Fever Plus Mitochondrial Disease Plus Vaccinations: Risk Factors for Autistic Regression

Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
October 02, 2009

Newly published findings renew concern for children who had mitochondrial pathology at the time of a vaccination. The carefully designed study found that some such children regressed into autism.

Titled "Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression", the study reports associations among fever, mitochondrial profiles, vaccination, and autistic regression (1).

These findings augment insights from Hannah Poling, who had mitochondria pathology markers and who regressed after a multiple-vaccinations incident (2-3). Importantly, Hannah and her mother have a specific mitochondrial genetic marker, even as her mother remains a high-achieving, well-spoken, non-autistic individual. Apparently, the mitochondria variant shared by mother and daughter was insufficient to induce autism in the absence of a sufficient environmental trigger which, for Hannah, was her being injected with five vaccines in one day.

The new study by Black et al is oriented towards classically defined mitochondrial disease and focused upon autistic children with thoroughly evaluated mitochondria issues. Importantly, the researchers mention that many children are never evaluated for markers of mitochondria pathology, which can be difficult to ascertain (1).

In contrast, non-classical mitochondria dysfunction (MtD) is not necessarily genetic in origin but has signs and symptoms very similar to those of classic mitochondrial disease. MtD is elaborated in a free-online, clinician-oriented review by autism specialists Jeffrey Bradstreet, M.D., and Dan Rossignol, M.D. (4)  These experienced clinicians delineate differences between and similarities of classic mitochondria disease and mitochondria dysfunction. Their review offers an important point: "Biomarkers for mitochondrial dysfunction have been identified, but seem widely under-utilized despite available therapeutic interventions." (4)

As Black et al discuss their own findings (1), their rhetoric seems to imply that fever in the context of mitochondrial disease was crucial for the vaccination-related regressions. However, as cited below, if an anti-pyrogen such as acetaminophen (Tylenol) was given somewhat concurrently to the vaccination that caused regression, then glutathione depletion and/or fever suppression may have been etiologic co-factors in the children who regressed. In other words, was the association among fever, vaccination, and regression into autism dependent upon treatment of the fever (in the context of mitochondria-related suboptimality)?

Due to the new findings' importance, we repeat: among the autistic children who regressed into autism, fever and vaccination together were more significant than was vaccination without fever (1). This finding and the way it's worded in the study prompt concern for anti-pyrogens such such as Tylenol, which utilizes and may deplete glutathione (5-8). Such studies subserve a question: Were the closely watched children given Tylenol or some other fever-reducing remedy?

Concern regarding treatment of fever is warranted because Tylenol diminishes glutathione (eg, 9), which is suboptimal in many autistic children (10-20) and which helps detoxify thimerosal (21-23). Problematically, thimerosal inhibits a glutathione transferase  (24); and, not surprisingly, thimerosal injections of infants are associated, among boys, with increased rates of special education services and with autism (25-26).

But lets return to the important new study by Black et al (1), paying close attention to the role of fever and possibly the role of anti-pyrogens such as Tylenol, which has been linked with autism (eg, 27-29). Here are several excerpts:

        "In this pilot study, autistic regression was identified in 60.7% (17 of 28) of the study participants representing a statistically significant increase over the estimated 25% reported in the general population of autistic spectrum disorders patients (w2, P < .0001; Table 2). Autistic regression was not identified in 39.3% (11 of 28). The 17 individuals with autistic regression could be divided into 2 groups, those who regressed with fever (70.6%, 12 of 17) and those who regressed without identifiable linkage to fever or vaccinations (29.4%, 5 of 17). Autistic regression and fever was not associated with vaccination in 8 of 12 (66.7%) and was associated with a febrile response to vaccination in 4 of 12 (33.3%). Information about the precise vaccine schedule associated with a febrile response was not available. No individual showed regression with vaccination unless a febrile response was present." (1)

The Black et al paper (1) ought prompt additional studies with similar focus, larger numbers - and, we hope, future studies will include data regarding Tylenol and other anti-pyretics.

