Mitochondrial Inheritance

Mitochondria are located in a cell’s cytoplasm and contain circular DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, called mitochondrial DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure (mtDNA). This DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure exists separately from a cell’s nuclear genome and is inherited solely through the maternal lineage—nonmendelian inheritance. Genetic mutations in mtDNA give rise to various rare diseases such as Leber hereditary optic neuropathy Leber hereditary optic neuropathy A maternally linked genetic disorder that presents in mid-life as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with missense mutations in the mtDNA, in genes for complex I, III, and IV polypeptides, that can act autonomously or in association with each other to cause the disease. Mitochondrial Myopathies ( LHON LHON A maternally linked genetic disorder that presents in mid-life as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with missense mutations in the mtDNA, in genes for complex I, III, and IV polypeptides, that can act autonomously or in association with each other to cause the disease. Mitochondrial Myopathies) and myoclonic epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy with ragged red fibers (MERRF).

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Mitochondrial DNA and Inheritance Pattern

Mitochondrial DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure (mtDNA)

  • Circular and double-stranded DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • 37 genes encoding 13 proteins
  • All proteins are part of the oxidative phosphorylation system (mitochondria = powerhouses of the cell).
  • Located within the mitochondria, therefore separate from a cell’s nuclear genome
  • Replication is not dependent on the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle.
  • Each mitochondrion contains several copies of its genome: 
    • Homoplasmy: all copies of mtDNA in a eukaryotic Eukaryotic Eukaryotes can be single-celled or multicellular organisms and include plants, animals, fungi, and protozoa. Eukaryotic cells contain a well-organized nucleus contained by a membrane, along with other membrane-bound organelles. Cell Types: Eukaryotic versus Prokaryotic cell identical
    • Heteroplasmy: copies of mtDNA in eukaryotic Eukaryotic Eukaryotes can be single-celled or multicellular organisms and include plants, animals, fungi, and protozoa. Eukaryotic cells contain a well-organized nucleus contained by a membrane, along with other membrane-bound organelles. Cell Types: Eukaryotic versus Prokaryotic cells differ from each other → most cases of mutated mtDNA are heteroplasmic (only some mtDNA copies carry the mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations).
Mitochondrial dna

Mitochondrial DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
Image showing the mitochondria located in the cell’s cytoplasm:
Note the circular DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, of which each mitochondrion contains several copies.

Image by Lecturio.

Inheritance pattern

  • Mitochondrial inheritance is a form of extranuclear, and therefore nonmendelian, inheritance.
  • mtDNA maternally inherited:
    • Most paternal mitochondria are found at the base of the sperm’s tail, which is used for propelling sperm cells.
    • In sexual reproduction, the mitochondria in mammalian sperm are destroyed by the egg cell (oocyte) following fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week
  • Role of heteroplasmy:
    • Severity of disease depends on the proportion of mutated versus nonmutated alleles that are inherited.
    • Because of heteroplasmy, mitochondrial disorders have a variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables presentation within a family.
Pedigree of mitochondrial inheritance

Pedigree of mitochondrial inheritance:
Note that the index person (A) has only a few mutated mtDNA copies (heteroplasmy). A child will have symptoms only if the amount of mitochondria with the mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations reaches a certain level. Children of the affected son (B) will not inherit the mitochondrial mutations.

Image by Lecturio.

Mitochondrial Disorders

Mitochondrial disorders are extremely variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables and may range from mild to severe clinical presentation within the same family owing to heteroplasmy. 

  • Leber hereditary optic neuropathy Leber hereditary optic neuropathy A maternally linked genetic disorder that presents in mid-life as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with missense mutations in the mtDNA, in genes for complex I, III, and IV polypeptides, that can act autonomously or in association with each other to cause the disease. Mitochondrial Myopathies ( LHON LHON A maternally linked genetic disorder that presents in mid-life as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with missense mutations in the mtDNA, in genes for complex I, III, and IV polypeptides, that can act autonomously or in association with each other to cause the disease. Mitochondrial Myopathies):
    • Degeneration of retinal ganglion cells and optic nerves
    • Typical age at onset: young adulthood
    • Acute or subacute bilateral vision loss
    • Causes permanent vision loss, predominantly in young men
  • Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS):
    • Typical age at onset: 2–10 years
    • Lactic acidosis leads to vomiting, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, fatigue, and muscle weakness.
    • Less common symptoms: stroke-like episodes, blindness, and seizure activity
  • Myoclonic epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy with ragged red fibers (MERRF):
    • Manifests in childhood after previously normal development
    • Symptoms: myoclonus, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, ataxia, and myopathy
    • Ragged red fibers (RRFs) can be seen in muscle biopsy.
  • Leigh syndrome:
    • Subacute necrotizing encephalopathy
    • Leads to focal lesions in the brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem, basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia, and cerebellum Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum
    • Can be caused by mutations in mtDNA or nuclear DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
    • Levels of thiamine triphosphate
    • Symptoms:
      • Typically begin in infancy, but can appear at any age
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, vomiting, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures 
    • Generally lethal within a few years after symptom onset

References

  1. O’Ferral, R. (2021). Mitochondrial myopathies: clinical features and diagnosis. UpToDate. Retrieved September 1, 2021, from https://www.uptodate.com/contents/mitochondrial-myopathies-clinical-features-and-diagnosis
  2. O’Ferral, R. (2021). Mitochondrial structure, function, and genetics. UpToDate. Retrieved September 1, 2021, from https://www.uptodate.com/contents/mitochondrial-structure-function-and-genetics
  3. Raby, B. (2021). Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian). UpToDate. Retrieved September 1, 2021, from https://www.uptodate.com/contents/inheritance-patterns-of-monogenic-disorders-mendelian-and-non-mendelian 
  4. Kang, P. (2021). Neuropathies associated with hereditary disorders. UpToDate. Retrieved September 1, 2021, from https://www.uptodate.com/contents/neuropathies-associated-with-hereditary-disorders
  5. Manickam, A. H., Michael, M. J., Ramasamy, S. (2017). Mitochondrial genetics and therapeutic overview of Leber’s hereditary optic neuropathy. Indian Journal of Ophthalmology 65:1087–1092. https://doi.org/10.4103/ijo.IJO_358_17 
  6. Howell, N. (2003). LHON and other optic nerve atrophies: the mitochondrial connection. Developments in Ophthalmology 37:94–108. https://doi.org/10.1159/000072041 
  7. Lake, N. J., Compton, A. G., Rahman, S., Thorburn, D. R. (2016). Leigh syndrome: one disorder, more than 75 monogenic causes. Annals of Neurology 79:190–203. https://doi.org/10.1002/ana.24551 

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