The similar profile in both the mental retardation and autistic disorder groups is suggestive of a biomarker for nonspecific developmental dysfunction. Overall, the large variety of neuropathologic changes noted and the variability seen across subjects imply that ASD is etiologically heterogeneous. Additionally, a number of the major anomalies observed, including cerebellar and brainstem findings, are very likely prenatal in origin. This, coupled with the recent findings of atypical neuropeptide profiles at birth, indicates strongly that the neuropathologic process underlying ASD begins in utero.
Two extensive reviews of the existing population-based ASD prevalence studies worldwide have appeared in the published literature within the last 2 years 2 , Both reviews acknowledge the extensive heterogeneity across studies. The authors of both reviews concur that the prevalence of all ASD is manifold, from two to five times higher than that for autistic disorder alone. At this point, the heterogeneity in study design, source population, and criteria for and methods of identifying cases temper the inferences about secular trends that can be made from these studies.
Administrative data, the routine information collected by service delivery programs, likely have contributed more than research studies to the rising public concern over ASD prevalence trends. However, the potential for case-to-case and year-to-year inconsistencies in the categorizations used in administrative data makes these data more susceptible to ascertainment biases than the research studies.
For example, the numbers of children classified with autism by state special education departments across the country have increased approximately 25 percent per year since In California, the Department of Developmental Services recently published a widely cited report on the numbers of individuals with autism registered with that agency, documenting large annual increases in the numbers of persons with an autism classification When population denominators were applied to these autism case counts, the prevalence in most recent years was still near what would be expected on the basis of epidemiologic research studies 2.
At this point, it is not possible to say that the available data, research and administrative, clearly support the hypothesis that the underlying risk of ASD has been increasing with time.
Knowing the true pattern in underlying risk over time is of great interest, because short-term increases in true disease risk would support a role for nonheritable mechanisms in ASD etiology. The only identifiable group known for certain to have substantively elevated ASD risk is siblings of affected individuals Certain rare medical disorders, in particular tuberous sclerosis, fragile X, and epilepsy, are also believed to place individuals at moderately higher risk for ASD 38 , Because the absolute ASD prevalence among males is still fairly low, males cannot be considered at high risk for ASD but, for unknown reasons, ASD does occur from three to four times more often in males than in females If, as suspected, ASD is an etiologic heterogenous condition, subclassification of cases by different phenotypic features might help to reveal etiologically distinct subgroups.
Cognitive impairment is one trait commonly used to subtype individuals with ASD. Approximately 70 percent of individuals with autistic disorder are cognitively impaired, 40 percent severely 2. The gender ratio among cases moves toward for those with more severe cognitive impairment 2. The proportion of persons with cognitive deficits among individuals with all ASDs is likely lower than 70 percent, but no good estimate is yet available.
Much interest has also been expressed in regressive autism as an ASD subtype potentially possessing a unique etiology. ASD symptoms must be present before the age of 3 years to meet DSM-IV diagnostic criteria, but among cases there is a subgroup whose development appears typical up to 15—19 months, after which language decays and social problems emerge. The size of this subgroup is unclear, estimates ranging from 15 to 40 percent of all children with ASD 41 , and population-based data are lacking.
Other approaches suggested for possibly meaningful subtyping of ASD are generally based on associated physiologic abnormalities, including the presence of minor morphologic anomalies 42 , 43 , seizure disorders 44 , 45 , gastrointestinal tract symptoms 46 — 48 , and sleep disturbances 49 , Several lines of evidence support a heritable component to ASD etiology, although no particular ASD-predisposing gene has been confirmed to date.
The studies supporting a genetic component to ASD are summarized in table 1. Accordingly, increased disease concordance rates among monozygotic twins versus dizygotic twins can provide compelling evidence for a heritable component to disease etiology. In the late s, the first study of multiple twin pairs reported four of 11 monozygotic pairs 36 percent concordant for autistic disorder compared with zero of 10 concordant dizygotic pairs 0 percent 51 , providing provocative evidence for heritability.
