Mitochondrial disease

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Mitochondrial diseases are a group of disorders relating to the mitochondria, the organelles that are the "powerhouses" of the eukaryotic cells that comprise higher-order lifeforms (including humans). The mitochondria convert the energy of food molecules into the ATP that powers most cell functions.

Mitochondrial diseases comprise those disorders that in one way or another affect the function of the mitochondria and/or are due to mitochondrial DNA. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease symptoms are often referred to as a mitochondrial myopathy.

[edit] Mitochondrial inheritance

Mitochondrial inheritance behaves differently from autosomal and sex-linked inheritance. Nuclear DNA has two copies per cell (except for sperm and egg cells). One copy is inherited from the father and the other from the mother. Mitochondria, however, contain their own DNA, and contain typically from five to ten copies, all inherited from the mother (for more detailed inheritance patterns, see Human mitochondrial genetics). When mitochondria divide, the copies of DNA present are divided randomly between the two new mitochondria, and then those new mitochondria make more copies. As a result, if only a few of the DNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria. Mitochondrial disease begins to become apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called 'threshold expression'.

Not all of the enzymes and other components necessary for proper mitochondrial function are encoded in the mitochondrial DNA. Most mitochondrial function is controlled by nuclear DNA instead.

Mutations to mitochondrial DNA occur frequently, due to the lack of the error checking capability that nuclear DNA has. This means that mitochondrial disorders often occur spontaneously and relatively often. Sometimes the enzymes that control mitochondrial DNA duplication (and which are encoded for by genes in the nuclear DNA) are defective, causing mitochondrial DNA mutations to occur at a rapid rate.

[edit] Defects and symptoms

The effects of mitochondrial disease can be quite varied. Since the distribution of defective DNA may vary from organ to organ within the body, the mutation that in one person may cause liver disease might in another person cause a brain disorder. In addition, the severity of the defect may be great or small. Some minor defects cause only "exercise intolerance", with no serious illness or disability. Other defects can more severely affect the operation of the mitochondria and can cause severe body-wide impacts. As a general rule, mitochondrial diseases are worst when the defective mitochondria are present in the muscles or nerves, because these are the most energy-hungry cells of the body.

However, even though mitochondrial disease varies greatly in presentation from person to person, several major categories of the disease have been defined, based on the most common symptoms and the particular mutations that tend to cause them:

Mendelian Inheritance in Man (OMIM) 157640 Progressive external ophthalmoplegia (PEO)
- progressive ophthalmoparesis is the cardinal feature
- symptomatic overlap with many of the illnesses described below
Mendelian Inheritance in Man (OMIM) 520000 Diabetes mellitus and deafness (DAD)
- this combination at an early age can be due to mitochondrial disease
- Diabetes mellitus and deafness can be found together for other reasons as well
Mendelian Inheritance in Man (OMIM) 535000 Leber hereditary optic neuropathy (LHON)
- visual loss beginning in young adulthood
- Wolff-Parkinson-White syndrome
- multiple sclerosis-type disease
Mendelian Inheritance in Man (OMIM) 540000 Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)
- varying degrees of cognitive impairment and dementia
- lactic acidosis
- strokes
- transient ischemic attacks
- hearing loss
- dysmotility
- weight loss
Mendelian Inheritance in Man (OMIM) 545000 Myoclonic epilepsy and ragged-red fibers (MERRF)
- progressive myoclonic epilepsy
- clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "ragged-red fibers" when muscle is stained with modified Gomori trichrome stain
- short stature
Mendelian Inheritance in Man (OMIM) 256000 Leigh syndrome, subacute sclerosing encephalopathy
- after normal development the disease usually begins late in the first year of life, but the onset may occur in adulthood
- a rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, ventilatory failure
Mendelian Inheritance in Man (OMIM) 551500 Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)
- progressive symptoms as described in the acronym
- dementia
Mendelian Inheritance in Man (OMIM) 530000 Kearns-Sayre syndrome (KSS)
- external ophthalmoplegia
- cardiac conduction defects
- sensory-neural hearing loss
Mendelian Inheritance in Man (OMIM) 603041 Myoneurogenic gastrointestinal encephalopathy (MNGIE)
- gastrointestinal pseudo-obstruction
- neuropathy