Advertisement

The Association Between Autism and Errors in Early Embryogenesis: What Is the Causal Mechanism?

Published:November 23, 2009DOI:https://doi.org/10.1016/j.biopsych.2009.10.010
      The association between embryonic errors and the development of autism has been recognized in the literature, but the mechanism underlying this association remains unknown. We propose that pleiotropic effects during a very early and specific stage of embryonic development—early organogenesis—can explain this association. In humans early organogenesis is an embryonic stage, spanning Day 20 to Day 40 after fertilization, which is characterized by intense interactivity among body parts of the embryo. This implies that a single mutation 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 autism and different kinds of physical anomalies, which agrees with the hypothesis that pleiotropic effects are involved in the development of autism. The proposed mechanism integrates findings from a variety of studies on autism, including neurobiological studies and studies on physical anomalies and prenatal influences on neurodevelopmental outcomes. The implication is that the origin of autism can be much earlier in embryologic development than has been frequently reported.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Volkmar F.R.
        • Pauls D.
        Autism.
        Lancet. 2003; 362: 1133-1141
        • Fombonne E.
        Epidemiology of pervasive developmental disorders.
        Pediatr Review. 2009; 65: 591-598
        • Freitag C.M.
        The genetics of autistic disorders and its clinical relevance: A review of the literature.
        Mol Psychiatry. 2007; 12: 2-22
        • Gupta A.R.
        • State M.W.
        Recent advances in the genetics of autism.
        Biol Psychiatry. 2007; 61: 429-437
        • Sander K.
        The evolution of patterning mechanisms: Gleaning from insect embryogenesis and spermatogenesis.
        in: Goodwin B.C. Holder N. Wylie C.C. Development and Evolution. Cambridge University Press, Cambridge, United Kingdom1983: 137-159
        • Raff R.A.
        Developmental mechanisms in the evolution of animal form: Origins and evolvability of body plans.
        in: Bengston S. Early Life on Earth. Columbia University Press, New York1994: 489-500
        • Galis F.
        • Metz J.A.J.
        Testing the vulnerability of the phylotypic stage: On modularity and evolutionary conservation.
        J Exp Zool. 2001; 291: 195-204
        • Arndt T.L.
        • Stodgell C.J.
        • Rodier P.M.
        The teratology of autism.
        Int J Dev Neurosci. 2005; 23: 189-199
        • Miller M.T.
        • Strömland K.
        • Ventura L.
        • Johansson M.
        • Bandim J.M.
        • Gillberg C.
        Autism associated with conditions characterized by developmental errors in early embryogenesis: A mini review.
        Int J Dev Neurosci. 2005; 23: 201-219
        • Biesecker L.G.
        Polydactyly: How many disorders and how many genes?.
        Am J Med Genet. 2002; 112: 279-283
        • Galis F.
        • van Dooren T.J.M.
        • Feuth J.D.
        • Metz J.A.J.
        • Witkam A.
        • Ruinard S.
        • et al.
        Extreme selection in humans against homeotic transformations of cervical vertebrae.
        Evolution. 2006; 60: 2643-2654
        • West-Eberhard M.J.
        Developmental Plasticity and Evolution.
        Oxford University Press, New York2003
        • Opitz J.M.
        • FitzGerald J.M.
        • Reynolds J.F.
        • Lewin S.O.
        • Daniel A.
        • Ekblom L.S.
        • et al.
        The Montana fetal genetic Pathology Program and a review of prenatal death in humans.
        Am J Med Genet Suppl. 1987; 3: 93-112
        • DeSesso J.M.
        • Harris S.B.
        Principles underlying developmental toxicity.
        in: Fan A.K. Chang L.W. Toxicology and Risk Assessment: Principles, Methods, and Applications. Marcel Dekker, New York1996: 37-56
        • Wilson J.G.
        Methods for administering agents and detecting malformations in experimental animals.
        in: Wilson J.G. Warkany J. Teratology: Principles and Techniques. University of Chicago Press, Chicago1965: 262-277
        • Wagner G.P.
        Homologues, natural kinds and the evolution of modularity.
        Am Zool. 1996; 36: 36-43
        • Larsen W.J.
        Human Embryology.
        3rd ed. Churchill Livingstone, Philadelphia2001
        • ten Donkelaar H.J.
        • Lammens M.
        • Cruysberg J.R.M.
        • Cremers C.W.J.R.
        Development and developmental disorders of the forebrain.
        in: ten Donkelaar H.J. Lammens M. Hori A. Clinical Neuroembryology: Development and Developmental Disorders of the Human Central Nervous System. Springer, Berlin2006: 269-308
        • Müller F.
