advertisement

Pages

Showing posts with label ASD. Show all posts
Showing posts with label ASD. Show all posts

Friday, October 5, 2012

Autism & Feral Children

The diagnosis for autism is based on behavioral differences, the first signs of which can be observed in infants. Autism is classified as a spectrum disorder. That is, its diagnosis covers a spectrum of abnormal behaviors that differ in severity, ranging from people who repetitively self-injure and may be considered mentally retarded to individuals who score extremely high on intelligence tests and may develop an intense, obsessive passion for a particular subject, but profoundly lack social skills. The Austrian pediatrician Hans Asperger was the first to recognize the latter as a distinct group of patients (Asperger's syndrome), and autism has been classified as a spectrum disorder with repetitive behaviors and difficulty with empathy as common symptoms.

Genetic modifications
The heritability of autism spectrum disorder (ASD) is high. ASD may run in families. The odds of developing autism are enhanced for a twin whose sibling is diagnosed with the disorder (Hallmayer and others, 2011). Gene sequencing has implicated a plethora of genes modified during late pregnancy. In addition, a recent genome-wide study showed that in sperm new genetic mutations known as single nucleotide polymorphisms (SNPs) increase with male age, increasing the odds of SNPs to effect developmental disorders like autism and schizophrenia in children sired by older fathers (Kong and others, 2012). In particular cases of familial autism, genetic deletions have been identified, the precise role of which needs to be elucidated (Morrow and others, 2008).

Cellular and molecular modifications
People with ASD show no striking differences in gross brain anatomy, except for a modest diminution in the size of the corpus callosum (see review by Booth and others, 2011). The nerve cell connections between the cerebral hemispheres travel through this structure. The precise cellular and molecular mechanisms underlying the disorder remain poorly understood. However, a particular type of nerve cell in cerebral cortex, which Constantin von Economo called spindle cells, has recently been found associated with empathy (see my post with the title "Constantin von Economo's Spindle Cells & The Mind" published on Aug. 21, 2009) and may play an instrumental role in asocial behavior.

On the molecular level, the excitatory neurotransmitter glutamate and its receptors, notably the ionotropic N-methyl-D-aspartate (NMDA) receptor, have been shown to be crucial for the plasticity of nerve cell connections important to learning and memory. The receptors, which are composed of voltage-gated calcium channels, help strengthen connections of nerve cells that are most active together. The American psychologist D.O. Hebb postulated this strengthening based on his observations on animal learning (see my post with the title "Cortical Development & Schizophrenia" published online Aug. 14, 2008).

Nerve cell connections in the developing brain undergo a period of exuberance during which nerve cells grow a multitude of arbors, seeking contact with other nerve cells (see my post with the title "Genes, Brain Plasticity & Memory" published online May 7, 2009). However, idle connections are subsequently pruned, while those that are used strengthen and endure as Hebb suggested. The survival of these connections depends on excitatory sensory input and is experience-dependent.

Potential treatments
Developmental mental disorders are thought to result from disruptions of Hebb's mechanism. Fragile X syndrome (FXS), which leads to behavior that can be considered autistic, may serve as example. The gene mutation involved in FXS blocks the synthesis of a regulatory protein, permitting excessive protein biosynthesis that leads to abnormalities in the development of glutamatergic nerve cell connections. Recent clinical trials have shown that some FXS patients improve with drugs affecting the glutamatergic nervous system (Berry-Kravis and others, 2012).

However, despite progress addressing the needs of specific groups of the spectrum, autism remains a disorder with manyfold causes affecting numerous molecular pathways in varied fashion. The effect of each genetic modification may be inconspicuous. Yet, molecular pathways crosstalk and their multiplexed interactions combined may decisively skew the experience-dependent development of cerebral nerve cell connections. In ASD, the synergism of the modified molecular pathways may diminish or defocus brain plasticity during a period in which the shaping of nerve cell connections peaks and the brain seems most susceptible to stimulation.

Because glutamate is the most prevalent neurotransmitter in the brain, the effects of the pathway modifications can be expected to be wide-spread, though the brain's most plastic structures may be particularly vulnerable. The latter include the hippocampus, which plays an instrumental role in memory, and the amygdala involved in fear responses. However, glutamate's ubiquitous role renders the development of a universal drug therapy specifically targeting autistic behavior difficult. Rather, each spectral subgroup's peculiar causes must be identified and therapies need to be developed that target these peculiarities.

