this type of study
must be repeated.
Genetic correlation between autistic traits and IQ in a
population-based sample of twins with autism spectrum disorders (ASDs).
Nishiyama T, Taniai H, Miyachi T, Ozaki K, Tomita M, Sumi S. J Hum Genet.
2009;54(1):56-61. They did not find
significant population based correlation but it would be extremely difficult to
carry this out.
Genetic calcium signaling abnormalities in the central
nervous system: seizures, migraine, and autism. Gargus JJ. Ann N Y
Acad Sci. 2009 Jan;1151:133-56
Lack of evidence to support the glyoxalase 1 gene (GLO1) as
a risk gene of autism in Han Chinese patients from Taiwan. Wu YY,
Chien WH, Huang YS, Gau SS, Chen CH. Prog
Neuropsychopharmacol Biol Psychiatry. 2008 Oct 1;32(7):1740-4. Epub 2008
Aug 5.
Unfortunately many models simply have turned out by accident and are picked simply because the owner thinks that they remind him of the ASD cases. This is a poor way to go about it but there appears to be little else possible. In other aspects of genetics for neurological illness there have been animal models that have created major gains, however.
Halladay AK, Amaral D, Aschner M, Bolivar VJ, Bowman A, Dicicco-Bloom E, Hyman SL, Keller F, Lein P, Pessah I, Restifo L, Threadgill DW. Animal models of autism spectrum disorders: Information for neurotoxicologists. Neurotoxicology. 2009 Jul 9
Recent
findings derived from large-scale datasets and biobanks link multiple genes to
autism spectrum disorders. Consequently, novel rodent mutants with deletions,
truncations and in some cases, overexpression of these candidate genes have
been developed and studied both behaviorally and biologically. What came
out from this meeting was that the researchers said that they would do their
best to look for useful models with multiple genetic sites that had been
modified (including drosophila!).
A triplet repeat expansion genetic mouse model of
infantile spasms syndrome, Arx(GCG)10+7, with Interneuronopathy, spasms in
infancy, persistent seizures, and adult cognitive and behavioral impairment.. Price MG, Yoo JW, Burgess DL, Deng F,
Hrachovy RA, Frost JD Jr, Noebels JL J Neurosci. 2009 Jul 8;29(27):8752-63.
Abnormal behavior in a chromosome-engineered mouse model for
human 15q11-13 duplication seen in autism.
Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S,
Watanabe Y, Chung YJ, Banerjee R, Iwamoto K, Kato T, Okazawa M, Yamauchi K,
Tanda K, Takao K, Miyakawa T, Bradley A, Takumi T. . Cell. 2009
Jun 26;137(7):1235-46. They admitted
that there may be the association between the genetics as found in a population
of ASD cases and there fore tried to make the equivalent in mice. The problem is simply that it is difficult to
demonstrate success!
Neuronal glucose transporter isoform 3 deficient mice
demonstrate features of autism spectrum disorders. Zhao Y, Fung C, Shin D, Shin BC, Thamotharan
S, Sankar R, Ehninger D, Silva A, Devaskar SU.
Mol Psychiatry. 2009 Jun 9.
Social approach in genetically engineered mouse lines
relevant to autism. Moy SS, Nadler JJ, Young NB, Nonneman RJ,
Grossman AW, Murphy DL, D'Ercole AJ, Crawley JN, Magnuson TR, Lauder JM. Genes Brain Behav. 2009 Mar;8(2):129-42.
Gene-environment interaction during early development in
the heterozygous reeler mouse: clues for modelling of major neurobehavioral
syndromes. Laviola G, Ognibene E, Romano E, Adriani W, Keller F. Neurosci Biobehav Rev. 2009 Apr;33(4):560-72. This is actually quite important in that it
is quite clear that the formation of autism seems to involve an environmental
factor as well as genetic ones. Also
there is data concerning how the mother and her hormones appear to make a
difference. Among candidate molecules, reelin (RELN) is a protein of the extracellular
matrix playing a key role in brain development and synaptic plasticity. The
heterozygous (HZ) reeler mouse provides a model for studying the role of reelin
deficiency for the onset of these syndromes.
