HM Medical Clinic

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
A. Ploeger et al. BIOL PSYCHIATRY 2009;xx:xxx 5 maternally or paternally expressed. Imprinted genes are involved Donkelaar HJ, Lammens M, Hori A, editors. Clinical Neuroembryology: in neurodevelopment and might play a role in the develop- Development and Developmental Disorders of the Human Central Nervous ment of autism and schizophrenia In addition, imprinted System. Berlin: Springer, 269 –308.
genes are highly pleiotropic and are expressed during early 19. Müller F, O'Rahilly R (1988): The development of the human brain from a closed neural tube at stage 13. Anat Embryol 177:203–224.
embryogenesis so it is likely that they play an important role 20. O'Rahilly R, Müller F (2006): The Embryonic Human Brain: An Atlas of during early organogenesis. Genomic imprinting might also Developmental Stages, 3rd ed. Hoboken, New Jersey: Wiley.
explain gender differences in autism, with autism being an 21. Müller F, O'Rahilly R (2006): The amygdaloid complex and the medial extreme paternally biased imprinted brain, which is more com- and lateral ventricular eminences in staged human embryos. J Anat mon in boys than in girls Perturbations during early organogenesis are, because of the abundance of pleiotropic 22. Müller F, O'Rahilly R (1988): The first appearance of the future cerebral effects during this stage, the start of disturbed developmental hemispheres in the human embryo at stage 14. Anat Embryol 177:495–511.
pathways that have cascading effects with far-reaching conse- 23. O'Rahilly R, Gardner E (1975): The timing and sequence of events in the development of the limbs in the human embryo. Anat Embryol 148:1–23.
24. O'Rahilly R (1971): The timing and sequence of events in human cardio- We would like to thank Conor Dolan, Catharina Hartman, genesis. Acta Anat 79:70 –75.
Chantal Kemner, Claus Rueffler, and Andrew Shaner for their 25. O'Rahilly R, Muecke EC (1972): The timing and sequence of events in the comments on earlier drafts of the manuscript. Dr. Ploeger reports development of the human urinary system during the embryonic pe- having received research funding from the Evolution and Be- riod proper. Z Anat Entwicklgesch 138:99 –109.
havior program of the Netherlands Organisation for Scientific 26. O'Rahilly R, Boyden EA (1973): The timing and sequence of events in the Research (NWO). Drs. Raijmakers, Van der Maas, and Galis development of the human respiratory system during the embryonicperiod proper. Z Anat Entwicklgesch 141:237–250.
reported no biomedical financial interests or potential conflicts 27. O'Rahilly R (1978): The timing and sequence of events in the develop- of interest. ment of the human digestive system and associated structures duringthe embryonic period proper. Anat Embryol 153:123–136.
1. Volkmar FR, Pauls D (2003): Autism. Lancet 362:1133–1141.
28. Holbrook KA, Odland GF (1975): The fine structure of developing human 2. Fombonne E (2009): Epidemiology of pervasive developmental disor- epidermis: Light, scanning, and transmission electron microscopy of the ders. Pediatr Review 65:591–598.
periderm. J Invest Dermatol 65:16 –38.
3. Freitag CM (2007): The genetics of autistic disorders and its clinical 29. O'Rahilly R (1983): The timing and sequence of events in the develop- relevance: A review of the literature. Mol Psychiatry 12:2–22.
ment of the human eye and ear during the embryonic period proper.
4. Gupta AR, State MW (2007): Recent advances in the genetics of autism.
Anat Embryol 168:87–99.
Biol Psychiatry 61:429 – 437.
30. ten Donkelaar HJ, Vermeij-Keers C (2006): The neural crest and cranio- 5. Sander K (1983): The evolution of patterning mechanisms: Gleaning facial malformations. In: ten Donkelaar HJ, Lammens M, Hori A, editors.
from insect embryogenesis and spermatogenesis. In: Goodwin BC, Clinical Neuroembryology: Development and Developmental Disorders of Holder N, Wylie CC, editors. Development and Evolution. Cambridge, the Human Central Nervous System. Berlin: Springer, 191–228.
United Kingdom: Cambridge University Press, 137–159.