In the following excerpts, notice how the description of mitochondrial disease offered by Black et al is akin to the concept "mitochondrial dysfunction" offered by Rossignol & Bradstreet:

        "The clinical suspicion of mitochondrial disease in autistic spectrum disorders is increased when patients have additional clinical features that include hypotonia and motor delay, fatigue with activity, metabolic abnormalities, poor growth, epilepsy, and affected siblings. Increases in metabolites such as lactate, pyruvate, and alanine in blood, urine, or cerebrospinal fluid can be important findings that support a diagnosis of mitochondrial disease. However, metabolic testing is often normal in mitochondrial disease, even in patients with severe disorders.... Although hypotonia, motor developmental delay, and fatigue are observed, the muscle histology shows only nonspecific changes. This finding is consistent with routine histopathologic assessments of most patients with mitochondrial disease who rarely have diagnostic features such as cytochrome c oxidase-deficient fibers and ragged-red fibers." (1)

        "The biochemical heterogeneity observed in the autistic spectrum disorder group is similar to the biochemical heterogeneity observed in other groups of patients with mitochondrial disease. Diagnosis of mitochondrial disease is complex, requiring a multifaceted and well-coordinated clinical and laboratory approach. In most individuals, no single test is sufficient for the diagnosis of mitochondrial disease." (1)

        "Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning." (4)

Important insights with clinical significance can occur if mitochonddrial evaluations occur:

"In all patients with mitochondrial disease, identification of treatable metabolic changes such as deficiencies in coenzyme Q10 and defects in cerebral folate metabolism is important. Patients with mitochondrial disease are at increased risk of developing a defect in cerebral folate metabolism... Cerebral folate deficiencies are also reported in autistic spectrum disorders..." (1, p4)

"Unfortunately, many children with abnormal development caused by mitochondrial diseases are not diagnosed..." (1; p4), yet most children are virtually forced to abide by one-size-fits-all vaccination policies.

Conclusion: The researchers who participated in Black et al are to be congratulated. Their findings add importantly to peer-reviewed literature about vaccinations and autistic regression in the presence of signs and symptoms of classical mitochondrial disorder and, we add, possibly MtD. Furthermore, the study calls attention to an important issue:  Had the anti-pyretic Tylenol been given to the children who regressed in response to vaccination while having fever and signs and/or symptoms of mitochondrial pathology?

More generally, as explained by William Egan, M.D., of the FDA's Center for Biologics Evaluation & Research, policy regarding vaccinations had long been to avoid the vaccinating of sick or recently sick children. However, so as to increase vaccination rates (ie, coverage), that policy had been changed to one of recommended that sick and recently sick children be vaccinated (30).

Unfortunately, that policy change and the vaccinating of sick or recently sick children -- particularly when multiple vaccines are injected during the same incident -- may have been etiologically significant in many cases wherein the child regressed into autism. And why this policy change may be been significant can be found (i) in peer-reviewed studies about glutathione (GSH), weak alleles of GSH-related genes, and Tylenol (eg, 9-24, 27-29), and  (ii) amid specific children's clinical lab data consistent with MtD (4).

Furthermore, as informed by the tragedy of Hannah Poling's vaccination-induced regression, these various risk factors may be all the more important among infants and toddlers who have at least some signs and symptoms of MtD but have not been properly evaluated prior to being vaccinated.

Science - even clinical lab science - is running far ahead of vaccination policies determined and enforced by zealotistic practitioners of vaccinology. 

Perhaps infants and toddlers ought be screened for weak alleles and for indications of mitochondrial dysfunction.


1. Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression
John Shoffner, MD, Lauren Hyams, PhD... and Keith Hyland, PhD1
Journal of Child Neurology 000(00) 1-6

Autistic spectrum disorders encompass etiologically heterogeneous persons, with many genetic causes. A subgroup of these
individuals has mitochondrial disease. Because a variety of metabolic disorders, including mitochondrial disease show
regression with fever, a retrospective chart review was performed and identified 28 patients who met diagnostic criteria for
autistic spectrum disorders and mitochondrial disease. Autistic regression occurred in 60.7% (17 of 28), a statistically
significant increase over the general autistic spectrum disorder population (P < .0001). Of the 17 individuals with autistic
regression, 70.6% (12 of 17) regressed with fever and 29.4% (5 of 17) regressed without identifiable linkage to fever or
vaccinations. None showed regression with vaccination unless a febrile response was present. Although the study is small, a subgroup of patients with mitochondrial disease may be at risk of autistic regression with fever. Although recommended
vaccinations schedules are appropriate in mitochondrial disease, fever management appears important for decreasing
regression risk.

