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Posts Tagged ‘mitochondrial disorder’

What is mitochondria disease? What does it have to do with autism, and are there treatments?

November 18, 2011 22 comments

This week’s “Got Questions?” answer comes from Deepa Menon, MD, assistant medical director of the Center for Autism and Related Disorders, at Baltimore’s Kennedy Krieger Institute—an Autism Speaks Autism Treatment Network (ATN) site. Her research interests include metabolic and mitochondrial disorders and their association with autism.

Mitochondria are cell structures, or “organelles,” whose primary function is to supply a cell with energy. In essence, they turn sugar and fatty acids from food into the energy-carrying molecule adenosine triphosphate (ATP).

Virtually every cell in the body depends on ATP and mitochondria for energy. As a result, mitochondrial disorders can produce a wide variety of symptoms. The most common involve body systems that use a lot of energy. Muscles are a classic example, and mitochondrial dysfunction often produces muscle weakness and fatigue. When mitochondrial dysfunction affects the gastrointestinal system, symptoms can include constipation or diarrhea. When it affects the immune system, it can lead to frequent infections. Mitochondrial disorders can likewise cause failure to grow, kidney dysfunction and a many other medical problems.

The brain is another energy-demanding system. Here, mitochondrial dysfunction can produce such symptoms as developmental delay, hearing problems and seizures.

Over the last decade, there has been great interest in the possibility that mitochondrial disorders may underlie some of the symptoms of autism spectrum disorder (ASD). Currently we believe that around 5 to 10 percent of children with autism have mitochondrial dysfunction as the underlying cause of their symptoms.

Research suggests that many children diagnosed with autism and underlying mitochondrial dysfunction experienced regression following a simple childhood illness (ear infection, common cold, etc.) or other cause of fever or inflammation. Regression refers to a loss of developmental skills such as language or motor abilities. It may be accompanied by other symptoms of mitochondrial disorder such as fatigue, gastrointestinal distress, seizures and/or motor delays.

Laboratory testing of blood samples and urine show that many of these children (with ASD and mitochondrial dysfunction) have abnormally high  levels of certain amino acids and cellular waste products. This suggests that their cells are generating energy inefficiently with an excess of damaging byproducts.

When a child is diagnosed with ASD and mitochondrial dysfunction, treatment goals include a bolstering mitochondrial activity and protecting the mitochondria from further damage. Parents and affected individuals may be counseled to avoid (as much as possible) situations that stress mitochondria. Examples of these stresses include going for long periods between meals (prolonged fasting), infections that produce fevers, inflammation associated with dietary sensitivities and certain medications such as the antipsychotic haloperidol (Haldol), which is known to impair mitochondrial function.

Supportive treatment can include a prescription nutrient mixture containing the protein L-carnitine and the B-vitamin pantothenate, which is thought to bolster mitochondrial activity. This prescription mixture usually contains additional nutrients such as thiamine, nicotinamide, lipoic acid, and vitamins C and E. Coenzyme Q10 may be added for those who show low levels of CoQ10 on testing.

[Editor’s note: Autism Speaks continues to support research into the association of mitochondrial disease and autism and their effective treatments. For more information on these and other funded studies, please explore our Grant Search portal, here.]

Have a question? Email us at gotquestions@autismspeaks.org. For more news and perspective, please visit the Autism Speaks science page.

Message from the Chief Science Officer regarding the Institute of Medicine’s report on Adverse Effects of Vaccines

August 26, 2011 58 comments

Geraldine Dawson, Ph.D., Autism Speaks Chief Science Officer

On Thursday, August 25, the Institute of Medicine’s Committee to Review Adverse Effects of Vaccines Board on Population Health and Public Health Practice released its report on the scientific evidence related to adverse effects of vaccines. The Institute of Medicine (IOM) is a non-profit, non-governmental organization which is part of the National Academy of Sciences. IOM members are scientific and medical experts who serve as pro bono as advisors to the U.S. Congress and other policy-makers. They are periodically asked to provide a review of the evidence on matters of public concern and welfare.

Among several other topics, the IOM committee specifically reviewed the evidence regarding whether the MMR vaccine or the DTaP vaccine is causally linked to autism. In addition to reviewing epidemiological evidence, they reviewed case studies and research on biological mechanisms that might explain a connection between a vaccine and an adverse outcome, such as autism. They specifically assessed the evidence that vaccines could alter neuronal development resulting in autism symptoms, arising from chronic encephalopathy, mitochondrial disorders or other underlying disorders. The committee reviewed 22 epidemiological studies that evaluated the connection between risk for autism and the MMR vaccine and concluded that the evidence does not support a causal link between the MMR vaccine and autism. The committee only found one study on the relationship between the DTaP vaccine and autism and concluded that the data were insufficient to assess an association.