        • O'Rahilly R.
        The development of the human brain from a closed neural tube at stage 13.
        Anat Embryol. 1988; 177: 203-224
        • O'Rahilly R.
        • Müller F.
        The Embryonic Human Brain: An Atlas of Developmental Stages.
        3rd ed. Wiley, Hoboken, New Jersey2006
        • Müller F.
        • O'Rahilly R.
        The amygdaloid complex and the medial and lateral ventricular eminences in staged human embryos.
        J Anat. 2006; 208: 547-564
        • Müller F.
        • O'Rahilly R.
        The first appearance of the future cerebral hemispheres in the human embryo at stage 14.
        Anat Embryol. 1988; 177: 495-511
        • O'Rahilly R.
        • Gardner E.
        The timing and sequence of events in the development of the limbs in the human embryo.
        Anat Embryol. 1975; 148: 1-23
        • O'Rahilly R.
        The timing and sequence of events in human cardiogenesis.
        Acta Anat. 1971; 79: 70-75
        • O'Rahilly R.
        • Muecke E.C.
        The timing and sequence of events in the development of the human urinary system during the embryonic period proper.
        Z Anat Entwicklgesch. 1972; 138: 99-109
        • O'Rahilly R.
        • Boyden E.A.
        The timing and sequence of events in the development of the human respiratory system during the embryonic period proper.
        Z Anat Entwicklgesch. 1973; 141: 237-250
        • O'Rahilly R.
        The timing and sequence of events in the development of the human digestive system and associated structures during the embryonic period proper.
        Anat Embryol. 1978; 153: 123-136
        • Holbrook K.A.
        • Odland G.F.
        The fine structure of developing human epidermis: Light, scanning, and transmission electron microscopy of the periderm.
        J Invest Dermatol. 1975; 65: 16-38
        • O'Rahilly R.
        The timing and sequence of events in the development of the human eye and ear during the embryonic period proper.
        Anat Embryol. 1983; 168: 87-99
        • ten Donkelaar H.J.
        • Vermeij-Keers C.
        The neural crest and craniofacial malformations.
        in: ten Donkelaar H.J. Lammens M. Hori A. Clinical Neuroembryology: Development and Developmental Disorders of the Human Central Nervous System. Springer, Berlin2006: 191-228
        • O'Rahilly R.
        The timing and sequence of events in the development of the human reproductive system during the embryonic period proper.
        Anat Embryol. 1983; 166: 247-261
        • Miller M.T.
        • Strömland K.
        Teratogen update: Thalidomide: A review, with a focus on ocular findings and new potential uses.
        Teratology. 1999; 60: 306-321
        • Lenz W.
        • Knapp K.
        Die thalidomide-embryopathie.
        Dtsch Med Wochenschr. 1962; 87: 1232-1242
        • Strömland K.
        • Nordin V.
        • Miller M.
        • Akerström B.
        • Gillberg C.
        Autism in thalidomide embryopathy: A population study.
        Dev Med Child Neurol. 1994; 36: 351-356
        • Desmond M.M.
        • Wilson G.S.
        • Melnick J.L.
        • Singer D.B.
        • Zion T.E.
        • Rudolph A.J.
        • et al.
        Congenital rubella encephalitis: Course and early sequelae.
        J Pediatr. 1970; 71: 311-331
        • Miller E.
        • Cradock-Watson J.E.
        • Pollock T.M.
        Consequences of confirmed maternal rubella at successive stages of pregnancy.
        Lancet. 1982; 320: 781-784
        • Ueda K.
        • Nishida Y.
        • Oshima K.
        • Shepard T.H.
        Congenital rubella syndrome: Correlation of gestational age at time of maternal rubella with type of defect.
        J Pediatr. 1979; 94: 763-765
        • Chess S.
        Autism in children with congenital rubella.
        J Autism Child Schiz. 1971; 1: 33-47
        • Chess S.
        Follow-up report on autism in congenital rubella.
        J Autism Child Schiz. 1977; 7: 69-81
        • Jick S.S.
        • Terris B.Z.
        Anticonvulsants and congenital malformations.
        Pharmacotherapy. 1997; 17: 561-564
        • Moore S.J.
        • Tumpenny P.
        • Quinn A.
        • Glover S.
        • Lloyd D.J.
        • Montgomery T.
        • et al.
        A clinical study of 57 children with fetal anticonvulsant syndromes.
        J Med Genet. 2000; 37: 489-497
        • Norman J.E.
