Mitochondrial diseases: what is it, examples, symptoms, treatment, prognosis

What are mitochondrial diseases?

Mitochondrial diseases Is a group of diseases caused by dysfunctional mitochondria, organelles that generate energy for cells. Mitochondria are found in every cell of the human body except red blood cells (erythrocytes), and convert the energy of food molecules into adenosine triphosphate (ATP), which provides most of the functions cells.

Mitochondrial diseases take on unique characteristics both because diseases are often hereditary and because mitochondria are so important for cell function. A subclass of these diseases that have neuromuscular symptoms are sometimes referred to as mitochondrial myopathies.

Signs and symptoms

Symptoms of mitochondrial disease include:

• poor growth;
• loss of muscle coordination;
• muscle weakness;
• vision problems
• hearing problems;
• inability to learn;
• heart diseases;
• liver disease;
• kidney disease;
• gastrointestinal diseases;
• respiratory disorders;
• neurological problems;
• autonomic dysfunction;
• dementia.

Acquired conditions in which mitochondrial dysfunction is implicated include:

• diabetes;
• Huntington's disease;
• cancer;
• Alzheimer's disease;
• Parkinson's disease;
• bipolar disorder, schizophrenia, anxiety disorders;
• cardiovascular diseases;
• sarcopenia;
• chronic fatigue syndrome.

The body and each mutation is modulated by other variants of the genome; a mutation that can cause liver disease in one person can cause a brain disorder in another. The severity of a particular defect can also be high or low. Some disorders include exercise intolerance. Defects often affect mitochondria and multiple tissues more strongly, leading to multi-systemic diseases.

Typically, mitochondrial diseases are worse when defective mitochondria are present in the muscles, the brain, or nerves, as these cells use more energy than most other cells in the body.

Although mitochondrial diseases vary greatly in manifestation from person to person, several main clinical categories have been identified. conditions based on the most common phenotypic traits, symptoms and signs associated with specific mutations, which are usually call them.

Causes

Mitochondrial disorders can be caused by mutations (acquired or inherited) in mitochondrial DNA (mtDNA) or nuclear genes that code for mitochondrial components. They can also be the result of acquired mitochondrial dysfunction due to side effects of drugs, infections, or other environmental factors.

Nuclear DNA has two copies per cell (except for sperm and eggs), one copy is inherited from the father and the other from the mother. However, mitochondrial DNA is inherited only from the mother (with a few exceptions), and each mitochondrial organelle usually contains 2 to 10 copies of mtDNA. During cell division, mitochondria are randomly split between two new cells. These mitochondria make more copies, typically reaching 500 mitochondria per cell. Because mtDNA is copied when mitochondria proliferate, they can accumulate random mutations - a phenomenon called heteroplasmy. If only a few copies of mtDNA inherited from the mother are defective, mitochondrial division can lead to the fact that most of the defective copies will be in only one of the new mitochondria. Mitochondrial disease can become clinically apparent when the number of affected mitochondria reaches a certain level; this phenomenon is called "expression threshold".

Mitochondria possess many of the same DNA repair pathways as nuclei, but not all; therefore, mutations occur more frequently in mitochondrial DNA than in nuclear DNA. This means that mitochondrial DNA abnormalities can occur spontaneously and relatively frequently. Defects in the enzymes that control mitochondrial DNA replication (all of which are encoded by nuclear DNA genes) can also cause mutations in mitochondrial DNA.

Much of mitochondrial function and biogenesis is controlled by nuclear DNA. Human mitochondrial DNA encodes 13 proteins in the respiratory chain, while most of the approximately 1,500 proteins and components targeting mitochondria are encoded by the nucleus. Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes, including anemia, dementia, arterial hypertension, lymphoma, retinopathy, epilepsy and developmental disorders of the nervous system.

In a study by scientists at Yale University (published February 12, 2004. in issue New England Journal of Medicine) studied the role of mitochondria in resistance to insulin in the descendants of patients with type 2 diabetes. Other studies have shown that this mechanism may involve interrupting mitochondrial signaling in the body's cells (intramyocellular lipids). A study at the Pennington Center for Biomedical Research in Baton Rouge, Louisiana found that this, in turn, partially disables genes that make mitochondria.

Examples of mitochondrial diseases

Examples of mitochondrial diseases include:

• Mitochondrial myopathy.
• Syndrome diabetes mellitus and deafness:
  • this combination at an early age may be associated with mitochondrial disease;
  • diabetes mellitus and deafness can occur simultaneously for other reasons.
• Leber's hereditary optic neuropathy:
  • loss of vision starting at a young age;
  • eye disease characterized by progressive loss of central vision due to degeneration of the optic nerves and retina;
  • affects 1 in 50,000 people in Finland.
• Leigh's syndrome, subacute sclerosing encephalopathy:
  • after normal development of the child, the disease usually begins at the end of the first year of life, although the onset may occur in adulthood;
  • there is a rapid decrease in function, which is accompanied by seizures, altered state of consciousness, dementia, and respiratory failure.
• Neuropathy, ataxia, retinitis pigmentosa and ptosis (from the English. Neuropathy, ataxia, and retinitis pigmentosa [NARP syndrome]):
  • progressive symptoms as described in the acronym
  • dementia.
• Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE):
  • intestinal pseudo-obstruction;
  • neuropathy.
• Myoclonic epilepsy with torn red muscle fibers (MERRF syndrome) Myoclonic Epilepsy with Ragged Red Fibers):
  • progressive myoclonic epilepsy;
  • “Torn red fibers” are accumulations of damaged mitochondria that accumulate in the sub-sarcolemmal region of the muscle fiber and appear when the muscle is stained with modified trichromic Gomori staining;
  • short stature;
  • hearing loss;
  • lactic acidosis;
  • intolerance to physical activity.
• MELAS syndrome (from the English. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes);
• Mitochondrial DNA depletion syndrome.

Conditions such as Friedreich's ataxia, can affect mitochondria, but are not associated with mitochondrial proteins.

Epidemiology

About 1 in 4,000 children will develop mitochondrial disease by age 10. Up to 4,000 babies a year are born with a type of mitochondrial disease. Because mitochondrial disorders contain many variations and subsets, some specific mitochondrial diseases are very rare.

Diagnostics

Mitochondrial diseases are usually detected by analyzing muscle samples in which the presence of these organelles is higher. The most common tests for these diseases are:

1. Southern blotting for a specific DNA sequence in a sample.
2. Polymerase chain reaction and testing for specific mutations.
3. Sequencing.

Treatment

Although research is ongoing, treatment options are currently limited; vitamins are often prescribed, although evidence for their effectiveness is limited. Pyruvate was proposed in 2007 as a treatment option. N-acetylcysteine ​​reverses many patterns of mitochondrial dysfunction. In the case of mood disorders, in particular bipolar disorder, it is assumed that N-acetylcysteine, acetyl-L-carnitine, S-adenosylmethionine, coenzyme Q10, alpha lipoic acid, creatine monohydrate, and melatonin may be potential options treatment.

- Gene therapy before conception.

Spindle transfer, in which nuclear DNA is transferred to another healthy egg, leaving a defective mitochondrial DNA is a potential treatment that has been successfully performed on monkeys. Using a similar pronucleus transfer technique, researchers at the University of Newcastle, led by Douglas Turnbull, have successfully transplanted healthy DNA from human eggs from women with mitochondrial diseases into unaffected eggs donor women. In such cases, ethical questions arise regarding biological motherhood, since the child receives genes and gene regulatory molecules from two different women. The use of genetic engineering in the attempt to produce children free of mitochondrial diseases is controversial in some quarters and raises important ethical questions. In 2016, a male child was born in Mexico to a mother with Leigh's syndrome using spindle transfer.

In September 2012 a public consultation has been launched in the UK to explore related ethical issues. Human genetic engineering has been used on a small scale to allow infertile women with genetic mitochondrial defects to have children. In June 2013, the UK government agreed to draft legislation to legalize IVF with using DNA from three people "as a treatment to correct or eliminate mitochondrial diseases that are transmitted from mother to child.

Forecast

In general, mitochondrial diseases are progressive diseases, and a significant number of children with mitochondrial disorders do not reach adulthood. The rate of progression can be variable and unpredictable, but most patients will eventually develop multiple organ damage.