In a post earlier this year, I summarized the findings of a comprehensive study published in the magazine Science in which the authors screened for faulty genes in people with schizophrenia. Numerous genes with small defects were identified. Some are known to play a role in the growth and stabilization of connections between nerve cells during brain development. The genes were damaged around birth. Schizophrenia's symptoms are narrowly defined compared with autism. Autism is a spectrum disorder with a wide range of behaviors. That is why, the illness is known as Autism Spectrum Disorder, or ASD for short. I suggested that the genes involved in autism may even be more numerous than those implicated in schizophrenia and that the underlying molecular mechanisms may be more diverse.
In a research study published in this week's issue of Science (Vol. 321:218-223), Morrow and others screened for inherited faulty genes in 104 families comprising 115 males and 24 females with ASD. The families were recruited from an ethnic group that allows cousin-to-cousin marriages. Family trees could be reconstructed for 393 members. Maggie Fox reported on the study in an article published on Reuters on July 10, 2008. The researchers concentrated their effort on damaged homozygous autosomal recessive genes. That is, these genes were unrelated to sex and their defects came to bear only when they were inherited in identical pairs. The identified genes differed considerably, involving 1-2 specific chromosomal loci per family. Notably, several families showed large genetic deletions. In one autistic boy suffering from seizures, the largest deletion was situated on chromosome 3q and comprised gene c3orf58 and the beginning of gene NHE9. Smaller deletions were found on chromosome 4q near genes PCDH10 and on chromosome 2q near genes CNTN3, RNF8 and SCN7A. The authors could provide evidence with studies in animal tissue cultures that this type of damage affects the expression of genes that are commonly activated by the electrical activity of nerve cells and are instrumental in the development of nerve cell networks. The products of these genes play crucial roles in the establishment and maintenance of the contacts that nerve cells use to transmit information, i.e. the synapses.
The number of synapses in our cerebral cortex continues to increase after birth and reaches a peak at about 3 years of age. Then, their number gradually declines. Synapses that are used to transmit information between nerve cells are known to stabilize. Synapses that remain underutilized are pruned. The brain is particularly plastic and sensitive to environmental stimuli during this critical period of synaptic exuberance and elimination. Experience-dependent nerve cell activity determines which synapses stay and which go. The behavioral symptoms of autism manifest themselves at that time and experts in special education strive to develop methods for their early detection and intervention.
Fifty years ago, Nicholas Hobbs and Susan Gray pioneered the early detection of behavioral abnormalities with non-interfering observational methods at Peabody College. The assessors examined the social interactions of the children and their care givers unnoticed through one-way mirrors. This type of research continues at the Susan Gray School to the day. My son was a student there. The Director at the time was convinced that an environment rich in sensory experience benefits the mental development of any child and is of special importance to children with learning differences. The curriculum was structured accordingly. In harmony with this concept, the findings of the genetic study discussed above suggest that exposure to enriched environments may be instrumental in the effort to compensate for the deficits caused by inherited genetic deletions in children with ASD.
- On Mar. 16, 2009, Donald G. McNeil Jr. reports in The New York Times on an unusually high occurrence of ASD among Somali children in Minnesota. Somali culture permits marriages among cousins. Taking the findings of the study discussed above into consideration, the most likely cause for this cluster is a genetic predisposition (03/17/09).
- Today, National Public Radio's Morning Edition broadcast a segment about the utility of a nation-wide register for families affected by ASD. You may wish to check out the interactive autism network site here (04/08/09).
- Two recent studies using genome-wide analysis across large numbers of participants identified more variants of genes associated with ASD. The studies were published online back-to-back in the journal Nature on Apr. 29, 2009. In the first study, Wang and others (2009) compared the DNA of children diagnosed with ASD and their families (3101 participants from 780 families) with that of 1204 adults with ASD and that of 6491 unaffected volunteers. The authors found 6 single nucleotide polymorphisms in genes CDH9 and CDH10 to be most tightly associated with ASD. Genes of this type encode nerve cell adhesion molecules that guide the growth of connections between nerve cells during brain development. In the second study, Glessner and others (2009) compared variations in the copy number (CNVs) of DNA segments in DNA from 859 children with ASD and 1409 children without ASD. The authors affirmed the identified gene candidates using DNA from 1336 other cases with ASD and 1110 volunteers without ASD. The authors detected CNVs associated with ASD in cell adhesion-related genes NRXN1, CNTN4, NLGN1 and ASTN2. In addition, CNVs were detected in and near genes, whose products are involved in the metabolism of ubiquitin. It is important to note that the methods used in both studies permit us to identify genetic modifications only for the whole sample. They may not be present in each case of ASD. Furthermore, the candidate genes were implicated only by association. Causalities between the genetic modifications and autistic behavior remain to be established (05/15/09).
