NORD gratefully acknowledges Kathryn Elliott, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling, and Hannah Wand, MS, Clinical Instructor (Affiliated), Dept of Pediatrics, Division of Medical Genetics, Stanford University, for assistance in the preparation of this report.
MERRF (myoclonus epilepsy with ragged-red fibers) syndrome is an extremely rare disorder that appears in childhood, adolescence or adulthood after normal development early in life. MERRF syndrome affects the nervous system, skeletal muscles and other body systems. The distinguishing feature in MERRF is muscle jerks (myoclonus), consisting of sudden, brief spasms that can affect the arms, legs or entire body. Individuals with MERRF syndrome may also have seizures (generalized epilepsy), impaired ability to coordinate movements (ataxia), muscle weakness (myopathy), exercise intolerance and a slow decline of intellectual function (dementia). Decreased body height (short stature), vision problems (optic atrophy), hearing loss, heart disease of the heart muscles (cardiomyopathy) and abnormal sensation from nerve damage (peripheral neuropathy) are other common symptoms. Individuals with MERRF syndrome will also have abnormal muscle cells that appear as ragged red fibers (RRF) when stained and viewed microscopically.
MERRF syndrome is a mitochondrial disorder. Mitochondria are structures found in the cell that produce energy. Mitochondrial disorders can occur when the mitochondrial genetic material (mtDNA) has a genetic change (mutation) that prevents the mitochondria from carrying out their function. As a result, parts of the body like the brain and muscles may not work properly due to lack of energy. MERRF syndrome is caused by mutations in mtDNA and is inherited from the mother.
MERRF syndrome was first reported in 1973 when a family was described with muscle jerks (myoclonus), seizures and abnormal muscle cells showing characteristic ragged red fibers (RRF). By 1988, 25 people had been identified with a similar collection of features. That same year it was determined that MERRF syndrome is caused by mutations in mitochondrial DNA, and two years later, in 1990, the first causal genetic mutation was discovered.
Today MERRF syndrome is typically diagnosed by a combination of clinical features (myoclonus, seizures, and ataxia) and RRF seen on muscle biopsy. However, not all individuals diagnosed with MERRF syndrome will have, or develop, the same symptoms. A molecular diagnosis of MERRF is made when a genetic mutation is identified in a mitochondrial gene that is known to be associated with the condition. A diagnosis of MERRF syndrome can help guide surveillance, treatment of symptoms and possibly aid in prevention of disease progression. A genetic diagnosis can also clarify risk to siblings, parents, extended family members and biological offspring, and can help in family planning.
Symptoms of MERRF syndrome can begin in childhood, adolescence or early adulthood after a period of normal early development. Signs, symptoms and physical findings associated with MERRF syndrome may vary greatly between affected individuals in the same family and between different families. The age of onset and how quickly the condition progresses can differ between individuals.
Brief, sudden, jerking muscle spasms (myoclonus) is usually the first symptom of MERRF syndrome followed by seizures (generalized epilepsy), impaired ability to coordinate movements (ataxia), muscle weakness (myopathy) and exercise intolerance. Decreased body height (short stature), hearing loss, decline of intellectual function (dementia) and altered sensation (pins-and-needles or pain) from nerve damage (peripheral neuropathy) are also common symptoms. Some individuals may have vision problems or vision loss, most commonly caused by degeneration of the optic nerve (optic atrophy). Vision impairment may also result from drooping upper eyelids (ptosis), progressive damage to the receptors that respond to light in the retina of the eye (pigmentary retinopathy) or weakness of the eye muscles (ophthalmoplegia). Heart problems may also arise, including heart disease of the heart muscle (cardiomyopathy) and problems of the heart rhythm (arrhythmia) such as Wolff-Parkinson-White syndrome. Occasionally, people with MERRF syndrome have benign fat cell tumors (lipomas) especially around the neck, too much sugar in the blood (diabetes mellitus) and involuntary muscle stiffness (spasticity) along with other differences in reflexes and movement (pyramidal signs). People with MERRF syndrome frequently have an accumulation of lactic acid in the blood (lactic acidosis) which can cause vomiting, abdominal pain, decreased appetite, unusual sleepiness or fatigue, muscle pain or weakness and difficulty breathing.
MERRF syndrome is caused by genetic changes (mutations) in mitochondrial DNA (mtDNA). Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. MtDNA encodes specific genes that are the instructions for making some of the essential parts of the mitochondria.
