Mitochondrial disease

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Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction.

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. A subclass of these diseases that have neuromuscular symptoms are known as mitochondrial myopathies.

Types

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Mitochondrial disease can manifest in many different ways^[1] whether in children^[2] or adults.^[3] Examples of mitochondrial diseases include:

• Mitochondrial myopathy^[2][3]
• Maternally inherited
  diabetes mellitus and deafness (MIDD)^[4]
  • While
    diabetes mellitus and deafness can be found together for other reasons, at an early age this combination can be due to mitochondrial disease, as may occur in Kearns–Sayre syndrome and Pearson syndrome^[2]
• Leber's hereditary optic neuropathy (LHON)^[3]
  • LHON is an eye disorder characterized by progressive loss of central vision due to degeneration of the optic nerves and retina (apparently affecting between 1 in 30,000 and 1 in 50,000 people^[5]); visual loss typically begins in young adulthood^[2]
• Leigh syndrome, subacute necrotizing encephalomyelopathy^[6]
  • after normal development the disease usually begins late in the first year of life, although 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
• MERRF syndrome
  • progressive myoclonic epilepsy
  • "Ragged Red Fibers" are clumps of diseased mitochondria that accumulate in the subsarcolemmal region of the muscle fiber and appear when muscle is stained with modified Gömöri trichrome stain
  • short stature
  • hearing loss
  • lactic acidosis
  • exercise intolerance
• MELAS syndrome, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
• Mitochondrial DNA depletion syndrome

Conditions such as

Presentation

Associated conditions

Acquired conditions in which mitochondrial dysfunction has been involved are:

• diabetes
• Huntington's disease
• cancer
• Alzheimer's disease,^[7]
• Parkinson's disease
• bipolar disorder,^[8][9][10] schizophrenia, aging and senescence,^[11] anxiety disorders^[12]
• cardiovascular disease
• sarcopenia
• chronic fatigue syndrome^[9]
• ALS^[13]

The body, and each mutation, is modulated by other genome variants; the mutation that in one individual may cause liver disease might in another person cause a brain disorder. The severity of the specific defect may also be great or small. Some defects include exercise intolerance. Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.^[14]

It has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria, which suggested an increase in mitochondrial biogenesis.^[15] Interestingly, a recent study in Nature Nanotechnology has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes.^[16]

As a rule, mitochondrial diseases are worse when the defective mitochondria are present in the muscles, cerebrum, or nerves,^[17] because these cells use more energy than most other cells in the body.

Although mitochondrial diseases vary greatly in presentation from person to person, several major clinical categories of these conditions have been defined, based on the most common phenotypic features, symptoms, and signs associated with the particular mutations that tend to cause them.^{[citation needed]}

An outstanding question and area of research is whether ATP depletion or reactive oxygen species are in fact responsible for the observed phenotypic consequences.^{[citation needed]}

Cerebellar atrophy or hypoplasia has sometimes been reported to be associated.^[18]

Causes

Mitochondrial disorders may be caused by

Mitochondria possess many of the same DNA repair pathways as nuclei do—but not all of them;[20] therefore, mutations occur more frequently in mitochondrial DNA than in nuclear DNA (see Mutation rate). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. Defects in enzymes that control mitochondrial DNA replication (all of which are encoded for by genes in the nuclear DNA) may also cause mitochondrial DNA mutations.

Most mitochondrial function and biogenesis is controlled by

Mechanisms

The effective overall energy unit for the available body energy is referred to as the daily glycogen generation capacity,^[24][25][26] and is used to compare the mitochondrial output of affected or chronically glycogen-depleted individuals to healthy individuals. This value is slow to change in a given individual, as it takes between 18 and 24 months to complete a full cycle.^[25]

The glycogen generation capacity is entirely dependent on, and determined by, the operating levels of the

1. Southern blot to detect large deletions or duplications
2. Polymerase chain reaction and specific mutation testing^[28]
3. Sequencing

Treatments

Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited.^[29]

In June 2018 Australian Senate's Senate Community Affairs References Committee recommended a move towards legalising Mitochondrial replacement therapy (MRT). Research and clinical applications of MRT were overseen by laws made by federal and state governments. State laws were, for the most part, consistent with federal law. In all states, legislation prohibited the use of MRT techniques in the clinic, and except for Western Australia, research on a limited range of MRT was permissible up to day 14 of embryo development, subject to a license being granted. In 2010, the Hon. Mark Butler MP, then Federal Minister for Mental Health and Ageing, had appointed an independent committee to review the two relevant acts: the Prohibition of Human Cloning for Reproduction Act 2002 and the Research Involving Human Embryos Act 2002. The committee's report, released in July 2011, recommended the existing legislation remain unchanged

Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in Leber's hereditary optic neuropathy.

Epidemiology

About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease.^[44] Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.

The average number of births per year among women at risk for transmitting mtDNA disease is estimated to approximately 150 in the United Kingdom and 800 in the United States.^[45]

History

The first pathogenic mutation in mitochondrial DNA was identified in 1988; from that time to 2016, around 275 other disease-causing mutations were identified.^[46]

Notable cases

Notable people with mitochondrial disease include:

• Mattie Stepanek, a poet, peace advocate, and motivational speaker who had dysautonomic mitochondrial myopathy, and who died at age 13.^[47]
• Rocco Baldelli, a coach and former center fielder in Major League Baseball who had to retire from active play at age 29 due to mitochondrial channelopathy.
• Charlie Gard, a British boy who had mitochondrial DNA depletion syndrome; decisions about his care were taken to various law courts.
• Charles Darwin, a nineteenth century naturalist who suffered from a disabling illness, is speculated to have MELAS syndrome.^[48]

References

External links

Wikimedia Commons has media related to Mitochondrial diseases.

• Mitochondrial disease at
  Curlie
• International Mito Patients (IMP)