Mitochondrial DNA Common Mutation Syndromes

Mitochondrial disorders impair the function of mitochondria, the tiny compartments in every cell of the body that produce the energy needed by cells. Depending on which cells have fewer or lower-functioning mitochondria, different symptoms may occur. Organs and other parts of the body that require more energy, such as the heart, muscles and brain, are often affected. Mitochondrial disease is the name for a large number of mitochondrial disorders, with different genetic causes and presentations.

Mitochondrial disease may be caused by genetic mutations in the body’s nuclear DNA (the DNA found in the nucleus of cells) or by genetic mutations or deletions in the body’s mitochondrial DNA (mtDNA < the DNA found in cells’ mitochondria). mtDNA common mutation syndromes are mitochondrial disorders caused by recurrent mtDNA mutations in unrelated families and populations. Despite the name, these are rare conditions; “common” means that these specific mutations recur across families and ethnic groups.

The most common forms of mitochondrial disease caused by recurrent mtDNA mutations first recognized 30 years ago include:

• Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome
• Myoclonic epilepsy with ragged red fibers (MERRF)
• Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome
• Leber hereditary optic neuropathy (LHON)

It is important to remember that although these are the most common forms of mitochondrial disease, each is individually rare, occurring in fewer than 1 in 1,000 people. 

Some cases of Leigh syndrome, a condition defined by progressive loss of movement and neurocognitive abilities, are caused by recurrent mtDNA mutations, including the ones that cause these classical clinical syndromes.

mtDNA common mutation syndromes are often inherited from the mother. Only women pass mtDNA mutations on to their children through the oocyte. Men with mtDNA mutations may be affected by the conditions, but do not pass them on to their children.

In some cases, mtDNA mutations are spontaneous (de novo) in the affected individual and are not inherited.

Symptoms of mtDNA common mutation syndromes vary widely by type and from case to case. There is also a great deal of overlap in symptoms among different mitochondrial conditions. Doctors now consider them to represent a broad spectrum of features and severity in diagnosis and treatment. Two patients may have the same symptoms with different genetic causes, and will therefore be diagnosed with different mitochondrial disorders. And two patients with the same genetic disorder may have very different symptoms and require different treatment.

Listed here are the most common symptoms for each of the classical clinical mtDNA mutation syndromes.

The diagnosis is usually made in adolescence or young adulthood, but symptoms typically begin earlier, between the ages of 2 and 15 years, after a period of normal development. In some cases, symptoms first appear in adulthood.

Symptoms may include:

• Stroke-like episodes (the distinguishing symptom of this condition) with temporary or permanent vision loss, muscle weakness, or paralysis on one side of the body
• Lactic acidemia or acidosis
• Decline in neurocognitive skills, abnormal thinking or dementia
• Seizures
• Recurrent headaches
• Poor appetite
• Recurrent vomiting
• Muscle weakness and/or cramping
• Exercise intolerance
• Extreme fatigue
• Hearing loss
• Regression, with loss of motor skills
• Heart disease (cardiomyopathy or arrhythmia)
• Diabetes mellitus

Symptoms usually appear in childhood after a period of normal development, and may include:

• Muscle twitches (myoclonus)
• Seizures
• Balance problems and difficulty coordinating movements (ataxia)
• Sensorineural hearing loss
• Muscle weakness and/or cramping
• Exercise intolerance
• Extreme fatigue
• Decline in neurocognitive skills, dementia
• Loss of feeling in limbs
• Vision loss
• Heart disease (cardiomyopathy or arrhythmia)
• Short stature
• Fatty skin tumors (lipomas)

Symptoms appear in childhood or early adulthood, and may include:

• Numbness, tingling or pain in arms and legs (sensory neuropathy)
• Balance problems, difficulty coordinating movements (ataxia)
• Vision loss (retinitis pigmentosa)
• Learning difficulties
• Muscle weakness and/or cramping
• Exercise intolerance and/or muscle

Symptoms usually appear in early adulthood, between the ages of 20 and 30, and may include:

• Blurred vision starting in one eye and eventually affecting both
• A blind spot in the middle of vision
• Decline in ability to perform visual tasks such as reading or recognizing faces

Symptoms usually appear in infancy, but in some cases appear later in childhood or in early adulthood. Symptoms may include:

• Loss of developmental milestones after an infection (regression)
• Seizures
• Abnormal body temperature
• Persistent vomiting
• Floppiness (hypotonia)
• Difficulty swallowing
• Poor growth or failure to thrive
• Muscle weakness
• Involuntary muscle contractions (dystonia)
• Balance problems, difficulty coordinating movements (ataxia)
• Numbness and weakness in the hands and feet (peripheral neuropathy)
• Weakness or paralysis of the eye muscles
• Vision loss
• Difficulty breathing
• Heart disease (cardiomyopathy)

If a mtDNA common mutation syndrome is suspected based on the patient’s physical symptoms and history, additional tests are performed to make a diagnosis. These tests may include:

• Blood tests to look for high concentrations of lactic acid and other abnormalities
• Cerebrospinal fluid (CSF) analysis to look for elevated protein levels
• MRI of the brain and/or spinal cord
• Electrocardiography (ECG or EKG) to detect heart rhythm abnormalities
• Echocardiography (Echo) to detect cardiomyopathy
• Muscle biopsy to obtain tissue in which to measure biochemical function, perform DNA testing, and detect ragged red fibers characteristic of MELAS syndrome and MERRF
• Genetic testing using blood, muscle, skin, urinary sediment or other tissue samples to look for mutations in mtDNA and nuclear DNA

Currently there is no highly effective treatment or cure for mtDNA common mutation syndromes. The conditions are managed with supportive therapy to address symptoms. These supportive treatments may include:

• Anti-convulsant drugs to prevent and control seizures (for MELAS syndrome, MERRF and Leigh Syndrome)
• Medications to improve symptoms during stroke-like episodes or to reduce their occurrence (for MELAS syndrome and Leigh Syndrome)
• Medication to control muscle twitches (for MERRF)
• Medication to treat heart problems
• Respiratory support
• Physical, occupational or speech therapy
• Hearing or vision aids
• Nutritional management
• Exercise
• Vitamin or amino acid supplements

Long-term care may involve a variety of specialists, including neurologists, biochemical and clinical geneticists, endocrinologists, ophthalmologists, audiologists, cardiologists and nephrologists.

Knowing the underlying cause of your or your child’s condition will help your medical team determine the best course of treatment. The Mitochondrial Medicine team at Children's Hospital of Philadelphia (CHOP) has expertise in diagnosing the many forms of mitochondrial disease, including mtDNA common mutation syndromes.

We work closely with your primary care physician, neurologist, and other specialists to optimize and determine best management approaches for your day-to-day medical needs. We also work closely with researchers to provide opportunities to participate in basic and clinical research programs to advance understanding and therapies for mitochondrial disease.

Our team will provide relevant mitochondrial disease counseling based on your or your child’s diagnosis, including an overview of mitochondrial disease features and genetics.