Mitochondrial disease

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Classification according to ICD-10
G31.81 Mitochondrial cytopathy
ICD-10 online (WHO version 2019)

Mitochondrial diseases are diseases caused by malfunction or damage to the mitochondria .

Since the cell organelles are primarily responsible for the provision of energy (in the form of ATP ) in the body cells, these diseases are usually noticeable through massive weakness, tiredness and the like.

There are two types of mitochondrial disease: inherited and environmental mitochondrial disease (also called secondary mitochondrial disease). The transition between the two forms of mitochondrial disease can be fluid: For example, inherited mitochondrial disease can only come into play in adulthood if it was initially less pronounced ( subclinical ) and only leads to symptoms that are no longer tolerable for the patient when certain environmental factors are also added have a negative effect. Acquired mitochondrial disease can also be inherited if a high proportion of the mitochondria of the fertilized egg cell have been (irreversibly) damaged by environmental influences.

Forms of mitochondrial disease

Inherited Mitochondriopathies

The inherited mitochondriopathies are caused by gene mutations that affect enzymes or metabolic pathways of the mitochondrion. These genetic defects can affect the 13 protein subunits of the respiratory chain complexes I, III, IV, V encoded on the mitochondrial DNA (16,569  bp ) , the 22 tRNAs and the two rRNAs (mitochondrially encoded mitochondriopathy) or one of the approximately 1000 im Cell nucleus encoded proteins that are imported into the mitochondria (nuclear encoded mitochondrial disease). Mitochondrially and nuclear-coded genetic defects are already present at birth. Symptoms of inherited mitochondrial disease usually appear in childhood and adolescence, so treatment is mainly used in pediatrics . The symptoms of inherited mitochondriopathies mainly affect the particularly energy-dependent nervous and muscular system. They are not causal, but only treatable to alleviate symptoms.

Acquired Mitochondrial Disorders

A dysfunction of the mitochondria that is only acquired in the course of life may play a role in the pathophysiology of various other diseases. It is assumed that the mitochondria themselves lose their function as a result of environmental influences or as a result of the disease and that the energy supply to the cells and organs deteriorates. This damage can be at the beginning of a disease or only become relevant when the disease is already well advanced. Significant involvement of mitochondrial damage can only be regarded as certain for a few diseases. Are called, among other neurodegenerative diseases ( Alzheimer's disease , Parkinson's disease , amyotrophic lateral sclerosis , diabetes mellitus , cardiovascular disease , cancer and obesity ).

Inherited Mitochondriopathies

Inherited mitochondriopathies result from mutations in genes that are important for the structure or metabolism of the mitochondria. Their effects can affect many organ systems. In practice, however, the diseases are particularly evident in organs that consume a lot of energy, for example the brain and nervous system with the sensory organs, the heart or the skeletal muscles , which are usually the most impaired in these diseases. The diagnosis is confirmed by a muscle biopsy.

Inheritance

Since mitochondria own DNA , the mtDNA have, and the mitochondria of the sperm are located exclusively in the tail part in the fertilization is discarded and thus remains outside the egg, are mutations of mitochondrial DNA exclusively maternal ( maternal ) inherited. In contrast, nuclear-coded mitochondriopathies, the cause of which is a mutation in the DNA of the cell nucleus, can be inherited as autosomal dominant, autosomal recessive or X-linked, depending on the chromosomal location and the mechanism of the mutation.

Since the egg cell contains hundreds of mitochondria, which are distributed unevenly over the embryo's tissues in the course of embryonic development, the proportion of mutated mitochondria in the child's organism can vary greatly (so-called heteroplasmia ). The ratio of mutated to original DNA is decisive for the phenotypic expression of the mutation, so that ultimately serious or even fatal diseases can be passed on unnoticed.

root cause

The main function of the mitochondria is to provide high- energy ATP for the cells through the burning of fatty acids, the breakdown of acetyl-CoA and oxidative phosphorylation in the respiratory chain . If one or more structural proteins of fatty acid oxidation , the citric acid cycle or the respiratory chain are disturbed due to mutations , this has an impact on the entire metabolism of the cell due to the inadequate availability of energy, since all energy-consuming steps are slowed down. Different respiratory chain enzymes have a tissue specificity so that only one or more organs can be affected in the various diseases.

