About 1 in 25 American boys ages 5 to 17 have a diagnosis of autism. Boys are four times more likely than girls to be diagnosed with the condition. Diagnoses of attention-deficit/hyperactivity disorder: 14.5 percent of American boys, 8 percent of girls. The likelihood of an ADHD diagnosis decreases as family income increases.
From the Washington Post.
Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets.
We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume.
Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups.
These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.
Controls were randomly selected from the full control cohort to roughly match a 1:4 ratio in cases and controls. . . . we excluded individuals with a moderate to severe mental retardation (ICD10: F71-F79) from both the case and control cohort.
Autism spectrum disorder cases were further categoried into four subtypes: childhood autism (cha, ICD10 F84.0); atypical autism (ata, ICD10 F84.1); Asperger’s syndrome (asp, ICD10 F84.5); and pervasive disorders, unspecified and others (pdm, ICD10 F84.8+9).
It appears that ADHD cases were not subtyped, which is something of a shame. There is good reasons to think that the genetic basis of ADHD predominantly inattentive type (i.e. without hyperactivity), has a different genetic basis than ADHD combined type (and ADHD predominately hyperactive which probably overlaps heavily with the combined type). This level of information ought to have been available although empirically efforts to further subtype ADHD probably wouldn't have been available in the data. See, e.g, prior posts at this blog from September 8, 2012, April 3, 2012, and October 18, 2017 (Genetics of ADHD hyperactivity/impulsivity and inattention dimensions are quite different),
A Key Figure From The Paper
A serious limitation of this study is that the design relies on the common psychiatric nosology that in particular for ASD and ADHD has been problematic, surely in the past when only one of both diagnosis was allowed. Given the high comorbidity between ADHD and ASD, and among other psychiatric disorders in general, plus the fact that recent research shows that ‘genes do not respect diagnostic classifications’ (see CDG publications) I would rather see a focus on the shared genetic findings for ADHD and ASD, in aiming to find general genetic/biological vulnerabilities for trans diagnostic neurodevelopmental problems, instead of relying on a classification system that has surely proven its value in clinical practice but does not seem to guide biological underpinnings of those disorders.
and
Concerning the used sample, I would appreciate getting some more details on the assessment of comorbid ASD and ADHD in the respective cohort. While some of the individuals might have been diagnosed under DSM-IV, which did not allow a comorbid diagnosis of ADHD, I wonder if and how this was accounted for in the datasets. In light of the cited Meta-study 25-32% of ASD individuals do fulfill the criteria for ADHD. In this study, the comorbid cohort accounts for 10% of the sample (assuming they were from both the ASD and the ADHD cohorts).
The responses gave rise to a table regarding the shared risk genes:
"We found that 4 major psychiatric disorders -- major depression, bipolar disorder, schizophrenia, and obsessive-compulsive disorder -- show a surprisingly high level of similarity in their brain structural abnormalities," said Dr. Opel. The shared brain areas showing structural aberrations were mainly in cortical areas associated with cognitive processing, memory and self-awareness.
On the flipside, Dr. Opel added, "we were able to identify regional abnormalities with high specificity for certain disorders." Interestingly, these distinct structural differences sometimes appeared in the same area for two disorders, but in opposite directions from the norm.
In contrast, attention-deficit/hyperactivity disorder and autism spectrum disorder did not share brain structural signatures with any other disorders. That may be because those disorders are considered developmental diseases with a distinct etiology from the other psychiatric conditions, which have more in common.
The researchers do not yet understand the mechanisms behind the shared structural elements, but a growing body of evidence shows that these psychiatric disorders also share common genetic as well as environmental influences, which might underlie the current findings.From Science Daily. The paper and its abstract are as follows:
Background
Neuroimaging studies have consistently reported similar brain structural abnormalities across different psychiatric disorders. Yet, the extent and regional distribution of shared morphometric abnormalities between disorders remains unknown.
Methods
Here, we conducted a cross-disorder analysis of brain structural abnormalities in 6 psychiatric disorders based on effect size estimates for cortical thickness and subcortical volume differences between healthy control subjects and psychiatric patients from 11 mega- and meta-analyses from the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) consortium. Correlational and exploratory factor analyses were used to quantify the relative overlap in brain structural effect sizes between disorders and to identify brain regions with disorder-specific abnormalities.