The committee noted that reports of case studies linking the onset of autism to infectious diseases such as encephalitis and malaria suggest that infection or inflammation may underlie some cases of autism. Furthermore, evidence from postmortem brain tissue suggests that autism may involve inflammatory processes affecting the brain. The authors argue that, at a minimum, prior to ascribing autism to vaccination it would be important to rule out chromosomal and single-gene defects, including a variety of metabolic (e.g. mitochondrial disorder) and inflammatory or infectious diseases that may exist prior to vaccination.

The IOM report is consistent with Autism Speaks’ policy statement on vaccines. Given the present state of the science, the proven benefits of vaccinating a child to protect them against serious diseases outweigh the hypothesized risk that vaccinations might cause autism. Autism Speaks continues to support research that explores the relationship between innate or acquired metabolic, inflammatory, or infectious diseases that may play a role in the etiology of autism.

Mitochondria and Autism Symposium

July 8, 2010 38 comments

For the second year in a row autism was featured at the United Mitochondrial Disease Foundation meeting. Following last year’s well-attended afternoon symposium, Robert Naviaux, M.D., Ph.D. (UCSD), in conjunction with Autism Speaks’ science team, successfully applied for an NIH conference grant to support a more extensive full-day meeting that included a family “Ask the Doc” panel discussion.

Why Mitochondria?

Mitochondria are the primary energy factories for all cells in the body.  When these factories reduce their output, critical cell functions begin to flicker or fade.  The energy is produced through a process called oxidative phosphorylation—an elaborate process that converts oxygen in body tissues to energy used for all cell functions. Although the metaphor of “energy factory” is the most common way to think of mitochondrial function, mitochondria are responsible for much more.  Mitochondria were once — long ago in the history of evolution — single-celled organisms like bacteria that functioned independently, responding to the environment and producing their own proteins encoded by a small circle of DNA.  Several billion years later, mitochondria are fully integrated into our cells, co-opting proteins encoded by the much larger nuclear genome of each cell to serve different functions. Proper mitochondrial function is tuned for each cell type since skin cells, heart cells, and brain cells all have different energy needs.  Mitochondria, like their bacterial predecessors, remain exquisitely sensitive to the local environment and as such function differently in developing versus mature cells, and also in response to differing temperatures, toxins and immune challenges.

Genetics and Epilepsy: finding common ground

The Saturday scientific session began with two primers, one on Autism Spectrum Disorders from Sarah Spence, M.D., Ph.D. (NIMH) and one on mitochondrial disorders from Salvatore DiMauro, M.D. (Columbia University). This background allowed the audience of parents, researchers and clinicians with different specialties to find some common ground for the later presentations and discussion.

One of the unique aspects of this meeting was the pairing of two talks on a topic, one taking the perspective of autism and the other mitochondrial disorders. Abha Gupta, M.D., Ph.D. (Yale) informed the group about our current understanding of autism genetics and focused specifically on what can be learned about the biology of autism by discovering rare mutations. Dr. Naviaux then wove the perspective of traditional mitochondrial genetics into a broader tapestry for the audience to consider. Over 1100 proteins are active in the mitochondria, and the DNA that codes for these proteins is scattered throughout the mitochondrial genome and all the chromosomes in the nuclear genome. This scatter and spread makes mitochondrial function an easy target for random mutations. Also, mutations in one gene can have complex effects on the expression of other genes.

Another area of Dr. Naviaux’s research has focused on a mitochondrial disease called Alper’s syndrome, in which the patient develops typically until a relatively mild viral infection stresses the system and uncovers the mitochondrial deficit, resulting in the onset of severe symptoms. Research into genetic vulnerabilities revealed by environmental stressors is relevant to our understanding in autism of the interaction of genes and the environment. In his presentation, Carlos Pardo, M.D., (Johns Hopkins University) considered the interaction with the immune system by focusing on how components of the immune system serve key roles in development. Dr. Pardo surprised the autism research world in 2005 when he showed clear marks of neuroinflammation—signs of an activated immune system in the brain—using postmortem tissue from individuals with autism. This intersection of immunology and the brain has been a major focus of his lab. At the symposium, Dr. Pardo showed how a specific class of receptors that are important for marshaling resources to fight infection and healthy brain development also affect mitochondrial function. The converse was also noted– the metabolic breakdown products from dysfunctional mitochondria can adversely affect this unique receptor system.

