Familiar Diseases

Mitochondrial disease can look like any number of better known diseases, including: Autism, Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, muscular dystrophy and chronic fatigue, among others. Adults and children with it can have features similar to other disorders like: Epilepsy, Myopathy, Developmental Delay, learning disabilities and, Fibromyalgia.

Research shows that mitochondrial dysfunction is often a central element of these more commonly recognized diseases. Studies and reports indicate the "orange" ones are more influenced. A cure for mitochondrial disease could impact cures for Autism, Parkinson's, Alzheimer's and Muscular Dystrophy.

Due to a lack of physician and public awareness, patients with mitochondrial disease are often misdiagnosed, or left without a diagnosis at all. Only in the past ten years, with advances in genetics and molecular biology, have we a better understanding of the complexity in mitochondrial disorders.

The most common form of cell death in neurodegeneration is through the intrinsic mitochondrial apoptotic pathway. There is strong evidence that mitochondrial dysfunction and oxidative stress play a role in neurodegenerative disease pathogenesis, including in four of the more well known diseases Alzheimer's, Parkinson's, Huntington's, and Lou Gehrig's disease (ALS - Amyotrophic lateral sclerosis).

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More attention has recently been focused on a potential link between Autism Spectrum Disorders (ASD) and dysfunctional mitochondria. A study published in 2009 in the Journal of Child Neurology further examined this link (Shoffner, JM et al. J Child Neurol. 2010 Apr;25(4):429-34; Epub 2009 Sep 22), finding that a subgroup of patients with mitochondria disorders may be at increased risk for autistic regression, especially around periods of fever.

Mitochondria are intimately tuned to the environment in which they reside and are built to respond quickly to fluctuations in the state of that environment. To characterize a relationship between mitochondria disorders and ASD, researchers from Atlanta identified a group of 28 children who had been diagnosed with both ASD and mitochondrial disease. (Shoffner, JM et al. J Child Neurol. 2010 Apr;25(4):429-34; Epub 2009 Sep 22) The most common clinical observation in children with both ASD and mitochondria disorder was "hypotonia," or muscles with low tone, followed closely by "fatigue with activity." They also found that approximately 60 percent (17 of 28) of these children experienced a regressive form of ASD, a rate of regression that is over two times greater than what is observed in the general population of individuals with ASD.

Notably, 12 of those 17 regressions occurred in conjunction with having suffered a fever within a two week period of the regression. However, this regression did not appear to be necessarily linked to vaccinations, as two-thirds of the children that regressed with fever had not received vaccination, and of those who did receive a vaccination, none regressed without also having a fever.

Although a small study, this mitochondrial research illuminates potentially useful new commonalities between children with both an ASD and mitochondria disorder, suggesting that children with mitochondrial disease may be at increased risk for autistic regression and that increased risk may be associated with some fever-response pathway. Although this mitochondrial research did not establish the temporal relationship between fever and autistic regression, fever-induced regression is a well-known feature of metabolic disorders overall, and the study brings another angle to the already intriguing relationship of fever and autism.

In 2008, researchers reported that some children with ASD actually improve around periods of fever, suggesting that subgroups of ASD exist in which the individuals react differently to fever. However, these children with ASD who improved during fever were not thought to have mitochondrial disease.

"In light of this new data, it is clear we need more research into the body's complex cascade of metabolic and immune actions that accompany fever, how those relate to the biology of autism, and the appropriateness of fever management," commented Dr. Colamarino. "By showing that a subgroup of individuals with mitochondrial disorders may be at risk for autistic regression, the publication highlights the continued need for enhanced awareness of the clinical signs of mitochondrial dysfunction as well."

FMM Board Member Dr. John Shoffner was recognized by Autism Speaks as one of the Top 10 Researchers for 2009.

To see the Autism Speaks Top 10 Autism Research Achievements of 2009 list: http://www.autismspeaks.org/science/science_news/top_ten_autism_research_events_2009_main.php.

A December 2010 mitochondrial research study in The Journal of the American Medical Association reports mitochondrial dysfunction may influence processes highly dependent on energy, such as neurodevelopment, and contribute to Autism. In this exploratory study, children with Autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.
Journal of American Medical Association December 1, 2010-Vol 304,No. 21.

This particular study has also been recognized by Autism Speaks as one of the Top 10 Research Achievements for 2010 establishing continued acknowledgement of the significance between mitochondrial dysfunction and Autism.

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Parkinson's disease (PD) is a common and disabling neurodegenerative disease marked by progressive motor dysfunction, which results from selective degeneration of the nigrostriatal pathway. Complex I defects may result in oxidative stress and increase the susceptibility of neurons to excitotoxic death. In this way, environmental exposures and mitochondrial dysfunction may interact and result in neurodegeneration.

Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD.

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Alzheimer's disease is a progressive neurodegenerative disorder, either assuming a sporadic, age-associated, late-onset form, or a familial form, with early onset, in a smaller fraction of the cases. Whereas in the familial cases several mutations have been identified in genes encoding proteins related with the pathogenesis of the disease, for the sporadic form several causes have been proposed and are currently under debate.

Mitochondrial dysfunction has surfaced as one of the most discussed hypotheses acting as a trigger for the pathogenesis of Alzheimer's disease. Mitochondria assume central functions in the cell, including ATP production, calcium homeostasis, reactive oxygen species generation, and apoptotic signaling. Although their role as the cause of the disease may be controversial, there is no doubt that mitochondrial dysfunction, abnormal mitochondrial dynamics and degradation by mitophagy occur during the disease process, contributing to its onset and progression.

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Mitochondrial myopathy is a type of metabolic muscular dystrophy. There are many different types of mitochondrial myopathy. Some have names like Kearns-Sayre syndrome (KSS); Leigh's syndrome; mitochondrial DNA depletion syndrome (MDS); mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS); myoclonus epilepsy with ragged red fibers (MERRF); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); neuropathy, ataxia and retinitis pigmentosa (NARP); Pearson syndrome; and progressive external ophthalmoplegia (PEO). Some of the mitochondrial myopathies do not have specific names and are defined by the biochemical or genetic abnormality.

Mitochondrial diseases are heterogeneous and complex as some patients will only have symptoms involving their muscles and other patients will have symptoms involving differing organ symptoms.

The first real insights into mitochondrial myopathies occurred with the discovery of mtDNA mutations that cause Kearns-Sayre syndrome (KSS) (Holt, IJ et al. Nature. 1988 Feb 25;331(6158):717-9) and myoclonus epilepsy with ragged red fibers (MERRF) (Shoffner, JM et al. Cell. 1990 Jun 15;61(6):931-937). Since those early days we know that these diseases can be caused by a huge array of nuclear DNA mutations (often inherited from both parents in an autosomal recessive fashion) or by mtDNA mutations that can be maternally transmitted or sporadic.

For more information, please see: www.mda.org/disease/mito.html.

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