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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Mitochondrial diseases due to mutations of nuclear DNA genes show typical autosomal or X-linked inheritance patterns and are not maternally inherited. On the other hand, mitochondrial diseases due to mutations of mtDNA show maternal inheritance, as well as wide variation in severity due to heteroplasmy. Maternal inheritance of mtDNA mitochondrial diseases occurs because essentially all mitochondria are inherited from the mother via the fertilized egg. However, the mother may be more mildly affected or even asymptomatic than the patient, even though she carries the same mtDNA mutation. This is because each mitochondrion has its own copy of mtDNA, and each cell contains hundreds of mitochondria. Therefore, any particular cell contains a mixture of normal and affected mitochondria, which is referred to as heteroplasmy. The overall ratio determines the severity of the phenotype, and it differs between each tissue within the body. This can lead to unexpected results on genetic testing because, for example, a patient with very severe neurological symptoms due to a high ratio of mutant mitochondria in the brain may have blood genetic testing that only shows a few abnormal mitochondria in white blood cells.
Myoclonic epilepsy and ragged red fiber (MERRF) disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Mitochondrial genetics differs from nuclear genetics in that the mitochondrial genome is inherited exclusively from the mother. The mitochondrial DNA is transmitted via the cytoplasm of the egg. A cell may contain hundreds of mitochondria; during ovum formation, the number of mitochondria increases while the number of DNAs per mitochondrion decreases to one from two [55]. With growth and development, differences emerge among tissues in mitochondrial content and amounts of mitochondrial DNA. The latter is highest in brain, the organ most vulnerable to diseases of oxidative phosphorylation [56]. Cells may contain more than one sequence of mitochondrial DNA; this is referred to as heteroplasmy.
Controversies in Recurrent Implantation Failure: From Theory to Practice
Published in Botros Rizk, Yakoub Khalaf, Controversies in Assisted Reproduction, 2020
Efstratios Kolibianakis, Pavlidi Olga, Christos A. Venetis
Cytoplasmic transfer between oocytes was initially developed in order to treat infertile patients exhibiting persistent poor embryonic development and recurrent implantation failure after IVF. This is performed by microinjection of 5%–15% of the ooplasm from a young fertile donor oocyte into a defective recipient oocyte (67), resulting in the birth of several children worldwide (68). However, besides the fact that the effectiveness of the method has not been tested in relevant RCTs, the long-term health effects of induced mitochondrial heteroplasmy in the children born is yet unknown, and thus the method is strictly experimental.
Forensic evaluation of mitochondrial DNA heteroplasmy in Gujarat population, India
Published in Annals of Human Biology, 2022
Mohammed H. M. Alqaisi, Molina Madhulika Ekka, Bhargav C. Patel
The mitochondrial DNA is homoplasmic when all mitochondrial DNA molecules are identical. On the other hand, if mutant mtDNA coexists alongside wild-type mtDNA and has two distinct populations of mtDNA, it is called heteroplasmy (Melton 2004; Wallace and Chalkia 2013; Li et al. 2016). Heteroplasmy is primarily caused by the higher mutation rates observed in mitochondrial genomes compared to nuclear genomes (Brown et al. 1982; Wallace et al. 1987; Wallace and Chalkia 2013). Moreover, hypervariable regions are more susceptible to having heteroplasmies than other mitochondrial genome regions (Greenberg et al. 1983; Li et al. 2015). In mtDNA sequences, two forms of heteroplasmy may be found: point heteroplasmy (PH) and length/C-stretch heteroplasmy (LH). PH is the most common type of heteroplasmy used in forensic analysis. It is possible to detect two nucleotides as two peaks at a single position in an electropherogram, indicating the presence of PH (Figure 1). However, LH (Figure 2) is generally triggered when C residues are inserted or when thymine is substituted for cytosine (Bendall and Sykes 1995; Bendall et al. 1997; Lutz-Bonengel et al. 2008; Parson et al. 2014).
The Natural History of Leber’s Hereditary Optic Neuropathy in an Irish Population and Assessment for Prognostic Biomarkers
Published in Neuro-Ophthalmology, 2022
Kirk A. J. Stephenson, Joseph McAndrew, Paul F. Kenna, Lorraine Cassidy
Heteroplasmy in LHON families (i.e., a subset of genetically normal mitochondria) may decrease penetrance and infer a better prognosis and treatment response.1,38 Heteroplasmy is more common in de novo (37.5–80%) versus inherited (5%) mtDNA mutations, suggesting a trend towards homoplasmy in subsequent generations.1,7,59 Blood leukocytes, hair cells, retina and optic nerve may each have different percentages of mutant mtDNA thus blood testing may not accurately represent the degree of mitochondrial dysfunction in RGCs.60,61 LHON-affected people usually have > 95% mutant mtDNA.7 Disease may still manifest in heteroplasmy due to unfavourable mitochondrial haplotype or nuclear modifiers; however, 13.6–19% of unaffected maternal relatives show mtDNA heteroplasmy and 1:300 UK citizens harbour an LHON mutation (1:1000 homoplasmic) without necessarily manifesting disease, thus other modifiers are likely.7,59,62,63 In our cohort, heteroplasmic patients had less severe visual loss over the study period. Kim et al. reported patients with the m.14459 G >A mutation manifesting LHON in heteroplasmy and neurological manifestations in homoplasmy thus degree of heteroplasmy may determine disease phenotype.14
New discoveries in progressive myoclonus epilepsies: a clinical outlook
Published in Expert Review of Neurotherapeutics, 2018
Shweta Bhat, Subramaniam Ganesh
It is reported that the pathogenic mutation of MT-TK results in direct inhibition of protein synthesis, thereby reducing the oxygen utilization and deficiency of cytochrome oxidase C (COX) in mitochondria [97]. Thus, RRFs vessels are deficient in COX activity and exhibit strong immunoreactivity for succinate dehydrogenase. However, a clear-cut genotype-phenotype correlation is not yet elucidated. The relative abundance of mutated mtDNA to the normal mtDNA can be different depending on the tissue type, a phenomenon called as ‘heteroplasmy.’ The severity of the disease depends upon this heteroplasmy, the type of tissue involved and the impaired oxidative phosphorylation affects the tissue. The variation of the mutation load is said to be responsible for the clinical diversity in the manifestations of the disease. Two hypotheses regarding the pathogenesis at the molecular level have been proposed. One is that, the disturbance in intracellular ion concentration due to an underlying defect in oxidative phosphorylation, which leads to abnormal action potential and hence abnormal neurotransmission and second being the mitochondrial cytopathy, which leads to loss of neuronal cells [98]. The exact mechanism that operates in multisystem manifestations in MERRF is still an enigma.