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, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed.

Diagnosis/testing.

A clinical diagnosis of MERRF can be established in a proband with the following four "canonic" features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy. A molecular diagnosis is established in a proband with suggestive findings and a pathogenic variant in one of the genes associated with MERRF. The m.8344A>G pathogenic variant in the mitochondrial gene MT-TK is present in more than 80% of affected individuals with typical findings. Pathogenic variants in MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1, and MT-TS2 have also been described in a subset of individuals with MERRF.

Management.

Treatment of manifestations: Ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex, and creatine may be of benefit to some individuals; traditional anticonvulsant therapy per neurologist for seizures; levetiracetam or clonazepam for myoclonus; physical therapy to improve any impaired motor function; aerobic exercise; standard pharmacologic therapy for cardiac symptoms; hearing aids or cochlear implants for hearing loss; diabetes mellitus treatment per endocrinologist.

Prevention of primary manifestations: Coenzyme Q₁₀ (50-200 mg 2-3x/day), L-carnitine (1000 mg 2-3x/day), alpha lipoic acid, vitamin E, vitamin B supplements, and creatine, often used to improve mitochondrial function, have been of modest benefit in some individuals. Doses for children should be adjusted appropriately.

Surveillance: Routine evaluations every six to 12 months initially; annual neurologic, ophthalmologic, cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (fasting blood sugar and TSH); audiology evaluations every two to three years.

Agents/circumstances to avoid: Mitochondrial toxins (e.g., aminoglycoside antibiotics, linezolid, cigarettes, alcohol); valproic acid should be avoided in the treatment of seizures.

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 of 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 a mtDNA pathogenic variant (whether symptomatic or asymptomatic) transmits the pathogenic variant to all of her offspring. Prenatal testing and preimplantation genetic testing for MERRF are possible if a mtDNA pathogenic variant has been detected in the mother. However, because the mutational load in embryonic and fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of all fetal tissues and because the mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.

Suggestive Findings

MERRF (myoclonic epilepsy with ragged red fibers) should be suspected in individuals with the following features.

Clinical features

• Myoclonus
• Generalized epilepsy
• Ataxia
• Myopathy
• Exercise intolerance
• Dementia
• Ptosis
• Sensorineural hearing loss
• Short stature
• Optic atrophy
• Peripheral neuropathy

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

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

Laboratory features

• 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.
• 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.

Histopathologic features on muscle biopsy. Ragged red fibers (RRF) are seen with the modified Gomori trichrome stain and hyperactive fibers with the succinate dehydrogenase stain. Both RRF and some non-RRF fail to stain with the histochemical reaction for cytochrome c oxidase. Occasionally, RRF may not be observed [Mancuso et al 2007].

Electrophysiologic features

• Electroencephalogram 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 and nerve conduction velocity studies are consistent with a myopathy, but neuropathy may coexist.

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

Establishing the Diagnosis

The clinical diagnosis of MERRF (myoclonic epilepsy with ragged red fibers) can be established in a proband based on clinical diagnostic criteria [Finsterer et al 2018] or the molecular diagnosis can be established in a proband with suggestive findings and a pathogenic variant in one of the genes listed in Table 1, identified by molecular genetic testing.

Clinical diagnosis. The clinical diagnosis is based on the following four "canonic" features:

• Myoclonus
• Generalized epilepsy
• Ataxia
• Ragged red fibers (RRF) in the muscle biopsy

Molecular diagnosis. The diagnosis of MERRF is established in a proband with suggestive findings and a pathogenic variant in one of the genes listed in Table 1.

Note: Pathogenic variants can usually be detected in mtDNA from 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, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected only in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with seizures and weakness are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, after normal early development. Table 2 lists the most frequent signs and symptoms reported [Hirano & DiMauro 1996, Mancuso et al 2013].

