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ARTICLE IN PRESS
The Association Between Autism and Errors in Early
Embryogenesis: What Is the Causal Mechanism?
Annemie Ploeger, Maartje E.J. Raijmakers, Han L.J. van der Maas, and Frietson Galis
The association between embryonic errors and the development of autism has been recognized in the literature, but the mechanismunderlying this association remains unknown. We propose that pleiotropic effects during a very early and specific stage of embryonicdevelopment— early organogenesis— can explain this association. In humans early organogenesis is an embryonic stage, spanning Day 20to Day 40 after fertilization, which is characterized by intense interactivity among body parts of the embryo. This implies that a singlemutation or environmental disturbance affecting development at this stage can have several phenotypic effects (i.e., pleiotropic effects).
Disturbances during early organogenesis can lead to many different anomalies, including limb deformities, craniofacial malformations,brain pathology, and anomalies in other organs. We reviewed the literature and found ample evidence for the association between autismand different kinds of physical anomalies, which agrees with the hypothesis that pleiotropic effects are involved in the development ofautism. The proposed mechanism integrates findings from a variety of studies on autism, including neurobiological studies and studies onphysical anomalies and prenatal influences on neurodevelopmental outcomes. The implication is that the origin of autism can be muchearlier in embryologic development than has been frequently reported.
Key Words: Autism, critical periods, early organogenesis, medical
stage of early organogenesis is so vulnerable, we first discuss this comorbidities, physical anomalies, prenatal complications stage more extensively.
ized by qualitative impairment of social interactions and Early organogenesis is a remarkable embryologic stage, be- communication, restricted patterns of behaviors or inter- cause all vertebrate embryos, including those of humans, look ests, and an onset before 3 years of age Autism spectrum similar during this stage (i.e., the stage displays striking evolu- disorders include autism, Asperger's syndrome, childhood disin- tionary conservation). Before this stage, embryos look remark- tegrative disorder, and pervasive developmental disorder—not ably different across species, and after this stage, development otherwise specified. The prevalence of autism is approximately diverges again. It has been hypothesized that high interactivity 20/10,000, whereas the prevalence of autism spectrum disorders among body parts during early organogenesis explains the is approximately 60 –70/10,000 It is well-established that evolutionary conservation of the stage Specifically, because autism has a strong polygenic basis Thus, as a polygenic of this high interactivity, a change in one part of the body affects disorder, autism is attributable to the effects of an unknown other body parts. Such side-effects are called "pleiotropic ef- number of mutations and their possible interaction However, fects." For example, changes in number of digits, which start to knowledge about the genetic background of autism does not develop during early organogenesis, are often accompanied by reveal the causal mechanism that underlies the relation between other anomalies and the same holds for an extra vertebra a particular genetic composition and the development of autism.
This implies that a mutation, which affects early organo- To find this causal mechanism it is necessary to take a develop- genesis, is usually selected against: any local beneficial effect is mental perspective on how genetic predispositions might lead to likely to be offset by pervasive pleiotropic effects, which are likely to be negative. It is assumed that because of the strong Studies have identified a particular stage during embryologic selection against new variants during the stage of early organo- development that is very susceptible to both genetic and envi- genesis, all vertebrates look very similar during this stage.
ronmental disturbances This stage is called early organo- For many genes a phenomenon called "gene-environment genesis and occurs in humans from approximately Day 20 to Day equivalence" is known In such cases perturbations of the 40 after fertilization. In the present article, we provide support for developmental process can be caused either by a mutation or by the hypothesis that the vulnerability that characterizes this stage an environmental stimulus. Because of the interactivity in the is often implicated in the causation of autism. It has been stage of early organogenesis, environmental stimuli can result in established that autism correlates with conditions due to errors in similar correlations between various conditions as with pleiotro- early embryogenesis but the underlying mechanism that pically induced correlations. A review of the literature showed causes autism remains unknown. We argue that insights from that in several species the incidence of anomalies and mortality studies on the vulnerability of early organogenesis reveal a as a result of teratological treatments (e.g., the administration of potential underlying mechanism. This mechanism can explain methanol) is greatest if the treatment is administered during early several research findings concerning autism, which so far have organogenesis In humans, it is estimated that 90% of the been treated separately in the literature. To understand why the pregnancies of embryos that experienced disturbances duringearly organogenesis result in a miscarriage Importantly, it isthe timing of the disturbance and not necessarily its nature that From the Department of Psychology (AP, MEJR, HLJvdM), University of Am- determines the incidence of mortality and anomalies sterdam, Amsterdam; and the Department of Biology (FG), Leiden Uni- Why is the stage of early organogenesis much more vulnera- versity, Leiden, The Netherlands.
