Myoclonus epilepsy with ragged-red fibers (MERRF) …

Neurogenetic Disorders

Updated 11.06.2023
Released 09.06.1993
Expires For CME 11.06.2026

Myoclonus epilepsy with ragged-red fibers

Authors: Michelangelo Mancuso MD PhD, Piervito Lopriore MD

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Editor: Aravindhan Veerapandiyan MD

Myoclonus epilepsy with ragged-red fibers

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Introduction

Overview

Myoclonus epilepsy with ragged-red fibers (MERRF) is a multisystem mitochondrial disorder defined by myoclonus, generalized epilepsy, ataxia, and myopathy with ragged-red fibers detected in muscle biopsy. MERRF is a clinical syndrome that has been associated with at least eight different point mutations of mitochondrial DNA; however, about 80% of MERRF patients harbor an A-to-G transition at nucleotide 8344 (m.8344A> G) of the MT-TK gene that is a hot spot for MERRF mutations. The pathogenesis of the disease is incompletely understood.

In this article, the authors refer to reports from Italian and German cohorts that the great majority of 8344A>G patients do not have myoclonus and that myoclonus, if present, is not inextricably linked to epilepsy but, at least in the Italian population, is linked with cerebellar ataxia. Hence, the term myoclonic epilepsy seems inadequate, and the acronym MERRF could better be read as myoclonic encephalomyopathy with ragged-red fibers.

Key points

	• Myoclonus epilepsy with ragged-red fibers (MERRF) is clinically defined by: myoclonus, generalized epilepsy, ataxia, and myopathy with ragged-red fibers.
	• In addition, MERRF patients often have sensorineural hearing loss, cognitive impairment, multiple lipomatosis, peripheral neuropathy, exercise intolerance, ptosis, ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, and migraine.
	• About 80% of patients with MERRF have a pathogenic m.8344A> G mutation in the MT-TK gene encoding tRNALys. Globally, four mutations in the MT-TK gene encoding tRNALys (m.8344A> G, m.8356T>C, m.8363G>A, and m.8361G>A) account for approximately 90% of pathogenic variants in individuals with MERRF, with m.8344A> G being the most common one (80% of total cases).
	• The term myoclonic epilepsy seems inadequate, and the acronym MERRF could better be read as myoclonic encephalomyopathy with ragged-red fibers.

Historical note and terminology

In 1921 Ramsay Hunt described six patients with a disorder resembling Friedreich ataxia characterized by ataxia, myoclonus, and epilepsy, which he called "dyssynergia cerebellaris myoclonica" (33). Several different disorders have been associated with this clinical triad; however, almost 50 years passed before mitochondrial abnormalities were described in one family with these clinical features (69). In 1980 Fukuhara and colleagues reported two patients with a syndrome that they named "myoclonus epilepsy associated with ragged-red fibers" (26). Eight years later, Shoffner and colleagues identified a mitochondrial DNA point mutation in myoclonus epilepsy with ragged-red fibers pedigrees (58).

Clinical manifestations

Presentation and course

Myoclonus epilepsy with ragged-red fibers (MERRF) is a multisystem disorder traditionally characterized by (1) myoclonus, (2) generalized epilepsy, (3) ataxia, and (4) myopathy with ragged-red fibers in the muscle biopsy (26).

Onset of the disease is usually in childhood and adolescence after normal psychomotor early development, but it is also possible in adulthood. About 80% of patients have a family history of mitochondrial encephalomyopathy, although not always full-blown MERRF (30). Oligosymptomatic and asymptomatic maternal relatives in MERRF pedigrees are frequently detected. Occasional patients that fulfill the clinical criteria for MERRF also may have additional neurologic manifestation such as migraine (70), hearing impairment, and peripheral neuropathy. Several individuals with depressive mood disorders have been reported.

Among non-neurologic manifestations, cardiac involvement and lipomatosis are frequent. Cardiopathy is common in MERRF and may require medical treatment; in a study of 18 patients with the m.8344A>G mutation, eight had cardiac involvement (dilated cardiopathy in four, Wolff-Parkinson-White syndrome in three, partial cardiac conduction block in one), and two died of heart failure (71). An Italian study showed that cardiac involvement was observed in 53% of 15 m.8344A>G MERRF patients, and a restrictive respiratory insufficiency requiring ventilatory support was observed in about half of the patients (10). Lipomatosis may be observed in adult MERRF patients, most commonly in the cervical region (14). Massive lipomas have also been reported.

Maternally inherited spinocerebellar degeneration, atypical Charcot-Marie-Tooth disease, and Leigh disease have been reported as unusual manifestations in a MERRF pedigree (31). One patient presented with parkinsonism without myoclonus, epilepsy, or ataxia (32), and a child presented with acute demyelination in the central and peripheral nervous system (24). A MERRF-resembling case of adolescent-onset and slowly progressive mitochondrial encephalomyopathy with epilepsy, ataxia, and dystonia in the absence of clinical myopathy, caused by a rare mutation in the MT-TW gene, was reported (72).

