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Neonatal and regressive forms of autism: Diseases with similar symptoms but a different etiology
Medical Hypotheses 109 (2017) 46–52
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Neonatal and regressive forms of autism: Diseases with similar symptoms but a different etiology William E. Barbeau
MARK
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Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA 24061, USA
A R T I C L E I N F O
A B S T R A C T
Keywords: Autism Spectrum Disorder (ASD) Neonatal Regressive autism Environmental trigger Etiology
Autistic Spectrum Disorder (ASD) can be a debilitating, life-long neurocognitive disease. ASD is caused by genetic and epigenetic factors and largely unknown and poorly understood environmental triggers. Signs and symptoms of ASD often appear in the first year of life while the disease strikes other infants who had previously been developing normally at around 2 years of age. Ozonoff and her colleagues recently suggested that there are three different pathways or trajectories for the development of ASD in infants 6–24 months of age. I hypothesize that pathway 1 is caused by in utero insult/injury, pathway 2 by obstetric complications at birth, and pathway 3 by environmental triggers of ASD affecting infants 0–3 years of age. Faster progress can be made in elucidating the underlying causes of neonatal and regressive forms of ASD if the diseases are investigated separately, instead of being part of the same disorder.
Introduction The American physician Leo Kanner first described the behavior patterns of autistic children in a 1943 journal article entitled “Autistic disturbances of affective contact” [1]. Autism or Autism Spectrum Disorder (ASD) as it is now called, is a group of neurodevelopment disorders that result in minor to major deficits in a person’s facility for interacting and communicating with others, their motor skills and cognitive abilities. Genetics play a key role in ASD etiology and pathogenesis with heritability estimates in monozygotic twins reported to be between 64% and 91% [2]. Males are approximately 4 times more likely to have ASD than females [3]. ASD was considered a relatively rare disease until the 1960s when incidence rates started climbing in industrialized countries increasing to a reported high of 1 in 68 live births in the U.S. in 2012 [4]. Some ASDs have well-defined genetic origins such as fragile X syndrome which is believed to be due to silencing of the fragile X mental retardation 1 (FMR1) gene that causes dendrites in the brain to be long, thin and fragile [5] and tuberous sclerosis which has been linked to TSC1 and TSC2 gene mutations [6]. Ninety percent of ASD cases however are idiopathic [7]. One ASD that until recently went under-reported is called regressive autism. Regressive autism accounts for about a 1/3 of all cases of autism [8]. It is called regressive autism because it strikes infants at around 18 months of age, who were developmentally “on track’ but now are losing some of their social skills and cognitive abilities, particularly related to language.
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Address: 1403 Locust Avenue, Blacksburg, VA 24060, USA. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.mehy.2017.09.015 Received 11 July 2017; Accepted 15 September 2017 0306-9877/ © 2017 Elsevier Ltd. All rights reserved.
There is some controversy about when regressive autism actually begins. Some clinicians and researchers believe that it starts in the first year of life [9]. However, there is little doubt that regressive autism is a recognizable clinical entity characterized by a sudden loss in an infant’s ability to understand and formulate words, and communicate with others. Videotape analysis has recently helped document the deterioration of language skills in children with regressive autism. One study found that a group of infants that were later diagnosed with regressive autism had higher than average language skills at 12 months of age that fell to well-below average at 24 months [10]. Some investigators have suggested that there may be different timelines or trajectories for the development of ASD. Trajectories for regressive autism may be different from neonatal autism where symptoms become apparent soon after birth. Recently, Ozonoff and her colleagues proposed that there are three general trajectories for the development of ASD that they designated as TRAJ1/Early Onset; TRAJ2/Regression and TRAJ3/Plateau [11]. These three trajectories are shown in Fig. 1 with an index for coded social communication behaviors per minute plotted on the y axis (higher numbers indicate better communications skills) vs age up to 24 months on the y axis. The trajectories were drawn following detailed analysis of data sets from a research study conducted on 52 autistic children and 23 with typical development over a period of 18 months, when the children were from 6 to 24 months of age. According to Fig. 1, children with early onset ASD started out at a disadvantage in terms of their social communication skills compared to
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Fig. 1. Reproduced with kind permission from ELSEVIER [11].
reported alterations in the FG and amygdala in autism. Van Kooten et al. [16] detected significant reductions in the number and size of neurons in the FG of ASD patients compared to normal controls. Another study found that autistic subjects had fewer GABAA receptors and benzodiazepine binding sites in the FG than normal controls [17]. In addition, autistic subjects were reported to have significantly lower levels of N-acetyl aspartate (NAA) in the right hippocampal-amygdala region of the brain than normal controls, which investigators attributed to immature neurons or hypo-activity of neurons in these brain centers [18]. There is also evidence from fMRI studies that when given face processing tasks autism patients do not activate the left amygdala, in the same way as normal controls [19,20]. Repetitive behavior(s) is another hallmark of ASD. Inflexible and repetitive behaviors in ASD have been associated with a part of the brain called the anterior cingulate cortex (ACC). Thakkar et al. [21] evaluated repetitive behaviors and ACC structure and function in 20 subjects with ASD and 14 healthy controls. ASD subjects had higher restricted and repetitive behavior scores than normal controls. Higher scores were positively associated with losses in the microstructural integrity of white matter underlying parts of the ACC. ASD subjects have a reduced ability to suppress inappropriate behaviors referred to as response inhibition. Agam and others have theorized that there is a connection between response inhibition and repetitive behaviors [22]. Using fMRI imaging, they found decreased activation of the frontal eye field (FEF) and dorsal anterior cingulate cortex (dACC) in ASD patients. Patients with higher repetitive behavior scores required a greater activation of the FEF to successfully inhibit inappropriate behaviors. Autism has also been linked to dysfunction of the cerebellum. The cerebellum may affect social skills, movement and cognition directly through its control of executive functions or indirectly via connections the cerebral cortex makes with the thalamus and basal ganglia. There are many reports of Purkinje cell loss within the cerebellum of ASD patients [23–26]. Purkinje cells express glutamate decarboxylase (GAD) enzyme which converts glutamate to gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in humans [23]. Loss of Purkinje cells in ASD leads to significantly lower levels of GAD enzymes in the cerebellum of ASD patients [23,27] and lower concentrations of
children in the three other cohorts, and stayed at a disadvantage throughout the study. Further, although the social communication skills of TRAJ3/Plateau children were indistinguishable from typical children (TD) at 6 months of age, they failed to make further progress, falling well-below TD children at 24 months. Children in the TRAJ2/Regression group exhibited well-above average skills at 6 months, but their skills eroded quickly thereafter, falling to the level of the early onset group by 24 months of age. The question arises: Do these data accurately represent the development paths of ASD children in the general population? Are there really three different types of ASD that can be differentiated on the basis of an infant’s social communication skills in the first two years of life? Furthermore, if the data are accurate, then what accounts for the different trajectories or timelines? How are symptoms of ASD related to disease pathology? Some symptoms of ASD, like savantism, occur only rarely, while others, the so-called “classical” ASD symptoms are present in the vast majority of diagnosed cases. The classical symptoms or core features of ASD include: a preference for established routines and repetitive behaviors, a strong tendency for avoiding eye contact with other people, motor skills that develop slowly and remain well below-average, underrecognized and poorly described deficits in smell, taste, hearing and touch [12–14]. Researchers are making substantial progress in establishing links between structural and biochemical changes that are found in the brains of autistic individuals and the symptoms of autism. Most ASD patients have an aversion to focusing their eyes on the faces of others. Two regions of the brain called the fusiform gyrus (FG) and the amygdala are believed to be involved in facial perception and recognition. One group of investigators tested “face processing” in ASD patients by showing them 24 photographs of peoples faces. Activation of the FG and amygdala regions of the brain of ASD patients was measured using MRI brain imaging, while the patients were looking at the photographs. A strong, positive correlation was found between FG and amygdala activation and time the ASD patients spent focusing their eyes on the faces in the photographs [15]. A number of studies have 47
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that the brain volume and head circumference of boys with regressive autism were significantly larger than boys with non-regressive forms of autism and a typically developing (TD) control group of children. Differences in brain volume and head circumference were not present in girls with regressive autism, only in boys. The amygdala, a part of the brain involved in regulation of social behaviors [46], is also reported to be enlarged in ASD children [47–49]. Nordahl discovered from a post hoc analysis of amygdala data from a 2011 study that there may be three different amygdala growth rates in ASD; a rapid growth rate, a growth rate similar to TD children, and a third that is actually slower than TD children [45]. Unfortunately, no data was collected in Nordahl’s study on the onset or the symptoms of ASD. Nevertheless, it is tempting to speculate that the 42% of children with rapid amygdala growth rates are those with regressive autism, while another 42% of children with typical growth rates suffered a brain injury at birth that led to neonatal autism, and 16% of children with slower growth rates had neonatal autism due to prematurity, low-birth weight, and/or in utero insult or injury. Evidence from two other studies also indicates that several regions of the brain of a subset of ASD children are reduced in size. Padilla et al. [50] performed MRI brain scans on children born < 27 weeks of gestation, approximately 3 months after their birth and at 6.5 years of age, and observed that the brains of children later diagnosed with ASD had grown more slowly than children born prematurely, but without ASD. Ure et al. [51] studied 172 children born prematurely < 30 weeks gestation or with low birth weights < 1250 g. MR brain images of the children were taken just after birth and at 2, 5 and 7 years of age to measure changes in total and regional brain volumes and the children were assessed for autistic traits beginning at age 2. Associations were reported in the study between reductions in the size of the cerebellum and smaller deep nuclear gray matter volume and increased odds of ASD.
GABA in the brains of autistic subjects than controls [28]. It has been postulated that loss of a critical mass of cerebellar Purkinje cells may upset the delicate balance in the brain of the excitatory neurotransmitter glutamate and its antagonist GABA [24]. Reasons for Purkinje cell loss in ASD are unclear. Abnormalities in cortical minicolumns of the brain are another consistent finding in ASD. Minicolumns are one of the primary structural units of the human brain. They consist of vertical bundles of 80–100 neurons that stretch between cortical layers of the brain. The width of minicolumns of the brain decreases in older individuals along with a decline in cognitive function [29,30]. Casanova et al. [31,32] found minicolumns of some cortical layers of the brain were narrower in ASD patients than controls; and Blatt et al. [33] likewise reported narrower minicolumns in the prefrontal regions of the brain in ASD. Observations from a recent study contradict these findings. In this case, minicolumns were wider in ASD than controls [34]. Other minicolumn associated abnormalities have been detected in ASD. The distance between minicolumns and the size of the peripheral neutrophil space surrounding minicolumns is reduced in ASD [35,36]. The peripheral neutrophil space is rich in GABAergic neurons that serve to inhibit excitatory signals coming from Glutamatergic neurons ASD also appears to adversely affect the ability that different parts of the brain have to communicate with each other. fMRI scans of autistic brains have shown that some parts of the brain may be underconnected in ASD, while others are over-connected. Specifically, corticocortical and interhemispheric connections are lacking in ASD and there is an over-abundance of subcortical connections [37,38]. In one study, investigators gave autistic and healthy children assigned tasks to do while they monitored their functional brain connectivity using fMRI brain imaging. Long range connections between the cerebellum and premotor areas of the brain appeared to be compromised in autistic children [39]. The Wernicke and Broca areas of the brain are critical to language skills. Veerly et al. [40] found evidence for decreases in functional connectivity between the Broca and Wernicke areas of the brain and the cerebellum in ASD subjects.
The etiology of ASD It is time to abandon the idea of the existence of a single environmental trigger for all forms of ASD. One of the hypotheses presented in this paper is that there are in fact many different environmental triggers of ASD. There is evidence that some of these triggers act in utero, and others at, or close to, the time of birth. I hypothesize that neonatal forms of ASD are caused by the action of these two sets of environmental triggers in newborns that are genetically susceptible to autism. Insults or injuries to the developing brain that occur in utero, well before birth, are among those that are most likely to lead to severe forms of ASD. The trajectory in Fig. 1 labeled Early-onset ASD best represents the developmental timeline for individuals with severe forms of ASD. The developmental trajectory in Fig. 1 labeled Early-onset ASD is, in my view, likely to be caused by insults or injuries that occur in utero, well before birth, that have severe, lasting (possibly irreversible) impacts on brain development.