        • Thong K.J.
        • Baird D.T.
        Uterine contractibility and induction of abortion in early pregnancy by misoprostol and mifepristone.
        Lancet. 1991; 338: 1233-1236
        • Population Council
        Misoprostol and teratogenicity: Reviewing the evidence: Report of a Meeting at the Population Council New York, New York, May 22, 2002.
        The Population Council Inc, New York2003
        • Bandim J.M.
        • Ventura L.O.
        • Miller M.T.
        • Almeida H.C.
        • Costa A.E.
        Autism and Möbius sequence: An exploratory study in northeastern Brazil.
        Arq Neuro Psiquiatr. 2003; 61: 181-185
        • Sudarshan A.
        • Goldie W.D.
        The spectrum of congenital facial diplegia (Moebius syndrome).
        Pediatr Neurol. 1985; 1: 180-184
        • Schmitz C.
        • Rezaie P.
        The neuropathology of autism: Where do we stand?.
        Neuropathol Appl Neurobiol. 2008; 34: 4-11
        • Wier M.L.
        • Yoshida C.K.
        • Odouli R.
        • Grether J.K.
        • Croen L.A.
        Congenital anomalies associated with autism spectrum disorders.
        Dev Med Child Neurol. 2006; 48: 500-507
        • Zafeiriou D.I.
        • Ververi A.
        • Vargiami E.
        Childhood autism and associated comorbidities.
        Brain Dev. 2007; 29: 257-272
        • Wiznitzer M.
        Autism and tuberous sclerosis.
        J Child Neurol. 2004; 19: 675-679
        • Clifford S.
        • Dissanayake C.
        • Bui Q.M.
        • Huggins R.
        • Taylor A.K.
        • Loesch D.Z.
        Autism spectrum phenotype in males and females with fragile X full maturation and premutation.
        J Autism Dev Disord. 2007; 37: 738-747
        • Lowenthal R.
        • Paula C.S.
        • Schwartzman J.S.
        • Brunoni D.
        • Mercadante M.T.
        Prevalence of pervasive developmental disorder in Down's syndrome.
        J Autism Dev Disord. 2007; 37: 1394-1395
        • Williams P.G.
        • Hersh J.H.
        Brief report: The association of neurofibromatosis type 1 and autism.
        J Autism Dev Disord. 1998; 28: 567-571
        • Crino P.B.
        • Nathanson K.L.
        • Henske E.P.
        The tuberous sclerosis complex.
        N Engl J Med. 2006; 355: 1345-1356
        • Visootsak J.
        • Warren S.T.
        • Anido A.
        • Graham Jr, J.M.
        Fragile X syndrome: An update and review for the primary pediatrician.
        Clin Pediatr. 2005; 44: 371-381
        • Reddy K.S.
        Cytogenetic abnormalities and fragile-X syndrome in autism spectrum disorder.
        BMC Med Genet. 2005; 6: 3-18
        • Roizen N.J.
        • Patterson D.
        Down's syndrome.
        Lancet. 2003; 361: 1281-1289
        • Reynolds R.M.
        • Browning G.G.P.
        • Nawroz I.
        • Campbell I.W.
        Von Recklinghausen's neurofibromatosis: Neurofibromatosis type 1.
        Lancet. 2003; 361: 1552-1554
        • Marden P.M.
        • Smith D.W.
        • McDonald M.J.
        Congenital anomalies in the newborn infant, including minor variations.
        J Pediatr. 1964; 64: 357-371
        • Leppig K.A.
        • Werler M.M.
        • Cann C.I.
        • Cook C.A.
        • Holmes L.B.
        Predictive value of minor anomalies.
        J Pediatr. 1987; 110: 531-537
        • Mehes K.
        Minor malformations in the neonate: Utility in screening infants at risk of hidden major defects.
        Prog Clin Biol Res. 1985; 163: 45-49
        • Ozgen H.M.
        • Hop J.W.
        • Beemer F.A.
        • van Engeland H.
        Minor physical anomalies in autism: A meta-analysis.
        Mol Psychiatry. 2008; ([published online ahead of print July 15])
        • Walker H.A.
        Incidence of minor physical anomalies in autism.
        J Autism Child Schiz. 1977; 7: 165-176
        • Rodier P.M.
        • Bryson S.E.
        • Welch J.P.
        Minor malformations and physical measurements in autism: Data from Nova Scotia.
        Teratology. 1997; 55: 319-325
        • Lauritsen M.B.
        • Mors O.
        • Mortensen P.B.
        • Ewald H.
