Inheritance and Genetics

by Richard Boles, M.D. and Terri Mason

Unraveling Environmental Effects on Mitochondria- Environmental Health Perspectives • volume 118 | number 7 | July 2010

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 deficient state.

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 deficiency.

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.

Autosomal Recessive Inheritance

autosomal_recessive_inheritanceAutosomal 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 the disorder.

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 energy deficiency.

Maternal Inheritance

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:

X-Linked Recessive Inheritance

x-linked_recessive_inheritanceX-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.

Autosomal Dominant Inheritance

autosomal_dominant_inheritanceAutosomal 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.

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 inheritance.

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 detect.

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.