Mitochondrial disease

Mitochondrial disease
Specialty	Endocrinology

Mitochondrial diseases are a group of disorders relating to the mitochondria, the organelles that are the "powerhouses" of the eukaryotic cells that compose 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.

Classification

In addition to the Mitochondrial myopathies, other examples include:

• 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

• Leber's hereditary optic neuropathy (LHON)
  • visual loss beginning in young adulthood
  • Wolff-Parkinson-White syndrome
  • multiple sclerosis-type disease

• 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

• Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)
  • progressive symptoms as described in the acronym
  • dementia

• Myoneurogenic gastrointestinal encephalopathy (MNGIE)
  • gastrointestinal pseudo-obstruction
  • neuropathy

Characteristics

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 worse when the defective mitochondria are present in the muscles, cerebrum, 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.

An outstanding question and active area of research is whether ATP depletion or reactive oxygen species are in fact responsible for the observed phenotypic consequences.

Causes

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 (see Heteroplasmy), all inherited from the mother (for more detailed inheritance patterns, see Human mitochondrial genetics). When the mitochondrion divides, 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.

Treatment

Although research is ongoing, treatment options are currently limited, though vitamins are frequently prescribed.

Pyruvate has been proposed recently as a treatment option. Some are pushing resveratrol to this end.

External links

• Mitochondrial disease at Curlie
• mt-overview at NIH/UW GeneTests - "Mitochondrial Disorders Overview"
• kss at NIH/UW GeneTests - "Mitochondrial DNA Deletion Syndromes"
• Genetics home reference overview at NLM
• Overview at Washington University in St. Louis
• Mitochondrial Disease Symptoms Guide for Clinicians at the Mitochondrial Disease Action Committee