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Important Events in Mitochondrial Disease Research - Doug Wallace:

Human Mitochondrial Map


"My colleagues and I were the first to prove that defects in energy metabolism can cause disease. This was accomplished by identifying the first pathogenic mitochondrial DNA mutation which altered a mtDNA-encoded protein. This mutation causes a form of blindness known as Leber’s Hereditary Optic Neuropathy (LHON), a mitochondrial disease. "

Since these discoveries in the late 1980s, many more mitochondrial diseases have been identified. Over 150 mtDNA mutations have been identified and hundreds of mtDNA rearrangements have been mapped. Examples of some of the symptoms that have already been linked to mitochondrial disorders include blindness, deafness, movement disorders, dementia, epilepsy, strokes, cardiomyopathy, progressive muscle weakness, vomiting and intestinal dysmotility, renal dysfunction, organic acidemia and aciduria, short stature, diabetes mellitus, neonatal hemochromatosis, and a variety of forms of cancer

Because of the systemic importance of the mitochondria and the variability in the phenotypes seen for each mutation, it is clear that no one set of diagnostic criteria can currently define mitochondrial disease. Indeed, much of disease that currently is viewed as idopathy (due to unknown causes) may eventually be shown to be caused by mitochondrial defects. Hence, it has almost become standard for many clinical geneticists to rule out all known forms of hereditary disease, and then refer some of the remaining complex cases to a comprehensive center like ours for a mitochondrial evaluation. This is being expanded even further since there there is growing evidence that mitochondrial dysfunction plays a role in a number of common clinical enigmatic diseases, including Alzheimer’s and Parkinson’s disease, cancer and even aging itself. Therefore, there is still a great deal of exploratory research that needs to be done to define the role of mitochondrial defects in disease.

Many of the methods that we and other state of the art centers around the world have pioneered in developing have become standard-of-care in the 14 years since we reported the LHON mutation and thus established Mitochondrial Medicine as a legitimate clinical discipline. Among these are the detection of certain organic and amino acids in blood, urine and cerebral spinal fluid profiles; the isolation of mitochondria from fresh muscle tissue and assay for specific mitochondrial enzyme defects; the screening of the mtDNA for rearrangements and mtDNA depletion; and the assaying for a number of known mtDNA pathogenic mutations. All of these tests are now considered standard-of-care and can be billed under established CPT codes. However, many of our patients with the same array of symptoms are subsequently shown to not have any of the known mtDNA or nDNA mitochondrial gene mutations.