Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) s
ID: 43643 • Letter: M
Question
Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome iscaused by an A --> G transversion at position 3243 in the human mitochondrial genome. Nearlyall individuals who have MELAS syndrome are heteroplasmic for the mutation. Also, there issubstantial variation for clinical manifestations of the syndrome among people who inherit themutation. In 1994 Matthews et al. traced the mutation through four generations in a family.They found that the amount of mutant mitochondrial DNA in tissues varied within an individualand that the proportion of mutant mitochondrial DNA in a tissue was correlated with clinicalmanifestations of symptoms in that tissue. For example, a woman who died of cardiomyopathy(disease of the heart muscle) had a higher proportion of mutant mitochondrial DNA in her heartthan in most other organs. Explain why the proportion of mutant DNA may be greater in oneorgan than another in the same individual. Also explain why heteroplasmy may cause partial penetrance and variable expressivity for mitochondrial genetic disorders.
Explanation / Answer
The presence of more than one type of organellar genome is called Heteroplasmy. The condition arises due to mutations in some mitochondrial Deoxyribo Nucleic Acid (DNA) but not the others. At each cell division, the mitochondria are distributed at random into daughter cells. Over time, cells may gather different mitochondria with differing alleles. Mitochondria are inherited from the mother only.
The consequences of inheritance vary with the expressivity of heteroplasmy. The expressivity is proportional to the number of mutation bearing mitochondria in the oocyte that underwent fertilization. Most severe mitochondrial illness are related to heteroplasmy because all mitochondria bearing the same mutation (homoplasmy) lead to impaired embryonic development and miscarriage.
AS said earlier, during each cell division, the mitochondria that bear the mutations are randomly distributed among the cells. Even in the early stages of embryonic development, the mutation bearing mitochondria if distributed to some of the cells in a zygote, all organs or tissues that descend from this stem cell or cells bear this mitochondria. It takes a long time for this cells to gather enough number of mutant mitochondria to show their effect.
The partial penetracne and variable expressitivity for mitochondrial genetic disorders are due to the fact that the cell contains a large number of mitochondria. Mitochondria that are normal make the cell function normally untill the mutated mitochondria accumulate in sufficient numbers to show their effect.