The Biology of Autism: An introduction

1. The Biology of Autism: An introduction Associate Professor David W Austin, PhD Director: Swinburne Autism Bio-Research Initiative (SABRI) Faculty of Life and Social Sciences Swinburne University of Technology Australia daustin@swin.edu.au

2. 1 out of 6 children are diagnosed with a developmental disorder and/or behavioural disorder 1 in 166 children are diagnosed with an autism spectrum disorder

3. Children with a cluster of symptoms that was to become known as ‘Autism’ were first noticed almost simultaneously on 2 continents (US and Europe) around 1940. Although initially rare (only 11 cases reported to 1940), prevalence exponentially increased over the ensuing decades, reaching a peak of 1 in every 120 children today. The emergence of a ‘new’ disorder

4. The genesis of the autism epidemic • Autism was first described in 1943 (Kanner), among children born in the early 1930s. • By the mid 1980s, 1 in 2,500 was diagnosed with autism. • By the mid 1990s, 1 in 250 children was diagnosed with autism • The most recent studies in Australia, the US and UK show the prevalence of autism to be 1 in 120 children

5. Autism Prevalence, 1993 - 2003

6. But aren’t we just getting better at diagnosing it? No. The argument that the rise in autism rates are attributable to improved identification have been dismissed (Blaxhill et al., 2003; Croen & Graether, 2003)

7. But isn’t autism genetic? “There is an autism epidemic. Epidemics happen because of environmental triggers.” ~Martha Herbert, MD, PhD Pediatric Neurologist, Harvard Medical School

8. So how is the medical system helping these children? Australian doctors are authorised to prescribe over 6,900 different medications. How many are approved and indicated for use in autism? None

9. World Health Organisation: Management of Mental Disorders • 2 volumes, 632 pages covering management of all DSM-IV listed disorders. • Typical subheadings include; Description, Diagnosis, Epidemiology, Course, Prognosis, Management/Treatment. • Example • Schizophrenia: All subheadings, 39 pages • PDD (incl autism): no subheadings, 1/3 page (p. 475) • “These conditions are difficult to treat and require ongoing intensive work to achieve even modest gains.”

10. So how do we get from this… To this…

11. Choices in the face of debate and uncertainty • Include plausible and informed hypotheses centrally in the research agenda • Look not only for environmental cause but also for the full range of mechanisms and consequences for the child.

12. Daring to change • Knowing the biological irregularities common to autism and having plausible causal hypotheses guides research options. • Instead of existing “no treatment” models of care, we open up a world of opportunity for research and treatment to improve the autistic child’s condition and prognosis.

13. Inflam. Bowel Disease Opioids Persistent Measles Reflux Esophagitis Gastritis Intestinal permeability Food Allergies Heavy Metal Burden Brain Autoimmunity GI Dysbiosis Seizures/Sensory Issues Perfusion Defects Purine Disorders Elevated Ammonia Sulfation Defect Serotonin Defect Dopamine Defect Omega 3 deficit Nutritional Deficits Melatonin Deficit Thrombophilia So what are the biological markers of autism?

14. “decreased glutathione levels and increased oxidative stress may play a role in the pathology” The brains of children with autism are experiencing severe oxidative stress and inflammation ~ Kern & Jones (2006). Journal of Toxicology and Environmental Health.

15. “The association between environmentally released mercury and special education rates were fully mediated by increased autism rates.” Higher levels of environmental mercury are associated with higher rates of autism ~ Palmer et al (2006). Health & Place.

16. Mercury levels in children with autism are higher than in neurotypical (normal) children “a significant relation does exist between the blood levels of mercury and diagnosis of an autism spectrum disorder.” ~ DeSoto & Hitlan (2007). Journal of Child Neurology.

17. Gastrointestinal Dysfunction • bad digestion • pathologic alterations in bowel flora • increased gut wall permeability • lymphoid nodular hyperplasia in ileum, in some cases

18. GI abnormalities

19. Methylation deficits

21. Immunological Irregularities • Decreased resistance to infections • Increased tendency to autoimmune problems • Shift away from effective cellular function (TH1) to antibody (TH2) response • Food sensitivities/allergies Jyonouchi, H., et al. (2005). Neuropsychobiology, 51:77-85

22. Central NervousSystem • Altered sensitivity • Abnormal processing of sensory and expressive information • Abnormal neurotransmitter functions

23. Brain inflammation ASD Control Neurons in autistic child: – larger than control – normal in appearance Kemper & Bauman, 1992 Bauman and Kemper, 2005

24. About 20% of young autistic heads are “macrocephalic” (> 97th %ile) Most are above average in volume. This is an atypical brain size distribution. It has no precedent in the literature. Herbert, The Neuroscientist, October 2005 References Dementieva, Y.A. (2005) Deutsch, C. K. (2003) Courchesne, E. (2003) Sparks, Friedman (2002) Gillberg, C. (2002) Alyward, E. H. (2002) Courchesne, E. (2001) Miles, J. H. (2001) Fidler, D. J. (2000) Fombonne, E. (1999) Ghaziuddin, M. (1999) Bailey, A. (1999) Lainhart, J. E. (1997) Rapin, I. (1996) Davidovitch, M. (1996) Woodhouse, W. (1996) Piven, J. (1996) Piven, J. (1995) Bailey, A. (1993) Bauman & Kemper (1985) Extensive documentation of large brains in autism

26. Oxidative Stress Chauhan, A.; Chauhan, V.; Brown, W. T., and Cohen, I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci. 2004 Oct 8; 75(21):2539-49 Sogut, S.; Zoroglu, S. S.; Ozyurt, H.; Yilmaz, H. R.; Ozugurlu, F.; Sivasli, E.; Yetkin, O.; Yanik, M.; Tutkun, H.; Savas, H. A.; Tarakcioglu, M., and Akyol, O. Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clin Chim Acta. 2003 May; 331(1-2):111-7. Yorbik, O.; Sayal, A.; Akay, C.; Akbiyik, D. I., and Sohmen, T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids. 2002 Nov; 67(5):341-3. Zoroglu, S. S.; Armutcu, F.; Ozen, S.; Gurel, A.; Sivasli, E.; Yetkin, O., and Meram, I. Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur Arch Psychiatry Clin Neurosci. 2004 Jun; 254(3):143-7. James, S. J.; Cutler, P.; Melnyk, S.; Jernigan, S.; Janak, L.; Gaylor, D. W., and Neubrander, J. A. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec; 80(6)1611-7.

27. Other patterns of abnormalities • Biochemical peculiarities • nutritional deficits • increased sensitivity to toxins • problems creating DNA building blocks • abnormal levels of sulfur • abnormal amino acids • impaired detoxification

28. Autism as systemic dysfunction GI dysfunction Methylation deficits Immune dysregulation CNS dysfunction Inflammation Oxidative stress All of these areas represent “in points” for our research into cause and potentially effective treatments.

29. SABRI: Who are we? Members are from the disciplines of : • Clinical Psychology • The Brain Sciences Institute • Biomedical Science • We have the right people and the most modern and extensive biomedical laboratory facilities • We have institutional-level support for the initiative • We have the necessary relationships with external institutions to facilitate collaborative research • And we are also parents, aunts, uncles, cousins and friends of Autistic children, professionally and personally invested in this area. • We are determined to make a difference. Thank you.