MERRF (Myoclonic Epilepsy with Ragged Red Fibres)

Myoclonic epilepsy with ragged-red fibres: a maternally inherited mitochondrial disease caused predominantly by the MT-TK m.8344A>G variant, including allelic phenotypes of the same variant (multiple symmetric lipomatosis, Ekbom syndrome, isolated myopathy) and MERRF/MELAS and MERRF/Kearns–Sayre overlaps

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From Clinical Descriptions to Recognition as a Distinct Entity

The history of MERRF intersects two lines of investigation: myoclonic epilepsies with ataxia, originating in clinical neurology, and mitochondrial myopathies, originating in muscle histochemistry. In 1921, James Ramsay Hunt described six patients with ataxia, myoclonus and epilepsy and termed the condition dyssynergia cerebellaris myoclonica, attributing it to primary atrophy of the dentate system [1, 16]. For decades, “Ramsay Hunt syndrome” served as a descriptive label for patients with progressive myoclonus and ataxia without a defined cause; in 1987, Berkovic and colleagues demonstrated that some of these patients had mitochondrial encephalomyopathy, and GeneReviews still recommends investigating individuals with that historical diagnosis for MERRF [1, 17].

The second line begins with Luft and colleagues, who in 1962 described the first recognised mitochondrial disease in a hypermetabolic woman with a normal thyroid and uncoupling of oxidative phosphorylation, and continues with Engel and Cunningham's modified Gomori trichrome stain (1963), which made visible the “ragged” (disorganised) and “red” (owing to subsarcolemmal mitochondrial accumulation) muscle fibres [17]. In 1965, Gonatas and Shy described the ultrastructural correlate: mitochondrial proliferation, giant mitochondria, disorganised cristae and paracrystalline inclusions [17].

In 1973, Tsairis, Engel and Kark reported a familial syndrome of myoclonic epilepsy with mitochondrial abnormalities of skeletal muscle, considered the first description of the disease [17]. In 1980, Fukuhara, Tokiguchi, Shirakawa and Tsubaki published two patients with progressive myoclonus since adolescence and childhood, respectively, generalised seizures, mental deterioration, intention tremor, ataxia, muscle atrophy and foot deformity; both biopsies showed ragged-red fibres (RRF) and, on electron microscopy, subsarcolemmal aggregates of abnormal mitochondria with paracrystalline inclusions, and one patient had elevated lactate and pyruvate; the article title asked whether this was a “disease entity or a syndrome”, and the acronym MERRF became established following this work [18]. In 1988, the Columbia University group reviewed 25 cases [17].

1.2. Molecular Discovery

In 1988, Wallace and colleagues demonstrated exclusively maternal transmission and the mitochondrial nature of the defect in a large family, with reduced activities of complexes I and IV in muscle [17, 19]. In 1990, Shoffner, Lott, Lezza, Seibel, Ballinger and Wallace identified the A>G transition at nucleotide 8344 of mitochondrial DNA (mtDNA), in the TΨC loop of the lysine tRNA gene; the variant created a restriction site for the enzyme CviJI, enabling a simple diagnostic test, was present in three independent lineages, absent in 75 controls and affected a conserved nucleotide [20]. Patients and less severely affected maternal relatives had between 2% and 27% normal mtDNA, and severity depended on age and the proportion of normal molecules, leading the authors to conclude that a small fraction of normal mtDNA has a disproportionately protective effect [20]. In 1991, Noer and colleagues confirmed the same variant in three patients, with an abnormal pattern of mitochondrial translation products, and showed through pedigree analysis that the mutations had arisen independently, supporting causality [21].

The second MT-TK variant, m.8356T>C, was described in 1992 by Silvestri and colleagues, almost homoplasmic in muscle and at 47% in blood, and absent in 20 patients with mitochondrial disease and 25 controls; the same authors estimated that m.8344A>G was absent in 10–20% of MERRF cases known at that time [22]. In 1993, Zeviani and colleagues found m.8356T>C in a three-generation Sardinian family with concurrent features of MERRF and MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), the first overlap described [23]. The third variant, m.8363G>A, was described in two Japanese families with typical MERRF by Ozawa and colleagues in 1997 [24].

1.3. Nomenclature and Reclassifications

The name MERRF describes a phenotype rather than a genotype, and the correspondence between the two is imperfect. Genotype-ascertained carrier series showed that most people with m.8344A>G do not have the complete syndrome, that myoclonus is more closely associated with ataxia than with seizures in adults, and that the disease could be described as “myoclonic ataxia” rather than myoclonic epilepsy [25]. In 2018, Finsterer, Zarrouk-Mahjoub and Shoffner proposed a classification based on the combination of variant and gene, with levels of gene–disease evidence (definitive for MT-TK, strong for MT-TL1 and POLG), and the distinction between “classical” MERRF, with the four canonical features, and “MERRF-plus”, with additional manifestations [6, 26]. In 2022, the North American Mitochondrial Disease Consortium (NAMDC) removed the presence of RRF from the clinical definition because muscle biopsies are less frequent in the era of next-generation sequencing and because some patients lack RRF [27].