Results
Brain structural abnormalities in major depressive disorder, bipolar disorder, schizophrenia, and obsessive-compulsive disorder were highly correlated ( r = .443 to r = .782), and one shared latent underlying factor explained between 42.3% and 88.7% of the brain structural variance of each disorder. The observed shared morphometric signature of these disorders showed little similarity with brain structural patterns related to physiological aging. In contrast, patterns of brain structural abnormalities independent of all other disorders were observed in both attention-deficit/hyperactivity disorder and autism spectrum disorder. Brain regions showing high proportions of independent variance were identified for each disorder to locate disorder-specific morphometric abnormalities.
Conclusions
Taken together, these results offer novel insights into transdiagnostic as well as disorder-specific brain structural abnormalities across 6 major psychiatric disorders. Limitations comprise the uncertain contribution of risk factors, comorbidities, and medication effects to the observed pattern of results that should be clarified by future research.
The findings suggest that an ASD diagnosis becomes stable starting at 14 months of age and overall is more stable than other diagnostic categories, including language or developmental delay.
Importance Universal early screening for autism spectrum disorder (ASD) in primary care is becoming increasingly common and is believed to be a pivotal step toward early treatment. However, the diagnostic stability of ASD in large cohorts from the general population, particularly in those younger than 18 months, is unknown. Changes in the phenotypic expression of ASD across early development compared with toddlers with other delays are also unknown.
Objectives To examine the diagnostic stability of ASD in a large cohort of toddlers starting at 12 months of age and to compare this stability with that of toddlers with other disorders, such as developmental delay.
Design, Setting, and Participants In this prospective cohort study performed from January 1, 2006, to December 31, 2018, a total of 2241 toddlers were referred from the general population through a universal screening program in primary care or community referral. Eligible toddlers received their first diagnostic evaluation between 12 and 36 months of age and had at least 1 subsequent evaluation.
Exposures Diagnosis was denoted after each evaluation visit as ASD, ASD features, language delay, developmental delay, other developmental issue, typical sibling of an ASD proband, or typical development.
Main Outcomes and Measures Diagnostic stability coefficients were calculated within 2-month age bands, and logistic regression models were used to explore the associations of sex, age, diagnosis at first visit, and interval between first and last diagnosis with stability. Toddlers with a non-ASD diagnosis at their first visit diagnosed with ASD at their last were designated as having late-identified ASD.
Results Among the 1269 toddlers included in the study (918 [72.3%] male; median age at first evaluation, 17.6 months [interquartile range, 14.0-24.4 months]; median age at final evaluation, 36.2 months [interquartile range, 33.4-40.9 months]), the overall diagnostic stability for ASD was 0.84 (95% CI, 0.80-0.87), which was higher than any other diagnostic group. Only 7 toddlers (1.8%) initially considered to have ASD transitioned into a final diagnosis of typical development. Diagnostic stability of ASD within the youngest age band (12-13 months) was lowest at 0.50 (95% CI, 0.32-0.69) but increased to 0.79 by 14 months and 0.83 by 16 months (age bands of 12 vs 14 and 16 years; odds ratio, 4.25; 95% CI, 1.59-11.74). A total of 105 toddlers (23.8%) were not designated as having ASD at their first visit but were identified at a later visit.
Conclusions and Relevance The findings suggest that an ASD diagnosis becomes stable starting at 14 months of age and overall is more stable than other diagnostic categories, including language or developmental delay. After a toddler is identified as having ASD, there may be a low chance that he or she will test within typical levels at 3 years of age. This finding opens the opportunity to test the impact of very early-age treatment of ASD.
The current study analyzed these mtDNA lineages among 1,624 patients with autism and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). Using data from genome-wide association studies on this AGRE cohort previously performed by the Center for Applied Genomics at CHOP, they determined patterns of functional mtDNA variants associated with ASD risk that emerged over human history.
The study team found that individuals with European haplogroups designated I, J, K, O-X, T and U (representing 55 percent of the total European population) had significantly higher risks of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also were at increased risk of ASD.
These findings support the idea that an individual already predisposed to ASD based on their mitochondrial haplogroup may develop the disease when additional genetic variants or environmental insults occur that lower mitochondrial function, impair OXPHOS, and alter brain activity.
Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (∼400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.Hadjixenofontos, A, et al., "Evaluating mitochondrial DNA variation in autism spectrum disorders." 77(1) Ann Hum Genet. 9-21 (2013 epublished November 6, 2012) doi: 10.1111/j.1469-1809.2012.00736.x. (Open access).
Importance Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored.
Objective To assess what impact mitochondrial lineages encompassing ancient mtDNA functional polymorphisms, termed haplogroups, have on ASD risk.
