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Synonym: Myoclonic Epilepsy Associated with Ragged Red Fibers

, MD and , MD.

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Initial Posting: ; Last Update: January 29, 2015.

Estimated reading time: 19 minutes


Clinical characteristics.

MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, occurring after normal early development. Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White (WPW) syndrome. Pigmentary retinopathy and lipomatosis are occasionally observed.


The clinical diagnosis of MERRF is based on the following four "canonic" features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy. The mitochondrial DNA (mtDNA) gene MT-TK encoding tRNALys is the gene most commonly associated with MERRF. The most common pathogenic variant, present in more than 80% of affected individuals with typical findings, is an A-to-G transition at nucleotide 8344 (m.8344A>G). Pathogenic variants in MT-TF, MT-TL1, MT-TI, and MT-TP have also been described in a subset of individuals with MERRF. Pathogenic variants are usually present in all tissues and are conveniently detected in mtDNA from blood leukocytes. However, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, in individuals having few symptoms consistent with MERRF or in asymptomatic maternal relatives of an affected individual, the pathogenic variant may be undetectable in mtDNA from leukocytes and may only be detected in other tissues, such as cultured skin fibroblasts, urinary sediment, oral mucosa, saliva, hair follicles, or (most reliably) skeletal muscle.


Treatment of manifestations: Conventional antiepileptic drugs for seizures; physical therapy to improve any impaired motor function; aerobic exercise; standard pharmacologic therapy for cardiac symptoms. Levetiracetam, clonazepam, zonisamide, and valproic acid (VPA) have been used to treat myoclonic epilepsy; however, VPA may cause secondary carnitine deficiency and should be avoided or used with L-carnitine supplementation.

Prevention of primary manifestations: Coenzyme Q10 (50-100 mg 3x/day) and L-carnitine (1000 mg 3x/day) are often used in hopes of improving mitochondrial function.

Surveillance: Routine evaluations every 6-12 months initially; annual neurologic, ophthalmologic, cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (fasting blood sugar and TSH) evaluations.

Pregnancy management: During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions.

Genetic counseling.

MERRF is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk for having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. A male with a mtDNA pathogenic variant cannot transmit the pathogenic variant to any of his offspring. A female with the pathogenic variant (whether affected or unaffected) transmits the pathogenic variant to all of her offspring. Prenatal diagnosis for MERRF is possible if an mtDNA pathogenic variant has been detected in the mother. However, because the mutational load in the mother's tissues and in the fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues and because the mutational load in tissues sampled prenatally may shift in utero or after birth secondary to random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.


Clinical Diagnosis

The clinical diagnosis of MERRF (myoclonic epilepsy with ragged red fibers) is based on the following four "canonic" features:

  • Myoclonus
  • Generalized epilepsy
  • Ataxia
  • Ragged-red fibers (RRF) in the muscle biopsy or identification of a mtDNA pathogenic variant

Additional frequent manifestations include the following:

  • Sensorineural hearing loss
  • Myopathy
  • Peripheral neuropathy
  • Dementia
  • Short stature
  • Exercise intolerance
  • Optic atrophy

Less common clinical signs (seen in <50% of affected individuals) include the following:

  • Cardiomyopathy
  • Pigmentary retinopathy
  • Pyramidal signs
  • Ophthalmoparesis
  • Multiple lipomas


Lactic acidosis both in blood and in the CSF. In individuals with MERRF, the concentrations of lactate and pyruvate are commonly elevated at rest and increase excessively after moderate activity.

Note: Other situations (unrelated to the diagnosis of MERRF or other mitochondrial diseases) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.

Elevated CSF protein concentration. The concentration of CSF protein may be increased but rarely surpasses 100 mg/dL.

Electroencephalogram (EEG) usually shows generalized spike and wave discharges with background slowing, but focal epileptiform discharges may also be seen.

Electrocardiogram often shows pre-excitation; heart block has not been described.

Electromyogram (EMG) and nerve conduction velocity (NCV) studies are consistent with a myopathy, but neuropathy may coexist.

Brain MRI often shows brain atrophy and basal ganglia calcification. Bilateral putaminal necrosis and atrophy of the brain stem and cerebellum have been reported [Orcesi et al 2006, Ito et al 2008].

