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Neurology Today:
doi: 10.1097/01.NT.0000337666.59903.13
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Questions About Links Between Mitochondrial Encephalopathies and Autism Raised in National Meeting: Role of Mitochondria and Immunity Needs Further Study, Experts Say

FALLIK, DAWN

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ARTICLE IN BRIEF

Experts convened for a meeting to discuss possible links between autism and mitochondrial disorders.

A new case out of Colorado has neurologists and pediatricians pondering possible links between mitochondrial encephalopathies, immune response, and autism.

In Colorado, a 6-year-old with mitochondrial dysfunction “became weak with multiple episodes of falling to the ground,” within a week of receiving a live attenuated influenza virus (LAIV) vaccine, or FluMist — according to a case file obtained by The New York Times and reported on June 28.

Over the next five months, the child's condition continued to worsen. She was hospitalized, underwent surgery, and died on April 5 after being withdrawn from life support. The details of the case are sketchy as the government has released no information.

What is known is that the death happened only months after the Department of Justice issued a concession awarding a yet-to-be determined financial compensation to the Poling family of Atlanta. In that case, 19-month-old Hannah Poling received five routine shots against nine infectious diseases. Two days later, she had a fever, screamed incessantly, and would not walk

Hannah was diagnosed with autism at 33 months and later with mitochondrial dysfunction. According to the 2006 report in the Journal of Child Neurology by John S. Poling, MD, PhD, the girl's father who is an Athens, GA, neurologist, and investigators at Johns Hopkins University, ”subtle abnormalities in the serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate led them to perform a muscle biopsy, which showed type I myofiber atrophy, increased lipid content, and reduced cytochrome c oxidase activity.”

Dr. Poling filed a lawsuit against the Department of Health and Human Services in 2002, stating that the stress of those vaccines aggravated his daughter's underlying condition. [See Neurology Today's June 5 article, “After Vaccine-Autism Case Settlement, MDs Urged to Continue Recommending Vaccines,” at www.neurotodayonline.com.]. Dr. Poling, and the co-authors of the 2006 report, declined to comment for this article.

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MEETING OF EXPERTS

On June 29, a group of scientists met in Indianapolis to discuss possible links between mitochondrial encephalopathies and autism. The meeting was sponsored by the FDA, the NINDS, the National Institute of Mental Health, the Centers for Disease Control and Prevention, and the Department of Health and Human Services.

Robert K. Naviaux, MD, PhD, president of the Mitochondrial Medicine Society and co-director of the Mitochondrial and Metabolic Disease Center at the University of California-San Diego (UCSD) School of Medicine, participated in the meeting session focusing on direct or indirect triggers for neurological regression in children with mitochondrial disorders. In a telephone interview, he told Neurology Today those triggers could include exercise, decreased caloric intake, infections, and vaccines.

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ROLE OF MITOCHONDRIA IN IMMUNITY

Dr. Naviaux said the group was specifically directed not to discuss the possibility of vaccines, but rather to focus on the similarities and differences of children with autism and mitochondrial disease. The specifics of the Colorado case were not discussed, he said, adding: “Mitochondrial disease and autism are not synonymous.”

Part of the issue, said Dr. Naviaux, is that the details of each patient's disease, and their reaction, could play a role, inviting these questions: What kind of infection did they have — viral or bacterial? What kind of mitochondrial dysfunction do they have? How many days after the infection did the reaction occur? Only by studying each scenario can investigators begin to see the larger picture, he said.

“The question is how mitochondria play a role in immunity,” said Dr. Naviaux. “That is an area just being explored and has really only been recognized explicitly on the gene level for the past five years.”

Bruce H. Cohen, MD, a pediatric neurologist specializing in mitochondrial disorders at the Cleveland Clinic, said the general triggers of deterioration usually include viral infections, dehydration, starvation, and fever. Although the doctors did not believe the vaccines themselves were a trigger, it could be that the fever that sometimes follows routine vaccination could cause problems.

“There's a huge amount of genetic biological variability out there, and we all react to biologic exposures in different ways,” said Dr. Cohen. Those variables could be what lead to adverse reactions, from vaccines to medications, he said.

Dr. Naviaux said that that when neurodegeneration occurs in mitochondrial disease patients after a natural infection, it typically occurs after the peak in symptoms of the cold or flu are resolving. Most commonly, it is delayed for five to 10 days after the onset of the infectious illness.

In contrast, the peak symptoms of fever and malaise that are associated with the innate immune response occur in the first two to four days. The neurodegenerative symptoms in patients with mitochondrial disease can range from muscle weakness and gastrointestinal problems, to stroke-like episodes, ataxia, and encephalopathy.

The symptoms in the Poling case appeared in the first two days, while the neurological symptoms in the Colorado case occurred one week after the vaccination, according to newspaper reports.

The character and timing of the symptoms in the first two to four days may reflect abnormal mitochondrial function in the innate immune response, according to Dr. Naviaux. The delayed response that occurs after five to 10 days appears to reflect a more generalized failure of the mitochondrial respiratory chain, and occurs at a time when children without mitochondrial disease are in the recovery phase from their illness, he said.

Richard Hass, MD, director of the UCSD Mitochondrial Disease Laboratory in San Diego and a professor of neuroscience and pediatrics, said that there could be several triggers for deterioration in patients with mitochondrial disease, including stress, extreme overexertion, and infection.

Patients who are prone to reactions tend to have widespread organ involvement, particularly in the brain. But it's unclear why some patients react severely within a day or two, as in the LAIV case, or why some develop problems 10 days out.

“From the group of doctors who were there, no one could think of a convincing case where one of our patients deteriorated after immunization,” said Dr. Haas, who attended the Indianapolis meeting.

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WHAT TO TELL PARENTS

The challenge is what to tell worried parents. Salvatore DiMauro, MD, a mitochondrial specialist at the Neurological Institute of Columbia University, said he has never told a parent not to vaccinate their child, because the stress of an infection like measles would be traumatic.

“We're dealing here with three dots,” said Dr. DiMauro, who attended most of the meeting but left before the triggers section. “Two of them have been connected — mitochondrial disease and autism — not that mitochondrial disease causes autism, but that there is a subgroup of patients with autism who do have mitochondrial disease.

”The third dot is vaccination,” he continued, “and I think everyone agrees that there has not been a connection between vaccines and autism or mitochondrial disease.”

There could be a link in that some preclinical mitochondrial disease could be unmasked by stress, he said. Even something like a urinary tract infection could worsen the patient. In Hannah Poling's case, her father believes the stress of the vaccines precipitated her autism.

“Maybe it was a factor, maybe not,” said Dr. DiMauro. “It might have developed anyway.”

The hope at the end of the meeting was to develop research into how patients with mitochondrial disease react to infection, and the role mitochondria play in recovery.

Dr. Haas emphasized that most children are not at risk, but that more study needs to be done to understand what happened with cases like the one in Colorado and with Hannah Poling.

“Our view is that these were children balanced on a knife's edge, and it's likely that any infection would have caused an episode deterioration, or it may be that immunization triggered it,” Dr. Haas said. “But we don't know, because these are diseases that spontaneously deteriorate without an obvious trigger.”

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REFERENCE:

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Poling JS, Frye RE, Zimmerman AW, et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol 2006;21(2):170–172.

©2008 American Academy of Neurology

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