        Medical disorders among inpatients with autism in Denmark according to ICD-8: A nationwide register-based study.
        J Autism Dev Disord. 2002; 32: 115-119
        • Canitano R.
        Epilepsy in autism spectrum disorders.
        Eur Child Adolesc Psychiatry. 2007; 16: 61-66
        • Mukaddes N.M.
        • Kilincaslan A.
        • Kucukyazici G.
        • Sevketoglu T.
        • Tuncer S.
        Autism in visually impaired individuals.
        Psychiatry Clin Neurosci. 2007; 61: 39-44
        • Manzi B.
        • Loizzo A.L.
        • Giana G.
        • Curatolo P.
        Autism and metabolic diseases.
        J Child Neurol. 2008; 23: 307-314
        • Yao Y.
        • Walsh W.J.
        • McGinnis W.R.
        • Pratico D.
        Altered vascular phenotype in autism.
        Arch Neurol. 2006; 63: 1161-1164
        • Nikolov R.N.
        • Bearss K.E.
        • Lettinga J.
        • Erickson C.
        • Rodowski M.
        • Aman M.G.
        • et al.
        Gastrointestinal symptoms in a sample of children with pervasive developmental disorders.
        J Autism Dev Disord. 2009; 39: 405-413
        • Cohly H.H.P.
        • Panja A.
        Immunological findings in autism.
        Int Rev Neurobiol. 2005; 71: 317-341
        • Leyfer O.T.
        • Folstein S.E.
        • Bacalman S.
        • Davis N.O.
        • Dinh E.
        • Morgan J.
        • et al.
        Comorbid psychiatric disorders in children with autism: Interview development and rates of disorders.
        J Autism Dev Disord. 2006; 36: 849-861
        • Rodier P.M.
        Converging evidence for brain stem injury in autism.
        Dev Psychopathol. 2002; 14: 537-557
        • Doja A.
        • Roberts W.
        Immunizations and autism: A review of the literature.
        Can J Neural Sci. 2006; 33: 341-346
        • Ghaziuddin M.
        • Al-Khouri I.
        • Ghaziuddin N.
        Autistic symptoms following herpes encephalitis.
        Eur Child Adolesc Psychiatry. 2002; 11: 142-146
        • Rice D.
        • Barone Jr, S.
        Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models.
        Environ Health Perspect. 2000; 108: 511-533
        • Meyer U.
        • Yee B.K.
        • Feldon J.
        The neurodevelopmental impact of prenatal infections at different times of pregnancy: The earlier the worse?.
        Neuroscientist. 2007; 13: 241-256
        • Kinney D.K.
        • Miller A.M.
        • Crowley D.J.
        • Huang E.
        • Gerber E.
        Autism prevalence following prenatal exposure to hurricanes and tropical storms in Louisiana.
        J Autism Dev Disord. 2008; 38: 481-488
        • Fatemi S.H.
        • Pearce D.A.
        • Brooks A.I.SidwellR.W.
        Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: A potential animal model for schizophrenia and autism.
        Synapse. 2005; 57: 91-99
        • Lane A.
        • Kinsella A.
        • Murphy P.
        • Byrne M.
        • Keenan J.
        • Colgan K.
        • et al.
        The anthropometric assessment of dysmorphic features in schizophrenia as an index of its developmental origins.
        Psychol Med. 1997; 27: 1155-1164
        • Arinami T.
        Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia.
        J Hum Genet. 2006; 51: 1037-1045
        • Vogels A.
        • De Hert M.
        • Descheemaeker M.J.
        • Govers V.
        • Devriendt K.
        • Legius E.
        • et al.
        Psychotic disorders in Prader–Willi syndrome.
        Am J Med Genet. 2004; 127A: 238-243
        • Reik W.
        • Walter J.
        Genomic imprinting: Parental influence on the genome.
        Nat Rev Genet. 2001; 2: 21-32
        • Davies W.
        • Isles A.R.
        • Wilkinson L.S.
        Imprinted gene expression in the brain.
        Neurosci Behav Physiol. 2005; 29: 421-430
        • Crespi B.
        • Badcock C.
        Psychosis and autism as diametrical disorders of the social brain.
        Behav Brain Sci. 2008; 31: 241-261
        • Tycko B.
        • Morison M.
        Physiological functions of imprinted genes.
        J Cell Physiol. 2002; 192: 245-258
        • Badcock C.CrespiB.
        Imbalanced genomic imprinting in brain development: An evolutionary basis for the aetiology of autism.
        J Evol Biol. 2006; 19: 1007-1032