Similarities and differences in the symptoms and pathology of neonatal and regressive forms of ASD Most ASD investigations make no attempt to differentiate between neonatal and regressive forms of autism when it comes to the selection of subjects for a study, in experimental design, or data analysis. There have been a few studies that have tried to discern if there are possible differences in the symptoms of non-regressive and regressive forms of autism. Davidovitch et al. [41] interviewed 39 mothers of children with ASD, 19 with children who had developmentally regressed, and 20 who did not regress. No significant differences were found in the mothers’ assessment of verbal and non-verbal skills and social and play abilities of the two groups of children. Minimal differences were reported in a second study in the family history, child characteristics, developmental concerns and behavioral concerns of a group of 51 autistic children without regression and 31 with regression [42]. There were no significant differences, in a third study, in the verbal and non-verbal IQ scores of ASD children without regression vs those who had regressed [43]. On the other hand, according to the results of a battery of diagnostic tests conducted by Matson et al. [44], ASD children who had been diagnosed with autistic regression at a mean age of 28 months exhibited more severe symptoms of autism and greater impairments in social skills and behavior than children with early onset ASD. Investigations into the pathology of ASD usually make no distinctions between non-regressive and regressive forms of autism. There is however some data in the scientific literature on ASD that points to the possibility of fundamental differences in the pathology of neonatal and regressive autism. Macrocephaly is more common in ASD children than their peers [45]. Nordahl et al. [45] examined the relationship between total brain volume and the onset of ASD in 2 to 4 year olds. They found
Etiology of neonatal forms of autism The prevalence of ASD rises dramatically in premature infants. Four large population studies conducted in Canada, the United States, Sweden and Norway found the relative risk of ASD was 2.5, 2.7, 3.0 and 9.7 times greater in infants born at ≤28 gestational weeks of age than at full-term [52–55]. The smaller, far less well-developed brain of extremely premature infants is susceptible to hemorrhage during delivery. Brain injuries have been observed to occur more often in premature infants, both as a result of, and in the absence, of brain hemorrhaging [56,57]. Cranial ultrasound scans have revealed that as the brain of the extremely premature infant develops the ventricles become abnormality enlarged and white matter is more diffuse than in normal infants. A strong association has been reported between enlarged ventricles and 48
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It is my hypothesis that ASD children affected primarily by perinatal risk factors for autism are likely to follow the TRAJ3/ Plateau developmental timeline in Fig. 1. These children are able to nearly catch-up to their peers in their first 6 months, but ASDdriven deficits prevent them from ever attaining their full potential.
losses in the structural integrity of white matter in the brain and later diagnosis with ASD [58]. The frequency of ventricular enlargement is also higher, and ASD risk is greater, in low birth weight infants than in full-term infants [58]. A few drugs, when taken during pregnancy, are known to increase the risk of ASD in newborns. Sodium valproate is prescribed for epilepsy. The offspring of women that took valproate while they were pregnant were found to have a three to sixfold greater risk of ASD than children not exposed to the drug [59,60]. Valproate has been shown in rat studies to have adverse effects on brain development. Watanabe et al. [61] found significant reductions in GAD+ interneurons and Purkinje brain cells of newborn rats whose mothers were given valproate in their drinking water [61]. Changes to the structural integrity of the prefrontal cortex and hippocampus of the brain similar to those present in ASD in humans have also been observed in the valproate-rat model of autism [62]. Weaker associations have been reported between ASD and thalidomide, formerly prescribed for morning sickness [63,64] and serotonin reuptake inhibitors (SRIs), a class of anti-depressants [65]. Mumps, measles, and cytomegaloviruses have also been implicated as possible environmental triggers of ASDs [66–68]. At least two possible mechanisms have been proposed for how congenital viral infections may lead to ASD in newborns: via direct attack of viruses on critical parts of the brain associated with ASD; and by a secondary autoimmune driven attack on fetal brain tissue [69]. Yasmashita studied the behavioral development and did cranial ultrasound scans on seven children with congenital CMV infections. Two out of seven displayed classical symptoms of ASD and dilation of the lateral ventricles of the brain [68]. IgG antibodies from ASD children were found in one study to react to the measles virus and also to two brain proteins, myelin basic protein and neuron-axon filament protein [70]. It is well-known that optimum supplementation of vitamin B6 (folate) during pregnancy prevents neural tube defects in newborns [71]. Recently, folate nutritional status has also been linked to ASD. Folate is necessary for DNA synthesis, repair and methylation and is critical for normal embryonic brain development [72]. There are two recent reports of an association between the risk of ASD in newborns and folic acid intakes during the first month of pregnancy [73,74]. ASD risk was significantly reduced by mean daily folic acid intakes of > 600 μg [73]. Furthermore, the link between ASD risk and folic acid intakes appears to be strongly influenced by inheritance of methylenetetrahydrofolate reductase (MTHRF) genes, the MTHFR C677T gene increases ASD risk and the MTHFR A1298C reduces it. MTHRF genes are involved in regulation of DNA methylation and in gene expression [75]. Epigenetic factors related to gene expression are believed to play an important role in overall ASD risk [76]. Vitamin D deficiency may be another contributing factor to the development of ASD. Data from several studies indicate that offspring of mothers with low blood levels of vitamin D are at an increased risk for the development of ASD [77–80]. This association may extend to the time of the year a child is born. In one study conducted in Sweden, where there is little sunlight during the winter, ASD rates were two times higher in children born in the Spring than during the Summer [78]. Susceptibility to ASD may be driven up even further by inheritance of certain vitamin D receptor (VDR) genes [81]. A number of perinatal risk factors are also thought to play a role in the development of some cases of ASD. These include risk factors that occur well before birth such as pre-eclampsia and maternal diabetes [82,83] and obstetric complications at birth like fetal hypoxia [84]. According to results of a meta-analysis of 40 studies, the perinatal risk factors most strongly associated with autism include abnormal fetal presentation, umbilical-cord complications, fetal distress, birth injury/ trauma, and maternal hemorrhage [85]. It should be pointed out that these perinatal risk factors are likely to be a “trigger” of autism only in cases of a strong genetic predisposition to ASD; and when they act in concert with other pre and postnatal risk factors.