Muscle biopsy typically shows ragged red fibers (RRF) with the modified Gomori trichrome stain and hyperactive fibers with the succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with the histochemical reaction for cytochrome c oxidase (COX). Occasionally, RRF may not be observed [Mancuso et al 2007].

Respiratory chain studies. Biochemical analysis of respiratory chain enzymes in muscle extracts usually shows decreased activity of respiratory chain complexes containing mtDNA-encoded subunits, especially COX deficiency. However, biochemical studies may also be normal.

Genes. MT-TK, MT-TF, MT-TL1, MT-TI, and MT-TP are the genes in which pathogenic variants are known to cause MERRF.

Table 1.

Molecular Genetic Testing Used in MERRF

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
MT-TKTargeted analysis of m.8344A>G>80% 2
Targeted analysis for pathogenic variants 3~10% 2
MT-TFSequence analysis / scanning for pathogenic variants 4, 5<5% 6
mtDNASequence analysis / scanning for pathogenic variants 490%-95% 7
Unknown 8NA<5%

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Four MT-TK pathogenic variants (m.8344A>G, m.8356T>C, m.8363G>A, and m.8361G>A) account for approximately 90% of pathogenic variants in individuals with MERRF.


Pathogenic variants detected: m.8356T>C, m.8363G>A, and m.8361G>A. Note: Pathogenic variants included in a panel may vary by laboratory.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Pathogenic variants detected: m.611G>A, m.3243A.G, m.4279A>G, m.4284G>A, and m.15967G>A


The proportion of MERRF caused by the pathogenic variants listed in footnote 4


Sequence analysis / scanning for pathogenic variants is used to detect pathogenic variants throughout mtDNA and is not specific for MERRF. The overall variant detection rate for MERRF by scanning/sequence analysis of mtDNA is 90%-95%.


One child with MERRF was found to have two mtDNA deletions in a buccal swab suggesting an autosomal disorder with multiple mtDNA deletions; however, the causative nuclear gene was not identified [Yorns et al 2012].

Testing Strategy

Establishing the Diagnosis in a Proband

Pathogenic variants are usually present in all tissues and can be detected in mtDNA from blood leukocytes in individuals with typical MERRF; however the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, in individuals having few symptoms consistent with MERRF or in asymptomatic maternal relatives, the pathogenic variant may be undetectable in mtDNA from leukocytes and may only be detected in other tissues, such as cultured skin fibroblasts, urinary sediment, oral mucosa, saliva, hair follicles, or (most reliably) skeletal muscle.

One genetic testing strategy is serial single-gene molecular genetic testing based on the order in which pathogenic variants most commonly occur:

  • Typically, blood leukocyte DNA is initially screened for pathogenic variants in MT-TK using targeted analysis for the m.8344A>G pathogenic variant followed by screening for the m.8356T>C, m.8363G>A, and m.8361G>A pathogenic variants.
    Alternatively, DNA from buccal mucosa, muscle, or urine sediment can be screened for mtDNA pathogenic variants.
  • If the four most frequent MT-TK pathogenic variants are excluded, sequence analysis of MT-TF, MT-TL1, MT-TI, and MT-TP may be considered.
    Note: In simplex cases (i.e., a single occurrence in a family) with myoclonus, epilepsy, and ataxia, muscle biopsy is often useful in detecting signs of mitochondrial dysfunction such as ragged red fibers, cytochrome c oxidase-deficient fibers, or biochemical defects of mitochondrial respiratory chain enzymes.

An alternative genetic testing strategy is use of a multigene panel that includes MT-TK, MT-TF, MT-TL1, MT-TI, and MT-TP, and other genes of interest (see Differential Diagnosis) or full mtDNA sequencing. Note: The genes included and the methods used in multigene panels vary by laboratory and are likely to change over time.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Characteristics

Clinical Description

MERRF is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, after normal early development. Table 2 lists the symptoms and signs seen in 62 affected individuals [Hirano & DiMauro 1996]. About 80% (34/42) had a family history compatible with maternal inheritance, but not all maternal relatives were affected and not all of those affected had classic features of MERRF. For example, seven symptomatic relatives had "limb-girdle myopathy" as the only manifestation. Depression may be an under-recognized feature of MERRF [Molnar et al 2009].