A second set of presentations focused on epilepsy.  Russell Saneto, D.O., Ph.D. (University of Washington) offered his clinical perspective from treating many cases of epilepsy in mitochondrial disorders.  Depending on the underlying cause of epilepsy in mitochondrial disease, different types of treatment tend to be more effective.  This theme was echoed in a presentation from autism expert Roberto Tuchman, M.D. (University of Miami) who talked about “the epilepsies” as a related group of disorders, but noting that optimal treatment comes from identifying underlying biological conditions when possible. A particular type of epilepsy called West syndrome was described by both speakers.  This severe form of epilepsy is thought to involve a dysfunction in a component of neural circuits known as “fast-spiking interneurons” that inhibit the activity of neighboring cells.  These fast-spiking cells are particularly expensive from an energetic perspective.  Therefore, any mitochondrial dysfunction would especially affect these energy-demanding cells.

Carolyn Schanen, M.D., Ph.D.  (University of Delaware) presented data on individuals with autism spectrum disorder that have a duplication in the long arm of chromosome 15. These individuals, who frequently present with epilepsy, exhibit an interesting pattern of gene expression and show evidence of mitochondria dysfunction in postmortem brain tissue. The portrait of this subgroup of autism punctuated the need for pursuing research studies of mitochondrial function in autism and simultaneously highlighting the immediate need for better diagnostic and treatment options.

Diagnosing and treating mitochondrial autism

Richard Haas, M.D. (UCSD) presented the state-of-the-art for diagnosing mitochondrial disorders. The diagnosis of mitochondrial dysfunction is dependent on the results of a series of tests, some of which, like a muscle biopsy or lumbar puncture, are relatively invasive. This presents a situation in which patients and parents need to elect how much testing to do with advice from an informed mitochondrial expert. Although there is no definitive test for mitochondrial disorders, there are agreed-upon checklists based on test results that indicate “likely” or “probably” mitochondrial dysfunction. Dr. Haas pointed to a set of “red flags” that should lead primary care doctors, including pediatricians, to consider a referral to evaluate mitochondrial function.

Treatments for mitochondrial disorders also share a commonality with autism—many complementary and alternative therapies exist with unfortunately little evidence as-of-yet to support their use. Bruce Cohen, D.O., M.D. (Cleveland Clinic) evaluated what we know about vitamin and supplement therapy. Few overall conclusions could be drawn, given the heterogeneity of presentation of mitochondrial dysfunction, but it is clear that more randomized clinical trials are needed especially in subgroups of patients. Until we have more data, exercise is recommended as therapy for all those living with mitochondrial disorders, and certain supplements to support good mitochondrial function and minimize reactive oxygen species may be used under the supervision of a physician to monitor benefit.

Ask the Doc

A group of parents and patients were fortunate to have five leading pediatric neurologists addressing their questions and concerns about mitochondrial disorders and autism. The panelist included Drs. Richard Haas, Sarah Spence, Bruce Cohen, Pauline Filipek, M.D. (University of Texas at Houston) and Roberto Tuchman.

Parents began by asking questions about the prevalence estimates for both autism and mitochondrial disorders, for which we have little population data in the US.  However, the panelists explained that data from a large Portuguese study and several smaller studies would suggest that approximately 5-10% of cases of autism may also have a likely mitochondrial dysfunction.

A lot of discussion centered around the utility of genetic testing, with the panel carefully making the distinction between the need to pursue genetic studies for research but taking caution to not put too much weight on genetic studies for individual diagnostics.  A comparative genomic hybridization (CGH) array study is definitely recommended as a good place to start for suspected mitochondrial disorders.

Questions surrounding treatment were another hot topic.  As noted previously, we would like to get to evidence-based medicine standards for the treatment of autism spectrum and mitochondrial disorders but that is difficult with disorders that present with such unusual heterogeneity.  Among the panelists, there was a general consensus that therapies such as chelation and hyperbaric oxygen were not recommended for this population due to a lack of evidence for positive effects paired with substantial evidence for the potential to harm.  In particular with hyperbaric oxygen therapy, the panelists were concerned about the potential for reactive oxygen species that can emerge from exposing a weakened mitochondrial system to more of what it can’t process well (that is, turning oxygen into energy).  For more innocuous potential therapeutic strategies (such as dietary interventions including some supplements), the panelists suggest that patients (or their parents) work with their physicians to conduct their own trials.  There was great hope for pharmacogenomics in that therapies of the future can be targeted to support a known deficit.

The meeting closed on a note of enthusiasm both for this topic and the pervasive sense of collaboration at this meeting.  Autism Speaks looks forward to more collaboration between our communities for continued progress in understanding and awareness of mitochondrial disorders in autism.

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