Design, Setting, and Participants In this cohort study, individuals with autism and their families were studied using the Autism Genetic Resource Exchange cohort genome-wide association studies data previously generated at the Children’s Hospital of Philadelphia. From October 2010 to January 2017, we analyzed the data and used the mtDNA single-nucleotide polymorphisms interrogated by the Illumina HumanHap 550 chip to determine the mtDNA haplogroups of the individuals. Taking into account the familial structure of the Autism Genetic Resource Exchange data, we then determined whether the mtDNA haplogroups correlate with ASD risk.
Main Outcomes and Measures Odds ratios of mitochondrial haplogroup as predictors of ASD risk.
Results Of 1624 patients with autism included in this study, 1299 were boys (80%) and 325 were girls (20%). Families in the Autism Genetic Resource Exchange collection (933 families, encompassing 4041 individuals: 1624 patients with ASD and 2417 healthy parents and siblings) had been previously recruited in the United States with no restrictions on age, sex, race/ethnicity, or socioeconomic status. Relative to the most common European haplogroup HHV, European haplogroups I, J, K, O-X, T, and U were associated with increased risk of ASD, as were Asian and Native American haplogroups A and M, with odds ratios ranging from 1.55 (95% CI, 1.16-2.06) to 2.18 (95% CI, 1.59-3) (adjusted P < .04). Hence, mtDNA haplogroup variation is an important risk factor for ASD.
Dimitra Chalkia, et al., "Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders" JAMA Psychiatry. (Published online August 23, 2017). doi:10.1001/jamapsychiatry.2017.2604Conclusions and Relevance Because haplogroups I, J, K, O-X, T, and U encompass 55% of the European population, mtDNA lineages must make a significant contribution to overall ASD risk.
The link is strongest in the second trimester, when a single fever is associated with a 40 percent increase in autism risk. Three or more fevers after the first trimester triples the risk of having a child with autism, according to the study, which appeared 13 June in Molecular Psychiatry.
The findings support the idea that a pregnant woman’s immune response, which often includes fever, can disrupt brain development in the fetus, says lead researcher Mady Hornig, associate professor epidemiology at the Columbia University.
The study is inconclusive on whether drugs that lower fever mitigate the risk, but the results hint that they might, says Sarkis Mazmanian, professor of biology at theCalifornia Institute of Technology. . . .15,701 of the mothers reported on a health questionnaire that they’d had one or more fevers while pregnant. The team followed all of the participants’ children until they reached age 9, on average, and found that 583 received an autism diagnosis.The timing of the fever matters for autism risk, the researchers found. Compared with the 40 percent increase in the second trimester, having a fever in the first trimester carries a 34 percent increase in the risk of autism, but that result is not statistically significant. Having a fever in the third semester has no effect on autism risk.The researchers also found a dose-response relationship for fever: The increase in risk ranges from 30 percent throughout pregnancy for one or two episodes of fever, to more than threefold for three or more episodes in the second trimester and beyond.Still, the vast majority of women who have a fever during pregnancy do not have a child with autism and the absolute increase in risk is small. Even among mothers who had three or more fevers, only 5 out of 308 children (about 1.6 percent) have autism, compared with 376 of 65,502 children (about 0.6 percent) whose mothers reported no fevers. . . .
Hornig’s team examined whether medications that lower body temperature would reduce the risk. More than 5,600 women took acetaminophen for fever during their second trimester. The team found an association between acetaminophen use and a decrease in autism risk, but it was not statistically significant. Only 161 women took ibuprofen during the second trimester, and none of them have a child with autism. (About half of pregnant women use acetaminophen at least once, but doctors generally advise against ibuprofen use during pregnancy.) . . .
A 2013 study led by Hertz-Picciotto found that drugs that lower fever mitigate the increase in autism risk associated with fever.
Genetic susceptibility to Intellectual disability (ID), autism spectrum disorder (ASD) and schizophrenia (SCZ) often arises from mutations in the same genes, suggesting that they share common mechanisms. We studied genes with de novo mutations in the three disorders and genes implicated by SCZ genome-wide association study (GWAS). Using biological annotations and brain gene expression, we show that mutation class explains enrichment patterns more than specific disorder. Genes with loss of function mutations and genes with missense mutations were enriched with different pathways, shared with genes intolerant to mutations. Specific gene expression patterns were found for each disorder. ID genes were preferentially expressed in fetal cortex, ASD genes also in fetal cerebellum and striatum, and genes associated with SCZ were most significantly enriched in adolescent cortex. Our study suggests that convergence across neuropsychiatric disorders stems from vulnerable pathways to genetic variations, but spatiotemporal activity of genes contributes to specific phenotypes.
