DiagnosisClinical DiagnosisThe clinical diagnosis of MERRF (myoclonic epilepsy with ragged red fibers) is based on the following four "canonical" features:Myoclonus Generalized epilepsy Ataxia Ragged red fibers (RRF) in the muscle biopsy Additional frequent manifestations include the following:Sensorineural hearing loss MyopathyPeripheral 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 TestingLactic 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. Molecular Genetic TestingGene The mitochondrial DNA (mtDNA) gene MT-TK encoding tRNA lysine (tRNA^Lys) is the gene most commonly associated with MERRF. One individual with the MERRF phenotype had the mutation m.611G>A in MT-TF, encoding tRNA phenylalanine (tRNA^Phe) [Mancuso et al 2004]. One patient presented with MERRF and pigmentary retinopathy caused by the m.15967G>A mutation in MT-TP [Blakely et al 2009]. Clinical testing Targeted mutation analysis. Four MT-TK mutations (m.8344A>G, m.8356T>C, m.8363G>A, and m.8361G>A; see Table 1 and Table 3) account for approximately 90% of mutations in individuals with MERRF. The most common mutation in MERRF, present in over 80% of affected individuals with typical findings, is m.8344A>G. Three additional mutations, m.8356T>C, m.8363G>A, and m.8361G>A, are present in 10% of affected individuals. Note: Mutations 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 mutation may be undetectable in mtDNA from leukocytes and may only be detected in other tissues, such as cultured skin fibroblasts, urinary sediment, oral mucosa (from mouthwash), hair follicles, or, most reliably, skeletal muscle. Mutation scanning/sequence analysis. The remaining 10% of affected individuals probably have other mutations in mtDNA, including the m.611G>A mutation in MT-TF and the m.15967G>A mutation in MT-TP (see Differential Diagnosis). Note: Mutation scanning/sequence analysis is used to detect mutations throughout mtDNA and is not specific for MERRF.Table 1. Summary of Molecular Genetic Testing Used in MERRFView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityMT-TKTargeted mutation analysism.8344A>G>80%Clinicalm.8356T>C~10%m.8363G>Am.8361G>AMT-TFMutation scanning / sequence analysism.611G>A2MT-TPm.15967G>AmtDNAMutation scanning / sequence analysisSequence variants 390%-95% 44. Mutation scanning/sequence analysis is used to detect mutations throughout mtDNA and is not specific for MERRF. The overall mutation detection rate for MERRF by scanning/sequence analysis of mtDNA is 90%-95%. 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. The proportion of MERRF caused by these two mutations3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected.Interpretation of test results For issues to consider in interpretation of sequence analysis results, click here. Individuals thought to have MERRF but without an identifiable MT-TK mutation may harbor the MT-TF mutation m.611G>A, the MT-TP mutation m.15967G>A transition, or another mtDNA mutation (see Differential Diagnosis). Testing StrategyEstablishing the diagnosis in a proband Typically, blood leukocyte DNA is initially screened for the m.8344A>G mutation followed by screening for the m.8356T>C, m.8363G>A, and m.8361G>A mutations. Alternatively, DNA from buccal mucosa, muscle, or urine sediment can be screened for mtDNA mutations. If MT-TK mutations are excluded, mtDNA sequencing can be performed in probands with family histories compatible with maternal inheritance. 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. Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersMT-TK m.8344A>G can also be associated with isolated myopathy, resembling limb-girdle muscular dystrophy, or with multiple lipomas, usually located in the neck and shoulders area (Ekbom syndrome). Other clinical presentations of the m.8344A>G mutation include spinocerebellar degeneration and Leigh syndrome or isolated Leigh syndrome. m.8356T>C. In two families with the m.8356T>C mutation, some affected individuals had typical MERRF but others also had stroke-like episodes and migraine (MERRF/MELAS overlap). m.8363G>A has been associated with typical MERRF, but also with cardiomyopathy or Leigh syndrome [Shtilbans et al 2000].}

Natural HistoryMERRF 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 a 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 those affected had the full MERRF picture. For example, seven oligosymptomatic relatives had "limb-girdle myopathy" as the only manifestation. Depression may be an under-recognized feature of MERRF [Molnar et al 2009]. 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].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. Unusual manifestations in individuals with the m.8344A>G mutation include: 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 46-year-old woman 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]. A six-year-old boy with the m.8631G>A mutation 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 mutation had mild truncal and proximal limb weakness, cerebellar ataxia, bilateral Babinski sign, and frequent myoclonic jerks [Mancuso et al 2004].Table 2. Signs & Symptoms Seen in 62 Individuals with MERRFView in own windowSign / SymptomPresent / EvaluatedPercentageMyoclonus62/62100%Epilepsy62/62100%Normal early development17/17100%RRF (ragged red fibers)47/5192%Hearing loss41/4591%Lactic acidosis24/2983%Family history34/4281%Exercise intolerance8/1080%Dementia39/5275%Neuropathy17/2763%Short stature4/757%Impaired sensation9/1850%Optic atrophy14/3639%Cardiomyopathy2/633%Wolff-Parkinson-White syndrome 2/922%Pigmentary retinopathy4/2615%Pyramidal signs8/6013%Ophthalmoparesis3/2811%Lipomatosis2/603%Hirano & DiMauro [1996]

