Mitochondrial diseases can be inherited via a gene mutation, which are known as primary mitochondrial diseases, or can be caused by the normal aging process.1 Inherited forms can be caused by mutations in either mitochondrial DNA or nuclear DNA, and they are classified as rare diseases because each affects only a small portion of the population.1,2 However, over 350 different kinds of mitochondrial disease have been identified that affect people of all ages and genders. That number is continuing to grow as more mutations associated with mitochondrial disease are identified.1
With that many different forms, it can be challenging to diagnose mitochondrial disease.1,3 Many symptoms overlap with those of more common diseases, and symptoms can range from muscle weakness and crippling fatigue to cardiac problems and even seizures.3
10 Types of Mitochondrial Diseases We Know About
Let’s break down 10 well-understood forms of mitochondrial diseases, including what the key symptoms are, when those symptoms develop, who is typically affected and how the disease can be diagnosed.
What: Leigh syndrome has neurological impact. A key feature is the formation of lesions in the brain. Symptoms can include vomiting, diarrhea and problems swallowing and eating, which may delay or impair growth. Additional features include poor muscle tone, involuntary muscle contraction and problems with coordination and balance. Many individuals with Leigh syndrome experience difficulty breathing, which can lead to respiratory failure.4
When: Infancy, although a few cases begin in adulthood.4
Who: Leigh syndrome affects roughly 1 in 40,000 newborns, including both boys and girls.4
How: Damaged brain tissue caused by Leigh syndrome can be seen through a brain imaging technique known as MRI. A diagnosis of Leigh syndrome is difficult to confirm because the disease may be caused by mutations in more than 35 different genes; two of the most common are SURF1 and MT-ATP6.5
Kearns Sayre Syndrome
What: Kearns Sayre syndrome affects muscles in and around the eyes. Symptoms include droopy eyelids, impaired eye movement and spots in the back of the eye that cause vision loss. Additional symptoms may include heart rhythm disorders, muscle weakness, impaired cognitive function, swollen brain and diabetes.6
When: Before age 20.6
Who: Kearns Sayre syndrome affects roughly 1 to 3 individuals per 100,000, including men and women.6
How: The diagnosis of Kearns Sayre syndrome involves a variety of tests, including examining a muscle tissue sample for abnormalities such as clumps of red muscle fibers.7
What: Alpers’ disease affects muscles, nerves and the brain. Symptoms include frequent seizures, liver disease, dementia and loss of muscle movement.8
When: Usually begins during early childhood, indicated by seizures between the ages of 3 months and 5 years.8
Who: Alpers’ disease affects roughly 1 in 100,000 individuals, including both girls and boys.8
How: Alpers’ disease is diagnosed through a genetic test to identify a mutation in the POLG gene.9
Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS)
What: MELAS affects the brain, nervous system and muscles. Symptoms include muscle weakness and pain, recurrent headaches, appetite loss, vomiting and seizures. In more severe cases, individuals can experience vision loss, stroke, dementia and weakness on one side of the body. One feature of MELAS is a buildup of lactic acid, which may cause vomiting, abdominal pain, extreme fatigue, muscle weakness and difficulty breathing.10
When: Usually during childhood.10
Who: Boys and girls; the exact number of individuals affected by MELAS is unknown.10
How: MELAS can be diagnosed through a genetic test for mutations in one of several genes (MT-ND1, MT-ND5, MT-TH, MT-TL1 and MT-TV).10
What: Barth Syndrome affects the heart, skeletal muscle and immune system. People with the disease often experience an enlarged and weakened heart, muscle weakness, extreme fatigue, short stature and frequent infections caused by a compromised immune system. Over time, heart muscles may become weak and unable to pump blood, leading to heart failure.11
When: While most symptoms appear in infancy, the most severe may not present until later.11
Who: Barth syndrome affects roughly 1 in 300,000-400,000 individuals, almost exclusively boys.11
How: Elevated levels of an acid called 3-methyglutaconic acid in blood or urine samples are a sign of Barth syndrome. A more definitive diagnosis requires a genetic test to identify a mutation in the TAZ gene, including urinary 3-MGCA testing, gene sequencing and testing of the ratio of monolysocadiolipin to cardiolipin.11
What: Pearson syndrome affects the pancreas and the bone marrow, where red and white blood cells are made. Symptoms include weakness, exhaustion, frequent illness and infections, anemia, pale skin and problems related to bruising or bleeding. Other symptoms include frequent diarrhea, stomach pain and diabetes.12
When: During infancy or childhood. Many children with Pearson syndrome may also develop a related disease called Kearns Sayre syndrome.12
Who: Boys and girls; the number of individuals affected by Pearson syndrome is unknown.12
How: A diagnosis of Pearson syndrome may involve several tests, including evaluation of bone marrow for changes in blood cells, urine for presence of certain acids and stool for presence of excess fat. A genetic test, including methods for detecting mitochondrial DNA deletions, can confirm Pearson syndrome.13
Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)
What: MNGIE primarily affects the digestive and nervous systems. MNGIE can cause problems swallowing and digesting food, since the muscles controlling digestion weaken. Additional symptoms may include nausea, vomiting, abdominal pain and intestinal blockage.14
When: Anytime, but symptoms typically appear by age 20.14
