Relationship between specificity and prevalence of autism

The greater than three-fold increase in autism diagnoses among students in that the tools for diagnosing autism lose specificity when applied to Texas showed no relationship between the prevalence of autism and that of. Is there an aetiological connection? Leveraging Robotics Research for Children with Autism: A Review ASD prevalence estimates and improve diagnostic specificity without a compromise in diagnostic sensitivity [15,16]. This review provides a broad overview of the history, prevalence, etiology, clinical The revision of Infantile Autism to Autistic Disorder in the DSM-III-R of the definition and reduction in the specificity of autism-related symptoms [1] of clarity over the relationship between functioning levels of autism and.

Received Apr 5; Accepted Oct Associated Data The datasets generated by the current study are not available publicly and are currently being further analyzed by the research group, but they are available on reasonable request from individual researchers who wish to use the data in their investigation. Previous findings in children with ASD have suggested that these symptoms are associated with an impairment in executive function EF abilities. However, studies rarely considered this association within a single framework that controls for other related factors such as Theory of Mind ToM abilities and ASD symptoms.

The study used a multi-measure and multi-informant approach, where performance of inhibition, planning, switching, and working memory tasks indexed EF and performance on tasks involving mentalizing indexed ToM. Shared source of symptom reporting was accounted for with a parental rating latent factor indexed by symptom measures reported by parents.

Results Impairments in EF abilities were specifically associated with ADHD symptoms while impaired ToM was specifically associated with ASD symptoms, when accounting for the associations of each cognitive domain with the other factors. ASD and ADHD symptom latent factors were also correlated, but this association became nonsignificant once the shared source of reporting from parents was accounted for and within a model that also controlled for the correlated pathway between EF and ToM factors.

An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options

The specific relations between the cognitive domains and behavioral symptoms remained even after controlling for IQ. The association between EF and ToM impairments is a likely partial explanation for the co-occurrence of ADHD symptoms in ASD, but the role of shared reporting effects is also important and supports the inclusion of independent informants and objective measures in future research.

Electronic supplementary material The online version of this article Individuals with ASD are impaired in reciprocal social communication and interaction and display various stereotyped and repetitive behaviors [ 2 ]. Therefore, neurocognitive approaches can be useful for explaining the mechanisms underpinning the co-occurring ADHD in the ASD population [ 10 — 12 ]. Two disorders can co-occur beyond chance level due to artifactual or non-artifactual reasons [ 1314 ].

The spectrum of need in terms of supports and services can be vast, with the ability to function across skill areas required for daily living and across the lifespan often independent of the severity of autistic symptoms.

The difficulties associated with the accurate assessment of functioning, an important factor in understanding the impact of severity on outcomes, is currently being addressed with the development of the International Classification of Functioning, Disability and Health core sets for ASD [ 52 ]. The core set is a shortlist of categories selected to encompass aspects of functioning most relevant when describing a person with ASD. Interestingly, the onset of ASD symptoms has been a focus of research that has identified an early onset pattern and a regressive onset pattern in which children appear to develop typically before losing skills and developing autism-like symptoms [ 53 ].

However, in-depth review of these conceptualizations concludes that the onset of ASD, or symptom emergence, is better considered a dimensional process and a continuum in which the early onset and regression patterns describe two extremes [ 47 ]. Heterogeneity Heterogeneity in etiology, phenotype, and outcome are hallmarks of ASD.

These factors contribute to a clinical heterogeneity which manifest as diverse deficits or impairments in behavioral features and communicative functioning.

An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options

The heterogeneity of clinical entities is in part a function of the multiple genes involved, the myriad of environmental factors impacting the developmental course of symptom expression, and the co-occurrence of medical and mental health dysfunctions in ASDs. Heterogeneity complicates the quest for personalized medicine in ASD. Three factors contributing to the heterogeneity of ASD, genetic variability, comorbidity, and gender, are now considered.

High-throughput genomic methods are rapidly increasing the pool of ASD genes and in doing so expanding the genetic variability associated with ASD heterogeneity [ 55 ]. Large datasets have not identified significant genome-wide associations with specific common variants, and associated analyses suggest that common variants exert weak effects on the risk for ASD [ 56 ].