Mild cognitive deficits associated to neocortical
microgyria in mice with genetic deletion of cellular prion protein.
Xikota JC, Rial D, Ruthes D, Pereira R, Figueiredo CP, Prediger RD, Walz R. Brain Res. 2008 Nov 19;1241:148-56. This would have been found out when the null
PrP mice would have been created.
Initially they did not think that the PrP null mice seemed to loose
anything but this may be involved.
Animal models of psychiatric disease.
The role of cerebellar genes in pathology of autism and
schizophrenia. Fatemi SH, Reutiman TJ, Folsom TD, Sidwell RW. Cerebellum. 2008;7(3):279-94. Schizophrenia and autism are
neurodevelopmental diseases that have genetic as well as environmental
etiologies. Both disorders have been associated with prenatal viral infection.
Brain imaging and postmortem studies have found alterations in the structure of
the cerebellum as well as changes in gene expression. Our laboratory has
developed an animal model using prenatal infection of mice with human influenza
virus. They describe altered expression
of cerebellar genes associated with development of brain disorder in a mouse
model for schizophrenia and autism
The loss of methyl-CpG binding protein 1 leads to
autism-like behavioral deficits. Allan AM, Liang X, Luo Y, Pak C, Li
X, Szulwach KE, Chen D, Jin P, Zhao X. Hum Mol Genet.
2008 Jul 1;17(13):2047-57. Methyl-CpG
binding proteins (MBDs) are central components of DNA methylation-mediated
epigenetic gene regulation. Alterations of epigenetic pathways are known to be
associated with several neurodevelopmental disorders, particularly autism. Here we show that Mbd1 mutant (Mbd1(-/-))
mice exhibit several core deficits frequently associated with autism, including
reduced social interaction, learning deficits, anxiety, defective sensory motor
gating, depression and abnormal brain serotonin activity. Furthermore, we find
that Mbd1 can directly regulate the expression of Htr2c, one of the serotonin
receptors, by binding to its promoter, and the loss of Mbd1 led to elevated
expression of Htr2c.
Transcription factor MEF2C influences neural
stem/progenitor cell differentiation and maturation in vivo. Li H,
Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD, Soussou W, Nie Z, Kang
YJ, Nakanishi N, Okamoto S, Roberts AJ, Schwarz JJ, Lipton SA. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9397-402.
MEF is known to regulate two genes implicated in the whole geneome study of
autism pedigrees namely PCDH10 (protocadherin10 another neuronal ell adhesion
protein) and DIA1 (deleted in autism, also known as c3orf58). By removing it there was an autistic effect.
The loss of methyl-CpG binding protein 1 leads to
autism-like behavioral deficits. Allan AM, Liang X, Luo Y, Pak C, Li
X, Szulwach KE, Chen D, Jin P, Zhao X. Hum Mol Genet.
2008 Jul 1;17(13):2047-57. They created
genetically modified mice and changes in the CpG methyl modification
genes. They then looked for changes in
various factors that might be good indicators of autism in terms of reliable
chemistry. E.g. serotonin
Observation of fetal brain in a rat valproate-induced
autism model: a developmental neurotoxicity study. Kuwagata M, Ogawa
T, Shioda S, Nagata T. Int J Dev Neurosci. 2009 Jun;27(4):399-405. Rats were treated with sodium valproate (VPA,
800 mg/kg) orally on gestational day (GD) 9 or 11 (VPA9 or VPA11), and the
fetal brains were examined on GD16 using immunohistochemistry for serotonin
(5-HT), tyrosine hydroxylase (TH), and TuJ1 (neuron specific class III
beta-tubulin). Hypoplasia of the cortical plate was induced in both VPA9 and
VPA11 groups. Abnormal migration of TH-positive and 5-HT neurons, possibly due
to the appearance of an abnormally running nerve tract in the pons, was
observed only in the VPA11 group. The present results demonstrate that
examination of the GD16 fetal brain was useful for detecting and characterizing
abnormal development of the brain after VPA exposure.
Interstimulus interval (ISI) discrimination of the
conditioned eyeblink response in a rodent model of autism.
Social approach in genetically engineered mouse lines
relevant to autism. Moy SS, Nadler JJ, Young NB, Nonneman RJ, Grossman
AW, Murphy DL, D'Ercole AJ, Crawley JN, Magnuson TR, Lauder JM. Genes Brain Behav. 2009 Mar;8(2):129-42. Deficits can include a lack of interest in
social contact and low levels of approach and proximity to other children. In
this study, a three-chambered choice task was used to evaluate sociability and
social novelty preference in five lines of mice with mutations in genes
implicated in autism spectrum disorders. Fmr1(tm1Cgr/Y)(Fmr1(-/y)) mice
represent a model for fragile X, a mental retardation syndrome that is
partially comorbid with autism. We tested Fmr1(-/y)mice on two genetic
backgrounds, C57BL/6J and FVB/N-129/OlaHsd (FVB/129). Overall, results show
that loss of Fmr1 or Slc6a4 gene function can lead to deficits in sociability.
Findings from the fragile X model suggest that the FVB/129 background confers
enhanced susceptibility to consequences of Fmr1 mutation on social approach.
Maternal infection leads to abnormal gene regulation and
brain atrophy in mouse offspring: implications for genesis of
neurodevelopmental disorders. Fatemi SH, Reutiman TJ, Folsom TD,
Huang H, Oishi K, Mori S, Smee DF, Pearce DA, Winter C, Sohr R, Juckel G. Schizophr Res.
2008 Feb;99(1-3):56-70.
A proposed primate animal model of autism.
Teitelbaum P. Eur
Child Adolesc Psychiatry. 2003 Jan;12(1):48-9. this used primates given thalidomide but
after the point at which they would have shown alteration in their limbs. Increased monoamine concentration in the brain and blood
of fetal thalidomide- and valproic acid-exposed rat: putative animal models for
autism. Narita N, Kato M,
Tazoe M,
Linking etiologies in humans and animal models: studies
of autism. Rodier PM, Ingram JL, Tisdale B, Croog VJ. Reprod Toxicol. 1997 Mar-Jun;11(2-3):417-22. (a
review)
Activation of the maternal immune system alters
cerebellar development in the offspring. Shi L, Smith SE, Malkova N,
Tse D, Su Y, Patterson PH. Brain Behav. Immun. 2009 Jan;23(1):116-23. They were using the histopathology of the
brain (change in numbers of Purkinje cells etc) to assess whether influenza
vaccine given to the pregnant maternal mouse would create the effect. They found that indeed it did.
Dopamine and serotonin levels following prenatal viral infection
in mouse--implications for psychiatric disorders such as schizophrenia and
autism. Winter C, Reutiman TJ, Folsom TD, Sohr R, Wolf RJ, Juckel G,
Fatemi SH. Eur Neuropsychopharmacol. 2008
Oct;18(10):712-6. Again they used the
influenza vaccine.
The role of cerebellar genes in pathology of autism and
schizophrenia. Fatemi SH, Reutiman TJ, Folsom TD, Sidwell RW. Cerebellum. 2008;7(3):279-94. They make it clear that their model of autism
in the mouse using the influenza vaccine was great and they were proud of
it. They justified it through the biochemistry
and the histopathology seen in the brain.
Prenatal viral infection in mouse causes differential
expression of genes in brains of mouse progeny: a potential animal model for
schizophrenia and autism. Fatemi SH, Pearce DA, Brooks AI, Sidwell
RW. Synapse. 2005 Aug;57(2):91-9. These results show for the first time that prenatal
human influenza viral infection on day 9 of pregnancy leads to alterations in a
subset of genes in brains of exposed offspring, potentially leading to
permanent changes in brain structure and function.
Maternal influenza infection causes marked behavioral and
pharmacological changes in the offspring. Shi L, Fatemi SH, Sidwell
RW, Patterson PH. J Neurosci. 2003 Jan
1;23(1):297-302
Prenatal viral infection leads to pyramidal cell atrophy
and macrocephaly in adulthood: implications for genesis of autism and
schizophrenia.Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES,
Patterson PH, Shi L, Sidwell R. Cell Mol Neurobiol.
2002 Feb;22(1):25-33
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