What are the other Names for this Condition? (Also known as/Synonyms)

• MGDs (Mitochondrial Genetic Disorders)

What is Mitochondrial Genetic Disorders? (Definition/Background Information)

• Mitochondrial Genetic Disorders refer to a group of conditions that affect the mitochondria (the structures in each cell of the body that are responsible for making energy)
• People with these conditions can present at any age with almost any affected body system; however, the brain, muscles, heart, liver, nerves, eyes, ears and kidneys are the organs and tissues most commonly affected. Symptom severity can also vary widely
• Mitochondrial Genetic Disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy
• Those caused by mutations in mitochondrial DNA are transmitted by maternal inheritance, while those caused by mutations in nuclear DNA may follow an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance
• The treatment of Mitochondrial Genetic Disorders varies based on the specific type of condition and the signs and symptoms present in each person

(Source: Mitochondrial Genetic Disorders; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Mitochondrial Genetic Disorders? (Age and Sex Distribution)

• Mitochondrial Genetic Disorders is a rare congenital disorder. The presentation of symptoms may occur at any age
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Mitochondrial Genetic Disorders? (Predisposing Factors)

• A positive family history may be an important risk factor, since Mitochondrial Genetic Disorders can be inherited
• Other risk factors may depend on the specific types of Mitochondrial Genetic Disorders

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Mitochondrial Genetic Disorders? (Etiology)

• Mitochondrial Genetic Disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria
• The conditions can be caused by sporadic mutation(s) in the DNA of mitochondria or nucleus, with no family history of such mutation(s)
• Mitochondrial Genetic Disorders can also 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
• The disorders caused by mutations in nuclear DNA may follow an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance

(Source: Mitochondrial Genetic Disorders; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Maternal or mitochondrial inheritance: If the causative gene for a disease or condition is located on the mitochondrion, then the inheritance is known as mitochondrial inheritance.

• Mitochondria are double-membrane cellular organelles present in numerous quantities inside cells
• These organelles are the sites of cellular respiration and energy generation, and are known as the “powerhouses” of cells
• Mitochondria carry their own DNA. Since the egg contributes the cellular environment for fertilization and subsequent embryonic development, the mitochondria are inherited exclusively from the mother (to the offspring)

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

X-linked dominant inheritance pattern: In this type of inheritance, the defective gene is carried on the X chromosome. A single copy of the defective gene in each cell of an individual is sufficient for the disease to manifest itself. Since males have only one X chromosome inherited from their mother, the defective gene is expressed in them, causing the condition. Although females carry two X chromosomes, the unaffected gene copy in the normal X chromosome may partially or completely mask the effects of a defective gene copy. Therefore, if females do have symptoms, they are likely to be less severe than those in males.

X-linked recessive pattern of inheritance: The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What are the Signs and Symptoms of Mitochondrial Genetic Disorders?

The signs and symptoms of 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 from one individual to another.

The most common signs and symptoms of Mitochondrial Genetic Disorders include:

• 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

(Source: Mitochondrial Genetic Disorders; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Mitochondrial Genetic Disorders Diagnosed?

The diagnosis of Mitochondrial Genetic Disorders may be made on the basis of:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms, such as multiple, unrelated systems being affected in the body
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary

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 such cases, the healthcare provider may start by evaluating the levels of certain substances in blood or cerebrospinal fluid samples. Other tests that can support a diagnosis include:

• 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
• Confirming a diagnosis with genetic testing

(Source: Mitochondrial Genetic Disorders; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Mitochondrial Genetic Disorders?

The complications of Mitochondrial Genetic Disorders may include:

• Poor movement
• Fall injuries due to seizures
• Impaired vision
• Hearing loss
• Problems with memory
• Recurrent infections, causing scarring in tissue and organs
• Single or multiple organ failure (liver, kidney, heart)

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Mitochondrial Genetic Disorders Treated?

The treatment for Mitochondrial Genetic Disorders is tailored to each affected individual’s signs and symptoms, with the goal of relieving symptoms and slowing disease progression. The treatment methods may include the following:

• Multivitamins and other supplements
• Medications for diabetes
• Medications for problems with thyroid gland function
• Surgery for cataract
• Cochlear implantation for hearing impairment
• Physical therapy to improve muscle tone

How can Mitochondrial Genetic Disorders be Prevented?

Currently, Mitochondrial Genetic Disorders may not be preventable, since they are, as the title suggests, genetic disorders.

• If a specific mutation is known to cause the condition within the family, then genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Mitochondrial Genetic Disorders? (Outcomes/Resolutions)

• The prognosis of Mitochondrial Genetic Disorders is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Mitochondrial Genetic Disorders:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/