Subsequent twin information from a University of California, Los Angeles, study reported 96 percent monozygotic concordance of 23 pairs versus 30 percent dizygotic concordance of 17 pairs 52 , confirming heritability. A contemporaneous Scandinavian twin study also reported a high monozygotic concordance 90 percent with no observable dizygotic concordance However, a more recent British twin study, including the initial pairs from Folstein and Rutter 51 , found only 60 percent monozygotic concordance among 25 pairs versus 0 percent dizygotic concordance among 20 pairs These recent twin data also generate high estimates of heritability but do not fit a particular pattern of inheritance.
Moreover, heritability estimates from twin studies may be overstated, one potential reason being the association between zygosity and chorionicity. Dizygotic twins always have separate sets of fetal membranes, while two thirds of monozygotic twins share a chorionic membrane Because the placenta is formed from chorionic tissue, these monozygotic twins will share a placenta while dizygotic twins, and dichorionic monozygotic twins, will have two placentas.
Immune Dysfunction in Autism Spectrum Disorder
Consequently, monozygotic and dizygotic twins may experience different prenatal environmental influences. Monochorionicity, as opposed to monozygosity, has been linked to a number of adverse perinatal outcomes in twins Taken together, the twin studies imply some influence of environmental factors in addition to heritable predisposition to autistic disorder An additional notable finding from the British twin studies was the reported excess concordance of broader ASD phenotypes among monozygotic twins 51 , This raises the possibility that the heritable trait, and therefore the predisposing genes, may be a broader underlying characteristic rather than with any particular disorders as clinically defined.
The large heritability estimates found in twin studies are supported by evidence of familial aggregation of ASD in sibling and population-based studies. For example, genealogic information available for a Utah-based population study allowed estimates of kinship relatedness to be calculated among all members of the study. Autistic disorder cases in this Utah registry had an estimated kinship greater than 20 times the average kinship among nonautistic individuals of the same birth year, suggesting familial aggregation Several studies have shown an increased risk for ASD among siblings of cases.
Estimates of the probability of autistic disorder among siblings of cases range from 2 percent to 6 percent 58 , 59 , although some estimates are as high as 7 percent for siblings of male cases and 14 percent for siblings of female cases Further, abnormalities on almost every chromosome have been associated with some form of ASD phenotype, most notably on chromosomes 7, 15, and X The most commonly cited of these are deletions and duplications of the proximal arm of chromosome 15 69 — Breakpoints for chromosomal inversions resulting in ASD features often lie within fragile regions of chromosomes, leading to speculation about the possible role of regions of unstable DNA and submicroscopic chromosomal deletions 73 , Given the evidence for a genetic component to ASD etiology, focus has naturally turned to gene discovery.
Such efforts would achieve maximum power if a correct genetic model could be specified and assumed for linkage and association analyses. Several studies have sought to identify a particular genetic model through formal segregation analyses or analogy to other known genetic disorders. Following up on their previous twin concordance results, Ritvo et al. However, a more comprehensive study of all identified autistic disorder cases born in Utah between and failed to support a recessive major gene model In the Utah families identified, segregation analysis offered the most evidence for combined polygenic many additive genes and environmental effects in the absence of a major gene effect.
This suggested a multifactorial threshold model in which several etiologic factors, perhaps some heritable and some nonheritable, would be needed to reach a critical liability threshold resulting in ASD In contrast to an additive threshold model, Pickels et al. An epistatic model, including at least 15 genes, has also been suggested from sibling allele-sharing estimates across the genome in families collected by Stanford University Multigene models, either polygenic or epistatic, are congruent with the aggregation of broad ASD features among family members of probands, possibly reflecting possession of only a few predisposing variants rather than the full complement necessary to evoke a diagnosis.
In addition to additive and epistatic multigene models, several investigators have suggested imprinting and sex-linked genetic mechanisms through analogy to known chromosomal abnormalities resulting in ASD features. For example, several chromosome 15 abnormalities resulting in features characteristic of ASD are inherited solely from mothers 70 , 71 , 78 , raising the possibility of an imprinting mechanism in gene expression.
This is supported by evidence that many regions of chromosomes X and 15 are known to be imprinted 79 and by findings of maternal inheritance An imprinting mechanism could explain the lack of convincing support for a Mendelian major gene model. The overlap with fragile X syndrome and the excess of male cases of ASD have led many to speculate on a recessive X-linked inheritance model However, family studies are incompatible with this hypothesis, given observations of some male-to-male transmissions and the exclusion of the X chromosome in some linkage studies 81 — Further, association studies of the fragile X region with ASD have not been decisive Recently, an intriguing model of imprinted X-linked inheritance has been proposed to explain both of these observations and has the further appeal of consistency with the male predominance in ASD 85 , To date, six genome scans searching for linkage to an ASD gene have been published.