Address correspondence to Annemie Ploeger, Dr., Department of Psychol- ble than other stages of embryologic development? At earlier ogy, University of Amsterdam, Roetersstraat 15, 1018 WB Amsterdam, stages there are fewer interactions among body parts, because The Netherlands; E-mail: organ primordia have yet to develop. At later stages, body parts Received Mar 26, 2009; revised Sep 23, 2009; accepted Oct 1, 2009.
show a relatively high degree of modularity. This implies that the BIOL PSYCHIATRY 2009;xx:xxx 2009 Society of Biological Psychiatry ARTICLE IN PRESS
2 BIOL PSYCHIATRY 2009;xx:xxx A. Ploeger et al. Table 1. Body Parts that First Appear During the Stage of Early
bances, but research on environmental influences gives a clear Organogenesis from Day 20 – 40 After Fertilization indication of the importance of the timing of the disturbance.
First Appearance of Body Part in Days After Fertilization Thalidomide was prescribed in the treatment of anxiety, insomnia, tension, gastritis, and pregnancy sickness In the Brain stem (including the 1960s, many pregnant women took thalidomide. Sadly, it turned out that thalidomide use during pregnancy produced a variety of congenital malformations in the newborns. These included limb Limbic structures and craniofacial anomalies and kidney, cardiovascular, genital, Cerebral hemispheres and lung malformations. Because most women knew the date they took the drug, timetables could be reconstructed that showed that thalidomide was teratogenic between 20 days and 36 days after fertilization Four percent of Swedish individ- uals whose mothers took thalidomide in this period developed Gastrointestinal Tract autism This is significantly higher than the .2% in the general population The studies of thalidomide defects con- firm that early organogenesis, in humans from Day 20 – 40 after fertilization, is a vulnerable stage of embryologic development, External Genitalia leading to many different anomalies. The large variety in effectsis likely caused by the high interactivity among different body The embryonic period is subdivided into 23 stages, termed Carnegie parts that characterize the stage. One of the possible negative stages, based on morphological criteria. Neurulation starts at Stage 8, which effects of this interactivity is a disturbance of normal brain is generally listed as 18 days after fertilization, but has recently been cor-rected to 23 days after fertilization (20). All postfertilization days in this table development, eventually leading to the development of autism.
are adapted to the new classification (20).
effects of mutations or other disturbances will be limited to the A rubella infection suffered during early pregnancy often module itself and not to other parts of the organism leads to serious malformations in the newborn. The 1964 rubella Many body parts undergo their first development during early epidemic in the United States resulted in 20,000 –30,000 neonates organogenesis, as shown in The pleiotropic born with congenital malformations These included heart effects during early organogenesis makes the early development defects, deafness, eye defects (e.g., cataracts, retinopathy), and of these body parts susceptible to disturbances. As the brain neurological impairment. Another study showed that 90% of starts to develop during early organogenesis, it is likely that a infants infected with the rubella virus during the first 10 weeks of disturbance in brain development, which could be either genetic pregnancy developed a defect, mostly heart defects and deaf- or environmental in origin, will also affect other body parts, and ness. In contrast, the percentage is much lower in children vice versa. For example, a mutation that results in the develop- infected after week 10 of pregnancy: 33% (week 11–12), 11% ment of an extra digit might also induce a neurodevelopmental (week 13–14), 24% (week 15–16), and, finally, 0% (any time after disorder. We propose that the presence of such pleiotropic week 16) Thus, prenatal exposure to the rubella virus effects during early organogenesis provides a plausible explan- during early organogenesis results in more different defects than atory mechanism for the development of autism due to errors later in pregnancy In a study on 243 children with prenatal during early embryogenesis. Support for this hypothesis comes exposure to rubella, it was found that 10 of them (4.1%) met the from studies that show the co-occurrence of autism and physical criteria of autism In a follow-up with the same sample, 4 abnormalities that originate in early organogenesis. We provide more individuals met the criteria of autism Thus, approxi- support from five categories of abnormalities: prenatal compli- mately 6% of the rubella-infected children developed autism.
cations, neuropathology, major structural anomalies, minor These two studies did not provide data on the exact timing of the physical anomalies, and other medical comorbidities. So far, this rubella exposure, but the association with physical anomalies diverse array of abnormalities in autism has not been explained suggests that negative pleiotropic effects during early orga- in the literature from a unitary point of view. For our present nogenesis played a role in the development of autism.
purposes, it is of minor importance whether the studies consid-ered specific autism or the broader category of autism spectrumdisorders, because we propose that early disturbance of devel- opment can play a role in all these disorders.