Neurologic manifestations

• Myopathy. The most common features are exercise intolerance, muscle weakness, and elevated blood creatine kinase level.
• Epilepsy. Generalized myoclonic seizures are the most frequent seizure type in individuals with MERRF. Other reported types of seizures include focal myoclonic, focal atonic, focal clonic, generalized tonic-clonic, generalized atonic, generalized myoclonic-atonic, typical absences, myoclonic absences, or tonic-clonic seizures of unknown onset [Finsterer & Zarrouk-Mahjoubb 2017].
• Migrainous headaches. Migraines are common in individuals with MERRF and can be present at the onset of symptoms. Vollono et al [2018] reported seven individuals with MERRF and migraines and found that migraines can present with or without aura. The frequency of migraine episodes in most individuals was every two months.
• Hearing impairment. Hearing loss is typically sensorineural and occurs in 35%-91% of individuals.
• Peripheral neuropathy. It has been reported that either sensory axonal neuropathy or sensory motor axonal neuropathy can be present.
• Early psychomotor development. Early development is typically normal in individuals with MERRF.
• Psychiatric illnesses. Although psychiatric illness is not a prominent feature in this disorder, several individuals with depressive mood disorders have been reported.

Cardiac involvement. Cardiomyopathy can be observed. Both hypertrophic and dilated cardiomyopathy have been described. Arrhythmias are common in individuals with MERRF and can accompany the cardiomyopathy or be an isolated cardiac finding.

Lipomatosis can be seen in adulthood in individuals with MERRF, with an average age of onset of 45.2 years [Chong et al 2003]. Lipomas can be infiltrative, progressive, and massive in size [Gilson & Osswald 2018]. The most common location of lipomas is the cervical region.

Phenotype Correlations by Gene

No phenotype correlations by gene have been identified.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

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.

Penetrance

See Genotype-Phenotype Correlations.

Nomenclature

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.

Prevalence

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

• 0-1.5:100,000 in the adult population of northern Finland [Remes et al 2005]
• 0.39:100,000 in the adult population of northern England [Schaefer et al 2008]
• 0-0.25:100,000 in a pediatric population of western Sweden [Darin et al 2001]
• 0.7:100,000 in a large population-based study in northeast England [Gorman et al 2015]

See Mitochondrial Disorders Overview for general prevalence information.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MERRF (myoclonic epilepsy with ragged red fibers), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

The administration of coenzyme Q₁₀ (CoQ₁₀) (50-200 mg 2-3x/day) and L-carnitine (1000 mg 2-3x/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].

The Mitochondrial Medicine Society published a consensus statement which recommends that CoQ₁₀, alpha lipoic acid, and riboflavin should be offered to individuals with mitochondrial disease. Folinic acid should be considered in those with central nervous system involvement. L-carnitine should be supplemented in those with documented deficiency and levels should continue to be monitored [Parikh et al 2015]. Despite the empiric rationale to administer these vitamins and supplements, there is limited clinical trial evidence supporting their use [Rodriguez et al 2007].

Surveillance

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.

Agents/Circumstances to Avoid

Individuals with MERRF should avoid mitochondrial toxins such as 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. Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• Complete neurologic evaluation, ophthalmologic and audiology evaluations, EKG, echocardiogram, and blood lactate if the pathogenic variant in the family is not known.

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

Mitochondrial replacement therapy (MRT) – replacement of a woman's abnormal mitochondrial DNA with healthy mitochondrial DNA from a donor [Sharma et al 2020] – has been under investigation as a way to prevent these disorders from continuing in a family. MRT includes three types of techniques: spindle transfer, pronuclear transfer, and polar body transfer. MRT was successfully approved by the United Kingdom Parliament and a clinical trial is underway. To date, these techniques are not approved in the United States.

Genetic therapy through the delivery of mitochondrially targeted zinc finger nucleases delivered by an adeno-associated virus has been studied in mouse models with mitochondrial disorders. The mutational load decreased by 20% in treated animals, and biochemical phenotypes were reversed [Gammage et al 2018].