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disease primarily characterized by deficits in verbal communication, impaired social interaction and repetitive behaviors. It exemplifies profound clinical heterogeneity, which poses challenges in diagnosis and treatment. Genetic studies have pointed to hundreds of presumptive causative or susceptibility genes in ASD, making it difficult to find common underlying pathogenic mechanisms and suggesting that multiple different genetic etiologies for ASDs influence a continuum of traits.
Deep phenotyping analysis allowed for re-categorization of genetic variants. Our previous analysis suggested the existence of two significant subgroups within the existing ASD classification. To investigate this hypothesis in greater detail we have performed in-depth analysis using phenotypic and genetic data from Autism Genetic Resource Exchange (AGRE) and Autism Genome Project (AGP). Our initial findings on both phenotypic and genetic data (1,262 cases and 2,521 controls using familial transmission disequilibrium test) suggest existence of two groups that range in severity. Findings were replicated in a validation dataset. Genetic risk scores (GRS) were used to sum up the total effect of several single-nucleotide polymorphisms characteristic of the two clusters. The high discriminatory ability of the genetic risk score to define cluster 1 from cluster 2 case group at different combinations of sensitivity and specificity was assessed and clearly demonstrates strong signal with AUC being 0.74. There is a significant signal differentiating the 2 clusters relying on non-genetic risk factors and even greater signal when using both non-genetic risk factors and GRS. The detection and validation of the two groups allowed us focus on convergence of findings at the pathway level. ASD heterogeneity was leveraged via large scale pathway analysis within those two categories, which led to identification of a driver gene set across significant pathways. The significant pathways in cluster 1 (severe, affected = 300) include autoimmune disease, vitamin B6 metabolism, whereas in cluster 2 (non-severe, affected = 921) included oxytocin signaling pathway, WNT signaling pathway and glutamatergic synapses (all at P < 0.001). We envision that systematic study of all genomic pathways obtained given a set of redefined categories will yield profound findings for ASD even in the absence of strong individual variant information.S. Smieszek and J.L. Haines., "Autism redefined: Genomic pathway approach to autism spectrum disorder." ASHG Conference Presentation 33 (October 2016).
Abuses at a Pueblo center for people with severe intellectual disabilities included a resident performing a sexual act in exchange for a soda and another burned with a blow dryer in an attempt to raise her body temperature, according to a federal report obtained by The Denver Post.
A group of men, some who are nonverbal, had words scratched into their skin, including “die,” “kill,” and “I’m back,” federal investigators found. When questioned, three staffers said they believed the markings were the result of “paranormal activity.” Staffers had posted photos of the etchings on social media, the report said.
The incidences of abuse at the Pueblo Regional Center — one of three centers in Colorado that are home to adults with developmental, physical and intellectual disabilities — occurred before November 2015. Yet federal investigators who visited the home in April found safety protocols still lacking. They notified Colorado Medicaid officials in an August letter that they were enacting a moratorium on new residents at the center and that Colorado must repay millions of dollars in Medicaid funding.
“These are some of our most vulnerable people in Colorado,” said Stephanie Garcia, executive director of The Arc in Pueblo, a nonprofit advocacy group for people with developmental disabilities. “To read some of the things going on, it’s shocking.
[A]bout a third of autism cases are due to non-age related mutations of in sperm or egg cells of parents who don't have an autism gene, about a third of autism cases are due to age regulated mutations in sperm cells of fathers aged 30 or more who don't have an autism gene, and about a third of autism cases are a result of inheriting an autism gene from a parent, usually a carrier mother or a mild ASD symptom parent of either sex.This estimate may be high, but is order of magnitude correct. For example, a 2014 study comparing whole genomes of individuals with ASD and their family members, found "de novo" mutations contributed to 30% of cases of male ASD and 45% of cases of female ASD (see also this 2015 study). Indeed, the cause of seriously developmental disabilities, in general, is roughly similar to the pattern observed in ASD spectrum disorders.
Background Features of the Broad Autism Phenotype (BAP) are disproportionately prevalent in parents of a child with autism, highlighting familial patterns indicative of heritability. It is unclear, however, whether the presence of BAP features in both parents confers an increased liability for autism. The current study explores whether the presence of BAP features in two biological parents occurs more frequently in parents of a child with autism relative to comparison parents, whether parental pairs of a child with autism more commonly consist of one or two parents with BAP features, and whether these features are associated with severity of autism behaviors in probands.From here.
