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 TechnologyAustralia

daustin@swin.edu.au

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

• 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

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

The genesis of the autism epidemic

Autism Prevalence, 1993 - 2003

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)

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

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

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.

Example1. Schizophrenia: All subheadings, 39 pages2. 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.”

So how do we get from this…

To this…

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.

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.

So what are the biological markers of autism?

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

“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.

“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

R2 = 0.97

0

50

100

150

200

250

100 150 200 250 300

Mercury Dose per Child (micrograms)

Pre

vale

nce

of

Au

tism

per

100

,000

C

hild

ren ~ Palmer et al

(2006). Health & Place.

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.

Gastrointestinal Dysfunction

bad digestion pathologic

alterations in bowel flora

increased gut wall permeability

lymphoid nodularhyperplasia in ileum, in some cases

GI abnormalities

Methylation deficits

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

Central NervousSystem

Altered sensitivity Abnormal processing of sensory and

expressive information Abnormal neurotransmitter functions

Brain inflammation

Kemper & Bauman, 1992Bauman and Kemper, 2005

Neurons in autistic child:– larger than control– normal in appearance

ASD Control

Extensive documentation of large brains in autism

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)

Oxidative StressChauhan, 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.

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

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.

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.