A significant number of disorders associated with the eye or visual system involve mitochondrial deletions and mutations. Mitochondrial diseases should be considered whenever the inheritance pattern of a trait suggests maternal transmission. Although the inheritance pattern might superficially resemble that of an X-linked trait, maternal transmission differs in that all of the offspring of affected females—both daughters and sons—can inherit the trait, but only the daughters can pass it on.
The phenotype and severity of mitochondrial disease appear to depend on the nature of the mutation, the presence or degree of heteroplasmy (coexistence of more than 1 species of mitochondrial DNA [mtDNA]—ie, wild type and mutant), and the oxidative needs of the tissues involved. Spontaneous deletions and mutations of mtDNA accumulate with age, and the effect of this accumulation is to decrease the efficiency and function of the electron transport system, reducing the availability of adenosine triphosphate (ATP). When energy production becomes insufficient to maintain the function of cells or tissue, disease occurs. There appears to be an important interaction between age and tissue threshold of oxidative phosphorylation and the expression of inherited mutations of mtDNA.
With each cell division, the number of mutant mtDNA copies that are partitioned to a given daughter cell is random, unlike in mendelian inheritance. After a number of cell divisions, some cells, purely by chance, receive more normal or more mutant copies of mtDNA, resulting in a drift toward homoplasmy in subsequent cell lines. This process is called replicative segregation. With mtDNA deletions, preferential replication of the smaller deleted molecules causes an increase of the deleted copy over time. The trend toward homoplasmy helps explain why disease worsens with age and why organ systems not previously involved in multisystem mitochondrial disease become involved.
Causes of mitochondrial diseases can be categorized as follows:
large rearrangements of mtDNA (deletions or insertions), such as chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome, and Pearson marrow-pancreas syndrome
mutations of mtDNA-encoded ribosomal RNA (rRNA), such as occur in maternally inherited sensorineural deafness and aminoglycoside-induced deafness
mutations of mtDNA-encoded tRNA, such as occur in the syndromes of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), MERRF (myoclonic epilepsy with ragged red fibers), MIDD (maternally inherited diabetes and deafness), and (in about 30% of cases) CPEO
missense and nonsense mutations, such as are present in Leber hereditary optic neuropathy; and neuropathy, ataxia, and RP
Chronic Progressive External Ophthalmoplegia
CPEO is a disorder involving progressive ptosis and paralysis of eye muscles associated with a ragged red myopathy, usually as a result of deletion of a portion of the mitochondrial genome. Patients with CPEO commonly have pigmentary retinopathy that does not create significant visual disability. Infrequently, they may have more marked retinal or other system involvement, the so-called CPEO-plus syndromes. In Kearns-Sayre syndrome, CPEO is associated with heart block and severe RP with marked visual impairment. Pearson marrow-pancreas syndrome results from a large deletion of mtDNA and presents in younger patients with an entirely different phenotype involving sideroblastic anemia and pancreatic exocrine dysfunction. However, in patients afflicted during their later years, Pearson marrow-pancreas syndrome can present with a phenotype resembling that of Kearns-Sayre syndrome.
Roughly 50% of patients with CPEO have demonstrable mtDNA deletions, whereas virtually all patients with Kearns-Sayre syndrome have large deletions. Of patients with CPEO who do not harbor demonstrable mtDNA deletions, up to 30% may have a point mutation at nucleotide position 3243, the same mutation in the tRNA for leucine that in other individuals is associated with MELAS syndrome. For all syndromes associated with deletions, such as Kearns-Sayre and CPEO, detection of the deletion usually requires study of the muscle tissue.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.