2. Developmental regression and mitochondrial dysfunction in a child with autism
Poling JS, Frye RE, Shoffner J, Zimmerman AW.
Department of Neurology and Neurosurgery, Johns Hopkins Hospital
J Child Neurol. 2006 Feb;21(2):170-2.
{free online}

Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative phosphorylation disorder in a 19-month-old girl. Subtle abnormalities in the serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate led us to perform a muscle biopsy, which showed type I myofiber atrophy, increased lipid content, and reduced cytochrome c oxidase activity. There were marked reductions in enzymatic activities for complex I and III. Complex IV (cytochrome c oxidase) activity was near the 5% confidence level. To determine the frequency of routine laboratory abnormalities in similar patients, we performed a retrospective study including 159 patients with autism (Diagnostic and Statistical Manual of Mental Disorders-IV and Childhood Autism Rating Scale) not previously diagnosed with metabolic disorders and 94 age-matched controls with other neurologic disorders. Aspartate aminotransferase was elevated in 38% of patients with autism compared with 15% of controls (P <.0001). The serum creatine kinase level also was abnormally elevated in 22 (47%) of 47 patients with autism. These data suggest that further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent.

3. Hannah Poling, her medical issues, and her post-vaccinal regression into autism have been widely discussed. Her father and mother have participated in some of these discussions. Noteworthy is the fact that the U.S. Department of Health & Human Services conceded a suit regarding Hannah's vaccination-induce autism. Here are three examples regarding the significance of the HHS concession regarding Hannah Poling, mitochondria disorders, vaccinations, and autism:

3a. Vaccine Injury Case Offers a Clue to the Causes of Autism
Could a group of disorders involving the "power plants of the cell" explain why some vaccinated children develop autism but the vast majority don't?
By Nikhil Swaminathan, April 22, 2008

3b. Father: Child's case shifts autism debate
By Jon S. Poling
Atlanta Journal-Constitution, 04/11/08

3c. Hanna Poling v. Secretary of HHS: Landmark First Concession of Vaccine-Induced Autism by U.S. Dept. of Health & Human Services

4. Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment
Daniel A. Rossignol, J. Jeffrey Bradstreet
American Journal of Biochemistry and Biotechnology 4 (2): 208-217, 2008
{free online}

Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning. Exposure to environmental toxins is the likely etiology for MtD in autism. This dysfunction then contributes to a number of diagnostic symptoms and comorbidities observed in autism including: cognitive impairment, language deficits, abnormal energy metabolism, chronic gastrointestinal problems, abnormalities in fatty acid oxidation, and increased oxidative stress. MtD and oxidative stress may also explain the high male to female ratio found in autism due to increased male vulnerability to these dysfunctions. Biomarkers for mitochondrial dysfunction have been identified, but seem widely under-utilized despite available therapeutic interventions. Nutritional supplementation to decrease oxidative stress along with factors to improve reduced glutathione, as well as hyperbaric oxygen therapy (HBOT) represent supported and rationale approaches. The underlying pathophysiology and autistic symptoms of affected individuals would be expected to either improve or cease worsening once effective treatment for MtD is implemented.

5. Tylenol acetaminophen pharmacology

6. Comparative efficacy of aspirin and acetaminophen in the reduction of fever in children
Yaffe SJ.
Arch Intern Med. 1981 Feb 23;141(3 Spec No):286-92.

Antipyretics should be employed in the pediatric population whenever it is the clinical judgment of the attending physician that fever should be lowered. Aspirin and acetaminophen are equally effective as antipyretics. The efficacy and safety of these two most common antipyretic agents are examined, and various studies with these agents are critically reviewed. Since acetaminophen has a greater margin of safety at antipyretic dosages, it is preferred to aspirin when an anti-inflammatory effect is not required. The efficacy and safety of combination therapy with acetaminophen and aspirin in pediatric patients--or an alternative treatment regimen with both these drugs--warrant investigation.

7. The antipyretic effect of ibuprofen and acetaminophen in children
Wahba H.
Pharmacotherapy. 2004 Feb;24(2):280-4.

OBJECTIVE: To determine whether evidence in the medical literature supports ibuprofen or acetaminophen for reducing fever in children. METHODS: Both MEDLINE and the Science Citation Index were searched using various medical subject headings for all articles published worldwide from 1966-2000. The language of publication was not restricted. RESULTS: Initially, 4132 articles were found that dealt with either ibuprofen or acetaminophen. Limiting these articles to humans and children, and cross-referencing with the Science Citation Index resulted in 68 articles; 22 satisfied the inclusion criteria and were further assessed for validity, design, and methods of reporting data. CONCLUSION: Acetaminophen and ibuprofen have equal tolerability. Acetaminophen produced a greater body temperature reduction at 0.5 hour after intervention compared with ibuprofen. However, ibuprofen provides a longer duration of antipyretic effect than acetaminophen 4 hours after intervention, and the initial temperature decrement lasts longer.

