What is mitochondrial disease? How often does it occur in individuals with ASD? Are their effective treatments?
“Got Questions?” is a new weekly feature on our blog to address the desire for scientific understanding in our community. We received over 3000 responses when we asked what science questions were on your mind. We answered a few here and the Autism Speaks Science staff will address the other themes we received in this weekly post.
Mitochondrial disease is caused by an error in the functioning of mitochondria, which are essential energy-producing compartments of nearly every cell in the body. Certain mutations can cause the mitochondria to function inefficiently. These mutations can be within the mitochondria itself, with its own small circle of DNA, or within the nucleus where the rest of the cell’s DNA resides. Over 1500 genes carry some part of the recipe for the optimal functioning of mitochondria. This means that there are many ways for mitochondria to function imperfectly but there are also complex means available to mask a deficit by altering some of the other protein interactions.
Mitochondria are responsible for the process of oxidative phosphorylation that turns nutrients into energy through a series of stages involving complexes of enzymes. A break at any particular stage results in an atypical balance of metabolites in affected body tissues and fluids.
Most people consider mitochondrial disease to be one of a growing number of disorders caused by a defined set of mutations and presenting with a set of characteristics that typically involve three or more organ systems. However, mitochondrial disorders are often diagnosed when no mutation is found despite observations of metabolic signatures of mitochondrial dysfunction. The symptoms may also be more mild.
We do not have a firm estimate of mitochondrial disease in ASD. However, if we use the broader definition of mitochondrial disorder then according to a population-based study in Portugal, there may be as many as 4% of the ASD population affected. Autism Speaks’ research is addressing this and related questions through a grant to Cecilia Giulivi, Ph.D. at UC Davis and also through a collaborative research project at UC Irvine and UC San Diego.
There is currently no cure for mitochondrial disease or disorder. There are, however, treatments and practices that can improve the quality of life and slow the progression of the disease. The most effective treatments are for specific symptoms that tend to accompany mitochondrial dysfunction such as seizures treated with anti-convulsants. Regular exercise, a healthy diet, stress and extreme temperature avoidance are among the common recommendations. Some dietary and supplement regimes have anecdotal support but there is a need for empirical studies to test the efficacy of these therapies.
For more information, please visit the United Mitochondrial Disease Foundation (UMDF) website. Also, read our report on a joint Autism Speaks’ supported symposium at the annual UMDF meeting.
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.
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.