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 life-forms (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 disorders may be caused by mutations, acquired or inherited, in mitochondrial DNA (mtDNA) or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes (see MeSH).

Mitochondrial DNA inheritance behaves differently from autosomal and sex-linked inheritance. Nuclear DNA has two copies per cell (except for sperm and egg cells), and one copy is inherited from the father and the other from the mother. Mitochondrial DNA, however, is strictly inherited from the mother and each mitochondrial organelle typically contains multiple mtDNA copies (see Heteroplasmy). During cell division, the mitochondrial DNA copies segregate randomly between the two new mitochondria, and then those new mitochondria make more copies. As a result, if only a few of the mtDNA 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 (for more detailed inheritance patterns, see Human mitochondrial genetics). Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called 'threshold expression'.

Mitochondrial DNA mutations occur frequently, due to the lack of the error checking capability that nuclear DNA has (see Mutation rate). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. In addition, defects in enzymes that control mitochondrial DNA replication (all of which are encoded for by genes in the nuclear DNA) may cause mitochondrial DNA mutations.

Most mitochondrial function and biogenesis is controlled by nuclear DNA. In human, the mitochondrial DNA encodes only 13 proteins of the respiratory chain, while most of the estimated 1,500 proteins and components targeted to mitochondria are nuclear-encoded. Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes including anemia, dementia, hypertension, lymphoma, retinopathy, seizures, and many neurodevelopmental disorders .

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.

More speculatively, embryonic mitochondrial transplant and protofection have been proposed as a possible treatment for inherited mitochondrial disease, and allotopic expression of mitochondrial proteins as a radical treatment for mtDNA mutation load.

External links

• United Mitochondrial Disease Foundation - Patient and clinician resources
• 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
• MitoPhenome at Stanford University