Classification

A classification of this very diverse group of diseases can be made from various points of view. On the one hand, one can use the underlying metabolic defect, on the other hand, the clinical picture of the disease for categorization.

Biochemical classification

Since various metabolic pathways involved in energy production take place within the mitochondria, each of which can be disturbed by corresponding enzyme defects, mitochondrial diseases can be classified according to the location of the (biochemical) disturbance.

Pyruvate Oxidation Defects

Pyruvate is a key substrate in the burning of grape sugar ( glucose ). If its further breakdown is disturbed, the end product of glucose combustion ( glycolysis ), acetyl-CoA , cannot be introduced into the citric acid cycle . Various subunits of the pyruvate dehydrogenase complex can be defective. The most common mutation is an X-linked semidominant inheritance.

Defects in lipid metabolism

As an alternative to burning sugar, the cells can also gain energy from burning fat. These metabolic processes also largely take place in the mitochondria. Among the disorders of lipid metabolism, the actual breakdown disorders ( disorders of β-oxidation ) and the disorders of the transport molecule necessary for the smuggling of fatty acids into the mitochondrion, the so-called carnitine (carnitine transporter defect, carnitine palmitoyl transferase deficiency I + II), be summarized. These diseases are inherited as an autosomal recessive trait.

Disorders of the citric acid cycle

In the citric acid cycle , acetyl-CoA is processed from glycolysis or fatty acid breakdown. It represents the penultimate step of the entire combustion process of carbohydrates before the respiratory chain. Defects on two levels are known, the ketoglutarate dehydrogenase (KDH) deficiency and the fumarase deficiency.

Respiratory chain defects

The respiratory chain is a system of five enzyme complexes and two electron carriers that are located in the inner membrane of the mitochondria. In the last step, it serves to produce high-energy ATP from ADP and a phosphate molecule as the cell's "general energy currency". This can lead to either disruption of the electron transport between complexes I , II , III , IV or a disruption of phosphorylation in ATP synthase (complex V). Since the respiratory chain complexes are made up of numerous subunits, some of which are encoded by mitochondrial and also by nuclear DNA, both X-linked and autosomal recessive inheritance patterns are possible.

Clinical Syndromes

To fulfill their tasks, the mitochondria are equipped with more than 50 enzymes, each of which consists of up to 40 proteins. Therefore, and due to the different organ specificity of individual mitochondrial enzymes, there are clinically extremely diverse combinations of different symptoms. Typical combinations are combined into syndromes, which in turn can be caused by different mutations. The following list does not claim to be complete.

Chronic Progressive External Ophthalmoplegia (CPEO)

The chronic progressive external ophthalmoplegia begins relatively late at the age of 15-40 years and is associated with progressive ( progressive ) Eye movement disorders and drooping eyelids ( ptosis ) accompanied. Individual deletions of mitochondrial DNA have been described as the cause . If multiple deletions are detected, there is more likely a nuclear defect, which leads to the incorrect reproduction of mitochondrial DNA.

Ophthalmoplegia plus (CPEOplus)

In addition to the paralysis of the external eye muscles, there are other symptoms such as involvement of the muscles, growth disorders, polyneuropathy, cognitive and other impairments. The transition to KSS is partly fluid.

Kearns-Sayre Syndrome (KSS)

In this syndrome, in addition to the symptoms of CPEO, there are also degenerative changes in the retina and cardiomyopathy with conduction disorders. The diagnosis can also be increased lactate and pyruvate levels in the cerebrospinal fluid .

Myoclonus epilepsy with " ragged red fibers "

This syndrome is commonly abbreviated as MERRF . It belongs to the group of progressive myoclonus epilepsies . In addition to the epilepsy that gives it its name, there is a serious general disease of the brain with progressive mental deterioration ( dementia ) and muscle weakness with a typical histological picture . The onset of the disease is usually between five and 15 years. The syndrome was first described in 1980.