Etiology of regressive autism Andrew Wakefield and his colleagues reported in a 1998 journal article in Lancet that they had found evidence linking autism to the MMR vaccine [86]. The idea that mercury-containing thiomerosal in the MMR vaccine could be a trigger of regressive autism was attractive in part because the vaccine is administered to children at roughly the same age that the peak onset of regressive autism occurs. However, the major findings of the Wakefield article were later judged to be fraudulent and the paper was retracted [87]. Subsequent epidemiological and laboratory investigations have further discredited Wakefield’s original hypothesis [88,89]. The true causes of regressive autism remain a mystery. It is conceivable that neonatal and regressive forms of autism share some of the same environmental risk factors. Viral infections are known to sometimes damage the fetal brain in utero and have been implicated as a possible trigger of ASD in newborn infants [90]. There is some experimental evidence both for, and against, the involvement of viruses in regressive autism. Lintas et al. [91] performed postmortem examinations of brain tissue samples from 15 autistic patients and 13 controls. Polyomavirus was detected in 67% of samples from autistic patients vs 23% of the controls. Significantly elevated levels of IgG antibodies to the measles virus were reported in ASD children compared to normal controls and their siblings [67] and ASD children also had significantly greater rates of exposure and IgG antibody titers to Varicella Zoster virus than healthy control children [92]. However, another study found no significant differences in titers of IgG and IgM antibodies to the measles, mumps and rubella viruses in autistic children, children with Tourette’s syndrome, and controls [93] and D’Sousa et al. detected no evidence of the measles virus in the peripheral blood mononuclear cells of ASD children [94]. Normal brain development requires adequate amounts of folate and vitamin D throughout childhood and adolescence [95]. The folate status of ASD individuals may be compromised by the presence of folate receptor autoantibodies (FRAAs)[96]. These autoantibodies are more prevalent in individuals with ASD than in the general population [96]. By binding to folate receptors, FRAAs inhibit passage of folate across the blood-brain-barrier [97]. FRAAs do not interfere with absorption and cerebral uptake of a reduced form of folate, folinic acid [96]. Frye et al. gave one group of ASD children high-dose folinic acid capsules daily for 12 weeks and a second group placebo capsules and tested the verbal communication skills and autism related behaviors of children at baseline and week 12. The group given folinic acid showed significant improvements in verbal communication at week 12 and had less behavioral problems and less stereotypic behavior than the placebo group [98]. Autistic children living in China, Brazil, Egypt, and the Faroe Islands have been reported to have significantly lower blood serum concentrations of 1, 25(OH)D3 than age-matched controls [99–102]. A significant negative correlation was noted in one study between the Childhood Autism Rating Scale (CARS) scores 3and serum concentrations of 1, 25-OH D3. CARS scores go up in severe cases of autism and high CARS scores were associated in this study with low levels of D3. After three months supplementation with vitamin D3, 81% of ASD children showed significant improvement in their CARS scores [103]. Autism is considered by some to be an autoimmune disease [104]. The likelihood of having ASD goes up in individuals with a family history of other autoimmune diseases [104]. Celiac disease is an autoimmune disease primarily affecting the gastrointestinal tract, which 49
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goes into remission if wheat proteins, i.e. wheat gluten, are removed from the diet. Gastrointestinal disturbances and problems are more prevalent in people with ASD than in the general population [105]. One of the hallmark pathological findings in celiac disease is a “leaky gut” [106]. de Magistris et al. [106] tested the intestinal permeability of 90 ASD patients, including 23 that were on casein-free, gluten-free CFGF diets, along with their first degree relatives, and healthy controls. They detected significant elevations in the permeability of the small intestine of ASD patients whose diets were unrestricted, compared to ASD patients on CFGF diets and healthy controls. In addition, some ASD patients have been found to have significantly greater levels of IgA and IgE antibodies to wheat gluten and cow’s milk proteins [107]. According to several reports [108–110], antibiotics are more often prescribed to treat infections in ASD children than their peers. Frequent antibiotic use may lead to dramatic changes in the types and numbers of bacteria in the GI tract. Substantial differences have been noted in the gut microflora of ASD subjects and controls including the presence of significantly higher numbers of Bacteroides vulgaris, Desulfovibrio and Clostridia species [111–113]. One unproven hypothesis is that these particular bacteria produce toxic metabolites that after passing the BBB have psychotropic effects on the brain leading to regressive autism [113]. Species of Clostridia also produce potent neurotoxins. Recently, Finegold et al. [114] detected the presence of Clostridium perfingens beta2-toxin in 79% of fecal samples from autistic patients vs 38% of controls. Conclusions ASD is a multifactorial disease that occurs through the interaction of genes and the environment. A different set of environmental factors may be responsible for triggering neonatal and regressive forms of autism. Faster progress can be made in ASD treatment and prevention if all these environmental risk factors are thoroughly investigated and identified. More well-controlled, double-blind studies need to be conducted on potential treatments for ASD including the use(s) of oxytocin to prevent neonatal autism [115], and folinic acid and vitamin D3 supplementation, and cow’s milk, gluten free diets for treatment and possible prevention of regressive forms of ASD. Conflict of interest statement The author has no conflict of interest with regard to the preparation, writing or publication of this article in Medical Hypotheses. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mehy.2017.09.015. References [1] Kanner L. Autistic disturbances of affective contact. Nervous Child 1943:217–50. [2] Tick B, Bolton P, Happe F, Rutter M, Rijsdijk F. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J Child Psychol Psychiatr 2016;57:585–95. [3] Baren-Cohen S, Lombardo M, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer Why are autistic spectrum conditions more prevalent in males? PLOS Biol, published online June 14, 2011 pbio 1001081. [4] Centers for Disease Control and Prevention http://www.cdc.gov/ncbddd/autism/ facts.htlm. [5] Berry-Kravis E. Mechanism based treatments in neurodevelopment disorders: Fragile X syndrome. Pediatr Neurol 2014;50:297–302. [6] Benvenuto A, Siracusano M, Graziola F. et al. Autism spectrum disorder in Tuberous Sclerosis: The preventive value of early detection. Biomed Prevent 2017; 1-(79)-DO1:10.19252-100000004F. [7] Yurov Y, Vorsanova S, Iourov Y, et al. Unexplained autism is frequently associated with low level mosaic aneuploidy. J Med Genet 2007;44:521–5. [8] Barger B, Campbell J, McDonough J. Prevalence and onset of regression with autism spectrum disorders: a meta-analytic review. J Autism Dev Disord 2013;43:817–28.