Anticonvulsants are prescribed, inter alia, to prevent seizures in epileptic persons. Women with epilepsy who take anticonvul- Autism and Prenatal Complications
sants during the first trimester of pregnancy have an increasedrisk of delivering a child with major congenital malformations The association between early prenatal complications and compared with women with epilepsy who do not take anticon- autism has been reviewed in the literature Here we discuss vulsants (3.4% vs. 1%) Another study showed that, among research findings that agree with our hypothesis that the associ- 57 children with fetal anticonvulsant syndromes (characterized ation is the result of pleiotropic effects during early organogen- by facial dysmorphic features and cardiac malformations), 4 were esis. The fact that we discuss environmental influences on the diagnosed with autism and another 2 with Asperger's syndrome.
development of autism first does not imply that genetic influ- Eighty-one percent showed autistic-type behaviors, such as poor ences are less important. Genetic disturbances (e.g., mutations) social interaction and communication skills The co-occur- are presumably more important than environmental distur- rence of autism and congenital malformations is consistent with ARTICLE IN PRESS
A. Ploeger et al. BIOL PSYCHIATRY 2009;xx:xxx 3 the hypothesis that pleiotropic effects during early organogenesis system were more frequent in children diagnosed with an autism resulted in the development of autism.
spectrum disorder.
A recent review showed that autism or autistic features are often observed in children with genetic syndromes, such as Misoprostol is prescribed in the treatment of gastric ulcers, but it tuberous sclerosis complex fragile X syndrome Down is in some countries also used to induce abortions Children syndrome and neurofibromatosis type 1 Tuberous born after use of misoprostol in the first trimester of pregnancy have sclerosis complex is a disorder characterized by anomalies of the several congenital malformations. In a review of 69 case reports of integumentary system, brain, retina, heart, kidney, and/or lungs congenital defects associated with misoprostol use during preg- Autism spectrum disorders are present in 25%–50% of nancy, it was found that 83% of the children had lower limb defects, people with this syndrome, and the prevalence of the syndrome 55% had central nervous system defects involved in the cranial in people diagnosed with autism spectrum disorder is 1%– 4% nerves, and 46% had upper limb anomalies Most pregnant women took misoprostol between the third and sixth week after Fragile X is a syndrome that is characterized by mental fertilization. Another remarkable consequence of misoprostol use retardation and several physical features, including macroceph- during early pregnancy is the presence of Möbius sequence in aly, prominent forehead, loose joints, soft skin, prominent ears, children Möbius sequence is a congenital syndrome charac- high arched palate, and, in male subjects, large testicles In terized by facial paralyses (i.e., the inability to smile or frown), being a group with 33 male and 31 female subjects with full mutation the result of absent or underdeveloped sixth and seventh cranial fragile X, 67% of the male subjects and 23% of the female subjects nerves. Other characteristics are malformations of orofacial struc- met the criteria for autism spectrum disorder In a group of tures, limb anomalies, and defects of the chestwall A study 316 people with autism spectrum disorder, 2.2% had fragile X found that 50% of 23 children with Möbius sequence had been prenatally exposed to misoprostol. Five of those 23 children met the The phenotypic features of Down syndrome are mental retarda- criteria for autism, and 2 other children showed autistic-like behav- tion, brachycephaly, hand and foot anomalies, duodenal atresia, ior. Of those 7 children, 4 had been prenatally exposed to miso- epicanthal folds, flat nasal bridge, and hypotonia In addition, prostol suggesting that disturbances during early organogen- approximately 50% of the children born with Down syndrome have esis influenced the development of autism.
