Mitochondrial Myopathy

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 disorders are named and classified by their genetic causes or by their symptoms and the results of non-genetic clinical tests. Because mitochondrial disorders are grouped in two ways — by genetic cause and by symptoms — particular disorders can fall into more than one category.

Mitochondrial myopathies are forms of mitochondrial disease that cause prominent muscle problems, a grouping based on both symptoms and non-genetic clinical tests. Three types of muscles can be affected by the myopathy:

• Skeletal — the muscles around the bones and eyes
• Cardiac — the heart muscles
• Smooth — the muscles lining the intestines, gastrointestinal tract, bladder and blood vessels

Some mitochondrial myopathies may also cause problems with other organs, including the brain. Myopathies that also cause prominent neurological problems may be alternatively classified as mitochondrial encephalomyopathies.

Forms of mitochondrial myopathy that have been identified based on genetic causes may also be classified into groups based on those causes: mitochondrial DNA common mutation syndromes, for example, or mitochondrial DNA deletion syndromes. For example, Kearns-Sayre syndrome is a form of mitochondrial myopathy and also a type of mitochondrial DNA deletion syndrome.

Where genetic testing is unable to identify a genetic cause for a mitochondrial condition in a particular patient, the symptoms and non-genetic clinical tests are used to provide a more general diagnosis and to determine treatment. So some patients are diagnosed as “suspected mitochondrial myopathy” when no specific genetic cause is found for their condition, but are considered to have and are treated for mitochondrial myopathy based on symptoms and non-genetic clinical tests.

There are nine main forms of mitochondrial myopathy:

• Kearns-Sayre syndrome (KSS)
• Leigh syndrome
• Mitochondrial DNA (mtDNA) depletion syndrome
• Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome
• Mitochondrial neurogastrointestinal encephalopathy (MNGIE)
• Myoclonic epilepsy with ragged red fibers (MERFF)
• Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome
• Pearson syndrome
• Progressive external ophthalmoplegia (PEO)

Mitochondrial myopathies may be caused by mutations in the body’s nuclear DNA (the DNA found in the nucleus of cells) or by mutations or deletions in the body’s mitochondrial DNA (mtDNA, the DNA found in cells’ mitochondria).

• Forms of mitochondrial myopathy that are caused by nuclear DNA mutations may be inherited from one parent or both parents, or they may be caused by spontaneous (de novo) gene mutations in the affected individual.
• Forms of mitochondrial myopathy that are caused by mtDNA mutations are most often inherited from the mother. Only women pass mitochondrial DNA mutations on to their children through the oocyte. Males with mtDNA mutations may be clinically 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.
• Forms of mitochondrial myopathy that are caused by mtDNA deletions are most often caused by spontaneous (de novo) gene deletions and are not inherited. In rare cases, the mtDNA deletion is inherited from the mother.

Symptoms of mitochondrial myopathies 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 fall along a broad spectrum in diagnosis and treatment. Two patients may have similar symptoms with different genetic causes, and will therefore be diagnosed with different mitochondrial disorders. Further, two patients with the same genetic disorder may have very different symptoms.

Listed here are the most common symptoms for each of the main mitochondrial myopathies.

Symptoms appear in childhood, before age 20, after a period of normal development. Symptoms may include:

• Drooping or partial closure of one or both eyelids (ptosis — often observed in infancy or early childhood, before other symptoms appear)
• Impaired night vision (early symptom)
• Gradual loss of vision due to accumulation of pigmented material on the membrane lining the eye and degeneration of the retina
• Progressive paralysis of the muscles controlling eye movement
• Rapid involuntary eye movements (nystagmus)
• Muscle weakness in the face, throat, neck or shoulders, leading to swallowing and speech problems
• Balance problems and difficulty coordinating movements (ataxia)
• Heart problems caused by abnormal nerve impulses controlling the heart muscles
• Sensorineural hearing loss
• Developmental delays
• Short stature
• Diabetes mellitus or other endocrine disorders

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

• Recurrent vomiting
• Diarrhea
• Difficulty swallowing
• Poor growth or failure to thrive
• Muscle weakness and/or cramping
• Exercise intolerance
• Involuntary muscle contractions (dystonia)
• Balance problems and difficulty coordinating movements (ataxia)
• Numbness and weakness in the hands and feet (peripheral neuropathy)
• Abnormal eye movements due to weakness or paralysis of the eye muscles
• Rapid involuntary eye movements (nystagmus)
• Vision loss
• Difficulty breathing
• Heart disease (cardiomyopathy)

Symptoms appear in infancy and may include:

• Muscle weakness or “floppiness”
• Reeding difficulties
• Developmental delays
• Liver disease or failure
• Drooping or partial closure of one or both eyelids (ptosis)
• Abnormal eye movements due to weakness or partial paralysis of the eye muscles
• Seizures

Symptoms usually appear in childhood, between the ages of 2 and 15, after a period of normal development. In some cases, symptoms first appear in adulthood. Symptoms may include:

