Mitochondrial Autism—

A Unique
Subpopulation and
Piece of the Puzzle?

Presented 5/25/2008
By Jon S. Poling MD PhD
Clinical Assistant Professor,
Department of Neurology, Medical
College of Georgia
Partner, Athens Neurological
Associates
“The Low Hanging Fruit”
for Diagnosis and
Treatment
1. Mitochondrial
Dysfunction

2. Immune
dysfunction/
inflammatory
biomarkers
 Guiding Principles
of New Paradigm
 Autism is a behavioral syndrome, not a medical
diagnosis, with multiple etiologies.
 The prevalence of Autism is increasing—which
autism(s)?
 The rise in Autism cases is due to a complex
interaction between genetics and environment.
 Autism is a systemic disorder with primary
neurological manifestations.
 Based on biological markers, subpopulations must
be distinguished to guide proper basic science,
epidemiology, diagnosis, treatment, and prevention.
 Epidemiology and Genetics have to date failed
Autism because the clinicians have not properly
defined the endophenotypes/subpopulations
 The Mighty
Mitochondria

 1000 proteins located in the mitochondria, 13 are encoded by the mitochondrial DNA (mtDNA), while
the remainder are nuclear-encoded (on the chromosomes) and imported into mitochondria.
 75% sporadic occurence
 Mitochondrial disease
 Young field, 1988 DC Wallace,
Leber’s
 Extremely complex genetics and
clinical phenotypes
 mtDNA and nuclear DNA
 Not just powerhouse—programmed
(apoptotic) cell death
 Genotypes known now to have
multiple phenotypes
http://neuromuscular.wustl.edu/pathol/diagrams/mito.htm
http://www.umdf.org/
http://www.clevelandclinic.org/health/health-info/docs/1600/167
 Autism
&
Mitochondrial
Dysfunction

A New Medical Finding?

 New Or Redux?

 Dr. Mary Coleman,

Georgetown U 1985
1. 4 of 80 (5%) of patients with
lactic acidemia
2. 1 of 4 pts with regression
3. Propose primary defect in
carbohydrate metabolism,
pyruvate dehydrogenase
4. Speculate that Ketogenic diet
may be helpful
 Autism
&
Mitochondrial
Dysfunction

A rare and
unique situation?
Mitochondrial Dysfunction emerging as
most common medical condition
associated with autism.
 Of 159 autism patients in one autism clinic, 38% had
non-specific biochemical abnormalities. Poling et al.
Developmental regression and mitochondrial
dysfunction in a child with autism. J Child Neurol,
2006. 21(2): p. 170-2.

 7.2% of patients with Autism could be classified as

having a ‘definite’ mitochondrial respiratory chain
disorder and 20% had elevated serum lactic acid
Oliveira, G., et al., Mitochondrial dysfunction in
autism spectrum disorders: a population-based
study. Dev Med Child Neurol, 2005. 47(3): p. 185-9.

 2nd study 4%; Oliveira, G., et al., Epidemiology of

autism spectrum disorder in Portugal: prevalence,
clinical characterization, and medical conditions. Dev
Med Child Neurol, 2007. 49(10): p. 726-33.
Mitochondrial Dysfunction emerging as
most common medical condition
associated with autism.
 36% of 100 autism patients have total carnitine levels
1SD below mean control, pattern suggestive mild
mitochondrial dysfunction. Filipek, P.A., et al., Relative
carnitine deficiency in autism. J Autism Dev Disord, 2004.
34(6): p. 615-23.

 65% of autism pts referred for mitochondrial evaluation to

specialty clinic positive for OxPhos disorder on muscle
biopsy. Shoffner, J., L.C. Hyams, and G.N. Langley,
Oxidative Phosphorylation (OXPHOS) Defects in Children
with Autistic Spectrum Disorders, in AAN. 2008: Chicago.
 Autistic Spectrum Cases--AST vs. Age
60

50
AST declines by
AST (IU/L)

40 3.2 IU/L/10years

30

20

10

0
0 10 20 30

Years
JS Poling Johns Hopkins Neurology Grand Rounds 6/21/2001
Metabolic Disturbances in Autistic Children: The KKI Experience from 1995-
JS Poling Johns Hopkins Neurology Grand Rounds 6/21/2001
Metabolic Disturbances in Autistic Children: The KKI Experience from 1995-
2001
Autistic Spectrum--CPK
300

250

200
IU/L

150 CK
7 of 14 elevated 50%
100
Mean 168
50 N=14

0
0 5 Age (years)
10 15 20
 Autistic Spectrum—Lactate
5

4
Mmol/L

3
Lactate
2
6 of 15 elevated
1
(40%)
0
0 5 10 15 20
Age (years)
In the prelim evaluation of Dr. Kelley’s data 12/36 (25%) of autistic children
have elevated alanine/lysine
Mitochondria

Corner Piece
of the
Puzzle??
Can Autism Be A
Mitochondrial Disease?
Clinical Convergent
Evidence 1
 3+ systems involved, fluctuating
symptoms, intolerance to
fasting/dietary changes
 Nervous system, muscle, gut,
immune system involvement—most
energy dependent tissues
 Response to carbohydrate exclusive
diets (GCFC, ketogenic, specific
carbohydrate)
 High heritability by family history with
near failure of classic Mendelian
genetics to explain
 Spectrum of severity
Can Autism Be A
Mitochondrial Disease?
Biochemical Convergent
Evidence 2
Proposed environmental precipitants may

selectively injury metabolically susceptible
individuals.
 Data analogous to Parkinson’s disease research.
 Environmental/Epigenetic toxins act via
mitochondrial mechanism
 Other non-mitochondrial genetic lesions which
increase oxidative stress increase ASD risk
1. GSTP1*A haplotype Williams, T.A., et al., Risk of autistic
disorder in affected offspring of mothers with a glutathione
S-transferase P1 haplotype. Arch Pediatr Adolesc Med,
2007. 161(4): p. 356-61.
2. James, S.J., et al., Metabolic endophenotype and related
genotypes are associated with oxidative stress in children
with autism. Am J Med Genet B Neuropsychiatr Genet,
2006. 141(8): p. 947-56.
Can Autism Be A Mitochondrial
Disease? Divergent Evidence