The genetic architecture in ASD varies substantially, from a single penetrant mutation being enough to cause ASD, to an accumulation of over one thousand low-risk alleles [ 57 ]. Rare variants affecting ASD risk collectively encompass hundreds of genes [ 58 ], while copy-number variant data and de novo protein-altering mutations suggest extreme locus heterogeneity [ 59 ].

Furthermore, the combined effect of common low-impact genetic variants has also been associated with ASD [ 60 ]. Large numbers of genes implicated in ASD are thought to converge on common pathways affecting neuronal and synaptic homeostasis [ 61 ], and play critical roles in fundamental developmental pathways [ 3959 ]. For example, mutation of a single copy of SHANK3, a synaptic scaffolding protein, has been associated with language and social communication impairment in individuals with ASD [ 62 ].

In contrast, pleiotropic effects have been identified whereby the same deleterious genetic variant increases the risk for ASD and other neuropsychiatric syndromes [ 6364 ]. Finally, findings from pathway network analyses of gene ontologies suggest that, in addition to contributing to the core features of ASD, associated genes may contribute to vulnerabilities in important molecular mechanisms leading to multiple systemic comorbidities that also overlap with other conditions [ 65 ].

Comorbid psychopathologies significantly over-represented in ASD include anxiety [ 67 ], depression [ 68 ], ADHD [ 69 ], and intellectual disability [ 57 ]; and medical comorbidities include seizures [ 70 ], sleep difficulties [ 71 ], gastrointestinal disorders [ 72 ], mitochondrial dysfunction [ 73 ], and immune system abnormalities [ 74 ]. The presence of one or more of these comorbidities is likely to be associated with more severe autism-related symptoms.

Furthermore, sleep problems exacerbate the severity of core ASD symptoms [ 7879 ] and sleep disturbance is associated with behavioral dysregulation in children with ASD [ 80 ]. Aberrant behaviors are correlated with gastrointestinal problems in young children with ASD [ 81 ], and markers of mitochondrial dysfunction are significantly correlated with autism severity [ 73 ].

The role of immune system abnormalities in ASD is a significant focus of ongoing research. Altered immunity involving cytokines, immunoglobulins, inflammation, cellular activation, and autoimmunity have all been implicated in ASD [ 82 ].

Furthermore, altered levels of cytokines have been associated with the severity of behavioral impairments [ 83 — 85 ]. There is limited characterization of these associations between comorbidities in general and the severity of autism-related symptoms due to the complex nature of these relationships.

Improved characterization of comorbidities is imperative for the development of a comprehensive understanding of ASD heterogeneity and may lead to the identification of distinct subgroups of ASD and subgroup-specific treatments [ 87 ]. Gender The male bias in ASD prevalence is most frequently reported as 4 males diagnosed to every 1 female [ 3288 ].

Intellectual functioning and sex-differential genetic and hormonal factors may modify this ratio [ 88 ]. The basis of this theory is that a normal male cognitive profile encompasses individuals who are better at systemizing the drive to analyze or construct systems than empathizing, and that autism can be considered an extreme of the normal male profile.

A potential mechanism for this theory is an elevation of fetal sex steroids, which is supported by a recent study reporting that amniotic fluid steroid hormones were elevated in males who later were diagnosed with ASD [ 91 ].

For example, a recent DNA study showed that girls display resilience to genetic insults in that they are more likely to have more extreme neurodevelopmentally related genetic mutations, including both copy-number variants and single-nucleotide variants, than males presenting with the same symptoms [ 92 ].

An alternative perspective is that females are under-identified and there may be a gender bias in the diagnostic criteria [ 93 ]. A large-scale study has found that females had greater impairments than males, presenting with more social communication and interaction symptoms, lower cognitive and language abilities, poorer adaptive function, and increased externalizing behavior and irritability, suggesting that females require more severe symptoms to be diagnosed as ASD [ 94 ].

However, females with ASD have been identified as having fewer repetitive behaviors than males [ 95 ], but equivalent impairments in social and communication skills [ 96 ]. There is an increased risk of ASD for a child with an older sibling who has been diagnosed with the condition. Predictors of an ASD diagnosis in a younger sibling include male gender of the infant and the number of affected older siblings.

In a large sample using a prospective design, the recurrence rate for multiplex families has been reported at A higher recurrence risk has been identified in families with at least one affected female proband compared to families with only male probands, suggesting female protective mechanisms may be operating in families with high genetic recurrence risk rates [ 99 ].

