Mitochondrial Autism—A Unique Subpopulation and Piece of the Puzzle

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Mitochondrial Autism—A Unique Subpopulation and Piece of the Puzzle Powered By Docstoc
					   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/1600/1678.asp?index=6957
       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 1995-2001
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          10              15           20
                               Age (years)
  Autistic Spectrum—Lactate
 Mmol/L




                                             (40%)


                                 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
  Populat   Effect             Effect
    ion               Power              Power
              Size               Size
    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%

				
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