What are mitochondrial DNA deletion syndromes?

Mitochondrial disorders impair the function of mitochondria, the tiny compartments in every cell of the body that produce the energy we need. 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 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 (the DNA found in cells’ mitochondria). Mitochondrial DNA deletion syndromes are mitochondrial disorders caused by deletions of the mitochondrial DNA.

Forms of mitochondrial DNA deletion syndromes

There are three main forms of mitochondrial disease caused by single large-scale mitochondrial DNA deletions involving thousands of nucleotides:

• Kearns-Sayre syndrome (KSS)
• Pearson syndrome
• Progressive external ophthalmoplegia (PEO)

Some cases of Leigh syndrome, a condition defined by progressive loss of movement and mental abilities, are caused by single large-scale mitochondrial DNA deletions and can be grouped with these syndromes. Some people with a mitochondrial DNA deletion do not fit into one of these classically described clinical syndromes but their symptoms may still be explained by having the deletion.

Multiple different mitochondrial DNA deletions, typically in muscle, may be seen in some individuals with a wide range of neurologic and muscle disorders.  When detected, this finding is often an indication that the individual has an underlying nuclear gene disorder impairing the production or maintenance of mitochondrial DNA, and further nuclear genome testing would be indicated.

Causes of mitochondrial DNA deletion syndromes

Single large-scale mitochondrial DNA deletion syndromes are most often caused by spontaneous (de novo) gene deletions and are not inherited. However, the CHOP Mitochondrial Medicine team recently helped to identify a new inheritance pattern in which a single large-scale mitochondrial DNA deletion was not sporadic but instead resulted from an autosomal dominant, de novo mutation in a nuclear gene involved in mitochondrial DNA replication.

In some cases, the mitochondrial DNA deletion may be inherited from the mother. Indeed, only women except in very rare cases pass mitochondrial DNA mutations present in their oocytes (eggs) on to their children. Men with mitochondrial DNA mutations may be affected by the conditions, but do not pass them on to their children.

Signs and symptoms of mitochondrial DNA deletion syndromes

Symptoms of single large-scale mitochondrial DNA deletion 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 consider them as a spectrum in diagnosis and treatment. Two patients can have the same symptoms but with different genetic causes, and will therefore be diagnosed with different forms of mitochondrial disease. Further, two patients with the same condition as diagnosed with genetic testing can have very different symptoms and require different treatment(s).

Listed here are the most common symptoms for each of the main mitochondrial DNA deletion syndromes.

Kearns-Sayre syndrome (KSS)

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

• partial closure of the eyelids (ptosis — often observed in infancy or early childhood, before other symptoms appear, often worse with fatigue)
• impaired night vision (nyctalopia - another early symptom)
• gradual loss of vision due to accumulation of pigmented material on the membrane lining the eye and to degeneration of the retina
• progressive paralysis of the muscles controlling eye movement (ophthalmoplegia)
• CPEO: chronic progressive external ophthalmoplegia: description of having both ptosis and ophthalmoplegia
• rapid involuntary eye movements (nystagmus)
• muscle weakness in the face, throat, neck or shoulders, leading to swallowing (dysphagia or achalasia) and speech problems (dysarthria)
• balance problems, difficulty coordinating movements (ataxia)
• heart problems caused by abnormal nerve impulses controlling the heart muscles (arrhythmia)
• hearing loss (sensorineural)
• developmental delays
• short stature
• pancreatic insufficiency, may require treatment to help absorb fat
• diabetes mellitus

Pearson syndrome

Symptoms appear in infancy or early childhood and may include:

• pale skin and fatigue due to underproduction of red blood cells (anemia); may require recurrent transfusions until often self-resolves by several years of life
• 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
• pancreatic insufficiency, may require treatment to help absorb fat
• muscle weakness
• liver problems
• diabetes mellitus

Progressive external ophthalmoplegia (PEO)

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

• drooping or partial closure of one or both eyelids (ptosis)
• weakness or partial paralysis of the muscles controlling eye movement (ophthalmoplegia)
• muscle weakness in the neck, arms or legs
• difficulty swallowing (dysphagia)

In some cases, ‘PEO plus’ occurs, which affects other parts of the body and causes additional symptoms, including:

• hearing loss (sensorineural)
• balance problems, difficulty coordinating movements (ataxia)
• slow movements and tremors (parkinsonism)
• loss of sensation in the arms and legs (peripheral neuropathy)

Leigh syndrome, when caused by single large-scale mitochondrial DNA deletions

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

• recurring vomiting
• diarrhea
• difficulty swallowing (dysphagia)
• 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 (ophthalmoplegia)
• rapid involuntary eye movements (nystagmus)
• vision loss
• difficulty breathing
• heart disease (cardiomyopathy)

Testing and diagnosis of mitochondrial DNA deletion syndromes

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

• blood tests, including complete blood count with differential, and tests to look for high concentrations of lactic acid and other biochemical abnormalities
• urine test to look for abnormal levels of amino acids, organic acids, glucose, protein, and other signs of possible kidney involvement
• stool sample analysis to look for high levels of fat and evidence of fat malabsorption
• 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 and other heart problems
• muscle biopsy to look for ragged red fibers characteristic of KSS and for large numbers of abnormal mitochondria; especially important for additional genetic testing if blood testing is negative for the mitochondrial DNA deletion
• bone marrow aspiration and biopsy for examination under a microscope in case of bone marrow failure or severe anemia
• genetic testing using blood, muscle, skin, saliva, hair follicles, urinary sediment or other tissue samples to look for deletions in mitochondrial DNA.  May consider nuclear exome or genome testing to evaluate for nuclear genes involved in mitochondrial DNA replication and maintenance.

Treatment of mitochondrial DNA deletion syndromes

Currently there is no highly effective treatment or cure for single large-scale mitochondrial DNA deletion syndromes. The conditions are managed with supportive therapy to address symptoms. These supportive treatments may include:

• eye surgery to correct drooping eyelids
• prophylactic placement of a prophylactic pacemaker to treat abnormal heart impulses and prevent sudden death
• respiratory support
• physical, occupational and/or speech therapy
• blood transfusions
• protection from or treatment for infections
• hearing or vision aids
• hormone replacement therapy
• nutritional management including possible need for feeding (gastrostomy) tube
• exercise
• vitamin or amino acid supplements
• pancreatic enzyme supplementation

Follow-up care

Long-term care may involve a variety of specialists, including neurologists, endocrinologists, metabolic physicians, ophthalmologists, audiologists, cardiologists, and nephrologists, dietician, and physical/occupational/speech therapists.

Why choose CHOP?

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 single large-scale mitochondrial DNA deletion syndromes.

We work closely with your primary care physician, neurologist, and other specialists to manage your day-to-day medical needs, both in the clinic and when needed upon admission to the hospital. Clinical research and treatments trials may be available to provide improved understanding, outcome measure development and monitoring, and access to new therapies being developed for mitochondrial disease.

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