Treatment Options in ASD Despite significant economic and societal costs, there are limited treatment options to ameliorate the symptoms associated with ASDs, including both symptoms related to diagnostic criteria and those that are considered to be a function of comorbid mental and medical conditions known to exacerbate the severity of presentation. While there are promising indications for new medical treatments for autism [ ], a recent systematic review found that while many children with ASDs are treated with medical interventions, there is minimal evidence to support the benefit of most treatments [ ].

There are numerous challenges for the identification of effective treatments for ASD. Systematic reviews highlight the possibility that genetic, environmental, cognitive, and social heterogeneity in the ASD phenotype produce highly variable study samples which reduce the potential effect size of an intervention [ ]. Other factors contributing to the difficulties in identifying efficacious treatments include small sample sizes, the lack of significantly impaired study participants and the use of outcome measures that are not uniformly adopted or used as intended [ ].

Cross-cultural differences, including what may be considered deviations from typical behavior in a particular culture but not in another culture, further complicate the quest for treatment options across the ASD population [ ].

Increasing prevalence of autism is due, in part, to changing diagnoses | Penn State University

Behavioral interventions undertaken early in life, using an intensive delivery format, are considered the current gold-standard treatment for behavioral symptoms associated with ASDs [ ]. However, methodologically weak studies with few participants and short-term follow-ups are common in this field []. Furthermore, early intensive behavioral interventions are expensive to implement and require extensive resources to execute effectively, making them inaccessible for many children with ASD and their families.

Risperidone, an adult antipsychotic, was approved in for the symptomatic treatment of irritability, including aggression, deliberate self-injury, and tantrums, in autistic children and adolescents. However, significant side-effects are associated with risperidone use, including weight gain from increased appetite, drowsiness, and increased levels of the hormone prolactin, which is produced by the pituitary gland and which can have a feminizing effect on both females and males [ ].

The frequency of side-effects appears to be dose-related [ ], and while weight gain is common, somnolence more significantly influences the discontinuation of treatment [ ]. Infollowing evaluation of short-term efficacy and safety, the FDA also approved aripiprazole, a third-generation atypical antipsychotic, for the treatment of irritability associated with ASD in children and adolescents [].

Such polymorphisms have been observed in higher frequencies in children with autism, suggesting that these children might be genetically predisposed to less efficient folate metabolism and function [ 6270 ]. In this section studies are reported in chronological order and by study design. A summary of these studies is presented in Table 4. With the exception of a prospective study in a Norwegian children cohort by Suren et al. A few investigators have also evaluated the effects of folate metabolites and their possible role as oxidative stressors as a risk factor for autism and the effect of interaction between maternal folate status and maternal genotype and risk of autism [ 5861 ].

Results of these studies indicate an association between maternal perinatal folate status and ASD. Currently several randomized clinical trials are underway to clarify and confirm the association between periconceptional folic acid intake and autism [ 71 ].

Vitamin D Status as a Risk Factor for Autism Vitamin D, a secosteroid, is structurally part of a group of sterols with a crucial role in calcium and phosphorous metabolism [ 72 ]. The main source of vitamin D is the solar ultraviolet B radiation related conversion of 7-dehydrocholesterol to previtamin D3 in the skin and a lesser amount of vitamin D from food [ 7374 ].

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There is a growing body of research that suggests that vitamin D status either in utero or early in life may be a risk of autism. Autism is considered an autoimmune disease and appears to have important risk factors in utero as indicated by a highly increased frequency of congenital malformations [ 75 — 78 ].

The Autism Blogcast- Diagnosis and Prevalence of Females with Autism

Also, several studies have reported seasonality to be associated with excess births of autistic infants, with March as a peak birth month in several countries including Boston, Denmark and Sweden [ 79 — 86 ]. Grant and Soles [ 72 ] used epidemiological data for seasonal variation of birth rates and prevalence of infantile autism disease IAD to examine whether maternal vitamin D deficiency was a risk factor for IAD for cohorts born before Investigators have advanced the hypothesis that association between vitamin D and autism could be explained by the relationship between seasonality and low maternal serum hydroxyvitamin D concentration a valid indicator of vitamin D status [ 73 ].

Because activated vitamin D 1, dihydroxy vitamin Da secosteroid, upregulates the DNA repair gene, vitamin deficiency during development may inhibit the repair of de novo DNA mutations in fetuses and infants and thus contribute to risk of autism.