Multiple
mitochondrial
lesions appear
to produce an
ASD phenotype
Divergent Evidence

1. 15q inverted duplication Filipek, P.A., et al.,

Mitochondrial dysfunction in autistic patients with 15q
inverted duplication. Ann Neurol, 2003. 53(6): p. 801-
4. PRADER WILLI TYPE MUTATION

2. A3243G mtDNA mutation and mtDNA depletion.

Pons, R., et al., Mitochondrial DNA abnormalities and
autistic spectrum disorders. J Pediatr, 2004. 144(1): p.
81-5. MIDD MELAS MUTATION

3. mitochondrial DNA G8363A transfer RNA(Lys)

mutation. Graf, W.D., et al., Autism associated with
the mitochondrial DNA G8363A transfer RNA(Lys)
mutation. J Child Neurol, 2000. 15(6): p. 357-61.
MERRF, LEIGH, CARDIOMYOPATHY, ATAXIA LIPOMA
SYNDROME

4. Rett Syndrome MECP2 knockout. Kriaucionis, S.,

et al., Gene expression analysis exposes
mitochondrial abnormalities in a mouse model of Rett
syndrome. Mol Cell Biol, 2006. 26(13): p. 5033-42.
RETT SYNDROME
Divergent Evidence

1. Filipek, P.A., et al., Relative carnitine deficiency

in autism. J Autism Dev Disord, 2004. 34(6): p.
615-23. NONSPECIFIC MITO DYSFUNCTION

2. Poling, J.S., et al., Developmental regression

and mitochondrial dysfunction in a child with
autism. NONSPECIFIC MITO DYSFUNCTION

3. J Child Neurol, 2006. 21(2): p. 170-2. Tsao,

C.Y. and J.R. Mendell, Autistic disorder in 2
children with mitochondrial disorders. J Child
Neurol, 2007. 22(9): p. 1121-3. CO Q10
DEFICIENCY AND THE OTHER NONSPECIFIC RC
DYSFUNCTION II/III & IV
 Mitochondrial Autism
—Immediate Clinical
Research Priorities 1
 Sib studies—biomarkers, growth
characteristics, phenotypic spectrum
1. Are biochemical markers detectable at
birth or shortly thereafter?
2. If yes, what is inheritance pattern—doubt
mtDNA?
3. If no, when do biomarkers appear, and
what is trigger or developmental
biochemical pathway maturation cycle?
Mitochondrial Autism—
Immediate Clinical
Research Priorities 2

Longitudinal case studies/high risk

 Biochemical markers vs. time

 Muscle biopsy, skin, leukocytes

 Clinical correlations with

regressions
Study that should be done
STAT
 Proposed selection criteria for Genome
wide DNA microarray analysis (NB ‘mito
autism’ may not be good enough
endophenotype)
1. Family with 2+ offspring on ASD spectrum
2. Biochemical fingerprint markers positive—
fasting PAA with inc alanine/lysine,
increased fasting lactate, increased AST
with nL ALT
3. One pt with regressive autism associated
with growth failure.
4. Motor findings also present including
hypotonia and weakness
 Mitochondrial Autism—
Immediate Clinical
Research Priorities 3
 Treatment trials—dietary
manipulation, immune
challenge avoidance, fever
treatment, rescue therapy
trials
 Cybrid mitochondrial platelet
studies—determines
contribution of mtDNA to
disorder
 Mitochondrial Autism—
Epidemiology &
Population Future
Studies
 Environmental exposures—pollutants,
ecological studies, vaccination history,
infection history, nutritional variables
 Mitochondrial/Metabolic Disorders
Vaccination registry to systematically
study susceptible subpopulations who
may need alternative schedule. There
are no safety studies to date on at risk
populations.
1. Brady, M.T., Immunization recommendations for children with metabolic
disorders: more data would help. Pediatrics, 2006. 118(2): p. 810-3.
2. Kingsley, J.D., et al., Immunizations for patients with metabolic disorders.
Pediatrics, 2006. 118(2): p. e460-70.
3. Yang, Y., et al., Acute metabolic crisis induced by vaccination in seven Chinese
patients. Pediatr Neurol, 2006. 35(2): p. 114-8.
Concession—Dr. Frye
Prior Epidemiology—
Evidence of Absence is
not Absence of Evidence
Study
 Estimated statistical power of the largest
population based study by Madsen et al.
refuting the association between Autism and
vaccines.
 The effect size and power are calculated for
four different proposed percentages of the
Autism population at risk for vaccine
associated regressive Autism.
 Two difference population prevalences are
used: the actual population prevalence of the
Danish study and the current estimated
population prevalence in the U.S.
 Power Analysis
Percent of 1:1273 Prevalence 1:150 Prevalence
Autism
PopulatioEffect Size Power Effect Size Power
n

7 0.0020 24.1% 0.0059 97.9%

5 0.0014 13.8% 0.0041 77.4%
3 0.0009 8.4% 0.0025 35.7%
1 0.0003 5.4% 0.0008 7.7%