Search ClinicalTrials.gov 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.

Mode of Inheritance

MERRF (myoclonic epilepsy with ragged red fibers) is caused by pathogenic variants in mitochondrial DNA (mtDNA) and transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

• The father of a proband is not at risk of having the mtDNA pathogenic variant.
• The mother of a proband usually has the mtDNA pathogenic variant and may or may not have clinical manifestations of the disorder. In some mothers, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
• Some individuals diagnosed with MERRF have no known family history of the disorder. The explanation for apparently simplex cases may be the absence of a comprehensive and/or reliable family history or, in rare cases, a de novo mtDNA pathogenic variant in the 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 the sibs of a proband will inherit the mtDNA pathogenic variant. Women with higher levels of mutated mtDNA in their blood may have a greater likelihood of having affected offspring [Chinnery et al 1998].
• Clinical expression in sibs depends on the percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution and threshold effect). Sibs often inherit different percentages of mutated mtDNA and have a wide range of clinical manifestations (see Genotype-Phenotype Correlations).

Offspring of a proband

• All offspring of females with a 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. The risk to other family members depends on the genetic status of the proband's mother: if the mother has a 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 percentage of mutated mitochondria (mutational load) and the organs and tissues in which they are found (tissue distribution). Family members 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/preimplantation genetic testing is 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.

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 Testing

Once the mtDNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MERRF are technically possible. However, prenatal testing for mtDNA pathogenic variants causing MERRF is of uncertain utility 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.
• The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.
• Prediction of phenotype, age of onset, severity, or rate of progression is not possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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 tRNA^Lys and aminoacylated tRNA^Lys. 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 frameshifting. Studies of engineered in vitro transcribed tRNA^Lys 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].

Mechanism of disease causation. Unknown

Author History

Salvatore DiMauro, MD; Columbia University Medical Center (2003-2021)
Gregory Enns, MB, ChB (2021-present)
Michio Hirano, MD; Columbia University Medical Center (2003-2021)
Chung Lee, MD (2021-present)
Frances Velez-Bartolomei, MD (2021-present)

Revision History

• 7 January 2021 (sw) Comprehensive update posted live
• 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