MELAS syndrome

The acronym stands for M itochondriale E ncephalomyopathie (brain / muscle disorder), L actat a cidose (lactic acid overload) and S chlaganfall-like episodes and thus lists already the most important clinical symptoms. The patients are often short and can also have migraines and diabetes mellitus . The disease begins around 5–15 years of age. Among other things, a genetic defect has been found in a gene that codes for a tRNA . The syndrome was first described in 1984.

Leber optic atrophy

Abbreviated as LHON (for Leber's hereditary optic neuropathy), Leber's optic atrophy is characterized by a special form of optic nerve damage with retinal changes and is associated with painless visual loss. It is more common in men than women and begins in the second decade of life . It is named after the German ophthalmologist Theodor Karl Gustav von Leber , who first described it in 1868.

Leigh syndrome

The Leigh syndrome , synonym subacute necrotizing encephalopathy , is an independent syndrome, which usually manifests itself in the first to second year of life. It can be caused by different primary mitochondrial defects. In addition to mental retardation or even the loss of acquired skills, general muscle weakness, eye movement and swallowing disorders as signs of brain stem damage and ataxia are noticeable. The disease sometimes worsens acutely after common infections. Various mitochondrial and nuclear mutations have been described, including on the mitochondrial ribosome . It is named after the British neuropathologist and psychiatrist Archibald Denis Leigh, who first described it in 1951.

Symptoms

As already expressed in the exemplary list of clinical syndromes, different mitochondrial diseases lead to a very diverse pattern of symptoms. The main common ground that can be worked out is that organs that are heavily dependent on energy are particularly affected. Almost all diseases have neuromuscular symptoms, i.e. disorders that affect the nervous system and the muscles. They are associated in different ways with symptoms in the heart muscle, kidneys, and other independent organ systems. The course is also very variable. This is explained by the fact that not all mitochondria have to carry the genetic defect and the relationship between mutated and unchanged mitochondria has an important influence on the severity of the disease. Unfortunately, most diseases are rapidly progressing.

Diagnosis

The main finding of mitochondrial disease is lactic acid overload ( lactic acidosis ), which can be explained by a build-up of pyruvate before the citric acid cycle. This in turn leads to the alternative route of breakdown via lactate. The determination of the organic acids in the urine and the amino acids in the serum is also part of the metabolic diagnosis . If there is sufficient suspicion, a removal of muscle tissue ( muscle biopsy ) can confirm the diagnosis. A characteristic feature here is the evidence of so-called ragged red fibers in the Gömöri trichrome staining . Since this and other enzyme histochemical stains are only meaningful on unfixed muscle tissue, a muscle biopsy should only be performed in a well-equipped center.

therapy

This article or the following section is not adequately provided with supporting documents ( e.g. individual evidence ). Information without sufficient evidence could be removed soon. Please help Wikipedia by researching the information and including good evidence.

As these are hereditary diseases, causal therapy is currently not possible. As general treatment measures, attention should be paid to a sufficient supply of energy in the form of glucose and fats (provided that fatty acid oxidation defects are excluded), fluids and minerals and conditions with increased energy consumption should be avoided or treated. This includes, for example, consistent lowering of fever, because with every increase in temperature, an increased metabolism goes hand in hand with increased energy consumption. Seizures are also associated with significantly increased energy consumption and should be treated consistently. However, it is important to ensure that drugs that inhibit the respiratory chain are avoided. This includes, for example, the anticonvulsant valproate . Lactic acid overload can be treated with buffer substances in the event of acute deterioration . There are also various attempts at treatment with vitamins and so-called cofactors of the respiratory chain (coenzyme Q10, biotin, thiamine, creatine), for which there is no exact proof of their effectiveness, but which can still be tried.

In the field of reproductive medicine there is Mitochondrial Replacement Therapy .