• Seizures
• Recurring headaches
• Loss of appetite
• Recurring vomiting
• Stomach pain
• Muscle weakness and/or cramping
• Exercise intolerance
• Extreme fatigue
• Difficulty breathing
• Recurrent stroke-like episodes (the distinguishing symptom of this condition) with temporary muscle weakness or paralysis on one side of the body
• Vision loss
• Sensorineural hearing loss
• Loss of motor skills
• Decline in neurocognitive skills or dementia

Symptoms usually appear in childhood, between the ages of 5 and 20, but in some cases appear in adulthood. Symptoms may include:

• Recurring vomiting
• Nausea
• Diarrhea
• Stomach pain
• Feeling full before eating sufficient amounts of food
• Stomach rumblings
• Weight loss, loss of muscle mass
• Drooping or partial closure of one or both eyelids (ptosis)
• Weakness or partial paralysis of the muscles controlling eye movement
• Muscle weakness in the neck, arms or legs
• Numbness and weakness in the hands and feet (peripheral neuropathy)
• Difficulty swallowing
• Hearing loss
• Short stature

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)
• Recurring vomiting
• Stomach pain
• Muscle weakness and/or cramping
• Progressive muscle stiffness (spasticity)
• Exercise intolerance
• Extreme fatigue
• Difficulty breathing
• Decline in neurocognitive skills or dementia
• Vision loss
• Sensorineural hearing loss
• Heart disease (cardiomyopathy)
• Abnormal heart rhythm
• Short stature

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

• Numbness, tingling or pain in arms and legs (sensory neuropathy)
• Muscle weakness
• Balance problems and difficulty coordinating movements (ataxia)
• Learning difficulties
• Developmental delays
• Vision loss
• Sensorineural hearing loss
• Seizures
• Abnormal heart rhythm

Symptoms appear in infancy or early childhood and may include:

• Pale skin and fatigue due to underproduction of red blood cells (anemia)
• Frequent infections due to underproduction of white blood cells (neutropenia)
• Bleeding due to underproduction of blood platelets (thrombocytopenia)
• Frequent diarrhea
• Stomach pain
• Poor growth, difficulty gaining weight or failure to thrive
• Muscle weakness
• Liver problems
• Diabetes mellitus

Symptoms typically appear in early adulthood, between the ages of 18 and 40 years, and may include:

• Drooping or partial closure of one or both eyelids (ptosis)
• Abnormal eye movements due to weakness or partial paralysis of the eye muscles
• Muscle weakness in the neck, arms or legs
• Difficulty swallowing

In some cases, PEO affects other parts of the body and causes additional symptoms, including:

• Sensorineural hearing loss
• Balance problems and difficulty coordinating movements (ataxia)
• Slow movements and tremors (Parkinsonism)
• Loss of sensation in the arms and legs (peripheral neuropathy)

If mitochondrial myopathy is suspected based on the patient’s physical symptoms and history, additional tests are performed to make a diagnosis. These clinical diagnostic tests may include:

• Blood tests, including complete blood count and tests to look for high concentrations of lactic acid and other abnormalities
• Urine test to look for abnormal levels of amino acids, glucose and other metabolites
• Stool sample analysis to look for high levels of fat suggestive of deficient pancreatic enzymes
• Cerebrospinal fluid (CSF) analysis to look for elevated protein levels
• MRI, CT scan or other imaging of the brain, muscle tissue or other organs
• Electrocardiography (ECG or EKG) to detect heart rhythm abnormalities
• Echocardiogram to evaluate for cardiomyopathy and other heart problems
• Muscle biopsy to look for ragged red fibers suggestive of mitochondrial proliferation that is characteristic of KSS and for large numbers of abnormal mitochondria
• Bone marrow aspirate and biopsy for microscopic examination
• Genetic diagnostic testing using blood, muscle, skin, saliva, hair follicles, urinary sediment or other tissue samples to look for mutations or deletions in mitochondrial and nuclear DNA

Currently there is no highly effective pharmacologic treatment or cure for mitochondrial myopathies. The conditions are managed with supportive therapy to address symptoms. These supportive treatments may include:

• Medication to control or prevent symptoms such as nausea, seizures and heart problems
• Eye surgery to correct drooping eyelids
• Placement of a pacemaker to treat abnormal heart rhythms
• Respiratory support
• Physical, occupational or speech therapy
• Hearing or vision aids
• Blood transfusions
• Protection from or treatment for infections
• Hearing or vision aids
• Hormone replacement therapy
• Nutritional management
• Exercise (aerobic and isotonic)
• Vitamin, cofactor, antioxidant, or amino acid supplements

Long-term care may involve a variety of specialists, including neurologists, biochemical or 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 mitochondrial myopathies.

We work closely with your primary care physician, neurologist, and other specialists to manage your day-to-day medical needs. You may also qualify for participation in clinical research studies, including clinical trials and other active efforts to achieve precision diagnostics and therapeutics for mitochondrial diseases.

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.