31. O'Rahilly R (1983): The timing and sequence of events in the develop- 6. Raff RA (1994): Developmental mechanisms in the evolution of animal ment of the human reproductive system during the embryonic period form: Origins and evolvability of body plans. In: Bengston S, editor. Early proper. Anat Embryol 166:247–261.
Life on Earth. New York: Columbia University Press, 489 –500.
32. Miller MT, Strömland K (1999): Teratogen update: Thalidomide: A re- 7. Galis F, Metz JAJ (2001): Testing the vulnerability of the phylotypic view, with a focus on ocular findings and new potential uses. Teratology stage: On modularity and evolutionary conservation. J Exp Zool 291: 60:306 –321.
33. Lenz W, Knapp K (1962): Die thalidomide-embryopathie. Dtsch Med 8. Arndt TL, Stodgell CJ, Rodier PM (2005): The teratology of autism. Int J Dev Neurosci 23:189 –199.
34. Strömland K, Nordin V, Miller M, Akerström B, Gillberg C (1994): Autism 9. Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C in thalidomide embryopathy: A population study. Dev Med Child Neurol (2005): Autism associated with conditions characterized by develop- mental errors in early embryogenesis: A mini review. Int J Dev Neurosci 35. Desmond MM, Wilson GS, Melnick JL, Singer DB, Zion TE, Rudolph AJ, et al. (1970): Congenital rubella encephalitis: Course and early sequelae.
10. Biesecker LG (2002): Polydactyly: How many disorders and how many J Pediatr 71:311–331.
genes? Am J Med Genet 112:279 –283.
36. Miller E, Cradock-Watson JE, Pollock TM (1982): Consequences of con- 11. Galis F, van Dooren TJM, Feuth JD, Metz JAJ, Witkam A, Ruinard S, et al. firmed maternal rubella at successive stages of pregnancy. Lancet 320: (2006): Extreme selection in humans against homeotic transformations of cervical vertebrae. Evolution 60:2643–2654.
37. Ueda K, Nishida Y, Oshima K, Shepard TH (1979): Congenital rubella 12. West-Eberhard MJ (2003): Developmental Plasticity and Evolution. New syndrome: Correlation of gestational age at time of maternal rubella York: Oxford University Press.
13. Opitz JM, FitzGerald JM, Reynolds, JF, Lewin SO, Daniel A, Ekblom LS, with type of defect. J Pediatr 94:763–765.
et al. (1987): The Montana fetal genetic Pathology Program and a review 38. Chess S (1971): Autism in children with congenital rubella. J Autism Child of prenatal death in humans. Am J Med Genet Suppl 3:93–112.
Schiz 1:33– 47.
14. DeSesso JM, Harris SB (1996): Principles underlying developmental tox- 39. Chess S (1977): Follow-up report on autism in congenital rubella.
icity. In: Fan AK, Chang LW, editors. Toxicology and Risk Assessment: J Autism Child Schiz 7:69 – 81.
Principles, Methods, and Applications. New York: Marcel Dekker, 37–56.
40. Jick SS, Terris BZ (1997): Anticonvulsants and congenital malformations.
15. Wilson JG (1965): Methods for administering agents and detecting mal- formations in experimental animals. In: Wilson JG, Warkany J, editors.
41. Moore SJ, Tumpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, et al. Teratology: Principles and Techniques. Chicago: University of Chicago (2000): A clinical study of 57 children with fetal anticonvulsant syn- Press, 262–277.
dromes. J Med Genet 37:489 – 497.
16. Wagner GP (1996): Homologues, natural kinds and the evolution of 42. Norman JE, Thong KJ, Baird DT (1991): Uterine contractibility and induc- modularity. Am Zool 36:36 – 43.
tion of abortion in early pregnancy by misoprostol and mifepristone.
17. Larsen WJ (2001): Human Embryology, 3rd ed. Philadelphia: Churchill 43. Population Council (2003): Misoprostol and teratogenicity: Reviewing 18. ten Donkelaar HJ, Lammens M, Cruysberg JRM, Cremers CWJR (2006): the evidence: Report of a Meeting at the Population Council New York, Development and developmental disorders of the forebrain. In: ten New York, May 22, 2002. New York: The Population Council Inc.
6 BIOL PSYCHIATRY 2009;xx:xxx A. Ploeger et al. 44. Bandim JM, Ventura LO, Miller MT, Almeida HC, Costa AE (2003): Autism 66. Mukaddes NM, Kilincaslan A, Kucukyazici G, Sevketoglu T, Tuncer S and Möbius sequence: An exploratory study in northeastern Brazil. Arq (2007): Autism in visually impaired individuals. Psychiatry Clin Neurosci Neuro Psiquiatr 61:181–185.
61:39 – 44.
45. Sudarshan A, Goldie WD (1985): The spectrum of congenital facial diple- 67. Manzi B, Loizzo AL, Giana G, Curatolo P (2008): Autism and metabolic gia (Moebius syndrome). Pediatr Neurol 1:180 –184.
diseases. J Child Neurol 23:307–314.
46. Schmitz C, Rezaie P (2008): The neuropathology of autism: Where do we 68. Yao Y, Walsh WJ, McGinnis WR, Pratico D (2006): Altered vascular phe- stand? Neuropathol Appl Neurobiol 34:4 –11.
notype in autism. Arch Neurol 63:1161–1164.
47. Wier ML, Yoshida CK, Odouli R, Grether JK, Croen LA (2006): Congenital 69. Nikolov RN, Bearss KE, Lettinga J, Erickson C, Rodowski M, Aman MG, anomalies associated with autism spectrum disorders. Dev Med Child et al. (2009): Gastrointestinal symptoms in a sample of children with Neurol 48:500 –507.
pervasive developmental disorders. J Autism Dev Disord 39:405– 413.
48. Zafeiriou DI, Ververi A, Vargiami E (2007): Childhood autism and associ- 70. Cohly HHP, Panja A (2005): Immunological findings in autism. Int Rev ated comorbidities. Brain Dev 29:257–272.
49. Wiznitzer M (2004): Autism and tuberous sclerosis. J Child Neurol 19: 71. Leyfer OT, Folstein SE, Bacalman S, Davis NO, Dinh E, Morgan J, et al. (2006): Comorbid psychiatric disorders in children with autism: Inter- 50. Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ view development and rates of disorders. J Autism Dev Disord 36:849 – (2007): Autism spectrum phenotype in males and females with fragile X full maturation and premutation. J Autism Dev Disord 37:738 –747.
72. Rodier PM (2002): Converging evidence for brain stem injury in autism.
51. Lowenthal R, Paula CS, Schwartzman JS, Brunoni D, Mercadante MT Dev Psychopathol 14:537–557.
(2007): Prevalence of pervasive developmental disorder in Down's syn- 73. Doja A, Roberts W (2006): Immunizations and autism: A review of the drome. J Autism Dev Disord 37:1394 –1395.
literature. Can J Neural Sci 33:341–346.
52. Williams PG, Hersh JH (1998): Brief report: The association of neurofibro- 74. Ghaziuddin M, Al-Khouri I, Ghaziuddin N (2002): Autistic symptoms following herpes encephalitis. Eur Child Adolesc Psychiatry 11:142–146.
matosis type 1 and autism. J Autism Dev Disord 28:567–571.
75. Rice D, Barone S Jr (2000): Critical periods of vulnerability for the devel- 53. Crino PB, Nathanson KL, Henske EP (2006): The tuberous sclerosis com- oping nervous system: Evidence from humans and animal models. En- plex. N Engl J Med 355:1345–1356.
viron Health Perspect 108:511–533.
54. Visootsak J, Warren ST, Anido A, Graham JM Jr (2005): Fragile X syn- 76. Meyer U, Yee BK, Feldon J (2007): The neurodevelopmental impact of drome: An update and review for the primary pediatrician. Clin Pediatr prenatal infections at different times of pregnancy: The earlier the worse? Neuroscientist 13:241–256.
55. Reddy KS (2005): Cytogenetic abnormalities and fragile-X syndrome in 77. Kinney DK, Miller AM, Crowley DJ, Huang E, Gerber E (2008): Autism autism spectrum disorder. BMC Med Genet 6:3–18.
prevalence following prenatal exposure to hurricanes and tropical 56. Roizen NJ, Patterson D (2003): Down's syndrome. Lancet 361:1281– storms in Louisiana. J Autism Dev Disord 38:481– 488.