8. Antipyretic efficacy and safety of ibuprofen and acetaminophen in children
Goldman RD et al. 
Ann Pharmacother. 2004 Jan;38(1):146-50.

OBJECTIVE: To evaluate the antipyretic effects and safety of ibuprofen compared with acetaminophen in febrile children. DATA SOURCES: Searches of MEDLINE (1966-November 2003) and EMBASE (1988-November 2003) were conducted using the terms ibuprofen and acetaminophen. Bibliographies of selected articles were reviewed. DATA SYNTHESIS: Ibuprofen was significantly more effective than acetaminophen in reducing fever after a single dose. Ibuprofen was found to be more effective after 6 hours, but not after a longer period of time. Studies with multiple doses have also failed to show that one drug is better than the other. CONCLUSIONS: The efficacy and effectiveness of acetaminophen and ibuprofen in their recommended dosages are similar, with slightly more beneficial effects shown with ibuprofen.

9. Glutathione, glutathione-dependent enzymes and antioxidant status in erythrocytes from children treated with high-dose paracetamol
Kozer E et al.
Br J Clin Pharmacol. 2003 Mar;55(3):234-40.
{free online}

AIM: To investigate glutathione and antioxidant status changes in erythrocytes from febrile children receiving repeated supratherapeutic paracetamol doses. METHODS: Fifty-one children aged 2 months to 10 years participated in the study. Three groups were studied: group 1 (n = 24) included afebrile children who did not receive paracetamol; and groups 2 (n = 13) and 3 (n = 14) included children who had fever above 38.5 degrees C for more than 72 h. Patients in group 2 received paracetamol at a dose of 50 +/- 15 (30-75) mg kg(-1) day(-1) and those in group 3 received paracetamol above the recommended therapeutic dose, ie 107 28 (80-180) mg kg(-1) day(-1). A blood sample was taken for the measurement of liver transaminases, gammaglutamil transferase (GGT), reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S-transferase (GST), superoxide dismutase (SOD) and antioxidant status. RESULTS: Aspartate aminotransferase activity in group 3 was higher than in the other groups (P = 0.027). GSH, SOD and antioxidant status were significantly lower in group 3 compared with groups 1 and 2 (mean differences: for GSH 3.41 micromol gHb(-1), 95% confidence interval (CI) 2.10-4.72, and 2.15 micromol gHb(-1), 95% CI 0.65-3.65, respectively; for SOD 856 U min(-1) gHb(-1), 95% CI 397-1316, and 556 U min(-1) gHb(-1), 95% CI 30-1082, respectively; and for antioxidant status 0.83 mmol l(-1) plasma, 95% CI 0.30-1.36, and 0.63 mmol l(-1) plasma, 95% CI 0.02-1.24, respectively). GR activity was significantly lower in groups 3 and 2 in comparison with group 1 (mean differences 3.44 U min(-1) gHb(-1), 95% CI 0.63-6.25, and 5.64 U min(-1) gHb(-1), 95% CI 2.90-8.38, respectively). Using multiple regression analysis, paracetamol dose was found to be the only independent variable affecting GR, GST and SOD activities (P = 0.007, 0.003 and 0.008, respectively). CONCLUSIONS: In febrile children, treatment with repeated supratherapeutic doses of paracetamol is associated with reduced antioxidant status and erythrocyte glutathione concentrations. These significant changes may indicate an increased risk for hepatotoxicity and liver damage.

10. Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism
Buyske S et al. BMC Genet. 2006 Feb 10;7:8.
{free online}

11. A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders
Geier DA, Geier MR. Horm Res. 2006;66(4):182-8.

12. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism
James SJ et al.  Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56.
{free online}

13. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype
Williams TA et al. Arch Pediatr Adolesc Med. 2007 Apr;161(4):356-61.
{free online}

14. Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism
James SJ et al. J Autism Dev Disord. 2008 Nov;38(10):1966-75.

15. Biomarkers of environmental toxicity and susceptibility in autism
Geier DA et al. J Neurol Sci. 2009 May 15;280(1-2):101-8.

16. Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15
Vojdani A et al. J Neuroimmunol. 2008 Dec 15;205(1-2):148-54.

17. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism
James SJ et al. Am J Clin Nutr. 2009 Jan;89(1):425-30.