Genotype-Phenotype CorrelationsNo clear correlation has been identified between genotype and clinical phenotype for affected individuals, nor is it clear why typical MERRF is associated with mutations in MT-TK. For all mtDNA mutations, clinical expression depends on three factors:Heteroplasmy. The relative abundance of mutant mtDNAs Tissue distribution of mutant mtDNAsThreshold 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 mutations in MT-TK.

Differential DiagnosisNeurologic findings. The differential diagnosis includes: Other mitochondrial disorders (see Mitochondrial Disorders Overview) POLG-related disorders. One individual with myoclonus, epilepsy, ataxia, peripheral neuropathy, but no ragged red fibers had autosomal recessive mutations in POLG, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma [Van Goethem et al 2003]. MERRF/MELAS overlap syndrome caused by mutations in MT-ND5, which may initially resemble MERRF (Table 3) [Crimi et al 2003, DiMauro & Davidzon 2005, Naini et al 2005]. A MERRF/Kearns-Sayre syndrome (KSS) overlap syndrome caused by a MT-TL1 mutation; reported in one individual [Nishigaki et al 2003] Syndromes characterized by ataxia (e.g., DRPLA) (see also Hereditary Ataxia Overview) and myoclonus epilepsy, including Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinosis, and sialidosis [Zupanc & Legros 2004]. 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) need to be considered.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease 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 Treatment of ManifestationsThe seizure disorder can be treated with conventional anticonvulsant therapy. No controlled studies have compared the efficacy of different anticonvulsants. The myoclonus improved substantially in three of four individuals treated with levetiracetam [Crest et al 2004, Mancuso et al 2007].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.SurveillanceReevaluation every six to 12 months for disease progression that may warrant symptomatic therapy (e.g., adjustment of anticonvulsant therapy) is appropriate. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameMT-TKMitochondriaNot applicableData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for MERRF (View All in OMIM) View in own window 545000MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS; MERRF 590060TRANSFER RNA, MITOCHONDRIAL, LYSINE; MTTKMolecular Genetic PathogenesisThe origin of mtDNA mutations is uncertain. It is also unclear how the mtDNA point mutations 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 mutation, 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 mutation, suggesting that the MT-TK mutation directly inhibits protein synthesis. Similarly, cultured myotubes containing more than 85% mutant mtDNA showed decreased translation, especially of proteins containing large numbers of lysine residues. Cells harboring the m.8344A>G mutation contained decreased levels of tRNA^Lys and aminoacylated tRNA^Lys. Also, the m.8344A>G mutation blocked a modification of the tRNA^Lys, resulting in impaired protein synthesis [Yasukawa et al 2001]. The mutation 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 mutation, and identified aberrant mitochondrial protein in both cell lines, which they attributed to ribosomal frame-shifting. Studies of engineered in vitro transcribed tRNA^Lys mutants showed that the mutations associated with MERRF had no effect on lysylation efficiency whereas the two mutations associated with encephalomyopathies without typical MERRF features (m.8313G>A and m.8328G>A in MT-TK) severely impaired lysylation [Sissler et al 2004].Normal allelic variants. Benign polymorphisms are especially frequent in mtDNA and are listed at www.mitomap.org. MT-TK is the only mtDNA gene that encodes tRNA^Lys.Pathologic allelic variants. See Table 3. Table 3. Pathologic Allelic Variants in Mitochondrial DNA Associated with MERRFView in own windowMitochondrial DNA
Nucleotide Change
(Alias ¹)Gene SymbolProtein Amino
Acid ChangeReference Sequence m.8344A>G
(A8344G)MT-TKNo protein translatedAC_000021​.2m.8356T>C
(T8356C)m.8363G>A
(G8363A)m.8361G>A
(G8361A)m.611G>A
(G611A)MT-TFm.15967G>A
(G15967A)MT-TPSee Quick Reference for an explanation of nomenclature. Variants named according to current nomenclature guidelines (www​.hgvs.org/) 1. Variant designation that does not conform to current naming conventionsFor more information, see Table A.Normal gene product. The normal gene product of MT-TK and MT-TF (tRNA^Lys and tRNA^Phe) are indispensable for the incorporation of these amino acids into nascent mitochondrial proteins. Abnormal gene product. See Molecular Genetic Pathogenesis.