Outlook
ASD may not be based on genetic mutations alone. The famous feral child Kaspar Hauser, who was left in social depravity for years (see my post with the title "Theory of Mind I: Feral Children & Language Development" published online Dec. 31, 2008), might have well been diagnosed with ASD today. Despite his delayed entry into civil life, the adolescent Kaspar was able to learn language, calculus, fine arts and social skills from various caretakers and a professor, in whose hands he seemed to have thrived. In his time, Kaspar was cast as a devious, good-for-nothing 'idiot'. By contrast, with emerging expertise in child psychology and special education, modern-day children on the spectrum may reap benefit from early behavioral interventions that stimulate and strengthen nerve cell connections mediated by our own endogenous neurotransmitters and neuromodulators without the need for genomic sequencing and psychoactive drugs (Dawson and others, 2009).

References

Related Posts

| More

Posted by Peter Melzer at 8:41 AM 1 comments

Labels: , , , , ,

Wednesday, October 1, 2008

Fundamental Research & Fragile X Syndrome

On Sep. 23, 2008, National Public Radio's Morning Edition aired a report on progress in research on Fragile X syndrome or FXS for short. You may listen to the podcast here. In FXS, the gene Fmr1 is not expressed in nerve cells. This gene encodes a messenger RNA-binding repressor protein known as fragile X mental retardation protein, or FMRP for short. The protein hinders the translation of the genetic code into protein in protein synthesis. Recent studies in the laboratory of Mark Bear, director of the Picower Institute at M.I.T., suggest that a specific type of receptor for the excitatory neurotransmitter glutamate plays a crucial role in the synthesis of FMRP. Neurotransmitters are molecules that convey information from one nerve cell to another across the synaptic cleft. The synapse constitutes the contact between the nerve cells. Glutamate and its receptors are instrumental in the strengthening of synapses. 

Mark Bear is fundamentally interested in the development of the cerebral cortex. As I summarized in my post dated Aug. 14, 2008, the strengthening of glutamatergic synapses is understood today as the basic mechanism underlying brain plasticity, learning and memory. The stabilization of synapses profoundly affects cortical development. Perturbation of synaptic growth and pruning is suspected to be involved in the development of mental disorders like autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), and manic depression.

I met Mark and his family for the first time when I was visiting Wolf Singer's laboratory at the Max-Planck-Institute for Brain Research where Mark was staying as a postdoctoral fellow. The Max-Planck Society funds 80 research establishments covering a broad range of topics from art, law and anthropology to biology, medicine, chemistry, material sciences and physics. The MPI for Brain Research comprised three laboratories at the time. The facilities were located in a cluster of brick-tiled buildings on the opposite bank of the Main in Frankfurt.

Mark proudly drove a very used green BMW 2000Ti and lived with wife and daughter in a small apartment in the western suburb of Schwanheim across the river from a huge chemical plant. Frankfurt's air quality was not as good as today. The river's water was pitch black. A subsidiary of the conglomerate Hoechst AG, Messer Griesheim, was still in full operation. On rainy days the air smelled like in Philadelphia when you pass the refineries.

I remember vividly one occasion on which Mark tried hard with little success to convince his Frankfurter colleagues of the refined taste of the All-American soul food: peanut butter-and-jelly sandwiches. His wife had prepared plates piled high with more than enough for everybody. Not unlike Frankfurt's Aeppelwoi, peanut butter-and-jelly sandwiches are an acquired taste. Only those who have raised children on them will fully appreciate the profound usefulness and true satisfaction they deliver.

By contrast, Mark's work with Wolf Singer and colleagues was a convincing success. The team showed with elegant experiments published in the journals Nature (Bear and Singer, 1986) and Science (Kleinschmidt and others, 1987) and Nature that glutamate and the neuromodulators acetyl choline and norepinephrine play fundamental roles in the plasticity of domains of ocular dominance in visual cortex during postnatal development. The discovery of ocular dominance plasticity had won D.H. Hubel and T.N. Wiesel the Nobel Prize half a dozen years earlier (Hubel and Wiesel, 1998).