18. Genetic variant of glutathione peroxidase 1 in autism.
Ming X et al. Brain Dev. 2009 Feb 3. [Epub ahead of print]

19. Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children
Al-Gadani Y et al.  Clin Biochem. 2009 Jul;42(10-11):1032-40.

20. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism
James SJ et al. FASEB J. 2009 Aug;23(8):2374-83.

21. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization
Westphal GA et al. Int Arch Occup Environ Health. 2000 Aug;73(6):384-8.

22. Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway
Makani S et al. Genes Immun. 2002 Aug;3(5):270-8.
{free online}

23. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors
James SJ et al. Neurotoxicology. 2005 Jan;26(1):1-8.

24. Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal
Muller M et al. Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81.

25. Hepatitis B triple series vaccine and developmental disability in US children aged 1-9 years
 Gallagher C, Goodman M. Toxicol Environ Chem 2008 90(5):997-1008.
{free online}

26. Hepatitis B vaccination of male neonates and autism
[conference abstract as published]
CM Gallagher, MS Goodman, Graduate Program in Public
Health, Stony Brook University Medical Center, Stony Brook, NY
Annals of Epidemiology, p659
Vol. 19, No. 9 Abstracts (ACE) September 2009: 651680

27. Is fever suppression involved in the etiology of autism and neurodevelopmental disorders?
Torres AR.
BMC Pediatr. 2003 Sep 2;3:9. Epub 2003 Sep 2.
{free online}

BACKGROUND: There appears to be a significant increase in the prevalence rate of autism. Reasons for the increase are unknown, however, there is a substantial body of evidence that suggests the etiology involves infections of the pregnant mother or of a young child. Most infections result in fever that is routinely controlled with antipyretics such as acetaminophen. The blocking of fever inhibits processes that evolved over millions of years to protect against microbial attack. Immune mechanisms in the central nervous system are part of this protective process. HYPOTHESIS: The blockage of fever with antipyretics interferes with normal immunological development in the brain leading to neurodevelopmental disorders such as autism in certain genetically and immunologically disposed individuals. TESTING THE HYPOTHESIS: Epidemiological studies to determine associations between the use of antipyretics and neurodevelopmental disorders should be undertaken. Biochemical tests will involve the examination of fluids/serum by mass spectrometry and the determination of cytokine/chemokine levels in serum and cell culture fluids after stimulation with fever-inducing molecules from bacteria, viruses and yeast. Postmortem brain can be examined by immunohistochemistry or other methods such as fluorescent in situ hybridization (FISH) to determine altered expression levels of chemokines/cytokines and other molecules. IMPLICATIONS OF THE HYPOTHESIS: 1) The use of antipyretics during pregnancy or in young children may be reserved for more severe fevers. 2) The perplexing genetic findings in autism may be better understood by categorizing genes along functional pathways. 3) New treatments based on immune, cell, pharmacological or even heat therapies may be developed.

28. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey
Schultz ST et al.
Autism. 2008 May;12(3):293-307.

The present study was performed to determine whether acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination could be associated with autistic disorder. This case-control study used the results of an online parental survey conducted from 16 July 2005 to 30 January 2006, consisting of 83 children with autistic disorder and 80 control children. Acetaminophen use after measles-mumps-rubella vaccination was significantly associated with autistic disorder when considering children 5 years of age or less (OR 6.11, 95% CI 1.42-26.3), after limiting cases to children with regression in development (OR 3.97, 95% CI 1.11-14.3), and when considering only children who had post-vaccination sequelae (OR 8.23, 95% CI 1.56-43.3), adjusting for age, gender, mother's ethnicity, and the presence of illness concurrent with measles-mumps-rubella vaccination. Ibuprofen use after measles-mumps-rubella vaccination was not associated with autistic disorder. This preliminary study found that acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder.

29. Similarities in features of autism and asthma and a possible link to acetaminophen use.
Becker KG, Schultz ST.
Med Hypotheses. 2009 Sep 10. [Epub ahead of print]

Autism and autism spectrum disorders are enigmatic conditions that have their origins in the interaction of genes and environmental factors. In this hypothesis, genes statistically associated with autism are emphasized to be important in inflammation and in innate immune pathways, including pathways for susceptibility to asthma. The role of acetaminophen (paracetamol) in an increased risk for asthma is described and a possible similar link to an increased risk for autism is suggested.

30. Personnel communication. William Egan, M.D., 2000, then acting director of the FDA's Center for Biologics Evaluation & Research (CBER), in their offices in Rockville, Maryland.


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