Other mechanisms which may explain the effect of vitamin D on autism symptoms are that vitamin D may reduce the severity of autism through its anti-inflammatory actions, increasing T-regulatory cells, antiautoimmune effects, and upregulating glutathione, a scavenger of oxidative byproducts [ 81 — 84 ]. Active vitamin D 1, dihydroxy vitamin Dlike other hormones, acts as a molecular switch, activating many target genes via the vitamin D receptor VDR.

Cannell proposed a theory for the genetic component of autism involving the vitamin D system [ 84 ]. Cannall used one of the inherited components of the vitamin D system and vitamin D related disease, atherosclerosis, as a model to illustrate the mechanism of association between autism and the vitamin D system. A strong negative association was found between inherited VDRs and severity of atherosclerosis.

Similarly, significant changes in composite health outcomes cancer, myocardial infarction, and hip fractures occurred with respect to a combination of serum OH vitamin D levels and VDR alleles.

Grant and Cannell proposed that a similar mechanism may describe autism. Heritability of autism may be explained by quantitative genetic variations in some facet of vitamin D metabolism, such as VDR or in the enzymes that activate vitamin D [ 86 ]. Lower levels of hydroxy vitamin D have been reported by several investigators.

A study conducted in Saudi Arabia found that despite the same amount of sun exposure, not only was there much lower levels of hydroxy vitamin D in autistic children as compared to controls about half of those of controlsbut also there was an extremely strong negative correlation coefficient between vitamin D levels and autism severity on the autism severity scale [ 75 ].

These observations imply that vitamin D levels in autistic children are highly heritable [ 87 ]. However, recent studies have indicated that a genetic disease may not be inherited [ 8889 ].

De novo genetic mutations, such as those seen in autism and schizophrenia may occur during the lifetime and may not be inherited. These observations may explain the genetic findings of autism, since the most common genetic finding is multiple small genetic de novo mutations. Some studies have indicated that most of the observed de novo point mutations are not related to the etiology of autism [ 90 ]. A few de novo mutations are associated with increased risk but are distributed across many chromosomes and are not severe enough to explain the disease [ 9192 ].

This implies that genetic defects in autism are often minor compared with well recognized defects such as those which occur in trisomy However, multiple studies have confirmed the contribution of rare de novo copy number variations to the risk of ASD [ 9394 ]. Using whole-exome sequencing of individuals, including phenotypically discordant sibling pairs, has shown that highly disruptive de novo mutations in brain-expressed genes are associated with ASD and carry large effects [ 89 ].

Dihydroxy D3 protects cells by upregulating a DNA repair gene that helps to repair double-strand breaks. Vitamin D may guard the genome via control of DNA repair [ 9697 ]. In a randomized controlled trial in humans, IU of vitamin D increased the levels of Bax, which helps to stop mutations by promoting apoptosis [ 98 ]. Thus, it is possible that widespread point mutation and de novo DNA mutation damage seen in autism could be an effect, not a cause. The effect of a genetically impaired vitamin D system combined with inadequate amounts of vitamin D may be associated with de novo mutations reported in autism.

The search for a genetic basis of autism is an ongoing complicated process. The quantitative genetic variation in various components of vitamin D, as proposed by Cannall, may be a piece of this puzzle.

The role or roles vitamin D may play in development of ASD may be resolved by randomized clinical trials of prenatal vitamin D supplementation or vitamin D supplementation of newborns or in early childhood. Maternal Metabolic Conditions, Prenatal Inflammation, and Risk of Autism Gestational diabetes is known to be associated with genetic development impairments in offspring. Also, diabetes is more common in autistic children []. However, research regarding specific associations between autism and maternal diabetes has produced inconsistent results.

Few studies have examined related conditions accompanied by underlying increased insulin resistance and their relation with developmental disorders []. In a well-designed population based case control study, Krakowiak et al. Information regarding maternal condition was ascertained from the medical records or a structured interview with the mother.

All metabolic conditions were more prevalent in case mothers were compared with controls. These studies indicate that maternal MCs, particularly diabetes, may be associated with neurodevelopmental problems in children and vitamin D supplementation early in childhood should be given further consideration in treatment of ASD [ — ].

Another emerging risk factor associated with the prenatal environment being examined as a possible risk factor for ASD is prenatal inflammation.