Cardiac involvement has been reported to be frequent in individuals with the m.8344A>G pathogenic variant in MT-TK [Wahbi et al 2010]. At diagnosis, eight (44%) of 18 affected individuals had cardiac abnormalities including: dilated cardiomyopathy in four, Wolff-Parkinson-White syndrome in three, incomplete left bundle branch block in one, and premature ventricular beats in one. On follow up, two additional affected individuals developed left ventricular dysfunction and two died of heart failure.

Occasionally individuals fulfilling the clinical criteria for MERRF also have strokes (MERRF/MELAS overlap) [Crimi et al 2003, Melone et al 2004, Naini et al 2005] or progressive external ophthalmoplegia and retinopathy, reminiscent of Kearns-Sayre syndrome [Nishigaki et al 2003, Emmanuele et al 2011, Fujioka et al 2014].

Maternally inherited spinocerebellar degeneration and Leigh syndrome, atypical Charcot-Marie-Tooth disease (see Charcot-Marie-Tooth Overview), and Leigh syndrome have been reported as unusual manifestations in families with individuals diagnosed with MERRF.

High clinical variability is seen in individuals with the m.8344A>G pathogenic variant in MT-TK. In a retrospective analysis of 42 affected individuals plus 282 previously reported individuals with this pathogenic variant, the large majority did not have all four of the canonic features of MERRF. The most common clinical features, in descending order of frequency, were: myoclonus, muscle weakness, ataxia (35%-45%); generalized seizures, hearing loss (25%-34.9%); cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15%-24.9%); and elevated creatine kinase, ptosis/PEO, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, myalgias, tremor, and migraine headaches (5%-14.9%) [Mancuso et al 2013].

Unusual manifestations in individuals with the m.8344A>G pathogenic variant in MT-TK include the following:

  • Sudden infant death syndrome (SIDS) in an infant girl who had an unsuspected cardiomyopathy with the histologic features of histiocytoid cardiomyopathy [Vallance et al 2004]
  • Spasmodic dysphonia in a woman age 46 years with otherwise fairly typical personal and family history of MERRF [Peng et al 2003]
  • Resting muscle pain as the initial symptom in children [van de Glind et al 2007]
  • Myoclonus, epilepsy, and ataxia without ragged red fibers [Mancuso et al 2007]
  • Parkinsonism, neuropathy, and myopathy [Horvath et al 2007]
  • Infantile-onset ataxia, myoclonus, and bilateral putaminal necrosis on brain MRI [Orcesi et al 2006]
  • Sudden respiratory failure in adulthood [Wiedemann et al 2008]
  • Acute central and peripheral nervous system demyelinating disease [Erol et al 2009]
  • Stroke-like episodes similar to MELAS [Vastagh et al 2011]
  • Distal limb weakness along with ptosis and respiratory muscle weakness [Blakely et al 2014]

A boy age six years with the m.8631G>A pathogenic variant in MT-TK developed seizures and myoclonus, followed by ataxia, cognitive impairment, and sensorineural hearing loss. Maternal relatives were oligosymptomatic [Rossmanith et al 2003].

An individual with the MT-TF m.611G>A pathogenic variant had mild truncal and proximal limb weakness, cerebellar ataxia, bilateral Babinski sign, and frequent myoclonic jerks [Mancuso et al 2004].

Table 2.

Signs and Symptoms Seen in 62 Individuals with MERRF

Normal early development17/17100%
RRF (ragged red fibers)47/5192%
Hearing loss41/4591%
Lactic acidosis24/2983%
Family history34/4281%
Exercise intolerance8/1080%
Short stature4/757%
Impaired sensation9/1850%
Optic atrophy14/3639%
Wolff-Parkinson-White syndrome2/922%
Pigmentary retinopathy4/2615%
Pyramidal signs8/6013%

Genotype-Phenotype Correlations

No clear correlation has been identified between genotype and clinical phenotype for affected individuals, nor is it clear why typical MERRF is associated with pathogenic variants in MT-TK.

For all mtDNA pathogenic variants, clinical expression depends on three factors:

  • Heteroplasmy. The relative abundance of mutated mtDNAs
  • Tissue distribution of mutated mtDNAs
  • Threshold effect. The vulnerability of each tissue to impaired oxidative metabolism

The tissue vulnerability threshold probably does not vary substantially among individuals, but variable mutational load and tissue distribution may account for the clinical diversity of individuals with MERRF.

The selective vulnerability of the dentate nucleus of the cerebellum and the olivary nucleus of the medulla is unexplained. Also unexplained is the pathogenesis of the multiple lipomas characteristically associated with pathogenic variants in MT-TK.


