Mitochondrial Disease

Mitochondrial disease or dysfunction is an energy production problem. Almost all cells in the body have mitochondria, which are tiny "power plants" that produce a body's essential energy.

Mitochondrial disease means the power plants in cells don't function properly. When that happens, some functions in the body don't work normally. It's as if the body has a power failure: there is a gradation of effects, like a 'brown out' or a 'black out'.

Scientifically, it is actually a category or group of diseases. That's why mitochondrial disease takes many different forms and no two people may look alike.

It can look like any number of better known diseases: Autism, Parkinson's, Alzheimer's, Lou Gehrig's disease, muscular dystrophy and, chronic fatigue. Staying with the power plant analogy, power plants provide energy to a large community with each part of the community requiring varying degrees of power; in the same way, mitochondria provide energy to various organs of the body. So, when there is a mitochondrial dysfunction, a "black out" looks like Leigh's Disease, severe and fatal, while a "brown out" might be severe, but not lethal.

Mitochondrial disease primarily affects brain, heart and muscle in varying levels of severity.

Depending on which cells of the body are affected, symptoms may include:

• Poor growth
• Loss of muscle coordination, muscle weakness
• Visual and/or hearing problems
• Developmental delays, learning disabilities
• Mental retardation
• Heart, liver or kidney disease
• Gastrointestinal disorders, severe constipation
• Respiratory disorders
• Diabetes
• Increased risk of infection
• Neurological problems, seizures
• Thyroid dysfunction
• Dementia

It ranges from intermittent difficulty thinking, remembering, moving and acting, to severe handicaps. Some results may be fatigue, muscle weakness and diabetes. And all this is overlaid by good and bad days caused by significant inconsistency-like the electricity flickering in different areas of a community.

Though the impression most have of mitochondrial disease is a disorder that presents itself at birth, it can appear at any age. For some it develops over time. We're learning it's not at all rare but, due to a lack of physician and public awareness, this disease is not often diagnosed. Only in the past 10 years, with advances in genetics and molecular biology, have we a better understanding of the complexity in mitochondrial disorders. Even so, the definitive cause (or causes) of mitochondrial disease continues to evolve.

1 in 3-4,000 are affected by mitochondrial disease
1 in 2,500 are affected by Cystic Fibrosis
1 in 110 individuals are affected by Autism
1 in 500 are affected by Parkinson's
1 in 85 are affected by Alzheimer's
1 in 25,000 are affected by Leigh's Disease, a fatal form of mitochondrial disease
1 in 50,000 are affected by Lou Gehrig’s Disease (ALS)

Currently there are no highly effective mitochondrial disease treatments. Though related symptoms, such as seizures or attention problems can be managed with various medications, the mitochondrial disease itself is unchanged. Unfortunately, supplements such as CoQ10 and L-Carnitine have little to no effect on most patients.

In 2009, FDA approval occurred for an EID (Emergency Intervention Drug) to treat a mitochondrial disease with the new drug from Edison Pharmaceuticals, EPI-743. This represents the first steps toward viable treatments and hopefully, the beginning of many more near-term advancements in mitochondrial medicine research.

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There is no single test to diagnose mitochondrial disease in most patients. Today, OXPHOS (oxidative phosphorylation) enzymology by itself is no longer sufficient for a diagnosis. OXPHOS is the process by which the mitochondria turn the food we eat into energy that can be used by key organs; in the same way that crude oil can't go directly into a car to make the engine run, it first needs to be refined and turned into gasoline. The mitochondria represent the most complicated enzyme system in the body, requiring over 1,000 genes to function properly. As you might guess, with so many genes, patients can present in hundreds of ways.

Diagnosis of mitochondrial disease can be made through a combination of clinical observations, laboratory evaluation, brain imaging, and muscle biopsies. And an experienced integrated approach is necessary - not just one test. Referral to a specialist in mitochondrial medicine is often needed for diagnosis. Rarely is genetic testing sufficient for the diagnosis of mitochondrial disease. Even with the advent of new gene sequencing techniques like Next Generation sequencing, many of the identified changes in genes require the information obtained from a muscle biopsy for interpretation.

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In order to apply diagnostic criteria patients need testing that specifically assesses the different mechanisms causing the abnormalities (the how and the why) associated with OXPHOS defects. This understanding has evolved significantly in the past five years. And because of the complexity of the disease, continued thinking, assessing and investigating are terribly important to diagnosis accuracy. Due to the rapid changes in our understanding of mitochondrial diseases and the tools available for diagnosis, physicians need to reassess the probability of a diagnosis of mitochondrial disease as they see the patients over time. The diagnosis may change.

Most importantly, when a diagnosis of mitochondrial disease or disorder is considered, patients need to be evaluated carefully for diseases other than mitochondrial disease. For example, the muscle biopsy can be used to look at other types of muscle diseases. When a mitochondrial disease evaluation is undertaken, the physician should approach the patient comprehensively with assessments for mitochondrial diseases and other categories of disease.

It is critical for patients and their families not to oversimplify the diagnosis. In most cases, calling a patient simply a "Complex I disease" or a "Complex I and Complex III disease" is an oversimplification. By carefully understanding the complexities of patients with mitochondrial disease or disorders, the probability of an accurate diagnosis can be increased and better clinical trials can be constructed.

Download Clinical Scoring for Diagnostic Assessment.

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There are three Categories of Diagnostic Criteria: Clinical, Biochemical and Genetic. Think of it as a very long restaurant menu but, instead of selecting one from column A and one from column B, physicians involve multiple tests from these three broader categories.

Once these tests have been performed, experienced physicians diagnose according to specific criteria categorization:
Unlikely: Criteria-- 1-7 tests are normal
Possible: Criteria-- a single test is abnormal and the other tests are normal or equivocal
Probable: Criteria--two tests are abnormal
Highly Probable: greater than two tests are abnormal

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