Literature Cited

• Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain. 1998;121:1889–94. [PubMed: 9798744]
• Chomyn A, Meola G, Bresolin N, Lai ST, Scarlato G, Attardi G. In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria. Mol Cell Biol. 1991;11:2236–44. [PMC free article: PMC359920] [PubMed: 1848674]
• Chong PS, Vucic S, Hedley-Whyte ET, Dreyer M, Cros D. Multiple symmetric lipomatosis (Madelung's disease) caused by the MERRF (A8344G) mutation: a report of two cases and review of the literature. J Clin Neuromuscul Dis. 2003;5:1–7. [PubMed: 19078716]
• Crest C, Dupont S, Leguern E, Adam C, Baulac M. Levetiracetam in progressive myoclonic epilepsy: an exploratory study in 9 patients. Neurology. 2004;62:640–3. [PubMed: 14981187]
• Crimi M, Galbiati S, Moroni I, Bordoni A, Perini MP, Lamantea E, Sciacco M, Zeviani M, Biunno I, Moggio M, Scarlato G, Comi GP. A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome. Neurology. 2003;60:1857–61. [PubMed: 12796552]
• Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol. 2001;49:377–83. [PubMed: 11261513]
• DiMauro S, Davidzon G. Mitochondrial DNA and disease. Ann Med. 2005;37:222–32. [PubMed: 16019721]
• Emmanuele V, Silvers DS, Sotiriou E, Tanji K, DiMauro S, Hirano M. MERRF and Kearns-Sayre overlap syndrome due to the mitochondrial DNA m.3291T>C mutation. Muscle Nerve. 2011;44:448–51. [PMC free article: PMC3197731] [PubMed: 21996807]
• Finsterer J, Zarrouk-Mahjoub S, Shoffner J. MERRF Classification: Implications for diagnosis and clinical trials. Pediatr Neurol. 2018;80:8–23. [PubMed: 29449072]
• Finsterer J, Zarrouk-Mahjoubb S. Management of epilepsy in MERRF syndrome. Seizure. 2017;50:166–170.
• Fujioka H, Tandler B, Rosca M, McCandless SE, Katirji B, Cohen ML, Rapisuwon S, Hoppel CL. Multiple muscle cell alterations in a case of encephalomyopathy. Ultrastruct Pathol. 2014;38:13–25. [PubMed: 24134831]
• Gammage PA, Viscomi C, Simard M, Costa ASH, Gaude E, Powell CA, Van Haute L, McCann BJ, Rebelo-Guiomar P, Cerutti R, Zhang L, Rebar EJ, Zeviani M, Frezza C, Stewart JB, Minczuk M. Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. Nat Med. 2018;24:1691–5. [PMC free article: PMC6225988] [PubMed: 30250142]
• Gilson RC, Osswald S. Madelung lipomatosis presenting as a manifestation of myoclonic epilepsy with ragged red fibers (MERRF) syndrome. JAAD Case Rep. 2018;4:822–3. [PMC free article: PMC6143699] [PubMed: 30238046]
• Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015;77:753–9. [PMC free article: PMC4737121] [PubMed: 25652200]
• Herrero-Martín MD, Ayuso T, Tuñón MT, Martín MA, Ruiz-Pesini E, Montoya J. A. MELAS/MERRF phenotype associated with the mitochondrial DNA 5521G>A mutation. J Neurol Neurosurg Psychiatry. 2010;81:471–2. [PubMed: 20360171]
• Hirano M, DiMauro S. Clinical features of mitochondrial myopathies and encephalomyopathies. In: Lane RJM, ed. Handbook of Muscle Disease. New York, NY: Marcel Dekker Inc; 1996:479-504.
• Hunt JR. Dyssynergia cerebellaris myoclonia-primary atrophy of the dentate system: a contribution to the pathology and symptomatology of the cerebellum. Brain. 1921;44:490–538.
• Ito S, Shirai W, Asahina M, Hattori T. Clinical and brain MR imaging features focusing on the brain stem and cerebellum in patients with myoclonic epilepsy with ragged-red fibers due to mitochondrial A8344G mutation. AJNR Am J Neuroradiol. 2008;29:392–5. [PMC free article: PMC8118999] [PubMed: 17989367]
• Kälviäinen R. Progressive myoclonus epilepsies. Semin Neurol. 2015;2015;35:293–9. [PubMed: 26060909]
• Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Bruno C, Caldarazzo Ienco E, Filosto M, Lamperti C, Martinelli D, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Santorelli FM, Sauchelli D, Scarpelli M, Sciacco M, Spinazzi M, Valentino ML, Vercelli L, Zeviani M, Siciliano G. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80:2049–54. [PubMed: 23635963]