congenital heart disease, hearing loss, and ophthalmologic disor-ders. Autism spectrum disorders are present in 16% of children with Neuropathologies Associated with Autism
Neurofibromatosis type 1 is characterized by six or more A recent review on the neuropathology of autism sum- café-au-lait spots on the skin and two or more neurofibromas, a marized the evidence that people diagnosed with autism often type of nerve sheath tumor, usually in the gastrointestinal tract have subtle abnormalities in the development of several brain Four percent of individuals with neurofibromatosis type 1 structures, including the cerebellum, limbic structures, brain- were diagnosed with autism As can be seen in all stem, and cerebral cortex. These abnormalities can be the result body structures involved in these syndromes are established of genetic disturbances or environmental influences or an inter- during early organogenesis. The co-occurrence of several anom- action between the two.
alies, including the development of autism, suggests that pleio- The prenatal brain starts to develop with neurulation, which tropic effects played a role in the development of the syndromes.
marks the start of early organogenesis. Neurulation starts whenthe neural plate is formed. At approximately Day 23 after Minor Physical Anomalies
fertilization, the neural plate starts to fold, resulting in the neuralgroove At approximately Day 26 after fertilization, the Minor physical anomalies are morphological abnormalities three major divisions (prosencephalon, mesencephalon, and that can be detected quite easily but have no serious medical or rhombencephalon) of the brain are visible on the folds of the cosmetic consequences for the individual. These anomalies are open neural groove. The neural crest, a temporary embryologic caused by genetic disturbances or are environmentally induced.
structure that gives rise to a variety of body structures, starts to Although minor physical anomalies are not life-threatening develop on the same day.
themselves, it is well-established that they are associated with At approximately Day 29 after fertilization, the neural folds major anomalies A meta-analysis of seven studies on start to fuse, resulting in the neural tube. The brain stem first the association between autism and minor physical anomalies appears, with distinguishable cranial nerve motor nuclei At revealed that this association is significant approximately Day 32 after fertilization, the cerebellum first Anomalies reported most frequently in people with autism appears, and one day later the future cerebral hemispheres and were low-seated ears hypertelorism (i.e., a large interpupil- the future amygdaloid region become visible Thus, the lary distance) syndactylia of toes (i.e., partially fused toes) brain structures that are commonly disturbed in people diag- hypotelorism (i.e., a short interpupillary distance) nosed with autism have their origin in early organogenesis.
smaller feet and an increased total hand length Mostminor physical anomalies observed in people diagnosed with Major Structural Anomalies
autism are established during early organogenesis (see Congenital anomalies were found in 11% of 45 children Other Medical Comorbidities
diagnosed with an autism spectrum disorder, compared with 6%of 128 children without this diagnosis The congenital In a case-control study, 12% of people diagnosed with autism anomalies included anomalies of the central nervous system, were given one or more diagnoses of medical disorders, includ- eye, ear, face, neck, heart, respiratory system, gastrointestinal ing congenital malformations of the cardiovascular system, the system, genito-urinary system, musculoskeletal system, and in- urinary system, the skeletal system, and the eyes Specific tegumentary system. Especially anomalies of the gastrointestinal medical problems that are found significantly more often in people ARTICLE IN PRESS
4 BIOL PSYCHIATRY 2009;xx:xxx A. Ploeger et al. diagnosed with autism compared with control subjects are epilepsy basic structures, such as all the organs and limbs, start to develop visual impairment, including blindness abnormal metab- during early organogenesis. Anomalies in structures that develop olism vascular changes and gastrointestinal problems later might be related to or the result of anomalies in some of the which are possibly related to general failure of the immune basic structures that arose during early organogenesis. However, system All these comorbidities involve body structures that are there are two ways to deal with the falsifiability problem. The established during early organogenesis.
first way is to perform animal studies in which our hypothesis can In addition, the comorbidity of autism with other psychiatric be tested experimentally. There are already several animal studies disorders is high: more than 70% of children with autism also indicating that the stage of early organogenesis is extremely vulner- meet the criteria of one or more other psychiatric disorders able for disturbances and that first trimester rather than second This shows that the psychological/behavioral phenotype of trimester disturbances result in negative neurodevelopmental out- people diagnosed with autism, like their physical phenotype, comes In the future, animal studies can be performed in which displays considerable variation. This suggests that pleiotropic pregnant animals are subjected to disturbances at various periods effects during early organogenesis result in a diverse array of during pregnancy (including early organogenesis). Neurodevelop- physical anomalies, including subtle brain anomalies that lead to mental and other physical outcomes then can be related to the a diverse pattern of psychological/behavioral problems.