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Neonatal and regressive forms of autism: Diseases with similar symptoms but a different etiology William E. Barbeau
MARK
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Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA 24061, USA
A R T I C L E I N F O
A B S T R A C T
Keywords: Autism Spectrum Disorder (ASD) Neonatal Regressive autism Environmental trigger Etiology
Autistic Spectrum Disorder (ASD) can be a debilitating, life-long neurocognitive disease. ASD is caused by genetic and epigenetic factors and largely unknown and poorly understood environmental triggers. Signs and symptoms of ASD often appear in the first year of life while the disease strikes other infants who had previously been developing normally at around 2 years of age. Ozonoff and her colleagues recently suggested that there are three different pathways or trajectories for the development of ASD in infants 6–24 months of age. I hypothesize that pathway 1 is caused by in utero insult/injury, pathway 2 by obstetric complications at birth, and pathway 3 by environmental triggers of ASD affecting infants 0–3 years of age. Faster progress can be made in elucidating the underlying causes of neonatal and regressive forms of ASD if the diseases are investigated separately, instead of being part of the same disorder.
Introduction The American physician Leo Kanner first described the behavior patterns of autistic children in a 1943 journal article entitled “Autistic disturbances of affective contact” [1]. Autism or Autism Spectrum Disorder (ASD) as it is now called, is a group of neurodevelopment disorders that result in minor to major deficits in a person’s facility for interacting and communicating with others, their motor skills and cognitive abilities. Genetics play a key role in ASD etiology and pathogenesis with heritability estimates in monozygotic twins reported to be between 64% and 91% [2]. Males are approximately 4 times more likely to have ASD than females [3]. ASD was considered a relatively rare disease until the 1960s when incidence rates started climbing in industrialized countries increasing to a reported high of 1 in 68 live births in the U.S. in 2012 [4]. Some ASDs have well-defined genetic origins such as fragile X syndrome which is believed to be due to silencing of the fragile X mental retardation 1 (FMR1) gene that causes dendrites in the brain to be long, thin and fragile [5] and tuberous sclerosis which has been linked to TSC1 and TSC2 gene mutations [6]. Ninety percent of ASD cases however are idiopathic [7]. One ASD that until recently went under-reported is called regressive autism. Regressive autism accounts for about a 1/3 of all cases of autism [8]. It is called regressive autism because it strikes infants at around 18 months of age, who were developmentally “on track’ but now are losing some of their social skills and cognitive abilities, particularly related to language.
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Address: 1403 Locust Avenue, Blacksburg, VA 24060, USA. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.mehy.2017.09.015 Received 11 July 2017; Accepted 15 September 2017 0306-9877/ © 2017 Elsevier Ltd. All rights reserved.
There is some controversy about when regressive autism actually begins. Some clinicians and researchers believe that it starts in the first year of life [9]. However, there is little doubt that regressive autism is a recognizable clinical entity characterized by a sudden loss in an infant’s ability to understand and formulate words, and communicate with others. Videotape analysis has recently helped document the deterioration of language skills in children with regressive autism. One study found that a group of infants that were later diagnosed with regressive autism had higher than average language skills at 12 months of age that fell to well-below average at 24 months [10]. Some investigators have suggested that there may be different timelines or trajectories for the development of ASD. Trajectories for regressive autism may be different from neonatal autism where symptoms become apparent soon after birth. Recently, Ozonoff and her colleagues proposed that there are three general trajectories for the development of ASD that they designated as TRAJ1/Early Onset; TRAJ2/Regression and TRAJ3/Plateau [11]. These three trajectories are shown in Fig. 1 with an index for coded social communication behaviors per minute plotted on the y axis (higher numbers indicate better communications skills) vs age up to 24 months on the y axis. The trajectories were drawn following detailed analysis of data sets from a research study conducted on 52 autistic children and 23 with typical development over a period of 18 months, when the children were from 6 to 24 months of age. According to Fig. 1, children with early onset ASD started out at a disadvantage in terms of their social communication skills compared to
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Fig. 1. Reproduced with kind permission from ELSEVIER [11].
reported alterations in the FG and amygdala in autism. Van Kooten et al. [16] detected significant reductions in the number and size of neurons in the FG of ASD patients compared to normal controls. Another study found that autistic subjects had fewer GABAA receptors and benzodiazepine binding sites in the FG than normal controls [17]. In addition, autistic subjects were reported to have significantly lower levels of N-acetyl aspartate (NAA) in the right hippocampal-amygdala region of the brain than normal controls, which investigators attributed to immature neurons or hypo-activity of neurons in these brain centers [18]. There is also evidence from fMRI studies that when given face processing tasks autism patients do not activate the left amygdala, in the same way as normal controls [19,20]. Repetitive behavior(s) is another hallmark of ASD. Inflexible and repetitive behaviors in ASD have been associated with a part of the brain called the anterior cingulate cortex (ACC). Thakkar et al. [21] evaluated repetitive behaviors and ACC structure and function in 20 subjects with ASD and 14 healthy controls. ASD subjects had higher restricted and repetitive behavior scores than normal controls. Higher scores were positively associated with losses in the microstructural integrity of white matter underlying parts of the ACC. ASD subjects have a reduced ability to suppress inappropriate behaviors referred to as response inhibition. Agam and others have theorized that there is a connection between response inhibition and repetitive behaviors [22]. Using fMRI imaging, they found decreased activation of the frontal eye field (FEF) and dorsal anterior cingulate cortex (dACC) in ASD patients. Patients with higher repetitive behavior scores required a greater activation of the FEF to successfully inhibit inappropriate behaviors. Autism has also been linked to dysfunction of the cerebellum. The cerebellum may affect social skills, movement and cognition directly through its control of executive functions or indirectly via connections the cerebral cortex makes with the thalamus and basal ganglia. There are many reports of Purkinje cell loss within the cerebellum of ASD patients [23–26]. Purkinje cells express glutamate decarboxylase (GAD) enzyme which converts glutamate to gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in humans [23]. Loss of Purkinje cells in ASD leads to significantly lower levels of GAD enzymes in the cerebellum of ASD patients [23,27] and lower concentrations of