See also

literature

Web links

Individual evidence

  1. ↑ Thomas Klopstock, Andreas Bender: Mitochondria: from early evolution to age-associated diseases in humans. In: Neuroforum. 3/08, pp. 224-232.
  2. ↑ MT Lin, MF Beal: Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. In: Nature . 443, 2006, pp. 787-795.
  3. ^ R. Scatena, P. Patrizia Bottoni, B. Giardina (Eds.): Advances in Mitochondrial Medicine. (= Advances in Experimental Medicine and Biology. 942). Springer, 2012, ISBN 978-94-007-2868-4 , pp. 276f.
  4. ^ R. Scatena, P. Patrizia Bottoni, B. Giardina (Eds.): Advances in Mitochondrial Medicine. (= Advances in Experimental Medicine and Biology. 942). Springer, 2012, ISBN 978-94-007-2868-4 , pp. 269ff.
  5. ↑ J. Giebelstein, G. Poschmann, K. Højlund, W. Schechinger, JW Dietrich, K. Levin, H. Beck-Nielsen, K. Podwojski, K. Stühler. HE Meyer, HH Klein: The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes. In: Diabetologia . 55, 2012, pp. 1114-1127.
  6. ^ R. Scatena, P. Patrizia Bottoni, B. Giardina (Eds.): Advances in Mitochondrial Medicine. (= Advances in Experimental Medicine and Biology. 942). Springer, 2012, ISBN 978-94-007-2868-4 , pp. 235ff.
  7. ^ H. Lemieux, CL Hoppel: Mitochondria in the human heart. In: Journal of Bioenergetic Biomembrane. 41 (2), Apr 2009, pp. 99-106, doi: 10.1007 / s10863-009-9211-0
  8. ^ H. Bugger, ED Abel: Mitochondria in the diabetic heart. In: Cardiovasc Res . 88 (2), Nov 1, 2010, pp. 229-240, doi: 10.1093 / cvr / cvq239 Epub 2010 Jul 16
  9. ^ R. Scatena, P. Patrizia Bottoni, B. Giardina (Eds.): Advances in Mitochondrial Medicine. (= Advances in Experimental Medicine and Biology. 942). Springer, 2012, ISBN 978-94-007-2868-4 , pp. 249ff.
  10. ↑ K. Singh, L. Costello: Mitochondria and Cancer. Springer-Verlag, 2009, ISBN 978-0-387-84834-1 .
  11. ^ T. Seyfried: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. John Wiley & Sons, 2012, ISBN 978-0-470-58492-7 .
  12. ^ R. Scatena, P. Patrizia Bottoni, B. Giardina (Eds.): Advances in Mitochondrial Medicine. (= Advances in Experimental Medicine and Biology. 942). Springer, 2012, ISBN 978-94-007-2868-4 , pp. 287ff.
  13. ↑ P. Polak et al. a .: Adipose-Specific Knockout of raptor Results in Lean Mice with Enhanced Mitochondrial Respiration. In: Cell Metabolism . (2008), doi: 10.1016 / j.cmet.2008.09.003
  14. ↑ T. Müller u. a .: P62 left β-adrenergic input to mitochondrial function and thermogenesis. In: Journal of Clinical Investigation. Volume 123 (1), 2012, doi: 10.1172 / JCI64209
  15. ^ TP Kearns, GP Sayre: Retinitis pigmentosa, external ophthalmoplegia and complete heart block. In: Arch Ophthalmol . tape 60 , 1958, pp. 280-289 .
  16. ^ TP Kearns: External ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy: a newly recognized syndrome. In: Trans Am Ophthalmol Soc. 63, 1965, pp. 559-625. PMID 16693635
  17. ↑ M. Kuriyama et al. a .: High CSF lactate and pyruvate content in Kearns-Sayre syndrome. In: Neurology. 34 (2), 1984, pp. 253-255. PMID 653802
  18. ↑ N. Fukuhara, S. Togikuschi, K. Shirakawa, T. Tsubaki: Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or syndrome? Light and electron microscopic studies of two cases and review of literature . In: J Neurol Sci . tape 47 , 1908, pp. 117-133 .
  19. ↑ SG Pavlakis, PC Philip S. Mauro di u. a .: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes: a distinctive clinical syndrome . In: Ann Neurol . tape 16 , 1984, pp. 481-484 .
  20. ↑ T. von Leber: Contributions to the knowledge of the atrophic changes in the optic nerve together with remarks on the normal structure of the nerve. In: Albrecht von Graefes Arch Ophthalmol (Abbot II) . tape 14 , 1868, p. 164-220 .
  21. ↑ AD Leigh: Subacute necrotizing encephalomyelopathy in an infant. In: J Neurol Neurosurg Psychiatry . tape 14 , 1951, pp. 216-221 .