These include the following: 1 a full scan of sibling pairs, predominantly British 84 , 87 ; 2 an autosomal scan of 75 families from the United States 88 , 89 ; 3 a full scan of 51 families of predominantly European origin 90 ; 4 a full scan of 90 families from the United States 77 ; 5 a scan of 10 regions among 17 Finnish families 91 ; and 6 a full scan of families from the United States recruited through the AGRE Program Table 2 summarizes the findings from these studies.
Each scan pursued parametric or model-free linkage analyses based primarily on sibling pairs affected with autistic disorder; see Gutknecht 93 for a review. Given the uncertainty about the underlying genetic model for ASD, most scan results have focused on model-free affected pair strategies that do not require an assumption of the mode of inheritance. Affected relative pair methods compare the observed allele sharing between two relatives with the expected sharing for that type of relative pair according to Mendelian laws.
Significant departures from expected sharing values can be taken as evidence for linkage to a putative ASD gene in the region of excess sharing.
Although general simulation results have provided guidelines for significance thresholds, the correct threshold will be unique to each study as it is based on the number of markers, the informativity of each marker in the study population, and the number and type of individuals studied.
Such ambiguity has led to confusion in comparing results across studies. Several current reviews of recent findings have been published 93 , 95 , The most promising ASD region is on chromosome 7q, where linkage to a gene has been observed in four different scans 84 , 88 , 90 , 97 , and this signal has intensified with the addition of further markers in the region 73 , In addition, a maternally inherited paracentric inversion in the linked region has been identified in two brothers with autistic disorder and in a daughter with language pathology A translocation involving this region has also been observed in an autistic disorder case Finally, a gene in this region with a mutation responsible for speech and language disorder has recently been identified, suggesting an overlap in genetic etiology of these disorders 99 — Yet, to date, no mutations in this or surrounding genes have been directly identified in ASD families.
- „Man opfert uns dem Staat, Und wer aus Sehnsucht liebt, begeht den Hochverrat“: Die Verknüpfung von Liebeskonzeptionen, Tugendhaftigkeit und Politik in ... ‚Sterbender Cato‘ (German Edition).
- Rise and Fall: The Life and Legacy of Jefferson Davis.
- Aberrant Brain Plasticity in Autism Spectrum Disorders - Oxford Medicine.
- Programming for Linguists: Perl for Language Researchers.
- Die Transformation des Arbeitsmarktes in Ostdeutschland: Auswirkungen auf die Erwerbsausstiegsprozesse nach der Wiedervereinigung (German Edition)?
Other regions identified in multiple studies include 2q and 16p 84 , Some scans have detected a suggestion of linkage to 15q, potentially reflecting the region containing abnormalities associated with other genetic disorders exhibiting behavioral features similar to those of ASD, such as Prader-Willi 88 , 90 , although linkage has not been observed consistently in this region. Notably, none of the scans provided strong evidence for linkage to the X chromosome, despite correlations between ASD and fragile X syndrome and the predominance of males However, these results do not preclude the possibility of an interaction between an X-linked gene and autosomal loci, which would be difficult to detect in the current reports.
In addition to genome scans, several groups have pursued association studies of plausible candidate genes for evidence of polymorphisms that predispose to ASD. Efforts have focused on genes associated with biologic pathways implicated in ASD. Table 2 also includes a summary of this work.
However, there has been no consistent replication of positive findings for any of these genes to date. For example, the repeat polymorphism in the promoter region of the 5-HTT gene has been associated with ASD in several studies — However, studies performed in Germany and the United States observed association with different repeat sizes , , A recent report suggests this may indicate an association between severity and repeat size However, this more likely represents the differential linkage disequilibrium patterns in these distinct populations, such that the repeat marker alleles are associated with different underlying haplotypes in each population.
