Introduction and Definition
Mitochondria are very complex organelles located in
virtually all cells of the body. A large degree of the complexity is due
to the fact that among the over 1000 proteins located in the
mitochondria, 13 are encoded by the mitochondrial DNA (mtDNA), while the
remainder are nuclear-encoded (on the chromosomes) and imported into
mitochondria. Before launching into the inheritance of mitochondrial
disease, I will define what this author defines as "mitochondrial
disease". Herein, mitochondrial disease refers to any illness resulting
from deficiency of any mitochondria-located protein which is involved in
energy metabolism. Thus, deficiencies of the respiratory (electron
transport) chain, either resulting from deficiency in one or more
mitochondrial or nuclear-encoded proteins, are mitochondrial disorders.
Also, by this definition, disorders of fatty acid (beta) oxidation,
Krebs cycle and pyruvate dehydrogenase complex deficiency are
mitochondrial disorders. Although the proteins involved are
nuclear-encoded, they are located in the mitochondria and are involved
in energy metabolism. Although genetically dissimilar, all of these
disorders share clinical similarities in that they result in an energy
Unfortunately, the multiple diseases classified as
mitochondrial disorders are inherited in different manners. In fact,
nearly every inheritance "model" known has been demonstrated to occur in
mitochondrial disease. However, most mitochondrial disorders known to
date are inherited in either an autosomal recessive or maternal manner.
The model of inheritance is important in that it can be helpful in
answering the following questions:
1. Are other family members, either existing or not yet born, at risk for developing mitochondrial disease?
2. What is the risk (percentage)?
3. When will other affected relatives become ill?
4. Will other affected relatives be as sick as my child/myself? Possibly even sicker?
5. What kinds of problems/diseases might other affected relatives suffer from?
As you will see, not all of these questions can be answered
at the present time in all families where someone suffers from
mitochondrial disease. The first step is to determine the inheritance
model in your family. This can be done in two basic manners:
1. Based on a confirmed diagnosis: For example, if the
individual caries the "MELAS" A3243G mtDNA mutation, your doctor can be
sure that the inheritance model in your family is maternal. This is
because this mtDNA mutation is maternally inherited, whether or not the
mother shows any symptoms. MCAD and SURF1 deficiencies are always
autosomal recessive in inheritance.
2. Based on the pedigree: Unfortunately, most of the time
the exact defect cannot be found. However, in many cases we can give an
educated guess of the inheritance model upon a careful look at the
family history (pedigree). However, this only works if there are other
family members affected with disease which likely is due to energy
As you read through the inheritance models below, understand
that all inheritance models involve nuclear genes/nuclear-encoded
proteins except one. That exception is that maternal inheritance
involves mitochondrial (mtDNA) genes/mitochondrial-encoded proteins.
Although long and complex, the information presented here is actually
just the basics, and important exceptions exist. This information should
not be considered to be an alternative to individualized genetic
counseling with a knowledgeable professional.
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Autosomal Recessive Inheritance
Autosomal recessive inheritance may be familiar to some
readers in that several non-mitochondrial disorders are inherited in
this manner, including cystic fibrosis and albinism. Autosomal recessive
inheritance is possibly the most common model in mitochondrial
disorders, including disorders of fatty acid oxidation, Krebs cycle,
nuclear-encoded subunits of the respiratory chain, assembly factors and
transporters. Remember that we all have two copies of virtually every
(nuclear-encoded) gene; one each from our mother and father. Only one of
these two genes randomly enters an egg or sperm as they are formed. One
gene from both egg and sperm results in the baby having two copies of
that gene. With autosomal recessive inheritance, both parents are
carriers in that they have one copy of the gene that is defective. They
are not affected because they also have a normal copy of the same gene.
If both the egg and sperm carried the defective (bad, mutant) gene, then
the child will have no working (good, normal) copies, and will manifest
Thus, in autosomal recessive inheritance, 25% of the
children will inherit the defective gene from both parents and manifest
the disease, 50% of the children will inherit the defective gene from
one parent and become unaffected carriers (like the parents), and 25% of
the children will not inherit either copy of the defective gene. Twenty
five percent, or 1 in 4, is the risk for each child. Of course by
random chance, many more or less than 1 in 4 siblings (brothers and
sisters) may inherit the disease. The chance that anyone other than a
sibling, i.e. niece, nephew, cousin, etc.) will inherit the disease is
very small. An important exception occurs in families where the parents
are blood related to each other or come from isolated communities in
which the likelihood of blood relation is high.
Although there are exceptions (especially the fatty acid
oxidation disorders), autosomal recessive inherited mitochondrial
disorders usually result in severe disease with infantile onset. Disease
in affected siblings is usually similar in terms of age of onset,
severity, and organ systems involved. In other words, if a future
sibling will inherit the disease, it will likely be quite similar in
many respects (but not identical).
EXAMPLE: Out of a family with ten siblings, two sisters and a
brother each developed severe seizures at a few months of age each.