- A genome-wide association study enrolling more than one thousand families with children diagnosed with ASD uncovered a single nucleotide polymorphism (SNP) statistically significantly associated with ASD on chromosome 5p15 between genes SEMA5A, involved in the growth of nerve cell connections, and TAS2R1, playing a role in gustation (Weiss and others, 2009). The expression of the former proved reduced in ASD (11/30/09).
- Researchers at the University of Washington recently published evidence in support of the contention that early behavioral intervention may ameliorate autism (Dawson and others, 2009). A novel play-at-home therapy called Early Start Denver Model, or ESDM for short, showed promising results after only 24 months. The 20 hour/week program is designed for toddlers diagnosed with autism as young as 18 months of age. Participants scored ten points higher in IQ tests than peers in conventional programs with enhanced scores in listening and understanding as well as motor and self-care skills (11/30/09).
- In a genome-wide analysis of rare genetic copy number variants (CNVs) in 996 people of European descent with ASD compared to 1,287 controls, Pinto and others (2010) identified genes SHANK2, SYNGAP1 and DLGAP2, in addition to previously implicated genes NRXN1, NLGN3, NLGN4X and SHANK3, as high-probability candidates playing a role in autism. The results of the study were published online yesterday in the journal Nature. The products of these genes are involved in the establishment and maintenance of nerve cell connections. Genes influencing the formation of excitatory nerve cell connections using the neurotransmitter glutamate are of particular interest because of their fundamental role in brain plasticity. Notably, SHANK2 regulates metabotropic glutamate receptors, and SYNGAP1 is engaged in AMPA receptor trafficking (06/10/10).
- Oller and others (2010) developed a method that allows us to record and analyze the utterances of children as young as ten months of age for speech modifications related to ASD. The LENA Foundation supports the method. Emma Ashburn summarizes the research in her post entitled "Screening speech may aid autism diagnosis: study" on Reuters yesterday. The method may help behavioral intervention experts in their assessment. Modified speech evident early during development suggests that nerve cell connections in Wernicke's area of the cerebral cortex may be the first to be affected in ASD (07/20/10).
- O'Roak and other (2012) sequenced the exomes, that is the DNA regions that code for the protein product of genes, of children with sporadic autism as well as of their parents and unaffected siblings. Sixhundredseventyseven exomes of 209 families were examined. Eighty percent of the discovered gene mutations were of paternal origin, increasing with age. Roughly 40 percent of the new protein-altering mutations were associated with a molecular signaling pathway regulating gene transcription through beta-catenin/chromatin remodeling. Recurrent mutations were found in genes CHD8 and NTNG1. The product of CHD8 is a protein involved in chromatin remodeling. This finding points at a specific molecular mechanism that may explain impaired transcription of the genetic code, representing the most disruptive genetic modification identified in this study according to the authors. NTNG1's product Netrin-G1 is a protein that serves as cue in nerve cell axon guidance and has been associated with schizophrenia. In addition, mutation screening identified genes GRIN2B, LAMC3 and SCN1A. GRIN2B encodes a subunit protein of N-methyl-D-aspartate (NMDA) receptors for the excitatory neurotransmitter glutamate. NMDA receptors are voltage-gated calcium channels playing an instrumental role in the plasticity of nerve cell connections, memory and learning and have been implicated in schizophrenia. LAMC3's product represents a laminin in the extracellular protein matrix of brain tissue that affects cell adhesion and may guide nerve cell connections. SCN1A codes for a subunit protein of voltage-gated nerve cell sodium channels the malfunction of which is instrumental in migraine and epilepsy. In a companion study, Neale and others (2012) using genetic models identified mutations of genes CHD8 and KATNAL2 as the greatest risk for autism. The latter encodes a protein involved in the organization of microtubule arrays in cells. As interesting as these candidates for a genetic basis of the disorder may seem, it remains difficult to conceive how proteins with such fundamental and ubiquitous influences on brain development that have also been associated with other developmental mental disorders like schizophrenia can cause a spectrum disorder with the diverse behavioral symptoms of autism (04/09/2012).
- Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J (2009) Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model. Pediatrics doi:10.1542/peds.2009-0958.
- Glessner JT, 58 others (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459: 569-573.
- 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 (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218-223.
- Oller DK, Niyogi P, Gray S, Richards JA, Gilkerson J, Xu D, Yapanel U, and Warren SF (2010) Automated vocal analysis of naturalistic recordings from children with autism, language delay, and typical development. Proc Natl Acad Sci doi: 10.1073/pnas.1003882107
- Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin C-F, Stevens C, Wang L-S, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature doi:10.1038/nature11011.
- O'Roak, BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature doi:10.1038/nature10989.
- Pinto D, 176 others (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature: doi:10.1038/nature09146.
- Wang K, 55 others (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528-533.
- Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802-808.