Method Seven hundred eleven parents of a child with an autism spectrum disorder and 981 comparison parents completed the Broad Autism Phenotype Questionnaire. Parents of a child with autism also completed the Social Communication Questionnaire.
Results Although parental pairs of a child with autism were more likely than comparison parental pairs to have both parents characterized by the presence of the BAP, they more commonly consisted of a single parent with BAP features. The presence of the BAP in parents was associated with the severity of autism behaviors in probands, with the lowest severity occurring for children of parental pairs in which neither parent exhibited a BAP feature. Severity did not differ between children of two affected parents and those of just one.
Conclusions Collectively, these findings indicate that parental pairs of children with autism frequently consist of a single parent with BAP characteristics and suggest that future studies searching for implicated genes may benefit from a more narrow focus that identifies the transmitting parent. The evidence of intergenerational transmission reported here also provides further confirmation of the high heritability of autism that is unaccounted for by the contribution of de novo mutations currently emphasized in the field of autism genetics.
Some of the common symptoms of broad autism phenotype include being shy socially, having a hard time making friends, the inability to read body language, having an obsessive behavior, being compulsive, and preferring routine to spontaneous actions.Obviously, "broad autism phenotype" is a term of art, but in ordinary plain English, I'm hard pressed to think of a word that describes it better than "nerdy" (other than the more derogatory term "dweeby").
At least a subset of autism — perhaps one-third, and very likely more — looks like a type of inflammatory disease. And it begins in the womb. . . . In autistic individuals . . . [i]nflammatory signals dominate. Anti-inflammatory ones are inadequate. A state of chronic activation prevails. And the more skewed toward inflammation, the more acute the autistic symptoms.
Nowhere are the consequences of this dysregulation more evident than in the autistic brain. Spidery cells that help maintain neurons — called astroglia and microglia — are enlarged from chronic activation. Pro-inflammatory signaling molecules abound. Genes involved in inflammation are switched on. . . .
A population-wide study from Denmark spanning two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu, during the first trimester of pregnancy triples the odds. Bacterial infection, including of the urinary tract, during the second trimester increases chances by 40 percent.
The . . . mother’s attempt to repel invaders — her inflammatory response — seems at fault. . . .Inflaming pregnant mice artificially — without a living infective agent — prompts behavioral problems in the young. In this model, autism results from collateral damage. It’s an unintended consequence of self-defense during pregnancy.
Yet to blame infections for the autism epidemic is folly. . . . the epidemiology doesn’t jibe. . . . Better clues to the causes of the autism phenomenon come from parallel “epidemics.” The prevalence of inflammatory diseases in general has increased significantly in the past 60 years. As a group, they include asthma, now estimated to affect 1 in 10 children — at least double the prevalence of 1980 — and autoimmune disorders, which afflict 1 in 20. Both are linked to autism, especially in the mother. One large Danish study, which included nearly 700,000 births over a decade, found that a mother’s rheumatoid arthritis, a degenerative disease of the joints, elevated a child’s risk of autism by 80 percent. Her celiac disease, an inflammatory disease prompted by proteins in wheat and other grains, increased it 350 percent. Genetic studies tell a similar tale. Gene variants associated with autoimmune disease — genes of the immune system — also increase the risk of autism, especially when they occur in the mother. . . .
Mothers of autistic children often have unique antibodies that bind to fetal brain proteins. A few years back, scientists . . . injected these antibodies into pregnant macaques. (Control animals got antibodies from mothers of typical children.) Animals whose mothers received “autistic” antibodies displayed repetitive behavior. They had trouble socializing with others in the troop. In this model, autism results from an attack on the developing fetus. . . .
A mother’s diagnosis of asthma or allergies during the second trimester of pregnancy increases her child’s risk of autism. . . . Amniotic fluid collected from Danish newborns who later developed autism looked mildly inflamed. . . .
Why are we so prone to inflammatory disorders? . . .
[P]eople living in environments that resemble our evolutionary past, full of microbes and parasites, don’t suffer from inflammatory diseases as frequently. . . . Generally speaking, autism also follows this pattern. It seems to be less prevalent in the developing world. Usually, epidemiologists fault lack of diagnosis for the apparent absence. A dearth of expertise in the disorder, the argument goes, gives a false impression of scarcity. Yet at least one Western doctor who specializes in autism has explicitly noted that, in a Cambodian population rife with parasites and acute infections, autism was nearly nonexistent.