After his return to the U.S., Mark continued to investigate the role of glutamate in the organization of nerve cell circuits in cerebral cortex. In a long series of studies, he and his colleagues examined long-term potentiation (LTP) and long-term depression (LTD) as mechanisms for cortical plasticity. The elucidation of the underlying molecular mechanisms led to the G-protein-coupled metabotropic glutamate receptor mGluR5. By contrast to ionotropic receptors that regulate ion fluxes across cellular membranes important to electrical nerve cell signaling, metabotropic receptors regulate cell protein activity and homeostasis. The mGluR5-receptor appears to play a major role in FXS and autism. I have written about this in my post dated April 1, 2008. Designing antagonists against the receptor's actions promises a treatment. Mark points out in his interview with NPR that he was not planning on finding a cure for mental disorders. Things came together serendipitously. It was only with the support and encouragement of the Fragile X Research Foundation (FRAXA) that the work on a potential treatment began.

The National Institutes of Health (NIH) provide most funding for biomedical research in the U.S. Measured in inflation-adjusted dollars, the NIH have seen their budget erode in the past 8 years. By contrast, the number of applications for research grants has doubled. As consequence according to the NIH online report, the success rate of competitive grant applications diminished from 32 percent in fiscal year (FY) 2000 to 21 percent in FY 2007. The NIH were able to award about 41 percent of the total cost to new investigator-initiated applications (R01). These are proposals for projects that scientists submit based on their most recent findings. They advance the most innovative ideas and are most likely to lead to new discoveries. The success rate of R01 applications decreased to 19 percent in FY 2007 from 26 percent in FY 2000. The mounting budgetary constraints inevitably result in increasingly conservative funding decisions. Under these circumstances, it is not surprising that Mark Bear and his colleagues sought funding outside government for their novel ideas.

Addenda

  • First federal funds for research dry up. Now nonprofit private support evaporates. Read here (12/21/08).
  • Brain plasticity and memory share similar underlying molecular mechanisms. Recent studies have provided evidence that the brain-specific protein-phosphorylating enzyme protein kinase Mzeta (PKMzeta) is necessary to sustain LTP (Sacktor, 2008). Such enzymes commonly upregulate the activity of other enzymes. An increase in enzyme activity resulted in the doubling of postsynaptic glutamatergic ionotropic AMPA receptors, augmenting synaptic transmission in rodents. Inhibiting PKMzeta disrupts long-term memory (Serrano and others, 2008). Benedict Carey published an article entitled "Brain Researchers Open Doors to Editing Memory" in The New York Times on this research and its potential implications for future medical treatments today (04/05/08).
  • According to Lauran Neergaard's report for Associated Press with the title "Experiment Takes Aim at Genetic Learning Disorder" published online in The New York Times today, the first clinical trials to treat FXS in adults with mGluR5 antagonists are underway at five medical centers (02/01/10).
  • According to Gardiner Harris' report with the title "Promise Seen in Drug for Retardation Syndrome" for the New York Times dated Apr. 29, 2010, Novartis completed its first double blind study using its mGluR5 drug on adults with FXS with encouraging results. Details of the study were not disclosed (05/01/10).
  • In her report with the title "Special Report: new drugs, fresh hope for autism patients" published online on Reuters today, Julie Steenhuysen informs us how the search for new drugs to treat FXS and ASD has been shaping up. The article's focus is on the use of derivatives of the established psychoactive compound baclofen. Seaside Therapeutics Inc., co-founded by Mark Bear, is testing arbaclofen (STX209) in clinical trials. The compound acts as an agonist of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA for short. Baclofen binds to G-protein-coupled metabotropic GABAB-receptors and has traditionally been used to relieve skeletal muscle spasms. In contrast to the compounds acting on mGluR5-receptors discussed in the post, this drug modulates the effects of glutamate indirectly (Fejgin and others, 2009). Considering that more than 100 genes have been identified to play a role in autism, Dr. Edwin Cook's claim in Julie Steenhuysen's report that “many of the genes related to autism are right in the same pathway that has been implicated and worked out in Fragile X” does not come as a surprise (05/31/2012).
  • Two studies of note have been published online in Science Translational Medicine yesterday. Henderson and others (2012) showed in a fragile X mouse model, that The GABAB-receptor agonist arbaclofen alleviated known biochemical (basal protein synthesis), molecular (AMPA-receptor internalization), and cellular (dendritic spine density) manifestations of the disorder. In addition, Barry-Kravis and others (2012) report first encouraging results for arbaclofen in phase II clinical trials. The drug seems to improve social function (09/20/2012).
References
Related Posts
-->

| More

Posted by Peter Melzer at 8:06 AM 0 comments

Labels: , , , , , , , , , , ,

Friday, July 11, 2008

Autism & Genes, Revisited

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.