MERRF syndrome is caused by mutations in the mtDNA. The genes associated with MERRF syndrome are the instructions for specific molecules called transfer RNAs. Transfer RNAs (tRNAs) help assemble proteins, which then carry out the mitochondrial function of producing energy. Mutations in the mtDNA genes associated with MERRF lead to abnormal tRNAs, and consequently reduce the ability of the mitochondria to build proteins and produce energy for the body. Parts of the body that require a lot of energy, like the muscles and brain, will be the most affected by these mutations.
More than 90% of cases of MERRF syndrome are caused by mutations in one mtDNA gene, MT-TK. One specific MT-TK mutation, called m.8344A>G, accounts for 80% of cases. Mutations in MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1, and MT-TS2 have also been associated with MERRF syndrome.
Genes for mitochondria (mtDNA) are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization. As a result, all human mtDNA comes from the mother. A mother with a non-working gene in mtDNA will pass on the non-working gene to all her children, but only her daughters will pass on the non-working gene to their children.
As cells divide, the number of normal mtDNA and non-working (mutated) mtDNA are distributed in an unpredictable fashion among different tissues. Consequently, mutated mtDNA accumulates at different rates among different tissues in the same individual. Thus, family members who have the identical non-working gene in mtDNA may exhibit a variety of different symptoms at different times and with varying degrees of severity.
Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of mitochondria with the non-working gene may be out-numbered by the number of mitochondria without the non-working gene. Symptoms may not appear in any given generation until a significant proportion of mitochondria have mutated mtDNA. The uneven distribution of normal and mutated mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.
It is generally thought that a higher number of mutated mtDNA relative to normal mtDNA corresponds with more severe symptoms. However, the number of mutated mtDNA relative to the normal mtDNAs cannot be used to accurately predict if symptoms will present, which symptoms may present or symptom severity.
A few rare cases of MERRF syndrome have occurred as the result of a new spontaneous mutation in a mitochondrial gene in the affected individual. These mutations are not inherited, but may be passed down to future generations if the affected individual is female.
MERRF syndrome is a rare disorder that affects males and females in equal numbers. Onset of symptoms of MERRF syndrome can occur in childhood, adolescence or early adulthood. It typically presents after a period of normal early development.
The prevalence of MERRF syndrome is unknown. However, several studies of mitochondrial disorders in European populations found that the common MT-TK mutation, m.8344A>G, has a prevalence between 0 and 1.5 per 100,000 adults in northern Finland, 0.39 per 100,000 adults in northern England, between 0 and 0.25 per 100,000 children in western Sweden and 0.7 per 100,000 individuals in northeast England. Consistent with these findings, it is widely considered that the prevalence of MERRF is likely less than 1 per 100,000 individuals.
Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like MERRF syndrome.
MERRF syndrome is diagnosed based on clinical findings and molecular genetic testing.
A clinical diagnosis of MERRF can be made based on the presence of four features: myoclonus (muscle spasms), generalized epilepsy (seizures), ataxia (impaired ability to coordinate movements) and abnormal muscle cells showing ragged red fibers (RRF) when a muscle biopsy is viewed microscopically.
Clinical testing may also reveal other features of MERRF syndrome. Concentrations of lactate and pyruvate are commonly elevated in blood and fluid surrounding the brain and spinal cord (cerebrospinal fluid). Concentrations of lactate and pyruvate may show large increases after moderate physical activity. The concentration of cerebrospinal fluid (CSF) protein may also be elevated in MERRF syndrome. Brain imaging techniques such as magnetic resonance imaging (MRI) may show stroke-like lesions or degeneration of cells (atrophy) and magnetic resonance spectroscopy (MRS) is used to look for lactate in the brain. Electroencephalogram (EEG) measures electrical activity in the brain and can help diagnose seizures. Electrocardiogram (EKG) may be used to diagnose heart rhythm abnormalities. Nerve conduction velocity studies may be consistent with a myopathy or a neuropathy in individuals with MERRF syndrome.
A molecular diagnosis of MERRF syndrome is made when an individual who has symptoms consistent with the syndrome is found to have a mutation in a mtDNA gene associated with MERRF. A molecular diagnosis can confirm a clinical diagnosis of MERRF syndrome or help clarify a diagnosis when a clinical diagnosis cannot be made because symptoms overlap with other related disorders. The mtDNA mutations associated with MERRF can usually be detected in white blood cells, but due to heteroplasmy (see Causes), other tissue samples such as skin, saliva, hair follicles, urinary sediment and skeletal muscle, may be necessary to establish a molecular diagnosis.