Although they differ in degree, all are mentally retarded. Both parents
and their family members are healthy without problems attributed to
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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
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
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
The following article from the MDA has a great explanation of mitochondrial genetics and can be found at:
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X-Linked Recessive Inheritance
X-linked recessive inheritance may be familiar to some
readers in that many well-publicized non-mitochondrial disorders are
inherited in this manner, including the most common forms of muscular
dystrophy, hemophilia and color blindness. Among mitochondrial
disorders, the most common type of pyruvate dehydrogenase complex
deficiency (E1 alpha) is X-linked.
In X-linked disease, the genetic defect is located on the
"X" chromosome and usually affects males only. This happens because
females have 2 X chromosomes - 1 each from the mother and father,
whereas males only have one X Chromosome, inherited from their mother
(they get a "Y" chromosome from their father). Females with one normal X
chromosome and one mutated X chromosome generally do not manifest the
disorder because of the presence of the normal gene. However, these
females are at risk for passing on genetic disease and are thus called
"carriers". On the other hand, since a male only has one X chromosome,
if it is mutated he has no normal copy and will develop the disorder
represented by the genetic defect.
If a female carrier has children, there is a 50/50 chance
that she will pass on the defective gene to her children. If that child
happens to be a girl and inherits the gene, she too will become a
carrier. If the child is a boy and inherits the defective gene, he will
develop the disease.
An important exception occurs in that some carrier females
can present with, usually mild, disease. In rare situations the disease
in boys is so severe as to be lethal before birth, such that only girls
are noted to be affected. However, in all cases of X-linked disease,
boys and girls are always affected differently, with boys more severely
affected than girls.
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Autosomal Dominant Inheritance
Autosomal dominant inheritance may be familiar to some
readers as the inheritance pattern in the non-mitochondrial disorders of
Huntington disease and familial hypercholestrolemia. Among
mitochondrial disorders, a rare form of Kearns-Sayre syndrome is
autosomal dominant in inheritance.
With dominant inheritance, only one copy of the defective
gene is required in order to develop the associated disorder. This means
that each person with the disorder has a 50/50 chance of passing on the
gene to any children they may have. Additionally, any child that
inherits the defect may develop the disorder and in turn have a 50/50
chance of passing on the defective gene. However, with one normal and
one mutated gene, all of these individuals may or may not develop
symptoms of disease. If they do develop disease, the severity can vary
markedly. In regards to the highly variable manifestations among
individuals with a defective gene, autosomal dominant and maternally
inherited mitochondrial disorders are similar. However, in autosomal
dominant, but never in maternally inherited, conditions boys can pass
the defective gene and disease to their children.
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Sporadic Cases — Where There Are No Affected Relatives
In the "real world", in the majority (perhaps about 75%)
of cases the patient is the only family member affected with
mitochondrial disease. These cases are called "sporadic", and present
much difficulty in answering the questions posed about regarding
The first question is whether the problem is due to
genetics, environment, or some combination of the two. Certainly, the
genetic aspects of mitochondrial disease are well known and were briefly
summarized above. However, not all mitochondrial disease is primarily
genetic. For example, anti-retroviral medications used to treat HIV/AIDS
can damage mitochondria and cause symptoms due to resultant energy
failure. Removal of these drugs reverses the process and the symptoms
resolve. There are other environmental causes of mitochondrial disease,
and likely many that we do not know about.
In the opinion of this author, most mitochondrial diseases
are probably both genetic AND environmental in origin. Even in the case
of anti-retroviral medications, thousands of individuals have no problem
on these drugs while only a handful do. Likely, there are genetic
reasons for the high susceptibility to these drugs in an unlucky few - a
genetic predisposition of an "environmental" disease. On the other
hand, in MELAS, which clearly is primarily genetic in origin,
neurological deterioration often occurs during a viral illness and/or
fasting - an environmental trigger of a "genetic" disease.
The second question is: If genetic, was the mutation
inherited? The answer is usually yes, but not always. New mutations do
exist. In particular, deletions (missing areas) of mtDNA tend to be new
mutations not present in the mother or siblings. However, deletions with
duplications are often inherited, and some duplications are hard to
What this all means is that there are very few answers in
most cases where only one person in a family has mitochondrial disease.
The condition probably is genetic, and it may or may not be inherited.
Either the nuclear or mitochondrial DNA could be involved. Inheritance
is probably autosomal recessive, maternal or sporadic (no inheritance),
but not necessarily.
Based on many families, some groups give an estimated
recurrence risk for mitochondrial disease (chance that each additional
child of the same two parents will be somehow affected) of 10-15%. This
is probably a reasonable rough estimate, but you should discuss the
probability of recurrence for your family with a genetics counselor
familiar with mitochondrial disease.
- Written by Richard Boles, M.D. and Terri Mason
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Unraveling Environmental Effects on Mitochondria- Environmental Health Perspectives • volume 118 | number 7 | July 2010