children in the three other cohorts, and stayed at a disadvantage throughout the study. Further, although the social communication skills of TRAJ3/Plateau children were indistinguishable from typical children (TD) at 6 months of age, they failed to make further progress, falling well-below TD children at 24 months. Children in the TRAJ2/Regression group exhibited well-above average skills at 6 months, but their skills eroded quickly thereafter, falling to the level of the early onset group by 24 months of age. The question arises: Do these data accurately represent the development paths of ASD children in the general population? Are there really three different types of ASD that can be differentiated on the basis of an infant’s social communication skills in the first two years of life? Furthermore, if the data are accurate, then what accounts for the different trajectories or timelines? How are symptoms of ASD related to disease pathology? Some symptoms of ASD, like savantism, occur only rarely, while others, the so-called “classical” ASD symptoms are present in the vast majority of diagnosed cases. The classical symptoms or core features of ASD include: a preference for established routines and repetitive behaviors, a strong tendency for avoiding eye contact with other people, motor skills that develop slowly and remain well below-average, underrecognized and poorly described deficits in smell, taste, hearing and touch [12–14]. Researchers are making substantial progress in establishing links between structural and biochemical changes that are found in the brains of autistic individuals and the symptoms of autism. Most ASD patients have an aversion to focusing their eyes on the faces of others. Two regions of the brain called the fusiform gyrus (FG) and the amygdala are believed to be involved in facial perception and recognition. One group of investigators tested “face processing” in ASD patients by showing them 24 photographs of peoples faces. Activation of the FG and amygdala regions of the brain of ASD patients was measured using MRI brain imaging, while the patients were looking at the photographs. A strong, positive correlation was found between FG and amygdala activation and time the ASD patients spent focusing their eyes on the faces in the photographs [15]. A number of studies have 47
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that the brain volume and head circumference of boys with regressive autism were significantly larger than boys with non-regressive forms of autism and a typically developing (TD) control group of children. Differences in brain volume and head circumference were not present in girls with regressive autism, only in boys. The amygdala, a part of the brain involved in regulation of social behaviors [46], is also reported to be enlarged in ASD children [47–49]. Nordahl discovered from a post hoc analysis of amygdala data from a 2011 study that there may be three different amygdala growth rates in ASD; a rapid growth rate, a growth rate similar to TD children, and a third that is actually slower than TD children [45]. Unfortunately, no data was collected in Nordahl’s study on the onset or the symptoms of ASD. Nevertheless, it is tempting to speculate that the 42% of children with rapid amygdala growth rates are those with regressive autism, while another 42% of children with typical growth rates suffered a brain injury at birth that led to neonatal autism, and 16% of children with slower growth rates had neonatal autism due to prematurity, low-birth weight, and/or in utero insult or injury. Evidence from two other studies also indicates that several regions of the brain of a subset of ASD children are reduced in size. Padilla et al. [50] performed MRI brain scans on children born < 27 weeks of gestation, approximately 3 months after their birth and at 6.5 years of age, and observed that the brains of children later diagnosed with ASD had grown more slowly than children born prematurely, but without ASD. Ure et al. [51] studied 172 children born prematurely < 30 weeks gestation or with low birth weights < 1250 g. MR brain images of the children were taken just after birth and at 2, 5 and 7 years of age to measure changes in total and regional brain volumes and the children were assessed for autistic traits beginning at age 2. Associations were reported in the study between reductions in the size of the cerebellum and smaller deep nuclear gray matter volume and increased odds of ASD.
GABA in the brains of autistic subjects than controls [28]. It has been postulated that loss of a critical mass of cerebellar Purkinje cells may upset the delicate balance in the brain of the excitatory neurotransmitter glutamate and its antagonist GABA [24]. Reasons for Purkinje cell loss in ASD are unclear. Abnormalities in cortical minicolumns of the brain are another consistent finding in ASD. Minicolumns are one of the primary structural units of the human brain. They consist of vertical bundles of 80–100 neurons that stretch between cortical layers of the brain. The width of minicolumns of the brain decreases in older individuals along with a decline in cognitive function [29,30]. Casanova et al. [31,32] found minicolumns of some cortical layers of the brain were narrower in ASD patients than controls; and Blatt et al. [33] likewise reported narrower minicolumns in the prefrontal regions of the brain in ASD. Observations from a recent study contradict these findings. In this case, minicolumns were wider in ASD than controls [34]. Other minicolumn associated abnormalities have been detected in ASD. The distance between minicolumns and the size of the peripheral neutrophil space surrounding minicolumns is reduced in ASD [35,36]. The peripheral neutrophil space is rich in GABAergic neurons that serve to inhibit excitatory signals coming from Glutamatergic neurons ASD also appears to adversely affect the ability that different parts of the brain have to communicate with each other. fMRI scans of autistic brains have shown that some parts of the brain may be underconnected in ASD, while others are over-connected. Specifically, corticocortical and interhemispheric connections are lacking in ASD and there is an over-abundance of subcortical connections [37,38]. In one study, investigators gave autistic and healthy children assigned tasks to do while they monitored their functional brain connectivity using fMRI brain imaging. Long range connections between the cerebellum and premotor areas of the brain appeared to be compromised in autistic children [39]. The Wernicke and Broca areas of the brain are critical to language skills. Veerly et al. [40] found evidence for decreases in functional connectivity between the Broca and Wernicke areas of the brain and the cerebellum in ASD subjects.
The etiology of ASD It is time to abandon the idea of the existence of a single environmental trigger for all forms of ASD. One of the hypotheses presented in this paper is that there are in fact many different environmental triggers of ASD. There is evidence that some of these triggers act in utero, and others at, or close to, the time of birth. I hypothesize that neonatal forms of ASD are caused by the action of these two sets of environmental triggers in newborns that are genetically susceptible to autism. Insults or injuries to the developing brain that occur in utero, well before birth, are among those that are most likely to lead to severe forms of ASD. The trajectory in Fig. 1 labeled Early-onset ASD best represents the developmental timeline for individuals with severe forms of ASD. The developmental trajectory in Fig. 1 labeled Early-onset ASD is, in my view, likely to be caused by insults or injuries that occur in utero, well before birth, that have severe, lasting (possibly irreversible) impacts on brain development.
Similarities and differences in the symptoms and pathology of neonatal and regressive forms of ASD Most ASD investigations make no attempt to differentiate between neonatal and regressive forms of autism when it comes to the selection of subjects for a study, in experimental design, or data analysis. There have been a few studies that have tried to discern if there are possible differences in the symptoms of non-regressive and regressive forms of autism. Davidovitch et al. [41] interviewed 39 mothers of children with ASD, 19 with children who had developmentally regressed, and 20 who did not regress. No significant differences were found in the mothers’ assessment of verbal and non-verbal skills and social and play abilities of the two groups of children. Minimal differences were reported in a second study in the family history, child characteristics, developmental concerns and behavioral concerns of a group of 51 autistic children without regression and 31 with regression [42]. There were no significant differences, in a third study, in the verbal and non-verbal IQ scores of ASD children without regression vs those who had regressed [43]. On the other hand, according to the results of a battery of diagnostic tests conducted by Matson et al. [44], ASD children who had been diagnosed with autistic regression at a mean age of 28 months exhibited more severe symptoms of autism and greater impairments in social skills and behavior than children with early onset ASD. Investigations into the pathology of ASD usually make no distinctions between non-regressive and regressive forms of autism. There is however some data in the scientific literature on ASD that points to the possibility of fundamental differences in the pathology of neonatal and regressive autism. Macrocephaly is more common in ASD children than their peers [45]. Nordahl et al. [45] examined the relationship between total brain volume and the onset of ASD in 2 to 4 year olds. They found
Etiology of neonatal forms of autism The prevalence of ASD rises dramatically in premature infants. Four large population studies conducted in Canada, the United States, Sweden and Norway found the relative risk of ASD was 2.5, 2.7, 3.0 and 9.7 times greater in infants born at ≤28 gestational weeks of age than at full-term [52–55]. The smaller, far less well-developed brain of extremely premature infants is susceptible to hemorrhage during delivery. Brain injuries have been observed to occur more often in premature infants, both as a result of, and in the absence, of brain hemorrhaging [56,57]. Cranial ultrasound scans have revealed that as the brain of the extremely premature infant develops the ventricles become abnormality enlarged and white matter is more diffuse than in normal infants. A strong association has been reported between enlarged ventricles and 48
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It is my hypothesis that ASD children affected primarily by perinatal risk factors for autism are likely to follow the TRAJ3/ Plateau developmental timeline in Fig. 1. These children are able to nearly catch-up to their peers in their first 6 months, but ASDdriven deficits prevent them from ever attaining their full potential.
losses in the structural integrity of white matter in the brain and later diagnosis with ASD [58]. The frequency of ventricular enlargement is also higher, and ASD risk is greater, in low birth weight infants than in full-term infants [58]. A few drugs, when taken during pregnancy, are known to increase the risk of ASD in newborns. Sodium valproate is prescribed for epilepsy. The offspring of women that took valproate while they were pregnant were found to have a three to sixfold greater risk of ASD than children not exposed to the drug [59,60]. Valproate has been shown in rat studies to have adverse effects on brain development. Watanabe et al. [61] found significant reductions in GAD+ interneurons and Purkinje brain cells of newborn rats whose mothers were given valproate in their drinking water [61]. Changes to the structural integrity of the prefrontal cortex and hippocampus of the brain similar to those present in ASD in humans have also been observed in the valproate-rat model of autism [62]. Weaker associations have been reported between ASD and thalidomide, formerly prescribed for morning sickness [63,64] and serotonin reuptake inhibitors (SRIs), a class of anti-depressants [65]. Mumps, measles, and cytomegaloviruses have also been implicated as possible environmental triggers of ASDs [66–68]. At least two possible mechanisms have been proposed for how congenital viral infections may lead to ASD in newborns: via direct attack of viruses on critical parts of the brain associated with ASD; and by a secondary autoimmune driven attack on fetal brain tissue [69]. Yasmashita studied the behavioral development and did cranial ultrasound scans on seven children with congenital CMV infections. Two out of seven displayed classical symptoms of ASD and dilation of the lateral ventricles of the brain [68]. IgG antibodies from ASD children were found in one study to react to the measles virus and also to two brain proteins, myelin basic protein and neuron-axon filament protein [70]. It is well-known that optimum supplementation of vitamin B6 (folate) during pregnancy prevents neural tube defects in newborns [71]. Recently, folate nutritional status has also been linked to ASD. Folate is necessary for DNA synthesis, repair and methylation and is critical for normal embryonic brain development [72]. There are two recent reports of an association between the risk of ASD in newborns and folic acid intakes during the first month of pregnancy [73,74]. ASD risk was significantly reduced by mean daily folic acid intakes of > 600 μg [73]. Furthermore, the link between ASD risk and folic acid intakes appears to be strongly influenced by inheritance of methylenetetrahydrofolate reductase (MTHRF) genes, the MTHFR C677T gene increases ASD risk and the MTHFR A1298C reduces it. MTHRF genes are involved in regulation of DNA methylation and in gene expression [75]. Epigenetic factors related to gene expression are believed to play an important role in overall ASD risk [76]. Vitamin D deficiency may be another contributing factor to the development of ASD. Data from several studies indicate that offspring of mothers with low blood levels of vitamin D are at an increased risk for the development of ASD [77–80]. This association may extend to the time of the year a child is born. In one study conducted in Sweden, where there is little sunlight during the winter, ASD rates were two times higher in children born in the Spring than during the Summer [78]. Susceptibility to ASD may be driven up even further by inheritance of certain vitamin D receptor (VDR) genes [81]. A number of perinatal risk factors are also thought to play a role in the development of some cases of ASD. These include risk factors that occur well before birth such as pre-eclampsia and maternal diabetes [82,83] and obstetric complications at birth like fetal hypoxia [84]. According to results of a meta-analysis of 40 studies, the perinatal risk factors most strongly associated with autism include abnormal fetal presentation, umbilical-cord complications, fetal distress, birth injury/ trauma, and maternal hemorrhage [85]. It should be pointed out that these perinatal risk factors are likely to be a “trigger” of autism only in cases of a strong genetic predisposition to ASD; and when they act in concert with other pre and postnatal risk factors.
