Mitochondrial disease

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Mitochondrial disease
Other namesMitochondrial cytopathy; mitochondriopathy (MCP)
Ragged red fibres - gtc - very high mag.jpg
Micrograph showing ragged red fibers, a finding seen in various types of mitochondrial diseases. Muscle biopsy. Gomori trichrome stain.
Specialty Medical genetics

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

Contents

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

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

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

Presentation

Associated conditions

Acquired conditions in which mitochondrial dysfunction has been involved include:

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] 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 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. [19]

Example of a pedigree for a genetic trait inherited by mitochondrial DNA in animals and humans. Offspring of the males with the trait don't inherit the trait. Offspring of the females with the trait always inherit the trait (independently from their own gender). Maternal Inheritance - mitochondrial DNA.png
Example of a pedigree for a genetic trait inherited by mitochondrial DNA in animals and humans. Offspring of the males with the trait don't inherit the trait. Offspring of the females with the trait always inherit the trait (independently from their own gender).

Nuclear DNA has two copies per cell (except for sperm and egg cells), one copy being inherited from the father and the other from the mother. Mitochondrial DNA, however, is inherited from the mother only (with some exceptions) and each mitochondrion typically contains between 2 and 10 mtDNA copies. During cell division the mitochondria segregate randomly between the two new cells. Those mitochondria make more copies, normally reaching 500 mitochondria per cell. As mtDNA is copied when mitochondria proliferate, they can accumulate random mutations, a phenomenon called heteroplasmy. 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".

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 nuclear DNA. Human mitochondrial DNA encodes 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 neurodevelopmental disorders. [21]

A study by Yale University researchers (published in the February 12, 2004, issue of the New England Journal of Medicine ) explored the role of mitochondria in insulin resistance among the offspring of patients with type 2 diabetes. [22] Other studies have shown that the mechanism may involve the interruption of the mitochondrial signaling process in body cells (intramyocellular lipids). A study conducted at the Pennington Biomedical Research Center in Baton Rouge, Louisiana [23] showed that this, in turn, partially disables the genes that produce mitochondria.

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. [25]

The glycogen generation capacity is entirely dependent on, and determined by, the operating levels of the mitochondria in all of the cells of the human body; [27] however, the relation between the energy generated by the mitochondria and the glycogen capacity is very loose and is mediated by many biochemical pathways. [24] The energy output of full healthy mitochondrial function can be predicted exactly by a complicated theoretical argument, but this argument is not straightforward, as most energy is consumed by the brain and is not easily measurable.

Diagnosis

Mitochondrial diseases are usually detected by analysing muscle samples, where the presence of these organelles is higher. The most common tests for the detection of these diseases are:

  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] Pyruvate has been proposed in 2007 as a treatment option. [30] N-acetyl cysteine reverses many models of mitochondrial dysfunction. [31]

Mood disorders

In the case of mood disorders, specifically bipolar disorder, it is hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options. [32]

Gene therapy prior to conception

Mitochondrial replacement therapy (MRT), where the nuclear DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind, is an IVF treatment procedure. [33] Using a similar pronuclear transfer technique, researchers at Newcastle University led by Douglass Turnbull successfully transplanted healthy DNA in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected. [34] [35] In such cases, ethical questions have been raised regarding biological motherhood, since the child receives genes and gene regulatory molecules from two different women. Using genetic engineering in attempts to produce babies free of mitochondrial disease is controversial in some circles and raises important ethical issues. [36] [37] A male baby was born in Mexico in 2016 from a mother with Leigh syndrome using MRT. [38]

In September 2012 a public consultation was launched in the UK to explore the ethical issues involved. [39] Human genetic engineering was used on a small scale to allow infertile women with genetic defects in their mitochondria to have children. [40] In June 2013, the United Kingdom government agreed to develop legislation that would legalize the 'three-person IVF' procedure as a treatment to fix or eliminate mitochondrial diseases that are passed on from mother to child. The procedure could be offered from 29 October 2015 once regulations had been established. [41] [42] [43] 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.

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:

Related Research Articles

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

<span class="mw-page-title-main">Mitochondrial DNA</span> DNA located in mitochondria

Mitochondrial DNA is the DNA located in the mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the DNA contained in a eukaryotic cell; most of the DNA is in the cell nucleus, and, in plants and algae, the DNA also is found in plastids, such as chloroplasts.

<span class="mw-page-title-main">Wolfram syndrome</span> Human disease

Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can start to appear as early as childhood to adult years. There is a 25% recurrence risk in children.

<span class="mw-page-title-main">Leigh syndrome</span> Metabolic disease

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Human mitochondrial genetics</span> Study of the human mitochondrial genome

Human mitochondrial genetics is the study of the genetics of human mitochondrial DNA. The human mitochondrial genome is the entirety of hereditary information contained in human mitochondria. Mitochondria are small structures in cells that generate energy for the cell to use, and are hence referred to as the "powerhouses" of the cell.

<span class="mw-page-title-main">Leber's hereditary optic neuropathy</span> Mitochondrially inherited degeneration of retinal nerve cells

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predominantly affects young adult males. LHON is transmitted only through the mother, as it is primarily due to mutations in the mitochondrial genome, and only the egg contributes mitochondria to the embryo. Men cannot pass on the disease to their offspring. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Muscle disorders caused by mitochondrial dysfunction

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">MELAS syndrome</span> Mitochondrial disease

MELAS is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

<span class="mw-page-title-main">MERRF syndrome</span> Mitochondrial disorder

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

<span class="mw-page-title-main">Neuropathy, ataxia, and retinitis pigmentosa</span> Medical condition

Neuropathy, ataxia, and retinitis pigmentosa, also known as NARP syndrome, is a rare disease with mitochondrial inheritance that causes a variety of signs and symptoms chiefly affecting the nervous system Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs ; muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have vision loss caused by changes in the light-sensitive tissue that lines the back of the eye. In some cases, the vision loss results from a condition called retinitis pigmentosa. This eye disease causes the light-sensing cells of the retina gradually to deteriorate.