For autoimmune and allergic diseases linked to autism, meanwhile, the evidence is compelling. . . . asthma and autism follow similar epidemiological patterns. They’re both more common in urban areas than rural; firstborns seem to be at greater risk; they disproportionately afflict young boys. In the context of allergic disease, the hygiene hypothesis — that we suffer from microbial deprivation — has long been invoked to explain these patterns. . . . it should apply to autism as well. (Why the male bias? Male fetuses, it turns out, are more sensitive to Mom’s inflammation than females.)
Scientists estimate that, in about 30% of the patients, a defect on the X-chromosome is the underlying cause. This is called X-linked mental retardation (XLMR). In over half of the XLMR patients, the gene responsible has not yet been identified.
The majority of mental retardation is caused by spontaneous mutations in paternal sperm or maternal egg cells. . . . The researchers read the genetic code of all 20,000 genes for 10 patients with mental retardation. A similar analysis was performed for their healthy parents. By comparing the genetic codes obtained, differences in genes between parents and child could be precisely determined.
For nine out of ten children, the researchers indeed found such changes, each time in a different gene. For three children, the change identified was irrelevant to their disorder. But more important, for the remaining six children, they found two changes that are definitely relevant to their disorder and the four other changes are most likely related to their disorder. Geneticist Joris Veltman: "Apparently, the mental retardation observed in six of these ten children can be explained by a novel genetic change, a de novo mutation. . . .
In the world of medical genetics, mental retardation reflects an intriguing paradox. Individuals with mental retardation seldom have children themselves; as such, they do not pass their impairment on to the next generation. Nonetheless, the frequency of mental retardation in the general population balances and remains around two percent. How can this be possible? . . .
Veltman and Brunner now offer a surprising resolution for this paradox. A majority of mental retardation occurred by chance; by novel mutations in the genetic code of the children. It is expected that approximately 1,000 of all 20,000 genes can cause mental retardation. When a de novo mutation hits one of these genes, it will result in mental retardation. . . .
In addition, we can now determine the recurrence risk for those families in which a de novo mutation caused the mental retardation. This risk will be only marginally increased compared to the general population. For many parents this is a reassuring message which may play a role in their decision making process for additional children. . . .
On average, one new mutation will appear during the process that copies all parental genes to their child. With 1,000 of all 20,000 genes potentially playing a role in mental retardation, the chance of having a child with mental retardation is relatively high. A similar scenario is likely to be true for other diseases in which a large number of genes play a role, such as schizophrenia and autism. The concept of de novo mutations might be equally important for these diseases. . . .
Veltman: "So far, mental retardation was thought to be caused by an interaction of multiple genes. We describe this as complex genetics. Indeed, in the general population mental retardation can be caused by as many as thousand genes. But on an individual level, each case -- as we now found -- is caused by a mutation in a single gene. This newly generated mutation can be readily identified by reading the genetic code of the parents and their child, because there is only one distinguishing factor, which is the causative mutation.
[M]utations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. . . . [DIA1 and DIA1R synthesize two very similar] signal peptides for targeting to the secretory pathway [probably for the same system in the brain]. Both genes are ubiquitously expressed, including in fetal and adult brain tissue.
[T]he risk of an autism diagnosis in a second-born child rose more than three-fold when the child was conceived within 12 months of the birth of the first baby . . . second-borns conceived between 12 and 23 months after a first child was born had twice the risk of being diagnosed with autism compared to babies conceived a full three years after an older sibling was born. . . . For the new study, researchers scrutinized birth records from 662,730 second-born children from California, all of whom were born between 1992 and 2002 and none of whom had an older sibling with autism. By age 6, 3,137 of the second-borns had received a diagnosis of autism, according to data provided by California’s Department of Developmental Services. Of those, 2,747 occurred in children born less than 36 months after their siblings[.]
Up to 70 percent of autistic children are considered high-functioning, though they have significant social communication challenges. . . . [A study included] 30 high-functioning 9 year olds with autism spectrum disorders. . . . 27 out of the 30 children -- that's 90 percent -- had discrepancies between their IQ score and scores on at least one of the [three] academic achievement tests" [ for word reading, spelling and basic number skills] . . . "Some scored higher and some scored lower than what their IQ score would predict." . . . . 18 of the 30 children tested higher than predicted on at least one of the academic tests. This was especially true for spelling and word reading. Across the three academic tests, 18 of the 30 children scored lower than what their IQs would predict, suggesting a learning disability.