1.4. Scope

This covers classical MERRF, partial or atypical m.8344A>G phenotypes (isolated myopathy, respiratory failure, multiple symmetric lipomatosis, Ekbom syndrome, infantile cardiomyopathy) and overlap syndromes in which MERRF is the dominant component. The general approach to mitochondrial diseases, mtDNA genetics, drugs to avoid and reproductive options provide the framework; MELAS and the other m.3243A>G phenotypes, including stroke-like episodes, and the POLG-related disorders enter the differential diagnosis; Leigh syndrome due to MT-TK variants is mentioned only within the general framework.

2. Molecular Genetics and Pathophysiology

2.1. The MT-TK Gene and Associated Genes

MT-TK encodes mitochondrial lysine tRNA, one of the 22 tRNA molecules required for translation of the 13 respiratory chain polypeptides encoded by mtDNA. Like all mitochondrial tRNA genes, it has no MANE (Matched Annotation from NCBI and EMBL-EBI) transcript, coding sequence or protein product; variants are described using the genomic coordinate of the revised Cambridge Reference Sequence (NC_012920.1:m.), and the historical form “A8344G” corresponds to m.8344A>G [1, 28]. GeneReviews lists eight genes associated with MERRF, all encoded in mtDNA: MT-TK (OMIM 590060), MT-TF (590070), MT-TH (590040), MT-TI (590045), MT-TL1 (590050), MT-TP (590075), MT-TS1 (590080) and MT-TS2 (590085) [1]. In a 2019 review, Finsterer counted 13 mtDNA genes and one nuclear gene associated with the phenotype, with the strongest evidence for MT-TK, MT-TL1 and POLG [29].

The proportion of patients attributed to MT-TK depends on how the denominator is defined. GeneReviews attributes “>80%” of typical cases to m.8344A>G and “>90%” to four MT-TK variants together (m.8344A>G, m.8356T>C, m.8363G>A and m.8361G>A), and fewer than 5% to MT-TF; the proportion for the remaining genes is unknown [1]. The two estimates do not contradict each other: approximately 80% for the common variant and approximately 10% for the other MT-TK variants. NAMDC and Finsterer's classification also give approximately 90% for MT-TK, and the Brazilian review by Lorenzoni and colleagues attributes almost 90% of cases to tRNA-Lys point variants [6, 27, 30]. One of the four variants counted by GeneReviews (m.8361G>A) is now classified as being of uncertain significance, reducing the proportion that can be attributed with confidence.

2.2. Variant Spectrum and Current Classification

The following descriptions were validated in VariantValidator without warnings, and the classification corresponds to ClinVar accessed on 10 October 2026; for almost all variants, the classification is from the ClinGen mitochondrial disease Variant Curation Expert Panel (VCEP) [4, 28].

Three corrections follow from the table. m.8361G>A and m.8296A>G, presented as causes of MERRF in textbooks and older reports, are now variants of uncertain significance (VUS) according to the expert panel and should not be used to confirm the diagnosis or for cascade testing [4, 31]. m.5521G>A, cited in GeneReviews among MERRF/MELAS overlaps in connection with MT-ND5 and MT-TC, is located in the MT-TW gene (tryptophan tRNA) [1, 4]. Furthermore, the notation “MTTK c.8344A>G”, used in some reports, is incorrect because the prefix c. presupposes a coding sequence [28, 32]. m.8315A>C and m.12300G>A (MT-TL2, described in an individual with features of MERRF and NARP, neuropathy, ataxia and retinitis pigmentosa) had no ClinVar record in the search performed [1, 4].

In the mitochondrial DNA variant interpretation system of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), as specified by ClinGen, m.8344A>G is one of the universally pathogenic reference variants used to calibrate the criteria, and MERRF is one of the classical syndromes allowing application of the phenotypic PS4 criterion; large families with this variant show phenotypes ranging from absence of symptoms to early death, correlating with mutant load, with classical MERRF at high loads and myopathy or sensorineural hearing loss at low loads [33].

