Mitochondrial genetic disorders

People with mitochondrial genetic disorders can present at any age with almost any affected body system. While some conditions may only affect a single organ, many involve multiple organ systems including the brain, muscles, heart, liver, nerves, eyes, ears and/or kidneys. Symptom severity can also vary widely. The most common signs and symptoms include:^[1][2]

• Poor growth
• Loss of muscle coordination
• Muscle weakness
• Seizures
• Autism
• Problems with vision and/or hearing
• Developmental delay
• Learning disabilities
• Heart, liver, and/or kidney disease
• Gastrointestinal disorders
• Diabetes
• Increased risk of infection
• Thyroid and/or adrenal abnormalities
• Autonomic dysfunction
• Dementia

The United Mitochondrial Disease Foundation's website features a comprehensive list of possible symptoms (click here to see this information) and symptoms categorized by type of mitochondrial genetic disorder (click here to access this page).

Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria. Most DNA (hereditary material that is passed from parent to child) is packaged within the nucleus of each cell (known as nuclear DNA). However, mitochondria (the structures in each cell that produce energy) contain a small amount of their own DNA, which is known as mitochondrial DNA.^[1][2]

When the mitochondria are not working properly, the body does not have enough energy to carry out its normal functions. This can lead to the variety of health problems associated with mitochondrial genetic disorders.^[1][2]

Mitochondrial genetic disorder can be inherited in a variety of manners depending on the type of condition and the location of the disease-causing change (mutation). Those caused by mutations in mitochondrial DNA are transmitted by maternal inheritance.^[1][3] Only egg cells (not sperm cells) contribute mitochondria to the next generation, so only females can pass on mitochondrial mutations to their children. Conditions resulting from mutations in mitochondrial DNA can appear in every generation of a family and can affect both males and females. In some cases, the condition results from a new (de novo) mutation in a mitochondrial gene and occurs in a person with no history of the condition in the family.

Mitochondrial genetic disorders caused by mutations in nuclear DNA may follow an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance.^[1][3] In autosomal dominant conditions, one mutated copy of the responsible gene in each cell is enough to cause signs or symptoms of the condition. In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. A person with an autosomal dominant condition has a 50% chance with each pregnancy of passing along the altered gene to his or her child.

When a condition is inherited in an autosomal recessive manner, a person must have a change in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

A condition is considered X-linked if the mutated gene that causes the condition is located on the X chromosome, one of the two sex chromosomes (the Y chromosome is the other sex chromosome). Women have two X chromosomes and men have an X and a Y chromosome. X-linked conditions can be X-linked dominant or X-linked recessive. The inheritance is X-linked dominant if one copy of the altered gene in each cell is sufficient to cause the condition. Women with an X-linked dominant condition have a 50% chance of passing the condition on to a son or a daughter with each pregnancy. Men with an X-linked dominant condition will pass the condition on to all of their daughters and none of their sons. The inheritance is X-linked recessive if a gene on the X chromosome causes the condition in men with one gene mutation (they have only one X chromosome) and in females with two gene mutations (they have two X chromosomes). A woman with an X-linked condition will pass the mutation on to all of her sons and daughters. This means that all of her sons will have the condition and all of her daughters will be carriers. A man with an X-linked recessive condition will pass the mutation to all of his daughters (carriers) and none of his sons.

Unfortunately, mitochondrial genetic disorders can be difficult to diagnose, and many affected people may never receive a specific diagnosis. They are often suspected in people who have a condition that effects multiple, unrelated systems of the body. In some cases, the pattern of symptoms may be suggestive of a specific mitochondrial condition. If the disease-causing gene(s) associated with the particular condition is known, the diagnosis can then be confirmed with genetic testing.^[1][5]

If a mitochondrial genetic disorder is suspected but the signs and symptoms do not suggest a specific diagnosis, a more extensive work-up may be required. In these cases, a physician may start by evaluating the levels of certain substances in a sample of blood or cerebrospinal fluid. Other tests that can support a diagnosis include:^[1]

• Exercise testing
• Magnetic resonance spectroscopy (detects abnormalities in the brain's chemical makeup)
• Imaging studies of the brain such as MRI or CT scan
• Electroencephalography (EEG)
• Tests that evaluate the heart including electrocardiography and echocardiography
• Muscle biopsy

When possible, confirming a diagnosis with genetic testing can have important implications for family members. Identifying the disease-causing gene(s) will give the family information about the inheritance pattern and the risk to other family members. It will also allow other at-risk family members to undergo genetic testing.^[1]

For more information regarding the diagnosis of mitochondrial genetic disorders, please visit the United Mitochondrial Disease Foundation's "Getting a Diagnosis" Web page.

GeneReviews also provides information on establishing a diagnosis of a mitochondrial disorder. Click on the link to view the article on this topic.

Treatment for mitochondrial genetic disorders varies significantly based on the specific type of condition and the signs and symptoms present in each person. The primary aim of treatment is to alleviate symptoms and slow the progression of the condition. For example, a variety of vitamins and other supplements have been used to treat people affected by mitochondrial conditions with varying degrees of success. Other examples of possible interventions include medications to treat diabetes mellitus, surgery for cataracts, and cochlear implantation for hearing loss.^[4][1]

For more general information about the treatment of mitochondrial genetic disorders, please visit GeneReviews.