<span class="mw-page-title-main">Mitochondrial neurogastrointestinal encephalopathy syndrome</span> Medical condition

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudoobstruction. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene.

Pearson syndrome is a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Other clinical features are failure to thrive, pancreatic fibrosis with insulin-dependent diabetes and exocrine pancreatic deficiency, muscle and neurologic impairment, and, frequently, early death. It is usually fatal in infancy. The few patients who survive into adulthood often develop symptoms of Kearns–Sayre syndrome. It is caused by a deletion in mitochondrial DNA. Pearson syndrome is very rare: fewer than a hundred cases have been reported in medical literature worldwide.

<span class="mw-page-title-main">MT-ND6</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the human MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.

<span class="mw-page-title-main">MT-ATP6</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP6 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Mutations in the MT-ATP6 gene have been found in approximately 10 to 20 percent of people with Leigh syndrome.

<span class="mw-page-title-main">NDUFS3</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11. This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase. Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.

<span class="mw-page-title-main">NDUFS6</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial is an enzyme that in humans is encoded by the NDUFS6 gene.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

<span class="mw-page-title-main">Mitochondrial DNA depletion syndrome</span> Medical condition

Mitochondrial DNA depletion syndrome, or Alper's disease, is any of a group of autosomal recessive disorders that cause a significant drop in mitochondrial DNA in affected tissues. Symptoms can be any combination of myopathic, hepatopathic, or encephalomyopathic. These syndromes affect tissue in the muscle, liver, or both the muscle and brain, respectively. The condition is typically fatal in infancy and early childhood, though some have survived to their teenage years with the myopathic variant and some have survived into adulthood with the SUCLA2 encephalomyopathic variant. There is currently no curative treatment for any form of MDDS, though some preliminary treatments have shown a reduction in symptoms.

Mitochondrial optic neuropathies are a heterogenous group of disorders that present with visual disturbances resultant from mitochondrial dysfunction within the anatomy of the Retinal Ganglion Cells (RGC), optic nerve, optic chiasm, and optic tract. These disturbances are multifactorial, their aetiology consisting of metabolic and/or structural damage as a consequence of genetic mutations, environmental stressors, or both. The three most common neuro-ophthalmic abnormalities seen in mitochondrial disorders are bilateral optic neuropathy, ophthalmoplegia with ptosis, and pigmentary retinopathy.

Taosheng Huang is a physician-scientist with substantial academic achievements and professional experience in translational research, specifically, in human mitochondrial genetics. He is a full Professor and Director of the Molecular Diagnostic Laboratory in the Division of Human Genetics at Cincinnati Children’s Hospital Medical Center (CCHMC). Huang has published over 100 manuscripts in many impactful journals.

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  35. ↑ Craven, Lyndsey; Tuppen, Helen A.; Greggains, Gareth D.; Harbottle, Stephen J.; Murphy, Julie L.; Cree, Lynsey M.; Murdoch, Alison P.; Chinnery, Patrick F.; Taylor, Robert W.; Lightowlers, Robert N.; Herbert, Mary; Turnbull, Douglass M. (2010). "Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease". Nature. 465 (7294): 82–85. Bibcode:2010Natur.465...82C. doi:10.1038/nature08958. PMC   2875160 . PMID   20393463. Open Access logo PLoS transparent.svg
  36. ↑ "UK urged to permit IVF procedure to prevent fatal genetic diseases". The Guardian. London. 2015-04-30.
  37. ↑ "Three parent baby law is 'irresponsible' says Church of England ahead of vote". The Telegraph. London. 2015-04-30.
  38. ↑ Hamzelou, Jessica (2016-09-27). "Exclusive: World's first baby born with new "3 parent" technique". New Scientist. Retrieved 2016-11-26.
  39. ↑ Sample, Ian (2012-09-17). "Regulator to consult public over plans for new fertility treatments". The Guardian. London. Retrieved 8 October 2012.
  40. ↑ "Genetically altered babies born". BBC News. 2001-05-04. Retrieved 2008-04-26.
  41. ↑ The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 No. 572
  42. ↑ "UK government backs three-person IVF". BBC News. 27 June 2013.
  43. ↑ Knapton, Sarah (1 March 2014) 'Three-parent babies' could be born in Britain next year The Daily Telegraph Science News, Retrieved 1 March 2014
  44. ↑ The Mitochondrial and Metabolic Disease Center
  45. ↑ Gorman, Gráinne S.; Grady, John P.; Ng, Yi; Schaefer, Andrew M.; McNally, Richard J.; Chinnery, Patrick F.; Yu-Wai-Man, Patrick; Herbert, Mary; Taylor, Robert W.; McFarland, Robert; Turnbull, Doug M. (26 February 2015). "Mitochondrial Donation — How Many Women Could Benefit?". New England Journal of Medicine. 372 (9): 885–887. doi:10.1056/NEJMc1500960. PMC   4481295 . PMID   25629662.
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  47. ↑ "Young poet, peace advocate Mattie dies | the Spokesman-Review".
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