2.3. Molecular Mechanism

m.8344A>G alters the TΨC loop of tRNA-Lys, and m.8356T>C disrupts a conserved base pair in the TΨC stem; both are located in the same arm of the molecule [17, 20, 22]. In transmitochondrial cells (mtDNA-depleted cell lines, ρ0, repopulated with patients' mitochondria), high mutant loads were associated with reduced mitochondrial protein synthesis, reduced oxygen consumption and cytochrome c oxidase (COX) deficiency, with a greater effect on lysine-rich polypeptides [34]. In 1995, Enriquez, Chomyn and Attardi showed a 50–60% reduction in tRNA-Lys aminoacylation and premature termination of translation at or near each lysine codon [35]. Masucci and colleagues obtained similar cellular phenotypes with m.8344A>G and m.8356T>C, with aberrant translation products attributed to ribosomal frameshifting [36]; conversely, Sissler and colleagues found that MERRF variants did not alter lysylation efficiency in vitro, unlike m.8313G>A and m.8328G>A, associated with encephalomyopathies without typical MERRF [37].

The current explanation centres on post-transcriptional modifications. In 2000, Yasukawa and colleagues demonstrated loss of uridine modification at the wobble position of the mutant tRNA-Lys anticodon [38]. According to the review by Chujo and Tomizawa (2025), the main effect of m.8344A>G is loss of taurinomethyl-2-thiouridine at position 34 (τm5s2U34), which prevents efficient decoding of AAA and AAG codons because the mutation prevents the MTO1–GTPBP3 and MTU1 enzymes from introducing the modification; TRMT61B-dependent m1A58 methylation is also lost, whereas aminoacylation is only moderately reduced [39]. The variant is functionally recessive: in cell cultures, approximately 15% normal mtDNA restores translation and COX activity to almost normal levels, and myotubes with more than 85% mutant molecules have reduced translation [1].

In muscle, the defect results in a combined reduction of complexes with mtDNA-encoded subunits (I, III, IV and V), predominantly COX deficiency, a pattern typical of tRNA and ribosomal RNA variants [17, 40]. At tissue level, fibres with a load above the threshold lose COX activity and accumulate mitochondria (RRF and “ragged-blue” fibres on succinate dehydrogenase, SDH, staining); in the nervous system, neuropathology shows degeneration of the dentatorubral and pallidal systems, cerebral cortex, cerebellum, pons and spinal cord [17, 40]. GeneReviews classifies the exact mechanism of causality as unknown and the origin of the variants as uncertain [1].

2.4. Heteroplasmy, Threshold and Tissue Segregation

m.8344A>G is almost always heteroplasmic: normal and mutant molecules coexist in the same cell, in a proportion (mutant load) that varies between individuals within a family and between tissues within the same individual [1, 17]. For common point variants, the biochemical threshold typically lies between 80% and 95% mutant load [40]. Quantitative data specific to m.8344A>G come from small studies, summarised in the following table.

These studies indicate that blood load underestimates muscle load, that muscle is the reference tissue for correlation with phenotype and that, unlike m.3243A>G, there is no evidence of a postnatal decrease in blood load with age [41, 44]. Lymphocytes, rapidly proliferating cells, have lower loads than muscle, consistent with selection against high-load cells [17].

2.5. Genotype–Phenotype Correlation, Penetrance and Expressivity

GeneReviews recognises no clinically useful genotype–phenotype correlations or gene-specific phenotypes; expression depends on load, tissue distribution and each organ's threshold, and clinical diversity is attributed more to load and distribution than to individual differences in threshold [1]. No numerical penetrance estimate exists. In the series of 150 patients tested at Columbia, the variant was strongly associated with MERRF but also occurred in Leigh syndrome, isolated myoclonus, myopathy with truncal lipomas and proximal myopathy, and four patients with typical MERRF lacked it [46]. For m.8363G>A, a multigenerational Italian family showed phenotypes ranging from MERRF to an isolated psychiatric disorder, and a meta-analysis of published cases found correlations between load and severity (p=0.00168) and age at onset (p<0.00001), with exceptions limiting application to individual patients [47]. Load does not reliably predict severity, as shown by families in which carriers with similar loads have different presentations [9, 48].

2.6. Allelic Disorders and Overlaps

The table reproduces the allelic phenotypes of MERRF-associated genes according to GeneReviews [1].

MERRF/MELAS overlap was described in three families with m.8356T>C, in which some affected individuals had typical MERRF and others had stroke-like episodes and migraine [1, 23]; in a Japanese family with the same variant, the proband had MERRF with migraine, dementia and lactic acidosis, the mother only migraine, and an aunt diabetes and stroke-like episodes [49]. Nakamura and colleagues described a patient with MERRF/MELAS overlap carrying two variants, m.3243A>G in MT-TL1 and m.8356T>C in MT-TK [50]. In a report cited by the Atlas of Inherited Metabolic Diseases, a 20-year-old proband had sudden migraine followed by left hemiparesis, homonymous hemianopia and seizures (a MELAS presentation) and, at age 25 years, myoclonus and ataxia (progression to MERRF) [17]. MERRF/Kearns–Sayre syndrome overlap was described with m.3255G>A in two individuals and with m.3291T>C in one [1, 51, 52]. MT-TL1 m.3256C>T was described in a patient with tonic–clonic seizures at age 28 years and, at age 45 years, limb myoclonus, mild neck and deltoid weakness, mild ataxia and RRF, without myoclonic seizures, alongside hypothyroidism, ptosis, ophthalmoparesis, hearing loss, diabetes, optic atrophy and retinal pigmentary degeneration [17].