In individuals with a clinical diagnosis or with symptoms that are highly suggestive of MERRF syndrome, molecular genetic testing may begin with a gene-targeted approach. An individual may first be screened for the common mutation, m.8344A>G, in the MT-TK gene. If this mutation is not found, broader genetic testing may be ordered that includes sequencing all genes associated with MERRF syndrome and other genes that cause related disorders (multigene panel testing). Genetic testing in other tissue samples may also be required.
In individuals that have general symptoms, such as seizures and muscle weakness that overlap with many other inherited conditions, molecular genetic testing may begin with a very broad approach. In these patients, genetic testing may include sequencing all mtDNA (mitochondrial genome) in addition to all genes (exome sequencing) or all DNA (genome sequencing).
Clinical Testing and Work-Up
Individuals with MERRF syndrome and their at-risk relatives should be followed by an interdisciplinary team at regular intervals to monitor any new symptoms and progression of disease.
After an initial diagnosis, baseline evaluations recommended include: (1) measurement of height and weight to detect short stature, (2) neurologic evaluation with a head MRI, MRS, EEG and neuropsychiatric testing to detect differences in the brain, presence of seizures and evidence of dementia, (3) hearing (audiologic) evaluation to detect hearing impairment, (4) eye (ophthalmologic) evaluation to detect vision problems, (5) physical and occupational therapy assessments, (6) cardiac evaluation with a EKG and echocardiogram to detect heart abnormalities, and (7) fasting serum glucose and glucose tolerance test to detect diabetes mellitus.
Genetic counseling is recommended for affected individuals and their families.
No specific treatment is available for MERRF syndrome. Some medications and therapies may be helpful in managing symptoms.
Traditional anticonvulsant drugs are used to help prevent and control seizures associated with MERRF syndrome. Valproic acid should be avoided in the treatment of seizures. Levetiracetam and clonazepam have been effective in controlling myoclonus in a small number of patients. Standard treatment for heart problems (cardiomyopathies and arrhythmias) can be used per cardiologist recommendation. Hearing aids and cochlear implants can improve hearing impairments. Physical therapy, occupational therapy and aerobic exercise may help to improve muscle weakness, stiffness, and motor function.
Therapies are sometimes used to increase energy production by the mitochondria and slow the effects of the condition. Coenzyme Q10 (CoQ10) and L-carnitine have been beneficial in some patients with different mitochondrial diseases. Additionally, supplements such as ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex and creatine may be of benefit to some individuals with mitochondrial disease with muscle involvement. Efficacy of these supplements is being studied in clinical trials. Individuals with MERRF should avoid mitochondrial toxins such as aminoglycoside antibiotics, linezolid, cigarettes and alcohol.
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Sharma H, et al. Development of mitochondrial replacement therapy: A review. Heliyon. 2020; e04643.
Finsterer J, et al. MERRF classification: implications for diagnosis and clinical trials. Pediatric neurology. 2018; 80, 8-23.
Lorenzoni PJ, et al. When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?. Arquivos de neuro-psiquiatria. 2014;72(10), 803-811.
Mancuso M, et al. Phenotypic heterogeneity of the 8344A> G mtDNA “MERRF” mutation. Neurology. 2013; 80(22), 2049-2054.
Nissenkorn A, et al, Neurologic presentations of mitochondrial disorders. J Child Neurol. 2000;15:44-48.
Velez-Bartolomei F, Lee C, Enns G. MERRF. 2003 Jun 3 [Updated 2021 Jan 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1520/ Accessed May 5, 2021.
Hameed S, Tadi P. (Updated 2021 Feb 7). Myoclonic Epilepsy and Ragged Red Fibers. In: StatPearls Published; 2021 Jan. Available at https://www.ncbi.nlm.nih.gov/books/NBK555923/. Accessed May 5, 2021.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:545000; Last Update: 11/19/2014. https://www.omim.org/entry/545000 Accessed May 5, 2021.
MedlinePlus. National Library of Medicine. Myoclonic epilepsy with ragged-red fibers. Reviewed May 1, 2014 http://ghr.nlm.nih.gov/condition/myoclonic-epilepsy-with-ragged-red-fibers. Accessed May 5, 2021.
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