Autosomal recessive inheritance was the “easy one”; maternal inheritance (also known as mitochondrial or cytoplasmic inheritance) is the most complicated of all. Maternally inherited mitochondrial disorders are not rare, and possibly are as common as autosomal recessive mitochondrial disorders. All maternally inherited diseases are mitochondrial disorders. Examples include MELAS, MERRF, NARP and LHON.
Children inherit their mitochondrial DNA only from their mother, unlike nuclear DNA which comes from the mother and father. Girls will always pass on a mtDNA mutation (genetic error or defect) and boys will never pass on a mtDNA mutation. Thus, a child shares the same mtDNA sequence as does his/her siblings and mother, but not his/her father. In addition, the mother’s siblings and her mother (the child’s maternal aunts, uncles and grandmother) and more distant maternal relatives also share this same mtDNA. In practice, siblings and the mother often are affected with variable manifestations of energy deficiency, while the maternal aunts, uncles and/or grandmother are sometimes affected.
To make matters worse is a concept called “heteroplasmy”. While each of our cells contain exactly 2 copies of virtually every nuclear gene, each cell contains varying numbers of mtDNA copies, often several thousand per cell. Most “normal” people have homoplasmic cells meaning that their cells contain only normal mtDNA. However, people with maternally inherited mitochondrial disease and their maternal relatives usually have heteroplasmic cells, meaning that some of the mtDNA are normal (do not contain the mutation) and some are not normal (do contain the mutation). Heteroplasmy proportions differ, often drastically, among maternal family members. Also, while one might assume that the more mutant DNA a cell has the more problems it will have, in practice the cell does quite well until the proportion of mutant mtDNA reaches a threshold, after which it can no longer cope, resulting in disease. This threshold varies among different tissues (some are more sensitive to energy deficiency than others) and different mutations.
All together, this means that the symptoms, severity, age of onset, etc., of a mitochondrial disorder can vary tremendously within a family. So, although a mother with a mtDNA mutation will pass that mutation onto all of her children, not all of her children will necessarily become symptomatic. Additionally, if the children are symptomatic, the disease that each child has can be very different dependent on the percentage of mutant mtDNA in each part of the body. This essentially creates an infinite number of manifestations of mitochondrial disease. For example, a boy with severe heart disease could have 94% mutant mtDNA (i.e. 6% normal) in the heart and 34% in the brain, while his sister with epilepsy could have 50% mutant in the heart and 80% mutant in the brain.
The above information explains why maternally inherited mitochondrial disorders are very broad in their clinical effects. Unlike autosomal recessive mitochondrial disorders, the onset of maternally inherited mitochondrial disorders is usually later in life, including in toddlers, preschoolers, school-aged children, adolescents, or adults. However they can appear very similar to autosomal recessive inherited mitochondrial disorders, including severe disease in infants.
Accurate percentile figures cannot be given for the recurrence of disease in additional children. This risk depends on the level of mutant heteroplasmy among a woman’s eggs (ova), which is different for each individual and is not practical to measure. Often the risk is quoted as “0-100%”, although in this author’s experience, most siblings are affected to some degree, while a minority are severely affected.
EXAMPLE: A 9 year old boy suffers from intermittent dysautonomia, seizures, learning disabilities and fatigue. His 8 year old sister has only severe delayed gastric emptying. A 11 year old brother is unaffected. Their mother has a new-onset seizure disorder, migraine and peripheral neuropathy.
There is also a mitochondrial disorder known as LHON (Leber’s Hereditary Optic Neuropathy) where the mitochondrial DNA mutations which causes the disease (acquired blindness) are homoplasmic – meaning that all of the mitochondria carry the defect. However, just because a person has one of the LHON mitochondrial DNA mutations does not mean they will become blind, only about 10% will. Confusing? You bet!
The following article from the MDA has a great explanation of mitochondrial genetics and can be found at: