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MERRF

Synonym: Myoclonic Epilepsy Associated with Ragged Red Fibers

, MD and , MD.

Author Information
, MD
H Houston Merritt Center
Department of Neurology
Columbia University Medical Center
New York, New York
, MD
H Houston Merritt Center
Department of Neurology
Columbia University Medical Center
New York, New York

Initial Posting: ; Last Update: August 18, 2009.

Summary

Disease characteristics. 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, 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. Occasionally pigmentary retinopathy and lipomatosis are observed.

Diagnosis/testing. The clinical diagnosis of MERRF is based on the following four "canonical" 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 mutation, present in over 80% of affected individuals with typical findings, is an A-to-G transition at nucleotide 8344 (m.8344A>G). Mutations 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 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, hair follicles, or, most reliably, skeletal muscle.

Management. Treatment of manifestations: Conventional antiepileptic drugs (AEDs) 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.

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

Genetic counseling. MERRF is caused by mutations in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk for having the disease-causing mtDNA mutation. The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. A male with a mtDNA mutation cannot transmit the mutation to any of his offspring. A female with the mutation (whether affected or unaffected) transmits the mutation to all of her offspring. Prenatal diagnosis for MERRF is possible if a mtDNA mutation 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 beuse 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.

Diagnosis

Clinical Diagnosis

The 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
  • 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

Testing

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.

Molecular Genetic Testing

Gene

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 MERRF

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
MT-TKTargeted mutation analysism.8344A>G>80%
m.8356T>C~10%
m.8363G>A
m.8361G>A
MT-TFMutation scanning / sequence analysism.611G>A<5% 2
MT-TPm.15967G>A
mtDNAMutation scanning / sequence analysisSequence variants 390%-95% 4

4. 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 gene

2. The proportion of MERRF caused by these two mutations

3. 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

Testing Strategy

Establishing 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.

Clinical Description

Natural History

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 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:

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 MERRF

Sign / SymptomPresent / EvaluatedPercentage
Myoclonus62/62100%
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%

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 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 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 mutations in MT-TK.

Anticipation

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

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

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

See Mitochondrial Disorders Overview for general prevalence information.

Differential Diagnosis

Neurologic findings. The differential diagnosis includes:

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.

Management

Evaluations Following Initial Diagnosis

To 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 Manifestations

The 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.

Surveillance

Reevaluation 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 Risk

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

Therapies Under Investigation

Search 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.

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 mutations in mtDNA and is transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

  • The father of a proband is not at risk of having the disease-causing mtDNA mutation.
  • The mother of a proband (usually) has the mtDNA mutation and may or may not have symptoms.
  • Alternatively, the proband may have a de novo (somatic) mitochondrial mutation.

Sibs of a proband

  • The risk to the sibs depends on the genetic status of the mother.
  • If the mother has the mtDNA mutation, all sibs of a proband will inherit the disease-causing mtDNA mutation and may or may not have symptoms.

Offspring of a proband

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

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 a mtDNA mutation, her sibs and mother are also at risk.

Related Genetic Counseling Issues

Phenotypic variability. The phenotype of an individual with a mtDNA mutation results from a combination of factors including the severity of the mutation, the percentage of mutant mitochondria (mutational load), and the organs and tissues in which they are found (tissue distribution). Different family members often inherit different percentages of mutant 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 mutation in one tissue (e.g., blood) does not guarantee that the mutation is absent 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Although results of prenatal diagnosis for MERRF cannot provide additional information, it is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). The specific mtDNA mutation in the mother must be identified before prenatal diagnosis can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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.

Resources

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.

  • 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
    Email: info@umdf.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov
  • 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

Gene SymbolChromosomal LocusProtein Name
MT-TKMitochondriaNot applicable
MT-TFMitochondriaNot applicable
MT-TPMitochondriaNot applicable

Data 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)

545000MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS; MERRF
590060TRANSFER RNA, MITOCHONDRIAL, LYSINE; MTTK
590070TRANSFER RNA, MITOCHONDRIAL, PHENYLALANINE; MTTF
590075TRANSFER RNA, MITOCHONDRIAL, PROLINE; MTTP

Molecular Genetic Pathogenesis

The 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 tRNALys and aminoacylated tRNALys. Also, the m.8344A>G mutation blocked a modification of the tRNALys, 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 tRNALys 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 tRNALys.

Pathologic allelic variants. See Table 3.

Table 3. Pathologic Allelic Variants in Mitochondrial DNA Associated with MERRF

Mitochondrial DNA
Nucleotide Change
(Alias 1)
Gene SymbolProtein Amino
Acid Change
Reference Sequence
m.8344A>G
(A8344G)
MT-TKNo protein translatedAC_000021​.2
m.8356T>C
(T8356C)
m.8363G>A
(G8363A)
m.8361G>A
(G8361A)
m.611G>A
(G611A)
MT-TF
m.15967G>A
(G15967A)
MT-TP

See 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 conventions

For more information, see Table A.

Normal gene product. The normal gene product of MT-TK and MT-TF (tRNALys and tRNAPhe) are indispensable for the incorporation of these amino acids into nascent mitochondrial proteins.

Abnormal gene product. See Molecular Genetic Pathogenesis.

References

Literature Cited

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Chapter Notes

Revision History

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