The largest cohort to date comprises 42 carriers of the m.8344A>G mutation (39). Clinical data were available for 39 subjects, and four of those were asymptomatic (10.3%). The mean age at onset of the 35 symptomatic patients was 30.1±18.4 years (range 0 to 66; 11/35 with clinical onset before the age of 16). The most frequent clinical manifestations were muscle weakness in 51.3%, exercise intolerance in 38.5%, seizures in 30.8%, hearing loss in 30.8%, multiple lipomatosis in 28.2%, ptosis/ophthalmoparesis in 25.6%, ataxia in 20.5%, and myoclonus in 20.5%. Moreover, the authors reviewed the literature and found 282 additional mutation carriers. Considering all 321 patients so far available at the mean age of approximately 35 years, the clinical picture was characterized by the following signs and symptoms: myoclonus, muscle weakness, ataxia (35% to 45% of patients), generalized seizures, hearing loss (25% to 34.9%), cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15% to 24.9%), increased creatine kinase levels, ptosis/ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, and migraine (5% to 14.9%) (10). Taken together, the phenotype of m.8344A>G mutation carriers showed marked heterogeneity, reaching from asymptomatic to lethal multisystem diseases.

The same authors pointed out that the great majority of 8344A>G patients (approximately 80%) do not have myoclonus and that myoclonus, if present, is not inextricably linked to epilepsy, but to cerebellar ataxia (40). Hence, the term myoclonic epilepsy seems inadequate and potentially misleading, and the acronym MERRF could better be read as myoclonic encephalomyopathy with ragged-red fibers. In a clinical cross-sectional investigation on movement disorders on an Italian cohort of individuals with childhood-onset primary mitochondrial diseases, ataxia (pure cerebellar, sensitive, or spinocerebellar) was widely observed in both pediatric and adult patients. Not surprisingly, myoclonus was commonly observed in mitochondrial encephalopathies, mainly in MERRF, as predominant features at onset or appearing at follow-up in ataxic patients (46).

The German mitoNET registry described the clinical features of 34 m.8344A>G MERRF patients (02). The canonical featured seizures, myoclonus, cerebellar ataxia, and ragged-red fibers that are traditionally associated with MERRF, and they occurred in 61%, 59%, 70%, and 63% of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72%), as well as migraine (52%), psychiatric disorders (54%), respiratory dysfunction (45%), gastrointestinal symptoms (38%), dysarthria (36%), and dysphagia (35%). In the German cohort, the association between myoclonus and ataxia in adult subjects was not significant, but a trend was observed (p=0.0699).

Prognosis and complications

MERRF is a chronic condition, which is slowly progressive. The disease gradually progresses over years. The age of death has ranged from seven to 79 years of age (30). The major complications are seizures and, less commonly, blindness and cardiac failure. Chronic pancreatitis has been reported in one MERRF patient (68). Overall, the exact prognosis is difficult to ascertain, given the wide heterogeneity of phenotypic spectrum.

Clinical vignette

The woman was normal at birth with normal early development. At 10 years of age she developed involuntary jerking of her head and limbs; soon thereafter, drop attacks began. Anticonvulsant therapy was initiated. She showed progressive gait ataxia, proximal limb weakness, and a decline in her school performance. By the age of 13 years, she had a marked intellectual decline, inability to stand, limb weakness with diffuse muscle wasting, and hearing loss. Serum lactate and pyruvate were elevated. A muscle biopsy showed many ragged-red fibers. Her brother and a sister were similarly affected. Her 22-year-old sister was clinically normal. Her mother, at 33 years of age, noted difficulty climbing stairs and lifting objects. At 38 years of age, she was given the diagnosis of limb-girdle muscular dystrophy. At 46 years of age serum lactate and pyruvate were elevated, and her muscle biopsy showed numerous ragged-red fibers. Mitochondrial DNA analysis revealed the presence of the m.8344A>G in the MT-TK gene.

Biological basis

Etiology and pathogenesis

An A-to-G transition mutation at nucleotide 8344 (m.8344A> G) in the MT-TK gene encoding tRNALys has been found in about 80% of MERRF patients tested (59; 30). A second point mutation was found in the MT-TK at nucleotide 8356 (m.8356T> C) in one pedigree with typical MERRF (60) and in another with a syndrome in which MERRF overlapped with MELAS (77; 78). Two additional mutations in the MT-TK gene have been identified in MERRF patients, one at nucleotide 8363 in two Japanese families (52) and the other at nucleotide 8361 (57). Thus, the mitochondrial MT-TK gene is clearly a hot spot for mutations causing MERRF.

However, MERRF and MERRF-like phenotypes have been associated with other possible or definite pathogenic alterations in different mitochondrial genes. For a complete list of genes see Table 1. Interestingly, in a unique family, a MERRF-MELAS overlap syndrome was found to be due to double mutations in mtDNA: the MERRF mutation at nucleotide 8356 and the MELAS mutation at nucleotide 3243 (50).

Table 1. Mutations in mtDNA Genes Associated with MERRF

Gene	Variant	Description	Phenotype	Reference
MT-TF	m.611G> A	Pathogenic	MERRF	(37)
MT-TH	m.12147G>A	Pathogenic	MERRF	(45)
MT-TI	m.4284G>A	Pathogenic	MERRF	(28)
MT-TI	m.4279A>G	Pathogenic	MERRF	(79)
MT-TK	m.8344A> G	Pathogenic	MERRF	(59; 30)
MT-TK	m.8356T> C	Pathogenic	MERRF, MERRF/MELAS	(60; 77; 78)
	m.8361G>A	Pathogenic	MERRF	(57)
	m.8363G>A	Pathogenic	MERRF	(52)
	m.8342G>A	Possibly pathogenic	MERRF/PEO	(66)
	m.8315A>C	Likely benign	MERRF	(63)
MT-TL1	m.3243A>G	Pathogenic	MERRF/MELAS	(08)
MT-TL1	m.3291T> C	Pathogenic	MERRF/KSS	(22)
	m.3255G>A	Pathogenic	MERRF/KSS	(51)
	m.3271T>C	Pathogenic	MERRF
MT-TL2	m.12300G>A	Pathogenic	MERRF/NARP	(44)
MT-TP	m.15967G>A	Pathogenic	MERRF + pigmentary retinopathy	(05)
MT-TS1	m.7512A>G	Pathogenic	MERRF	(49)
MT-TS1	m.7472insC	Pathogenic	MERRF	(67)
MT-TS2	m.12207G>A	Possibly pathogenic	MERRF/MELAS or Leigh syndrome?	(73)
MT-TT	m.15923A>G	Possibly pathogenic	MERRF	(19)
MT-TW	m.5521G>A	Pathogenic	MERRF/MELAS	(29)
MT-ND3	m.10191T>C	Pathogenic	MERRF lacking RRFs	(65)
MT-ND5	m.13042G>A	Possibly pathogenic	MERRF/MELAS	(48)

In addition, MERRF-like phenotypes were described with mutations in MT-TF (m.611G> A) (37), in MT-TI (m.4284 G> A) (28), and also in association with the classical MELAS mutation, m.3243A>G in MT-TL1 (08). In a patient with MERRF plus pigmentary retinopathy, a MT-TP mutation was identified (05). A single patient with MERRF was found to have multiple mitochondrial DNA deletions (06). In addition to the m.8356T> C mutation, point mutations at nucleotide 7512 in MT-TS1 (49), nucleotide 12147 in MT-TH (45), nucleotide 12207 in MT-TS2 (73), nucleotide 13042 in ND5 encoding subunit 5 of complex I (48), and nucleotide 5521 in the MT-TW (29) have also been associated with MERRF/MELAS overlap syndromes. In a unique family, a MERRF-MELAS overlap syndrome was found to be due to double mutations in mtDNA: the MERRF mutation at nucleotide 8356 and the MELAS mutation at nucleotide 3243 (50). MERRF and Kearns-Sayre syndrome overlap syndromes have been described in single patients with point mutation in MT-TK (51) and in MT-TL1 (m.3291T> C) (22). A unique patient with an overlap MERRF-NARP syndrome harbored the mutation m.12300G>A in the mitochondrial MT-TL2 gene (44). Shih-Jie Chou demonstrated that cardiomyocyte-like cells or neural progenitor cells differentiated from MERRF-iPSCs (induced pluripotent stem cells) harboring the A8344G mutation contain mitochondria with an abnormal ultrastructure, produce increased ROS levels, and express upregulated antioxidant genes.

Moreover, Wu and colleagues successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation starting from the patients skin fibroblasts (75). MERRF neural cells exhibited impaired mitochondrial bioenergetic function, elevated ROS levels, and imbalanced expression of antioxidant enzymes. Furthermore, neural cells were characterized by neural immaturity and synaptic protein loss leading to the impairment of neuronal activity and plasticity. In vivo electrophysiological recordings found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities. These in vitro-modelling approach, which exploit PSCs capacity to differentiate into many cell types, permits both detailed investigation of cellular pathomechanisms and validation of promising treatment options.

The origin of the mitochondrial DNA mutations is uncertain. The MERRF mutations are maternally transmitted. Clinical expression of the mutation depends on three factors: (1) mitochondrial DNA heteroplasmy, (2) mitochondrial DNA tissue distribution, and (3) tissue threshold. Silvestri and colleagues found that there was no clear correlation between the percentage of the m.8344A> G mutation in muscle and clinical severity (59). However, the amount of mutation in muscle might not reflect the amount in the central nervous system, to which most clinical symptoms are related. In one of the very few postmortem examinations, mutation loads in 43 different tissue samples of a 16-year-old MERRF patient varied merely between 89% and 100% (09). However, mtDNA copy numbers were increased three- to seven-fold in predominantly affected brain areas and in skeletal muscle while normal in unaffected tissues. Brinckmann and colleagues concluded that "futile" stimulation of mtDNA replication per se or a secondary failure to increase the mitochondrial mass may contribute to the regionalized pathology seen in MERRF syndrome.

Analyses of respiratory chain enzymes in muscle biopsies have demonstrated variable or no defects of respiratory chain complexes. Cytochrome c oxidase activity seems to be most consistently decreased. Skeletal muscle biopsies demonstrate mitochondrial abnormalities. Modified Gomori trichrome stain shows ragged-red fibers in over 90% of patients with myoclonus epilepsy with ragged-red fibers (30); the succinate dehydrogenase histochemical stain reveals fibers with darker than normal reaction and represents a more sensitive indicator of mitochondrial proliferation. Ultrastructural studies have confirmed the increased number of mitochondria, as well as morphologically abnormal mitochondria, which sometimes contain paracrystalline inclusions. Cytochrome c oxidase stain demonstrates individual muscle fibers lacking histochemical activity. Pathological studies have shown neuronal loss in the dentate nucleus, inferior olivary nucleus, degeneration of the posterior columns of the spinal cord, and diffuse gliosis of the cerebellar white matter and of the brain (26). It is unclear how the mitochondrial DNA point mutations cause the MERRF clinical phenotype. Chomyn and colleagues, using the rho-0 cell line repopulated with mitochondria harboring the m.8344A> G mutation, found that high proportions of the mutation correlated with decreased protein synthesis, decreased oxygen consumption, and cytochrome c oxidase deficiency (13). The polypeptides containing higher numbers of lysine residues were more severely affected by the mutation, suggesting that the tRNA mutation directly inhibits protein synthesis. Similarly, cultured myotubules containing greater than 85% mutant mitochondrial DNA showed a decrease in translation, affecting proteins that contained larger numbers of lysine residues more severely (07). Decreased levels of tRNALys and aminoacylated tRNALys (transfer RNA with covalently bound lysine) have been observed in cells harboring the m.8344A> G mutation (23). The mutation appears to be functionally recessive, because only about 15% wild-type mitochondrial DNA was needed to restore translation and cytochrome c oxidase activities to near-normal levels. Masucci and colleagues confirmed the decreased protein synthesis and oxygen consumption in rho-0 cell repopulated with the m.8344A> G mutation and found similar results with the MERRF-8356 mutation (43). They also identified aberrant mitochondrial protein in both mutant cell lines, which they attributed to ribosomal frameshifting. Studies of 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 (G8313A and G8328A) severely impaired lysylation (61). Yasukawa and colleagues observed that the m.8344A> G mutation caused a lack of modification in tRNALys leading to impaired protein synthesis (76). The m.8344A> G-induced protein synthesis defects not only reduce oxygen consumption and ATP synthesis but may also increase oxidative stress (74). Human cybrid cells harboring either the classical MERRF or MELAS mutation are more prone to undergo apoptosis then their wild-type counterpart when challenged with various apoptotic inducers, such as staurosporine. This may be mediated by perturbed calcium homeostasis induced by mitochondrial dysfunction (56).

The common cause of MERRF, m.8344A> G mutation, is also a common cause of multiple symmetric lipomatosis (47). The Nation-wide Italian Collaborative Network of Mitochondrial Diseases analyzed the incidence and characteristics of lipomas among an Italian cohort of patients with mitochondrial diseases (47). A total of 22 patients (1.7% of the cohort) with lipomas have been identified. In about 18%, multiple systemic lipomatosis was the only clinical manifestation, whereas 54% of patients showed a classical MERRF syndrome, and 86% had mutations in the mtDNA tRNA lysine. Finally, in patients with MERRF, lipomas have been shown to harbor a deletion in chromosome 6 (6q24) in addition to the m.8344A> G mutation (34).

Diagnostic workup

Screening patients for MERRF should begin with routine blood tests, including complete blood count, serum electrolytes, liver function tests, blood urea nitrogen, creatinine, lactate, and pyruvate. These tests may reveal kidney or liver dysfunction. Lactate and pyruvate at rest might be elevated in MERRF patients and may increase dramatically after moderate exercise. Blood leukocyte and urine sediment DNA should be screened for a mitochondrial DNA point mutation because identification of a mitochondrial DNA mutation will obviate the need for a costly and invasive muscle biopsy.

ECG may reveal pre-excitation or partial cardiac conduction block. Echocardiogram may demonstrate cardiomyopathy. Lumbar puncture may show elevated cerebrospinal fluid protein, but no patients have had cerebrospinal fluid protein greater than 100 mg/dL. Electromyography and nerve conduction studies are typically consistent with a myogenic process, although a neuropathy may also be present. Typically, there are decreased amplitudes of compound muscle or nerve action potentials indicating axonal degeneration (15). Electroencephalography may show atypical generalized spike and wave discharges, with abnormal background slowing; focal epileptiform discharges may also be seen (62). As for any epilepsy secondary to mitochondrial disease, in MERRF patients there is an increased propensity for seizures arising from the posterior cerebral regions (25). Somatosensory evoked responses may show giant cortical evoked responses (62). Brain imaging with CT or MRI may show basal ganglia calcification and atrophy (04). In the Italian cohort, MRI was normal in 58% of the cases; the remaining patients presented cortical/subcortical atrophy, white matter abnormalities, periaqueductal lesions, cysts or vacuolated lesions, brainstem atrophy, and stroke-like lesions. In the German cohort, cerebral atrophy, cerebellar atrophy, or both was present at brain MRI in 43%. In two further patients, brain white matter abnormalities were noted. No definitive data on brain MRI spectroscopy are available from the two cohorts.

Finally, muscle biopsy can be performed to confirm the diagnosis. Ragged-red fibers on modified Gomori trichrome stain are the hallmark histological feature and a defining criterion. In addition, a mosaic pattern of cytochrome c oxidase (COX) deficient fibers is typically seen; however, at least one MERRF patient with the m.8344A>G mutation lacked ragged-red and COX-deficient fibers (41). Mitochondrial enzyme activities can be measured in whole muscle homogenate or in isolated mitochondria and usually demonstrate multiple respiratory chain defects, particularly in complex IV (35). Muscle mitochondrial DNA should be screened for the mutations associated with MERRF.

Management

The seizures of MERRF can be treated with conventional anticonvulsant therapy but are usually refractory. Thus, multi-anticonvulsant therapies may be needed. An international consortium of experts published a consensus on safe medication use in patients with a primary mitochondrial disease, including antiepileptic drugs (20). In this scenario, valproic acid should be avoided in mitochondrial disease, mainly in patients with POLG mutations because it could be toxic and cause liver failure. There are no controlled studies to compare efficacy of different antiepileptic regimens. Myoclonus in MERRF improved in individuals treated with levetiracetam (16; 38). A double-blind placebo-controlled study to evaluate efficacy and safety of vatiquinone for treating mitochondrial disease in participants with refractory epilepsy, including MERRF patients, is currently running (no more recruiting). More information can be accessed at the following website: https://www.clinicaltrials.gov/search?cond=Mitochondrial%20Diseases.

Aerobic exercise is helpful in MERRF and other mitochondrial diseases (64).

No treatment for primary mitochondrial diseases is available so far, beside idebenone in Leber optic atrophy. Coenzyme Q10 (200 to 1000 mg/day), L-carnitine (up to 2 g/day), riboflavin and other mitochondrial vitamins have been used to improve mitochondrial function without clear benefit. In MERRF fibroblasts and cybrids, supplemental coenzyme Q10 showed partial efficacy in restoring respiratory chain activity, mitochondrial protein expression, increased oxidative stress, and increased mitophagy (18).

Aerobic exercise is helpful in MERRF and other mitochondrial diseases (64).

With recent advances in molecular technologies, the understanding of the pathological mechanism of a growing list of mitochondrial disorders has been expanded. Consequently, there is an increasing number of clinical trials in mitochondrial disorders, including MERRF, aiming for more specific, molecular-targeted and effective therapies (01). For a detailed list please visit: https://www.clinicaltrials.gov/ct2/results?cond=Mitochondrial+Diseases&term=&cntry=&state=&city=&dist=.

References

01: Almannai M, El-Hattab AW, Ali M, Soler-Alfonso C, Scaglia F. Clinical trials in mitochondrial disorders, an update. Mol Genet Metab 2020;131(1-2):1-13. PMID 33129691
02: Altmann J, Büchner B, Nadaj-Pakleza A, et al. Expanded phenotypic spectrum of the m.8344A>G "MERRF" mutation: data from the German mitoNET registry. J Neurol 2016;263(5):961-72. PMID 26995359
03: Andermann F, Berkovic S, Carpenter S, Andermann E. The Ramsay Hunt syndrome is no longer a useful diagnostic category. Mov Disord 1989;4:13-7. PMID 2494436
04: Berkovic SF, Carpenter S, Evans A, et al. Myoclonus epilepsy and ragged-red fibers (MERRF): a clinical, pathological biochemical magnetic resonance spectrographic and positron emission tomographic study. Brain 1989;112:1231-60. PMID 2508988
05: Blakely EL, Trip SA, Swalwell H, et al. A new mitochondrial transfer RNAPro gene mutation associated with myoclonic epilepsy with ragged-red fibers and other neurological features. Arch Neurol 2009;66:399-402. PMID 19273760
06: Blumenthal DT, Shanske S, Schochet SS, et al. Myoclonus epilepsy with ragged red fibers and multiple mtDNA deletions. Neurology 1998;50(2):524-5. PMID 9484389
07: Boulet L, Karpati G, Shoubridge EA. Distribution and threshold expression of the tRNA mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 1992;51:1187-200. PMID 1334369
08: Brackmann F, Abicht A, Ahting U, Schroder R, Trollmann R. Classical MERRF phenotype associated with mitochondrial tRNA(Leu) (m.3243A>G) mutation. Eur J Pediatr 2012;171(5):859-62. PMID 22270878
09: Brinckmann A, Weiss C, Wilbert F, et al. Regionalized pathology correlates with augmentation of mtDNA copy numbers in a patient with myoclonic epilepsy with ragged-red fibers (MERRF-syndrome). PLoS One 2010;5(10):e13513. PMID 20976001
10: Catteruccia M, Sauchelli D, Della Marca G, et al. "Myo-cardiomyopathy" is commonly associated with the A8344G "MERRF" mutation. J Neurol 2015;262(3):701-10. PMID 25559684
11: 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(Pt 10):1889-94. PMID 9798744
12: Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 2000;48:188-93. PMID 10939569
13: 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. PMID 1848674
14: Chong PST, 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):1-7. PMID 19078716
15: Chu CC, Huang CC, Fang W, Chu NS, Pang CY, Wei YH. Peripheral neuropathy in mitochondrial encephalomyopathies. Eur Neurol 1997;37:110-5. PMID 9058067
16: Crest C, Dupont S, Leguern E, Adam C, Baulac M. Levetiracetam in progressive myoclonic epilepsy: an exploratory study in 9 patients. Neurology 2004;62(4):640-3. PMID 14981187
17: 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. PMID 11261513
18: De la Mata M, Garrido-Maraver J, Cotán D, et al. Recovery of MERRF fibroblasts and cybrids pathophysiology by Coenzyme Q(10). Neurotherapeutics 2012;9(2):446-63. PMID 22354625
19: del Mar O'Callaghan M, Emperador S, Lopez-Gallardo E, et al. New mitochondrial DNA mutations in tRNA associated with three severe encephalopamyopathic phenotypes: neonatal, infantile, and childhood onset. Neurogenetics 2012;13(3):245-250. PMID 22638997
20: De Vries MC, Brown DA, Allen ME, et al. Safety of drug use in patients with a primary mitochondrial disease: an international Delphi-based consensus. J Inherit Metab Dis 2020;43(4):800-18.** PMID 32030781
21: Eberhardt O, Topka H. Myoclonic disorders. Brain Sci 2017;7(8):103. PMID 28805718
22: 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(3):448-51. PMID 21996807
23: Enriquez JA, Chomyn A, Attardi G. MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNA(Lys) and premature translation termination. Nat Genet 1995;10(1):47-55. PMID 7647790
24: Erol I, Alehan F, Horvath R, Schneiderat P, Talim B. Demyelinating disease of central and peripheral nervous systems associated with a A8344G mutation in tRNALys. Neuromuscul Disord 2009;19:275-8. PMID 19269823
25: Fine AL, Liebo G, Gavrilova RH, Britton JW. Seizure semiology, EEG, and imaging findings in epilepsy secondary to mitochondrial disease. Front Neurol 2021;12:779052. PMID 34912288
26: Fukuhara N, Tokigushi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or syndrome. Light and electron microscopic studies of two cases and review of the literature. J Neurol Sci 1980;47:117-33. PMID 6774061
27: Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015;77(5):753-9. PMID 25652200
28: Hahn A, Schänzer A, Neubauer BA, Gizewski E, Ahting U, Rolinski B. MERRF-like phenotype associated with a rare mitochondrial tRNA-Ile mutation (m.4284 G>A). Neuropediatrics 2011;42(4):148-51. PMID 21766266
29: Herrero-Martin MD, Ayuso T, Tunon MT, Martin 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. PMID 20360171
30: Hirano M, DiMauro S. Clinical features of mitochondrial myopathies and encephalomyopathies. In: Lane RJ, editor. Handbook of muscle disease. New York: Marcel Dekker, 1996;479-504.
31: Howell N, Kubacka I, Smith R, Frerman F, Parks JK, Parker WD Jr. Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease. Neurology 1996;46:219-22. PMID 8559379
32: Horvath R, Kley RA, Lochmuller H, Vorgerd M. Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys. Neurology 2007;68:56-8. PMID 17200493
33: 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.
34: Larsson NG, Tulinius MH, Holme E, Oldfors A. Pathogenetic aspects of the A8344G mutation of mitochondrial DNA associated with MERRF syndrome and multiple symmetric lipomas. Muscle Nerve 1995;3:S102-6. PMID 7603509
35: Lombes A, Mendell JR, Nakase H, et al. Myoclonic epilepsy and ragged-red fibers with cytochrome c oxidase deficiency: neuropathology, biochemistry, and molecular genetics. Ann Neurol 1989;26:20-33. PMID 2549843
36: Lopriore P, Ricciarini V, Siciliano G, Mancuso M, Montano V. Mitochondrial ataxias: molecular classification and clinical heterogeneity. Neurol Int 2022;14(2):337-56. PMID 35466209
37: Mancuso M, Filosto M, Mootha VK, et al. A novel mitochondrial tRNAPhe mutation causes MERRF syndrome. Neurology 2004;62(11):2119-21. PMID 15184630
38: Mancuso M, Galli R, Pizzanelli C, Filosto M, Siciliano G, Murri L. Antimyoclonic effect of levetiracetam in MERRF syndrome. J Neurol Sci 2006;243(1-2):97-9. PMID 6414077
39: Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology 2013;80(22):2049-54.** PMID 23635963
40: Mancuso M, Orsucci D, Angelini C, et al. Myoclonus in mitochondrial disorders. Mov Disord 2014;29(6):722-8. PMID 24510442
41: Mancuso M, Petrozzi L, Filosto M, et al. MERRF syndrome without ragged-red fibers: the need for molecular diagnosis. Biochem Biophys Res Commun 2007;354:1058-60. PMID 17275787
42: Marsden C, Obeso J. Viewpoints on the Ramsay Hunt syndrome. The Ramsay Hunt syndrome is a useful clinical entity. Mov Disord 1989;4:6-12. PMID 2494439
43: 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 tRNALys gene: two genotypes produce similar phenotypes. Mol Cell Biol 1995;15:2872-81. PMID 7739567
44: Martín-Jiménez R, Martín-Hernández E, Cabello A, et al. Clinical and cellular consequences of the mutation m.12300G>A in the mitochondrial tRNA(Leu(CUN)) gene. Mitochondrion 2012;12(2):288-93. PMID 22094595
45: Melone MAB, Tessa A, Petrini S, et al. Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERRF phenotype. Arch Neurol 2004;61(2):269-72. PMID 14967777
46: Montano V, Orsucci D, Carelli V, et al. Adult-onset mitochondrial movement disorders: a national picture from the Italian Network. J Neurol 2022;269(3):1413-21.** PMID 34259909
47: Musumeci O, Barca E, Lamperti C, et al. Lipomatosis incidence and characteristics in an Italian cohort of mitochondrial patients. Front Neurol 2019;10:160. PMID 30873109
48: Naini AB, Lu J, Kaufmann P, et al. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF. Arch Neurol 2005;62(3):473-6. PMID 15767514
49: Nakamura M, Nakano S, Goto Y, et al. A novel point mutation in the mitochondrial tRNA(Ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome. Biochem Biophys Res Commun 1995;214(1):86-93. PMID 7669057
50: Nakamura M, Yabe I, Sudo A, et al. MERRF/MELAS overlap syndrome: a double pathogenic mutation in mitochondrial tRNA genes. J Med Genet 2010;47(10):659-64. PMID 20610441
51: Nishigaki Y, Tadesse S, Bonilla E, et al. A novel mitochondrial tRNALeu(UUR) mutation in a patient with features of MERRF and Kearns-Sayre syndrome. Neuromusc Disord 2003;13:334-40. PMID 12868503
52: Ozawa M, Nishino I, Horai S, Nonaka I, Goto YI. Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(lys) in two families. Muscle Nerve 1997;20:271-8. PMID 9052804
53: Penisson-Besnier I, Degoul F, Desnuelle C, et al. Uneven distribution of mitochondrial DNA mutation in MERRF dizygotic twins. J Neurol Sci 1992;110:144-8. PMID 1324294
54: Racca F, Mongini T, Wolfler A, et al. Recommendations for anesthesia and perioperative management of patients with neuromuscular disorders. Minerva Anestesiol 2013;79(4):419-33. PMID 23419334
55: Remes AM, Karppa M, Moilanen JS, et al. Epidemiology of the mitochondrial DNA 8344A>G mutation for the myoclonus epilepsy and ragged red fibres (MERRF) syndrome. J Neurol Neurosurg Psychiatry 2003;74:1158-9. PMID 12876264
56: Rommelaere G, Michel S, Malaisse J, Charlier S, Arnould T, Renard P. Hypersensitivity of A8344G MERRF mutated cybrid cells to staurosporine-induced cell death is mediated by calcium-dependent activation of calpains. Int J Biochem Cell Biol 2012;44(1):139-49. PMID 22037425
57: Rossmanith W, Raffelsberger T, Roka J, et al. The expanding mutational spectrum of MERRF substitution G8361 in the mitochondrial tRNALys gene. Ann Neurol 2003;54:820-3. PMID 14681892
58: Shoffner JM, Lott MT, Lezza A, Seigel P, Ballinger S, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 1990;61:931-7. PMID 2112427
59: Silvestri G, Ciafaloni E, Santorelli F, et al. Clinical features associated with the A-->G transition at nucleotide 8344 of mtDNA ("MERRF" mutation). Neurology 1993;43:1200-6. PMID 8170567
60: Silvestri G, Moraes CT, Shanske S, Oh S, DiMauro S. A new mtDNA mutation in the tRNALys gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 1992;51:1213-7. PMID 1361099
61: Sissler M, Helm M, Frugier M, Giege R, Florentz C. Aminoacylation properties of pathology-related human mitochondrial tRNA(Lys) variants. RNA 2004;10(5):841-53. PMID 15100439
62: So N, Berkovic S, Andermann F, Kuziecky R, Gendron D, Quesney L. Myoclonus epilepsy and ragged-red fibres (MERRF) 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain 1989;112:1261-76. PMID 2508989
63: Stufkova H, Kolářová H, Lokvencová K, et al. A novel MTTK gene variant m.8315A>C as a cause of MERRF syndrome. Genes (Basel) 2022;13(7):1245. PMID 35886028
64: Taivassalo T, Haller RG. Implications of exercise training in mtDNA defects--use it or lose it. Biochim Biophys Acta 2004;1659(2-3):221-31. PMID 25590412
65: Taylor RW, Singh-Kler R, Hayes CM, Smith PE, Turnbull DM. Progressive mitochondrial disease resulting from a novel missense mutation in the mitochondrial DNA ND3 gene. Ann Neurol 2001;50(1):104-7. PMID 11456298
66: Tiranti V, Carrara F, Confalonieri P, et al. A novel mutation (8342G-->A) in the mitochondrial tRNA(Lys) gene associated with progressive external ophthalmoplegia and myoclonus. Neuromuscul Disord 1999;9(2):66-71. PMID 10220860
67: Tiranti V, Chariot P, Carella F, et al. Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. Hum Mol Genet 1995;4(8):1421-7. PMID 7581383
68: Toyono M, Nakano K, Kiuchi M, et al. A case of MERRF associated with chronic pancreatitis. Neuromuscul Disord 2001;11(3):300-4. PMID 11297946
69: Tsairis P, Engel W, Park P. Familial myoclonic epilepsy syndrome associated with skeletal muscle abnormalities. Neurology 1973;23:408.
70: Vollono C, Primiano G, Della Marca G, Losurdo A, Servidei S. Migraine in mitochondrial disorders: prevalence and characteristics. Cephalalgia 2018;38(6):1093-106. PMID 28762753
71: Wahbi K, Larue S, Jardel C, et al. Cardiac involvement is frequent in patients with the m.8344A>G mutation of mitochondrial DNA. Neurology 2010;74:674-7. PMID 20177121
72: Wang S, Miao J, Feng J. Case report: mitochondrial encephalomyopathy presents as epilepsy, ataxia, and dystonia with a rare mutation in MT-TW. Front Neurol 2021;12:679302. PMID 34276539
73: Wong LJ, Yim D, Bai RK, et al. A novel mutation in the mitochondrial tRNA(Ser(AGY)) gene associated with mitochondrial myopathy, encephalopathy, and complex I deficiency. J Med Genet 2006;43:e46. PMID 16950817
74: Wu SB, Ma YS, Wu YT, Chen YC, Wei YH. Mitochondrial DNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression in cultured cells of patients with MERRF syndrome. Mol Neurobiol 2010;41:256-66. PMID 20411357
75: Wu YT, Tay HY, Yang JT, Liao HH, Ma YS, Wei YH. Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients. J Biomed Sci 2023;30(1):70. PMID 37605213
76: Yasukawa T, Suzuki T, Ishii N, Ohta S, Watanabe K. Wobble modification defect in tRNA disturbs codon-anticodon interaction in a mitochondrial disease. EMBO J 2001;20(17):4794-802. PMID 11532943
77: Zeviani M, Amati P, Bresolin N, et al. Rapid detection of the A>G (8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 1991;48:203-11. PMID 1899320
78: Zeviani M, Muntoni F, Savarese N, et al. A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNALys gene. Eur J Hum Genet 1992;1:80-7. PMID 8069654
79: Zsurka G, Becker F, Heinen M, et al. Mutation in the mitochondrial tRNA(Ile) gene causes progressive myoclonus epilepsy. Seizure 2013;22(6):483-6. PMID 23601850

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Michelangelo Mancuso MD PhD

Dr. Mancuso of the University Hospital of Pisa has no relevant financial relationships to disclose.
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Piervito Lopriore MD

Dr. Lopriore of the University of Pisa has no relevant financial relationships to disclose.
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Editor

Aravindhan Veerapandiyan MD

Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
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Former Authors

Michio Hirano MD and Thomas Klopstock MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: Heredity may be a factor: matrilineal inheritance
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Myoclonus epilepsy with ragged-red fibers: 277.87
ICD-10: Metabolic disorder, unspecified: G71.3
OMIM: Myoclonic epilepsy associated with ragged-red fibers: #54500

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Myoclonus epilepsy with ragged-red fibers

Associated Disorders

Ataxia
Myoclonus
Epilepsy
Lactic acidosis
Dementia
- Progressive external ophthalmoplegia (cPEO)
- MELAS
- Stroke
- Cognitive impairment
- Psychiatric disorders
- Limb-girdle myopathy
- Hearing loss

Differential Diagnosis

Unverricht-Lundborg disease
Lafora body disease
neuronal ceroid lipofuscinosis
sialidosis
Ramsay Hunt syndrome
- limb-girdle myopathy
- Degenerative cerebellar ataxias

Also Relevant

Ataxia
Epilepsy in mitochondrial disorders
MELAS
Myoclonus
Progressive external ophthalmoplegia (cPEO)

Myoclonus epilepsy with ragged-red fibers (MERRF) …

Myoclonus epilepsy with ragged-red fibers

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. Mutations in mtDNA Genes Associated with MERRF

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

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Myoclonus epilepsy with ragged-red fibers

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. Mutations in mtDNA Genes Associated with MERRF

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Photosensitive occipital lobe epilepsy

Carnitine palmitoyltransferase II deficiency

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Intermittent explosive disorder

Pyruvate carboxylase deficiency

Pelizaeus-Merzbacher disease

This is an article preview.
Start a Free Account
to access the full version.