specific timing of the disturbance. Studies by Fatemi et al. already showed that brain anomalies of newborn mice after prenatalexposure to the influenza virus during early organogenesis are similar to those in people with autism. Also in animal studies, Our present overview of the literature has shown that autism detailed experiments can be performed that show the causal is often associated with: 1) errors during early embryogenesis, 2) relatedness between different pleiotropic effects (e.g., the interac- neuropathologies, 3) major structural anomalies, 4) minor phys- tivity during early patterning of the anterior-posterior axis and brain ical anomalies, and 5) several other medical conditions.
So far most studies on the association between autism and The best support for our hypothesis in humans would come physical anomalies have focused on only one of these topics, from a study that examines a large sample of people diagnosed although a few researchers have recognized the combination of with autism with respect to a variety of physical deviations. So autism, errors during embryogenesis, neuropathologies, and far, research has shown that people diagnosed with autism have physical malformations However, so far no hypothesis significantly more physical anomalies compared with control has been advanced to explain and integrate all these different subjects, but it has not been shown that most people with autism research findings. We hypothesized that autism and the associ- have physical anomalies. However, no study has been published ated physical anomalies are most likely the result of disturbances in which all physical anomalies that can be caused by pleiotropic during early organogenesis, the embryonic stage from Day 20 to effects during early organogenesis were systematically exam- Day 40 after fertilization. During this stage, high interactivity ined. These anomalies would include major and minor physical among body parts renders the organism highly susceptible to anomalies, brain deviations, limb abnormalities, and organ dys- pervasive effects of developmental disturbances. Consequently, function. It is our expectation that a majority of people diagnosed a single mutation or environmental disturbance can have many with autism will show a diverse pattern of anomalies, due to different, often deleterious, pleiotropic effects. We proposed that pleiotropic effects that occur during early organogenesis.
the abundance of pleiotropic effects during early organogenesis A systematic study can also examine whether the different is the mechanism that explains why disturbances during embry- kinds of expected anomalies are randomly spread over the ogenesis can have severe effects such as the development of sample or whether there are specific kinds or subgroups of anomalies that co-occur with autism. In a forthcoming report, we Is it possible to develop autism after the stage of early show that there is evidence that schizophrenia also originates organogenesis? It has been suggested that there is an association from disturbances during early organogenesis, because people between autism and vaccinations, but studies could not confirm diagnosed with schizophrenia also show more physical anoma- this In the literature, cases are described of late-onset autism lies established during this stage, compared with control subjects after a herpes infection which suggest it is possible to There seems to be an overlap in physical anomalies found develop autism after an environmental insult later in life. How- in people with autism and schizophrenia, but there are also ever, late-onset autism does not necessarily imply a later cause of remarkable differences. For example, the major structural anom- autism (i.e., originating in a stage of development later than early alies that frequently co-occur with schizophrenia are Velo- organogenesis). An early developmental disturbance might result cardio-facial syndrome and Prader–Willi syndrome in a cascade of effects, which might only be detected relatively which are different from the ones found in people with autism.
later in life It is possible that there are other vulnerable This implies that the physical anomalies that co-occur with either prenatal periods after the stage of early organogenesis but autism or schizophrenia are not entirely random. Thus, the it cannot be excluded that the later vulnerability was associated genetic or environmental disturbance has pleiotropic effects with disturbances during early organogenesis.
during early organogenesis, resulting in a variety of anomalies, Does this imply that our hypothesis is hardly falsifiable? An but there seems to be a pattern in these anomalies. For example, ideal situation to test our hypothesis would be to create a list of exposure to thalidomide during early organogenesis resulted in a body parts that start to develop during early organogenesis and variety of anomalies, including autism, but not schizophrenia.
a separate list of body parts that start to develop later and to study With the research available to us, we can only speculate why whether autism is associated with anomalies in structures that this would be the case. One possibility might be the influence of arose during early organogenesis and whether it is not associated genomic imprinting, which results in the expression of genes with structures that arose later. Unfortunately, a strict division from only one of the two parental chromosomes The between anomalies in structures that arise during early organo- expression of an imprinted gene can lead to two different genesis and structures that arise later is not possible, because the developmental pathways, depending on whether the genes are ARTICLE IN PRESS
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