78. Fatemi SH, Pearce DA, Brooks AI, Sidwell, RW (2005): Prenatal viral infec- 57. Reynolds RM, Browning GGP, Nawroz I, Campbell IW (2003): Von Reck- tion in mouse causes differential expression of genes in brains of mouse linghausen's neurofibromatosis: Neurofibromatosis type 1. Lancet 361: progeny: A potential animal model for schizophrenia and autism. Syn- 58. Marden PM, Smith DW, McDonald MJ (1964): Congenital anomalies in 79. Lane A, Kinsella A, Murphy P, Byrne M, Keenan J, Colgan K, et al. (1997): the newborn infant, including minor variations. J Pediatr 64:357–371.
The anthropometric assessment of dysmorphic features in schizophre- 59. Leppig KA, Werler MM, Cann CI, Cook CA, Holmes LB (1987): Predictive nia as an index of its developmental origins. Psychol Med 27:1155–1164.
value of minor anomalies. I. Association with major malformations.
80. Arinami T (2006): Analyses of the associations between the genes of J Pediatr 110:531–537.
22q11 deletion syndrome and schizophrenia. J Hum Genet 51:1037– 60. Mehes K (1985): Minor malformations in the neonate: Utility in screen- ing infants at risk of hidden major defects. Prog Clin Biol Res 163:45– 49.
81. Vogels A, De Hert M, Descheemaeker MJ, Govers V, Devriendt K, Legius 61. Ozgen HM, Hop JW, Beemer FA, van Engeland H (2008): Minor physical E, et al. (2004): Psychotic disorders in Prader–Willi syndrome. Am J Med anomalies in autism: A meta-analysis [published online ahead of print Genet 127A:238 –243.
July 15]. Mol Psychiatry.
82. Reik W, Walter J (2001): Genomic imprinting: Parental influence on the 62. Walker HA (1977): Incidence of minor physical anomalies in autism.
genome. Nat Rev Genet 2:21–32.
J Autism Child Schiz 7:165–176.
83. Davies W, Isles AR, Wilkinson LS (2005): Imprinted gene expression in 63. Rodier PM, Bryson SE, Welch JP (1997): Minor malformations and phys- the brain. Neurosci Behav Physiol 29:421– 430.
ical measurements in autism: Data from Nova Scotia. Teratology 55: 84. Crespi B, Badcock C (2008): Psychosis and autism as diametrical disor- ders of the social brain. Behav Brain Sci 31:241–261.
64. Lauritsen MB, Mors O, Mortensen PB, Ewald H (2002): Medical disorders 85. Tycko B, Morison M (2002): Physiological functions of imprinted genes.
among inpatients with autism in Denmark according to ICD-8: A nation- J Cell Physiol 192:245–258.
wide register-based study. J Autism Dev Disord 32:115–119.
86. Badcock C, Crespi, B (2006): Imbalanced genomic imprinting in brain 65. Canitano R (2007): Epilepsy in autism spectrum disorders. Eur Child development: An evolutionary basis for the aetiology of autism. J Evol Adolesc Psychiatry 16:61– 66.


Expert evidence report - survival of the "fryest": a review of recent state supreme court decisions analyzing frye's general acceptance standard and a 50 state survey of the standards for admissibility of expert testimony.

Expert Evidence Report - Survival of the "Fryest": A Review of Recent State.d a 50 State Survey of the Standards for Admissibility of Expert Testimony. Volume 2 Number 5 Monday, March 18, 2002ISSN 1536-190X Survival of the "Fryest": A Review of Recent State Supreme Court Decisions Analyzing Frye's General Acceptance Standard and a 50 State Survey of the Standards for Admissibility of Expert Testimony.

UNIVERSITY OF PORT HARCOURT LIVING WITH DIABETES IN NIGERIA The Care, Cure & Prevention An Inaugural Lecture PROFESSOR SUNDAY CHINENYE MBBS (Ibadan), FWACP (West African College of Physicians), FACE (American College of Endocrinology), FNSEM (Nigerian Society of Endocrinology)