Maternally inherited diseases

Fourteen mtDNA tRNA mutations have been associated with maternally inherited disease. Such mutations are typically associated with severe mitochondrial myopathies, characterized by ragged red skeletal muscle fibers upon Gomori trichrome staining and the accumulation of structurally abnormal mitochondria in muscle. Mutations in tRNAs exemplify the threshold effect whereby (due to replicative segragation) individuals may not exhibit clinical signs until the proportion of mutant mtDNA exceeds 80-90%. Myoclonic epilepsy and ragged red fiber (MERRF) disease, mitochondrial encephalomyo-pathy tactic acidosis (MELAS), as well as maternally inherited myopathy and cardiomyopathy (MMC) are well-characterized mitochondrial diseases. 

As described above, maternal inheritance has been documented in diseases due to point mutations of mtDNA, while most diseases due to mtDNA deletions or duplications are sporadic. 

The circular mitochondrial chromosome encodes 13 of the more than 80 proteins that comprise the major complexes of oxidative phosphorylation as well as 22 tRNAs and 2 rRNAs. Mutations in these genes affect highly aerobic tissues (nerves, muscle), and the diseases exhibit characteristic mitochondrial pedigrees (maternal inheritance). 

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

Shoffner, J. M., Maternal inheritance and the evaluation of oxidative phosphorylation diseases. Lancet 348, 1283-1288 (1996). 

LHON is a distinct form of optic atrophy. LHON is a point mutation in the mitochondrial genome.These mutations occur at nucleotide sites 3,460,11,778, and l4,484.These DNA mitochondrial mutations are transmitted with the cytoplasm, making this disease maternally inherited. Environmental epigenetic triggers (smoking, alcohol) have been identified. 

Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disease and the first linked to maternal inheritance through a mutation in the mtDNA. LHON is characterized by bilateral subacute loss of central vision caused by focal degeneration of the retinal ganglion cell layer and of the optic nerve. After initial symptoms, both eyes are usually affected within 6 months. Approximately 50% to 60% of males and only 8% to 32% of females who possess the mtDNA mutation will actually develop this optic neuropathy. Nuclear-encoded factors that affect mtDNA expression, mtDNA products, or mitochondrial metabolism may modify the phenotypic expression of LHON. Genetic coimseling in LHON is complicated in that the amount of mutant mtDNA transmitted by heteroplasmic females cannot be predicted, and testing cannot predict which individuals will develop visual symptoms. ... 

Strauss AW, Beimett MJ, Rinaldo P, Sims HF, O Brien LK, Zhao Y, et al. Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal-maternal interaction cause maternal fiver disease and other pregnancy complications. Sem Perinatol 1999 23 100-12. 

PHP, a rare heterogeneous genetic disorder characterized by end-organ resistance to parathyroid hormone, is discussed further in Chapter 8. Heterozygous inactivating GNAS mutations lead to PHP type la (PHP-Ia) when maternally inherited, or pseudopseudohypoparathyroidism (PPHP), if paternally derived [48]. To date, only variants of the Ga- and Gp-subunits of the G protein have been implicated in human disease—no Gy-subunit disruptions have been identified. 

Mt5178A is not the only mitochondrial variant to be linked with ageing and disease in people. Several others have been identified, although their effects are less pervasive. We get a sense of their overall importance from a looser relationship the maternal inheritance of longevity. Mitochondria, as we have seen, are only passed on in the egg, so all 13 mitochondrial genes come from our mothers. If these genes really do influence lifespan, and we can only inherit them from our mothers, then our own... 

Like the mitochondria themselves, some genetic diseases of energy metabolism are maternally inherited. One such disease, Leber s hereditary optic neuropathy (LHON), causes blindness and heart problems. People with LHON have a reduced ability to make ATP. As a result, sensitive tissues that demand a great deal of energy eventually die. LHON sufferers eventually lose their sight because the optic nerve dies from lack of energy. 

Deficiencies of electron transport In cells, complete transfer of electrons from NADH and FAD(2H) through the chain to O2 is necessary for ATP generation. Impaired transfer through any complex can have pathologic consequences. Fatigue can result from iron-defeciency anemia, which decreases Fe for Fe-S centers and cytochromes Cytochrome Cj oxidase, which contains the O2 binding site, is inhibited by cyanide Mitochondrial DNA (mtDNA), which is maternally inherited, encodes some of the subunits of the electron transport chain complexes and ATP synthase. Oxphos diseases are caused by mutations in nuclear DNA or mtDNA that decrease mitochondrial capacity for oxidative phosphorylation. 

Dominant mutation A change in a gene such that it only needs to happen in one of the two copies (maternal and paternal) in order to produce a characteristic change, e.g. an inherited disease, hair colour, etc. 

There are several disorders of the respiratory chain. Many are transmitted by maternal inheritance as generally aU mitochondria in the ovum are of maternal origin. The thousands of mtDNA molecules in one cell are distributed randomly to the daughter cells, therefore different tissues may harbour a mixture of both normal and mutant mtDNA (heteroplasmy). Accordingly the clinical phenotype is highly variable. Mutations in nuclear genes encoding proteins for the respiratory chain are transmitted autosomally and usually cause a more severe disease. 

The metabolic myopathies are exceptionally complex. Mitochondrial disorders are usually multisystem disorders, in which metabolic dysfunction affects muscle, liver, CNS, and special senses (especially vision) in almost any combination. There is evidence that some forms of mitochondrial disease are inherited, and the preponderance of maternal rather than paternal inheritance is consistent with an abnormality in the mitochondrial genome because almost all (and perhaps all) mitochondria are derived from the ovum. 

Mitochondrial DNA is inherited maternally. What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides nuclear DNA (nDNA) controls the synthesis of 90-95% of all mitochondrial proteins. All known mito-chondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I the apoprotein of cytochrome b the three larger subunits of cytochrome c oxidase, also termed complex IV and two subunits of ATPase, also termed complex V. 

Inheritance is maternal, as in X-linked diseases, but children of both sexes are affected. 

The disease is inherited only maternally, since only the mother contributes mitochondrial DNA to the progeny. 

---