Addenda

  • 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).
References
Related Posts:

| More

Posted by Peter Melzer at 12:07 PM 0 comments

Labels: , , , , , , , , ,

Tuesday, April 1, 2008

Autism, Schizophrenia & Time

When Seymour S. Kety accepted the challenge to lead the scientific endeavor of the National Institutes of Health dedicated to research in mental health, neurological disorders and stroke fifty years ago, he identified the unraveling of the causes of schizophrenia as one immediate and urgent aim. He devoted himself to this mission, directing a landmark study to elucidate the possible causes of this horrible mental disorder in Danish twins. Denmark happened to be the country with the most detailed health records on her citizens at the time. Dr. Kety can be heard commenting on the results of this pivotal research in a taped autobiographical interview available through the Society for Neuroscience. In this conversation, he was careful to point out that though the twin study had provided evidence for a genetic component in schizophrenia, other factors may play an equally important role in the disorder.

Half a century later, much has been learned about the changes in brain structure and function accompanying the symptoms of schizophrenia. Drugs have been developed that ameliorate these symptoms. Genes have been identified that encode proteins involved in the disorder. Last week, the journal Science electronically published the results of a major study authored by Walsh and others screening a large number of schizophrenic patients for small gene mutations. B. Carey commented on the findings in his article for The New York Times entitled "Study Hints of Gene Link to Risk of Schizophrenia" dated Mar. 28, 2008. The study has been published in print in Science Vol. 320. A plethora of genes was identified. How the products of these genes are precisely involved in the disorder remains to be examined. Notably, products of two sets of genes play a role in mechanisms crucial to brain development and function. One set is engaged in the growth of nerve cell connections during development. The other is involved in the action of glutamate.

Glutamate is the most prevalent excitatory neurotransmitter in the brain. Neurotransmitters are the chemical compounds that nerve cells use to transmit information. Glutamate is fundamental to the plasticity of nerve cell connections. Schizophrenic patients are known to contain unusually low levels of glutamate receptors in distinct areas of the cerebral cortex (Konradi and Heckers, 2003). The product of one gene that was found disrupted in schizophrenics, GRM7, affects a specific type of glutamate receptor on nerve cells known as metabotropic glutamate receptor mGluR5. Merck & Co. and Addex Pharmaceuticals currently develop a new generation of pharmaceuticals that modulate the action of glutamate at a subtype of this receptor and may ameliorate schizophrenia without enhancing the negative symptoms commonly observed with the currently available drugs.

Most significantly, however, the large number of genes identified in the study published in Science suggests that schizophrenia is the result of complex interactions among diverse processes in the brain. Despite this complexity, the observed mutations of genes crucial for brain development and function constitute intriguing findings. Nerve cells predominantly grow and establish connections with each other during brain development. They mostly transmit and process information in maturity. Nerve cells may respond to injury and loss of input in different fashion while they fulfill these two fundamentally distinct functions. During brain development, the points in time when control genes are activated play a particularly sensitive role. The proper ingredients have to come together at the right moment. Diversion from the schedule may result in deleterious consequences. Moreover, the influence of ambient stimuli and environmental factors comes to bear at critical junctures. The intricate interaction between the intrinsic clockwork of gene expression and extrinsic influences ultimately determines brain structure and function. Taking the temporal sensitivity of brain development into consideration, the observation that the symptoms of schizophrenia manifest themselves commonly at a specific age, i.e. in early adulthood, suggests that changes in the scheduling of developmental processes may play a fundamental role in the disorder.

The above interpretation also applies to another mental disorder that has attracted mounting attention (CNN, Apr. 1, 2008): autism. Autism has been diagnosed as early as in the second year of life. A genetic component is known to exist. Hallmeyer and others (2011) found a significant chance for twins to develop autism if one is diagnosed with the disorder and a high prevalence among males. The authors attribute this chance to genetic as well as epigenetic factors. However, the implicated genes remain elusive. Whereas the symptoms of schizophrenia are comparably narrowly defined, the symptoms of autism can range from mildly affected and highly intelligent to self-mutilating and mentally retarded. That is why the disorder is known today as Autism Spectrum disorder, or ASD for short. Because of this broad range, it seems even more unlikely than for schizophrenia that a common cause for autism can be found. However, the identification of the differences in brain mechanisms underlying autism may help to afford more effective individualized treatments.