Evidence from twin studies, familial aggregation, and rare chromosomal abnormalities provide a compelling argument for some substantive heritable component in ASD etiology. However, no specific genes have been implicated. The results of genome scans and candidate gene studies are difficult to interpret given the differences in populations, designs, and analytic techniques used.
Meta-analysis may help to elucidate truly linked or associated regions across studies. However, these largely conflicting results more likely highlight the limitations of performing linkage and association studies in a complex and heterogeneous disorder. Etiologic mechanisms may include genetic variants in separate genes locus heterogeneity , different variants within the same gene allelic heterogeneity , and complicated epistasis and gene-environment interactions. As this proportion is likely to fluctuate between data sets, it is unlikely that a particular linkage finding could be replicated in many other data sets, even if the same underlying model were at play.
Considering these complexities, gene identification studies would benefit most from better definition of phenotypes that correspond to a particular genetic etiology. Restriction to that phenotype may decrease heterogeneity and allow a stronger detectable effect.
Incorporation of particular models or interactive factors would also serve to reduce heterogeneity and focus on a particular etiologic class. The potential role of environmental influences, the observed overrepresentation of boys, and the potential for imprinting should be incorporated into genetic predisposition models and analyses. It is only through better characterization of phenotypes and inclusion of interactive factors or important covariates that genes underlying such a complex etiology will be discovered and consistently replicated.
Recently, nonheritable ASD risk factors have again begun receiving attention , In part, this is because a single, parsimonious model explaining ASD inheritance has not emerged. In addition, a small but compelling Swedish study , reported a significantly greater than expected proportion of autistic disorder cases among members of a cohort prenatally exposed to thalidomide during days 20—24 of gestation, suggesting that exposure to an exogenous agent during a critical developmental period, in this case the time when the neural tube is formed, might cause ASD — Finally, the widely discussed idea that ASD prevalence may have risen markedly over the last decade has also promoted debate over nonheritable risk factors.
However, given the evidence on heritability, it seems unlikely that truly sporadic cases of ASD would account for a substantial proportion of the disease in the population. Therefore, if environmental factors have a role in ASD etiology, they would most likely be important in mechanisms also involving some element of genetic susceptibility. As previously discussed, neurobiologic evidence points to prenatal initiation of pathophysiologic changes in the natural history of ASD.
Composite scores have been used in a number of epidemiologic studies , , — , with most reporting lower optimality or higher composite risks among ASD cases than controls , , table 3. However, aggregate measures of suboptimality, developed mainly to optimize small sample sizes, may not be the most appropriate means of examining prenatal and perinatal risk factors.
Confounding by parity is one concern, since birth order effects are documented in ASD whether due to stoppage or other phenomena Adjusting for parity, however, has not consistently changed the association between ASD and suboptimality , , , Genetic predisposition may also be a confounding factor, because both ASD and obstetric suboptimality have familial components. Using unaffected siblings as controls is only a crude means of controlling for family loading, and the possibility of residual confounding is supported by the observation of a positive association between the proportion of relatives affected with the broad autism phenotype and obstetric suboptimality in ASD probands 62 , Finally, the heterogeneity of suboptimality scores, typically a mix of antepartum, intrapartum, and postpartum factors, is a potential limitation.
These varied factors are combined in a simple additive or multiplicative fashion to derive optimality scores that have been applied to perinatal mortality risk , but this model may not be appropriate to ASD etiology. Three published case-control studies with primary data analyses of obstetric suboptimality included at least 50 in the case group and showed subanalyses for specific prenatal contributors to suboptimality , , Two other published studies included over 50 cases but were secondary data analyses containing limited prenatal data , Summaries of selected findings on nonheritable factors are included in table 3 , and findings from studies that specifically include maternal infection and maternal medication use are discussed below in more detail.
Each reported odds ratios above 1.http://nn.threadsol.com/26075-cellphone-message-location.php
Elaine Hsiao Lab at UCLA — Publications
Prior to their suboptimality paper, Deykin and MacMahon published a more detailed analysis using the same sample of subjects but focusing on common viral diseases and infection markers during pregnancy. Data were derived from medical records or self-report of clinically diagnosed illness or illness exposure defined as a case within the house.
After adjusting for sibship size, odds ratios were significantly above 1. Of specific infections known to affect the developing brain, rubella has been most commonly reported to be associated with ASD.