No evidence of anticipation has been found, but knowledge of the molecular defect may favor earlier diagnosis in subsequent generations.


Ramsay Hunt [1921] described six individuals with a disorder characterized by ataxia, myoclonus, and epilepsy, which he called "dyssynergia cerebellaris myoclonica." Individuals with the diagnosis of Ramsay Hunt syndrome should be investigated for MERRF.


Three epidemiologic studies of mtDNA-related diseases in northern Europe gave concordantly low estimates for the prevalence of the m.8344A>G pathogenic variant:

See Mitochondrial Disorders Overview for general prevalence information.

Differential Diagnosis

Neurologic findings. The differential diagnosis includes the following:

The multisystem involvement, lactic acidosis, evidence of maternal inheritance, and the muscle biopsy with RRF (ragged red fibers) distinguish MERRF from other conditions.

Lipomas. Other syndromes that cause multiple lipomas (e.g., multiple symmetric lipomatosis [OMIM 151800]) need to be considered.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MERRF (myoclonic epilepsy associated with ragged red fibers), the following evaluations are recommended:

  • Measurement of height and weight to assess growth
  • Audiologic evaluation
  • Ophthalmologic evaluation
  • Assessment of cognitive abilities
  • Physical therapy assessment
  • Neurologic evaluation, including MRI, MRS, and EEG if seizures are suspected
  • Cardiac evaluation
  • Clinical genetics consultation including genetic counseling

Treatment of Manifestations

The seizure disorder can be treated with conventional anticonvulsant therapy. No controlled studies have compared the efficacy of different anticonvulsants. Levetiracetam, clonazepam, zonisamide, and valproic acid (VPA) have been used to treat myoclonic epilepsy; however, VPA may cause secondary carnitine deficiency and should be avoided or used with L-carnitine supplementation.

The myoclonus improved substantially in three of four individuals treated with levetiracetam [Crest et al 2004, Mancuso et al 2007]. Clonazepam can also reduce myoclonus.

Physical therapy is helpful for any impaired motor abilities.

Aerobic exercise is helpful in MERRF and other mitochondrial diseases [Taivassalo & Haller 2004].

Standard pharmacologic therapy is used to treat cardiac symptoms.

Prevention of Primary Manifestations

The administration of coenzyme Q10 (CoQ10) (50-100 mg 3x/day) and L-carnitine (1000 mg 3x/day) has been of some benefit to some individuals. In a small randomized double-blind placebo-controlled study of affected individuals with heterogeneous mitochondrial diseases, CoQ10 combined with creatine and lipoic acid produced modest benefits including slowing progression of ankle weakness and lower resting plasma lactate concentration [Rodriguez et al 2007].


Affected individuals and their at-risk relatives should be followed at regular intervals (e.g. every 6-12 months initially) to monitor progression of disease and the appearance of new symptoms.

  • Annual neurologic, ophthalmologic, cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (fasting blood sugar and TSH) are recommended.
  • If normal for three years, less frequent evaluations can be considered.

Agents/Circumstances to Avoid

Individuals with MERRF should avoid mitochondrial toxins including aminoglycoside antibiotics, linezolid, cigarettes, and alcohol. Valproic acid should be avoided in the treatment of seizures.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.

If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions.

Therapies Under Investigation

The transfer of nuclear DNA from fertilized oocytes or zygotes harboring a mtDNA pathogenic variant to a recipient enucleated recipient cell could theoretically prevent transmission of mtDNA diseases and proof of this concept has been demonstrated in pronuclear transfers from abnormally fertilized zygotes that were allowed to undergo several replications in vitro [Craven et al 2010].

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MERRF is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs of a proband will inherit the mtDNA pathogenic variant and may or may not have symptoms.

Offspring of a proband

  • All offspring of females with an mtDNA pathogenic variant will inherit the pathogenic variant.
  • Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's mother: if the mother has an mtDNA pathogenic variant, her sibs and mother are also at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Phenotypic variability. The phenotype of an individual with a mtDNA pathogenic variant results from a combination of factors including the severity of the pathogenic variant, the percentage of mutated mitochondria (mutational load), and the organs and tissues in which they are found (tissue distribution). Different family members often inherit different percentages of mutated mtDNA and therefore can have a wide range of clinical symptoms.