Addenda

  • Jane Brody provides an informative update entitled "Trying Anything and Everything for Autism" of the therapeutic strategies parents currently pursue with their children in The New York Times on Jan. 19, 2009 (01/20/2009).
  • Yesterday, National Public Radio's All Things Considered broadcast a segment entitled "Schizophrenia May be Linked to Immune System" on recent findings of genome-wide studies on the genetic background of schizophrenia. The studies are authored by the International Schizophrenia Consortium (2009) and Shi and others (2009) and were published online in the journal Nature this week. Kate Kelland reported on the results in her post entitled "Gene variation hinder mental illness tests: study" on Reuters and Nicholas Wade in his post entitled "Hoopla, and Disappointment, in Schizophrenia Research" for The New York Times, both dated Jul. 1, 2009. The methods used in both studies are similar to those employed in recent studies on the genetic background of autism. I have described the autism studies in an addendum to my post dated Jul. 11, 2008. The studies on schizophrenia report genetic variations associated with the disorder, attaining statistical significance when the genetic sequences of thousands of people with and without the disorder are compared. The researchers identified segments in the genetic code that showed statistically significant differences in sequence in the population of schizophrenic participants. The results are based on the grand averages across the populations of participants. That is, a single person may not possess the uncovered variations to any measurable degree. The differences are so small that they become detectable only in the sum of genetic sequences of large numbers of participants. The International Schizophrenia Consortium study demonstrated that small variations of tens of thousands of genes may additively contribute to a statistically significant effect in the disorder. The result constitutes no more than a long list of possibilities, the exact implementation of which remains yet unknown.  Shi and others (2009) found that the greatest difference linked to schizophrenia pertains to genes encoding major histocompatibility complexes (MHCs) involved in our immune response. These genes exhibit great variability. The findings are associative. A causality remains to be established (07/02/09).
  • Consistent with the findings of Shi and others (2009), Stefansson and others report in a letter to Nature published online this week that using genome-wide association methods they were able to identify in schizophrenic patients single nucleotide polymorphisms affecting genes involved in immune response (MHCs). In addition, the study implicates genes NRGN, playing a role in the stabilization of excitatory nerve cell connections during brain development, and TCF4, the product of which is a transcription factor (07/09/09).
  • 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).
  • The genes NRG1 and ERBB4 have been implicated in schizophrenia (Li and others, 2006). Their products neuregulin 1, or NRG1 for short, and erbB-4, a tyrosine kinase receptor for NRG1, may influence the formation of connections among nerve cells in the cerebral cortex. In this week's issue of the journal Nature, Fazzari and others (2010) provide evidence in mice that both are instrumental in the development of inhibitory nerve cell circuits that use the neurotransmitter GABA and thereby indirectly influence the formation of excitatory connections using the neurotransmitter glutamate. Perhaps malfunctioning inhibition plays a more fundamental role in schizophrenia than previously thought (04/14/10).
  • Green and others (2010) have accomplished to sequence the Neanderthal genome with extracts from fossilized bones of three female Neanderthals and compared this code to known genomes of modern humans. The comparison identified regions that underwent wide-ranging genetic code alterations. The regions contained genes NRG3, CADPS2 and AUTS2. Mutations in these genes have been associated with schizophrenia (NRG3, a member of neuregulin family, see above) and autism (CADPS2 and AUTS2). Their products are presumed to play a role in the differentiation of nerve cells, the formation of nerve cell connections and nerve cell function. The findings of Green and others (2010) suggest that these genes may contribute fundamentally to the mental abilities that distinguish modern humans from Neanderthals (05/07/10).
Neandertal (courtesy M. Möller, Naturfreunde Düsseldorf)

References
Literature
with
Google Scholar
Related Links:
Autism & Genes, Revisited
Fundamental Research & Fragile X Syndrome



| More

Posted by Peter Melzer at 2:51 PM 0 comments

Labels: , , , , , ,

Subscribe to: Posts (Atom)