Who: Men and women; the exact number of individuals affected by MNGIE is unknown.14
How: MNGIE can be diagnosed through a genetic test to identify mutations in the TYMP gene.17
Myoclonic Epilepsy with Ragged-Red Ribers (MERRF)
What: MERRF affects the nervous system and muscles throughout the body. Symptoms of MERRF include muscle weakness, muscle stiffness and muscle twitches. Additional symptoms include seizures, dementia, problems with balance or coordination and loss of feeling in the hands and feet.15
When: Occurs during childhood or adolescence.15
Who: Girls and boys; the exact number of individuals affected by MERRF is unknown.15
How: Muscle tissue from a patient with MERRF may contain abnormal clumps of red fibers. A MERRF diagnosis can be confirmed through a genetic test for mutations in one of several genes (MT-TK, MT-TL1, MT-TH and MT-TS1).15
Neuropathy, Ataxia and Retinitis Pigmentosa (NARP)
What: NARP affects the nervous system. Symptoms of NARP include muscle weakness, problems with balance and coordination, vision loss and tingling or pain in the arms and legs. Those who develop NARP as children may experience learning disabilities and developmental delays, and those who develop NARP as adults may develop dementia.16
When: Symptoms can begin in childhood through early adulthood.16
Who: Men and women; the exact number of individuals affected by NARP is unknown.16
How: NARP may be diagnosed through a genetic test to identify mutations in the MT-ATP6 gene.16
Leber’s Hereditary Optic Neuropathy (LHON)
What: LHON affects vision. Vision problems may begin in both eyes at once, or in just one eye, although the second eye will typically also be affected within a few weeks to months. Individuals typically experience severe, permanent vision loss. Individuals with additional symptoms can be described as “LHON plus” and experience tremors, cardiac defects, muscle weakness and issues with coordination and numbness.17
When: Typically begins in adolescence or early adulthood, although few cases begin in childhood.17
Who: Predominantly men; the exact number of individuals affected by LHON is unknown, although estimates suggest that approximately 10,000 people in the U.S. are affected.17
How: LHON may be diagnosed through a genetic test to identify mutations in one of several genes (MT-ND1, MT-ND4, MT-ND4L or MT-ND6).17
Learn more about mitochondria and mitochondrial disorders.
Disclaimer: This article does not intend to be an exhaustive list of all the variations of mitochondrial disease, nor does it intend to simplify the complex diagnostic process many patients face. The article intends to provide an educational overview of several well-understood types that have been researched and help the community to understand how mitochondrial dysfunction can differ. If you have questions about symptoms and whether you might be affected by mitochondrial disease, speak with a healthcare professional.
Ref 1. Alston CL, Rocha MC, Lax NZ, et al. The genetics and pathology of mitochondrial disease. J Pathol. 2017 Jan;241(2):236-250.
Ref 2. NIH National Center for Advancing Translational Sciences. GARD (Genetic and Rare Diseases Information Center). FAQS About Rare Diseases. Accessed July 2019: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases
Ref 3. Children’s Hospital of Philadelphia. Mitochondrial Disease. Accessed July 2019: https://www.chop.edu/conditions-diseases/mitochondrial-disease.
Ref 4. NIH U.S. National Library of Medicine: Genetics Home Reference. Leigh syndrome. Accessed July 2019: https://ghr.nlm.nih.gov/condition/leigh-syndrome
Ref 5. Rohoy IS and Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet. 2014;7:221-234.
Ref 6. NIH U.S. National Library of Medicine: Genetics Home Reference. Kearns-Sayre syndrome. Accessed July 2019: https://ghr.nlm.nih.gov/condition/kearns-sayre-syndrome#sourcesforpage
Ref 7. NORD (National Organization for Rare Disorders): Rare Disease Database. Kearns Sayre Syndrome. Accessed July 2019: https://rarediseases.org/rare-diseases/kearns-sayre-syndrome/
Ref 8. NORD (National Organization for Rare Disorders): Rare Disease Database. Alpers Disease. Accessed July 2019: https://rarediseases.org/rare-diseases/alpers-disease/
Ref 9. Stumpf JD, Saneto RP, Copeland WC. Clinical and Molecular Features of POLG-Related Mitochondrial Disease. Cold Spring Harbor Perspect Biol. 2013;5(4):a011395.
Ref 10. NIH U.S. National Library of Medicine: Genetics Home Reference. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Accessed July 2019: https://ghr.nlm.nih.gov/condition/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes
Ref 11. Clarke SLN, Bowron A, Gonzalez IL, et al. Barth Syndrome. Orphanet J of Rare Diseases. 2013;8:23.
Ref 12. NIH U.S. National Library of Medicine: Genetics Home Reference. Pearson marrow-pancreas syndrome. Accessed July 2019: https://ghr.nlm.nih.gov/condition/pearson-marrow-pancreas-syndrome
Ref 13. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015 Sep;17(9):689-701.
Ref 14. NIH U.S. National Library of Medicine: Genetics Home Reference. Mitochondrial neurogastrointestinal encephalopathy disease. Accessed July 2019: https://ghr.nlm.nih.gov/condition/mitochondrial-neurogastrointestinal-encephalopathy-disease
Ref 15. NIH U.S. National Library of Medicine: Genetics Home Reference. Myoclonic epilepsy with ragged-red fibers. Accessed July 2019: https://ghr.nlm.nih.gov/condition/myoclonic-epilepsy-with-ragged-red-fibers
Ref 16. NIH U.S. National Library of Medicine: Genetics Home Reference. Neuropathy, ataxia, and retinitis pigmentosa. Accessed July 2019: https://ghr.nlm.nih.gov/condition/neuropathy-ataxia-and-retinitis-pigmentosa
Ref 17. NIH U.S. National Library of Medicine: Genetics Home Reference. Leber hereditary optic neuropathy. Accessed July 2019: https://ghr.nlm.nih.gov/condition/leber-hereditary-optic-neuropathy