Interpretation of testing results of asymptomatic at-risk family members is extremely difficult. Prediction of phenotype based on test results is not possible. Furthermore, absence of the mtDNA pathogenic variant in one tissue (e.g., blood) does not guarantee its absence in other tissues.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk; however, it is not possible to make specific predictions about the potential severity of disease in offspring.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the mtDNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MERRF are possible.

Interpretation of prenatal diagnostic results is complex for the following reasons:

  • The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.
  • Prediction of phenotype, age of onset, severity, or rate of progression is not possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
  • International Mito Patients
  • Mito Foundation (formerly the Australian Mitochondrial Disease Foundation)
    21 Mary Street
    Suite 3
    Surry Hills New South Wales 2010
    Phone: 61-1-300-977-180
    Fax: 61-2-9999-3474
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • The Lily Foundation
    31 Warren Park
    Surrey CR6 9LD
    United Kingdom
    Phone: 07947 257247
    Fax: 01883 623799
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

MERRF: Genes and Databases

GeneChromosome LocusProteinClinVar
MT-TFMitochondrionNot applicableMT-TF
MT-TIMitochondrionNot applicableMT-TI
MT-TKMitochondrionNot applicableMT-TK
MT-TL1MitochondrionNot applicableMT-TL1
MT-TPMitochondrionNot applicableMT-TP

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MERRF (View All in OMIM)


Molecular Pathogenesis

The origin of mtDNA pathogenic variants is uncertain. It is also unclear how the mtDNA single nucleotide variants cause MERRF. Using rho0 cell lines (permanent human cell lines emptied of their mtDNA by exposure to ethidium bromide) repopulated with mitochondria harboring the m.8344A>G pathogenic variant, Chomyn et al [1991] found that high mutational loads correlated with decreased protein synthesis, decreased oxygen consumption, and cytochrome c oxidase deficiency. The polypeptides containing higher numbers of lysine residues were more severely affected by the pathogenic variant, suggesting that the MT-TK pathogenic variant directly inhibits protein synthesis. Similarly, cultured myotubes containing more than 85% mutated mtDNA showed decreased translation, especially of proteins containing large numbers of lysine residues. Cells harboring the m.8344A>G pathogenic variant contained decreased levels of tRNALys and aminoacylated tRNALys. The variant appears to be functionally recessive because only about 15% wild type mtDNA restores translation and cytochrome c oxidase activity to near-normal levels.

Masucci et al [1995] confirmed that protein synthesis and oxygen consumption were decreased in rho0 cells repopulated with mtDNA harboring either the m.8344A>G or the m.8356T>C pathogenic variant, and identified aberrant mitochondrial protein in both cell lines, which they attributed to ribosomal frame-shifting. Studies of engineered in vitro transcribed tRNALys mutants showed that the pathogenic variants associated with MERRF had no effect on lysylation efficiency whereas the two pathogenic variants associated with encephalomyopathies without typical MERRF features (m.8313G>A and m.8328G>A in MT-TK) severely impaired lysylation [Sissler et al 2004].

Gene structure. The mitochondrial genome is 16,569 bp in length. See MITOMAP for genes and nucleotide variants of the mitochondrion. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Benign polymorphisms are especially frequent in mtDNA and are listed at MITOMAP.

Pathogenic variants. See Table 3.

Table 3.

Pathogenic Variants in Mitochondrial DNA Associated with MERRF

Mitochondrial DNA Nucleotide Change
(Alias 1)
GenePredicted Protein ChangeReference Sequence
MT-TKNo protein translatedNC_012920​.1

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. The genes encode tRNAs that are indispensable for the incorporation of these amino acids into nascent mitochondrial proteins:

GeneAmino Acid
MT-TKMitochondrially encoded tRNA lysine
MT-TFMitochondrially encoded tRNA phenylalanine
MT-TL1Mitochondrially encoded tRNA leucine UUR
MT-TIMitochondrially encoded tRNA threonine
MT-TPMitochondrially encoded tRNA proline

Abnormal gene product. See Molecular Pathogenesis.


Literature Cited

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Chapter Notes

Revision History

  • 29 January 2015 (me) Comprehensive update posted live
  • 18 August 2009 (me) Comprehensive update posted live
  • 27 September 2005 (me) Comprehensive update posted live
  • 3 June 2003 (ca) Review posted live
  • 8 May 2003 (sdm) Original submission
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