• Mancuso M, Petrozzi L, Filosto M, Nesti C, Rocchi A, Choub A, Pistolesi S, Massentani R, Fontanini G, Siciliano G. MERRF syndrome without ragged-red fibers: the need for molecular diagnosis. Biochem Biophys Res Commun. 2007;354:1058–60. [PubMed: 17275787]
• Martín-Jiménez R, Martin-Hernandez E, Cabello A, Garcia-Silva MT, Arenas J, Campos Y. Clinical and cellular consequences of the mutation m.12300G>A in the mitochondrial tRNA(Leu(CUN)) gene. Mitochondrion. 2012;12:288–93. [PubMed: 22094595]
• Masucci JP, Davidson M, Koga Y, Schon EA, King MP. In vitro analysis of mutations causing myoclonus epilepsy with ragged-red fibers in the mitochondrial tRNA(Lys)gene: two genotypes produce similar phenotypes. Mol Cell Biol. 1995;15:2872–81. [PMC free article: PMC230518] [PubMed: 7739567]
• Naini AB, Lu J, Kaufmann P, Bernstein RA, Mancuso M, Bonilla E, Hirano M, DiMauro S. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF. Arch Neurol. 2005;62:473–6. [PubMed: 15767514]
• Nakamura M, Yabe I, Sudo A, Hosoki K, Yaguchi H, Saitoh S, Sasaki H. MERRF/MELAS overlap syndrome: a double pathogenic mutation in mitochondrial tRNA genes. J Med Genet. 2010;47:659–64. [PubMed: 20610441]
• Nishigaki Y, Tadesse S, Bonilla E, Shungu D, Hersh S, Keats BJ, Berlin CI, Goldberg MF, Vockley J, DiMauro S, Hirano M. A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome. Neuromuscul Disord. 2003;13:334–40. [PubMed: 12868503]
• Orcesi S, Gorni K, Termine C, Uggetti C, Veggiotti P, Carrara F, Zeviani M, Berardinelli A, Lanzi G. Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case. J Child Neurol. 2006;21:79–82. [PubMed: 16551460]
• Parikh S, Goldstein A, Koenig M, Scaglia F, Enns GM, Saneto R, Anselm I, Cohen BH, Falk MJ, Greene C, Gropman AL, Haas R, Hirano M, Morgan P, Sims K, Tarnopolsky M, Van Hove JL, Wolfe L, DiMauro S. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17:689–701. [PMC free article: PMC5000852] [PubMed: 25503498]
• Perera U, Kennedy BA, Hegele RA. Multiple symmetric lipomatosis (Madelung disease) in a large Canadian family with the mitochondrial MTTK c.8344A>G Variant. J Investig Med High Impact Case Rep. 2018:6. [PMC free article: PMC6166310] [PubMed: 30283804]
• Remes AM, Majamaa-Voltti K, Karppa M, Moilanen JS, Uimonen S, Helander H, Rusanen H, Salmela PI, Sorri M, Hassinen IE, Majamaa K. Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population. Neurology. 2005;64:976–81. [PubMed: 15781811]
• Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007;35:235–42. [PubMed: 17080429]
• Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM. Prevalence of mitochondrial DNA disease in adults. Ann Neurol. 2008;63:35–9. [PubMed: 17886296]
• Sharma H, Singh D, Mahant A, Sohal SK, Kesavan AK. Samiksha. Development of mitochondrial replacement therapy: a review. Heliyon. 2020;6:e04643. [PMC free article: PMC7492815] [PubMed: 32984570]
• Sissler M, Helm M, Frugier M, Giege R, Florentz C. Aminoacylation properties of pathology-related human mitochondrial tRNA(Lys) variants. RNA. 2004;10:841–53. [PMC free article: PMC1370574] [PubMed: 15100439]
• Taivassalo T, Haller RG. Implications of exercise training in mtDNA defects--use it or lose it? Biochim Biophys Acta. 2004;1659:221–31. [PubMed: 15576055]
• Vollono C, Primiano G, Della Marca G, Losurdo A, Servidei S. Migraine in mitochondrial disorders: Prevalence and characteristics. Cephalalgia. 2018;38:1093–106. [PubMed: 28762753]
• Yoon KL, Ernst SG, Rasmussen C, Dooling EC, Aprille JR. Mitochondrial disorder associated with newborn cardiopulmonary arrest. Pediatr Res. 1993;33:433–40. [PubMed: 8511015]
• Yorns WR Jr, Valencia I, Jayaraman A, Sheth S, Legido A, Goldenthal MJ. Buccal swab analysis of mitochondrial enzyme deficiency and DNA defects in a child with suspected myoclonic epilepsy and ragged red fibers (MERRF). J Child Neurol. 2012;27:398–401. [PubMed: 22114216]