By Dr. Jon Poling, father of Hannah Poling.
OPEN LETTER TO DR. STEVEN NOVELLA
IN RESPONSE TO "Has the Government Conceded Vaccines Cause Autism?"
Thank you for generating interesting discussion regarding my little girl, Hannah Poling. I would like to give you additional information in order to generate further productive discussions on this matter amongst the neurology community. This information should assist you, Dr. DiMauro, and Dr. Trevethan, who have also commented publicly, to formulate better theories as to the significance of Hannah’s mitochondrial dysfunction in relation to her autism.
1. Mito Dysfunction or Mito Disease? Chicken or Egg?
To begin with, I would like to point out that the spectrum of mitochondrial dysfunction is probably considered more broad and complex than the spectrum of neurobehavioral abnormalities seen with autism. Dysfunction of the mitochondria, specifically dysfunction of the oxidative phosphorylation pathway, most likely contributes, but may not be the cause of many diseases—including Parkinson’s disease, Friedreich’s Ataxia, Alzheimer disease, etc. Thus, it is probably incorrect to refer to mitochondrial dysfunctional and mitochondrial disease interchangeably. Indeed, the role of the dysfunctional mitochondrial are yet to be clarified in these diseases. Thus, I will refer to Hannah’s metabolic condition as a mitochondrial dysfunction, not a mitochondrial disease.
2. Mito Genetic Finding? Mito mtDNA ‘red herring’ ?
ADDITIONAL GENETIC TESTING NOT AVAILABLE IN THE J CHILD NEUROL CASE REPORT: Dr. Shoffner performed genetic testing on both Hannah’s muscle and her mother’s leukocytes subsequent to our case report. Hannah (muscle mtDNA) and her mother (leukocyte mtDNA) were both found to be HOMOPLASMIC for the mtDNA T2387C transition mutation.
Our analysis of this genetic finding in the mtDNA was significantly different than those of other physicians that I’ve seen in scientific blogs or commentary. I suspect it would have been fatal to both Hannah and her mother if this homoplasmic mutation was pathogenic since (as I am sure you are aware) the mutation is on the 16S ribosomal subunit which is highly conserved. Thus, this mutation probably represents a benign polymorphism rather than pathogenic mutation. It is unlikely, but possible, that the mutation is significant to Hannah, but in such a case, it must work in concert with other nuclear genes to cause her mitochondrial dysfunction. To our knowledge, this point mutation has not been reported in cases similar to Hannah’s.
3. Encephalitis? Metabolic Encephalopathy? Or “Regressive Encephalopathy with Features of Autism Spectrum Disorder”
The other interesting term you used was encephalitis rather than encephalopathy. We are not sure that she had an “-itis” but we did clearly document a regressive encephalopathy based on not only our parental reporting, but also based on the pediatrician’s documents, affidavits from other family members, and the growth curve measurements (injury pattern). Early on in the regression we did note back arching (opisthotonus), fever, and disrupted sleep. Although fever occurred a lumbar puncture was not performed.
An interesting developing story in autism research is the immune/inflammatory connection. In her senior resident thesis, Dr. Anne Comi, a former JHU colleague, along with Dr. Andy Zimmerman, reported, the increased prevalence of autoimmune disease in families of autistic offspring. Interesting, Hannah also has a maternal family history of autoimmune disease. Dr. Carlos Pardo, another one of my former chief residents, along with Andy and Dr. Vargas, published a beautiful study in the Archives of Neurology, demonstrating neuroinflammation on autopsy of brain samples and inflammation cytokine markers in the CSF of individuals with Autism. The interesting thing was that inflammation was demonstrated in autopsy specimens from adults as old as 44 years of age. The conclusion was that further research would be required to determine if inflammation was a primary disorder in autism or; alternatively, if inflammation and microglial activation was secondary to neurodegeneration. Dr. Sudhir Gupta at UC Irvine has a nice model of how the two pathways of neuroinflammation and mito dysfunction may not be mutually exclusive. This remains to be seen; however, study of mitochondrial dysfunction and neuroinflammation hold the promise of treatment development. The two avenues of research deserve funding at the highest levels.
4. How many Hannah Polings are out there?
The short answer is that nobody knows. However, there is emerging data to suggest that she is not alone.