Etiology of regressive autism Andrew Wakefield and his colleagues reported in a 1998 journal article in Lancet that they had found evidence linking autism to the MMR vaccine [86]. The idea that mercury-containing thiomerosal in the MMR vaccine could be a trigger of regressive autism was attractive in part because the vaccine is administered to children at roughly the same age that the peak onset of regressive autism occurs. However, the major findings of the Wakefield article were later judged to be fraudulent and the paper was retracted [87]. Subsequent epidemiological and laboratory investigations have further discredited Wakefield’s original hypothesis [88,89]. The true causes of regressive autism remain a mystery. It is conceivable that neonatal and regressive forms of autism share some of the same environmental risk factors. Viral infections are known to sometimes damage the fetal brain in utero and have been implicated as a possible trigger of ASD in newborn infants [90]. There is some experimental evidence both for, and against, the involvement of viruses in regressive autism. Lintas et al. [91] performed postmortem examinations of brain tissue samples from 15 autistic patients and 13 controls. Polyomavirus was detected in 67% of samples from autistic patients vs 23% of the controls. Significantly elevated levels of IgG antibodies to the measles virus were reported in ASD children compared to normal controls and their siblings [67] and ASD children also had significantly greater rates of exposure and IgG antibody titers to Varicella Zoster virus than healthy control children [92]. However, another study found no significant differences in titers of IgG and IgM antibodies to the measles, mumps and rubella viruses in autistic children, children with Tourette’s syndrome, and controls [93] and D’Sousa et al. detected no evidence of the measles virus in the peripheral blood mononuclear cells of ASD children [94]. Normal brain development requires adequate amounts of folate and vitamin D throughout childhood and adolescence [95]. The folate status of ASD individuals may be compromised by the presence of folate receptor autoantibodies (FRAAs)[96]. These autoantibodies are more prevalent in individuals with ASD than in the general population [96]. By binding to folate receptors, FRAAs inhibit passage of folate across the blood-brain-barrier [97]. FRAAs do not interfere with absorption and cerebral uptake of a reduced form of folate, folinic acid [96]. Frye et al. gave one group of ASD children high-dose folinic acid capsules daily for 12 weeks and a second group placebo capsules and tested the verbal communication skills and autism related behaviors of children at baseline and week 12. The group given folinic acid showed significant improvements in verbal communication at week 12 and had less behavioral problems and less stereotypic behavior than the placebo group [98]. Autistic children living in China, Brazil, Egypt, and the Faroe Islands have been reported to have significantly lower blood serum concentrations of 1, 25(OH)D3 than age-matched controls [99–102]. A significant negative correlation was noted in one study between the Childhood Autism Rating Scale (CARS) scores 3and serum concentrations of 1, 25-OH D3. CARS scores go up in severe cases of autism and high CARS scores were associated in this study with low levels of D3. After three months supplementation with vitamin D3, 81% of ASD children showed significant improvement in their CARS scores [103]. Autism is considered by some to be an autoimmune disease [104]. The likelihood of having ASD goes up in individuals with a family history of other autoimmune diseases [104]. Celiac disease is an autoimmune disease primarily affecting the gastrointestinal tract, which 49
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goes into remission if wheat proteins, i.e. wheat gluten, are removed from the diet. Gastrointestinal disturbances and problems are more prevalent in people with ASD than in the general population [105]. One of the hallmark pathological findings in celiac disease is a “leaky gut” [106]. de Magistris et al. [106] tested the intestinal permeability of 90 ASD patients, including 23 that were on casein-free, gluten-free CFGF diets, along with their first degree relatives, and healthy controls. They detected significant elevations in the permeability of the small intestine of ASD patients whose diets were unrestricted, compared to ASD patients on CFGF diets and healthy controls. In addition, some ASD patients have been found to have significantly greater levels of IgA and IgE antibodies to wheat gluten and cow’s milk proteins [107]. According to several reports [108–110], antibiotics are more often prescribed to treat infections in ASD children than their peers. Frequent antibiotic use may lead to dramatic changes in the types and numbers of bacteria in the GI tract. Substantial differences have been noted in the gut microflora of ASD subjects and controls including the presence of significantly higher numbers of Bacteroides vulgaris, Desulfovibrio and Clostridia species [111–113]. One unproven hypothesis is that these particular bacteria produce toxic metabolites that after passing the BBB have psychotropic effects on the brain leading to regressive autism [113]. Species of Clostridia also produce potent neurotoxins. Recently, Finegold et al. [114] detected the presence of Clostridium perfingens beta2-toxin in 79% of fecal samples from autistic patients vs 38% of controls. Conclusions ASD is a multifactorial disease that occurs through the interaction of genes and the environment. A different set of environmental factors may be responsible for triggering neonatal and regressive forms of autism. Faster progress can be made in ASD treatment and prevention if all these environmental risk factors are thoroughly investigated and identified. More well-controlled, double-blind studies need to be conducted on potential treatments for ASD including the use(s) of oxytocin to prevent neonatal autism [115], and folinic acid and vitamin D3 supplementation, and cow’s milk, gluten free diets for treatment and possible prevention of regressive forms of ASD. Conflict of interest statement The author has no conflict of interest with regard to the preparation, writing or publication of this article in Medical Hypotheses. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mehy.2017.09.015. References [1] Kanner L. Autistic disturbances of affective contact. Nervous Child 1943:217–50. [2] Tick B, Bolton P, Happe F, Rutter M, Rijsdijk F. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J Child Psychol Psychiatr 2016;57:585–95. [3] Baren-Cohen S, Lombardo M, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer Why are autistic spectrum conditions more prevalent in males? PLOS Biol, published online June 14, 2011 pbio 1001081. [4] Centers for Disease Control and Prevention http://www.cdc.gov/ncbddd/autism/ facts.htlm. [5] Berry-Kravis E. Mechanism based treatments in neurodevelopment disorders: Fragile X syndrome. Pediatr Neurol 2014;50:297–302. [6] Benvenuto A, Siracusano M, Graziola F. et al. Autism spectrum disorder in Tuberous Sclerosis: The preventive value of early detection. Biomed Prevent 2017; 1-(79)-DO1:10.19252-100000004F. [7] Yurov Y, Vorsanova S, Iourov Y, et al. Unexplained autism is frequently associated with low level mosaic aneuploidy. J Med Genet 2007;44:521–5. [8] Barger B, Campbell J, McDonough J. Prevalence and onset of regression with autism spectrum disorders: a meta-analytic review. J Autism Dev Disord 2013;43:817–28.
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