Dr. Shoffner will be presenting his experience with 37 patients with combined autism and mitochondrial dysfunction at the AAN meeting in Chicago this April. 65% of his referrals are positive for mitochondrial dysfunction. Of course, his yield is subject to referral bias as a mito expert, so the prevalence of mitochondrial dysfunction in Autism is surely less than 65%.
The best estimate to date of the prevalence of mitochondrial dysfunction in autistic patients comes from Oliviera et al. in a population of 120, 5 of 69 (or 7.2%) showed mitochondrial dysfunction. If this is generalized to the US estimate of 1 million patients with ASDs, then the number of kids like Hannah could be 72,000! Isn’t this worth further study?
Dr. Shoffner furthermore advocates, along with us, that vaccination is important even for kids with mitochondrial dysfunction. I would argue that you should not give nine at one time and that none of them should contain Thimerosal (mercury).
5. Thimerosal—On or Off the Table?
I don’t want to dwell on mercury, as this theory is not why HHS conceded Hannah’s case (imo). Dr. DiContanzo just wrote an interesting blog about how his opinion of mercury in vaccines has changed (http://drugs.about.com/b/2008/03/08/mercury-in-vaccines-and-autism-the-burden-of-proof-may-shift.htm).
My opinion is that mercury is a potent neurotoxin. Therefore, don’t inject it into kids! Interestingly, basic research studies have shown that Thimerosal toxicity occurs through mitochondrial pathways. Officials point to the large epidemiology studies as proof that there is no link between thimerosal and autism. However, these studies are not powered to disprove the null hypothesis when considering that the mitochondrial autistic population may be just a small percent of the case totals. Remember that while the CDC sponsored Verstraten study is hyped as a negative study, it DID find a statistically significant increase in childhood tics in those exposed to higher doses of thimerosal.
6. Hannah was destined to regress? Or was she?
Some experts have already stated that ‘mitochondrial disease’ is degenerative so the vaccine reaction was just the start of an inevitable decline. This was neither the opinion of Dr. Richard Kelley at KKI nor Dr. John Shoffner. In fact, the markers that led us down the mitochondrial trail (inc AST but not ALT, low serum bicarbonate, and slight increased CK, increase in the alanine to lysine ratio on PAA) are no longer present. Furthermore, in our pilot study (unpublished but mentioned in the J child neurol paper), Dr. Frye (the statistician for our study and also a child neurologist) found a non-significant trend that AST decreased toward normal with increasing age. With further studies we hoped to examine the hypothesis that this abnormality may be representative of a developing/immature biochemical pathway present in some children.
7. Triple Hit Hypothesis—#1Underlying genetic susceptibility #2Insult must occur during specific developmental period #3 A certain vaccination or combination thereof is the environmental trigger (?vaccine component like thimerosal ?direct immune stim/fever reaction ?live virus reaction?)
The implication is that Hannah’s type of autism requires a genetic susceptibility and properly timed insult to manifest disease. We have not subjected Hannah to another muscle biopsy or re-examined ox phos functional assays that were published in the paper. I can inform your readers though that the serum biochemical markers have resolved, growth resumed and continues along a normal trajectory, and there have been no other episodes of regression since 2000. We are however left with autism and later in 2006, epilepsy.
It is recommended that studies be initiated immediately to screen siblings of cases to identify biochemical markers so as to identify potential screening tests.
I agree with the mainstream that my daughter’s case has raised many intelligent discussions and questions. I’m very proud of her for starting this discussion. Our hope is that further research into this case and others like it, we will be also to find screening tests to prevent what happened to my daughter from happening to anybody else.
(Dr. Poling acknowledges the editorial comments and insightful suggestions of Dr. Richard E. Frye. He also would like to declare his conflicts of interest. First of all, he is the father of Hannah Poling. Dr. Poling has also accepted consultancy or speakers honoraria from Pfizer, Eisai, Ortho-McNeil, Biogen, Teva, Immunex (now Amgen), and Allergan.)
PS While I thought it useful to clarify some of the neurological issues raised by the government's concession of my daughter's case, please understand that I will not be able to respond to individual comments posted. Thank-you. Jon