m.8344A>G has its own allelic phenotypes: multiple symmetric lipomatosis (Madelung disease), which may be the sole manifestation in an entire family [32]; Ekbom syndrome (photomyoclonus, cerebellar ataxia, skeletal deformities and cervical lipoma), in which Träff and colleagues found the variant in all nine maternal descendants studied, with 33–87% in lymphocytes, 59–92% in muscle and 96% in lipoma tissue [53]; distal myopathy with respiratory failure [5]; and Leigh syndrome and infantile histiocytoid cardiomyopathy [46, 54]. The Oxford Desk Reference includes m.8344A>G among the mtDNA variants most associated with late-onset disease that may also cause Leigh encephalopathy [55]. Leigh syndrome due to MT-TK variants and cardiomyopathy with hearing loss due to m.8363G>A belong to the general spectrum of mitochondrial diseases [56].

2.7. Other Mechanisms and Modifiers

The MERRF phenotype can occur with nuclear variants. Autosomal recessive POLG-related disorders produce myoclonus, epilepsy, ataxia and neuropathy, and Saudubray includes POLG among causes of the phenotype, whereas GeneReviews places it in the differential diagnosis because RRF are usually absent [1, 40]. GeneReviews also refers to a child with MERRF and two mtDNA deletions in the buccal mucosa, suggesting a nuclear disorder with multiple deletions, whose gene was not identified [1]. No nuclear modifiers with clinical value have been identified; the sources consulted attribute variability predominantly to load and tissue distribution.

3. Clinical Spectrum and Manifestations by System

3.1. Two Perspectives on Natural History: Phenotype-Based Series and Genotype-Based Cohorts

MERRF is a multisystem disease in which myoclonus, often the first symptom, is followed by generalised epilepsy, ataxia, weakness, exercise intolerance and dementia; onset ranges from childhood to adulthood after initially normal development [1]. Published frequencies vary according to the inclusion criterion. Older series comprised patients selected for the classical phenotype and, by definition, reported 100% myoclonus and epilepsy; recent cohorts comprise genotype-identified carriers and show a much broader spectrum. GeneReviews summarises three series in the following table [1, 25, 57].

The abstract of Mancuso and colleagues' article reports 42 Italian carriers identified through the national mitochondrial disease network (a retrospective study), rather than 34; GeneReviews does not explain the denominator difference [1, 25]. In the abstract, myoclonus occurs in one in five of the 42 patients; the most frequent manifestations are myopathic signs, generalised seizures, hearing loss, ptosis and multiple lipomatosis, and asymptomatic carriers are present [25]. For the combined group of 321 patients (their own data plus published cases), with a mean age of approximately 35 years, the abstract groups manifestations into ranges: myoclonus, muscle weakness and ataxia in 35–45%; generalised seizures and hearing loss in 25–34.9%; cognitive impairment, multiple lipomatosis, neuropathy and exercise intolerance in 15–24.9%; elevated creatine kinase (CK), ptosis or ophthalmoparesis, optic atrophy, cardiomyopathy, muscle atrophy, respiratory failure, diabetes, myalgia, tremor and migraine in 5–14.9% [25]. The values GeneReviews attributes to the same column (61% myoclonus, 43% epilepsy, 39% hearing loss) do not match the ranges in the abstract; without the full text, the abstract ranges constitute the article's data.

The other cohorts described in the literature are summarised below; none is population-based and all reflect reference centres.

The combined interpretation is that m.8344A>G has a heterogeneous phenotype and many carriers lack the complete syndrome; Finsterer's review (2025) cites a mean age at onset of 45 years, a figure that does not match the cohorts (24.5 years in the German cohort; mean age approximately 35 years at assessment of the 321 patients) and is not used as a reference [9, 25, 26].

3.2. Central Nervous System

Myoclonus and epilepsy. Generalised myoclonic seizures are the most frequent type; focal myoclonic, focal atonic, focal clonic, generalised tonic–clonic, generalised atonic and myoclonic–atonic seizures, typical absences, myoclonic absences and tonic–clonic seizures of unknown onset have also been described [1, 10]. Myoclonus may be almost continuous, stimulus-sensitive and dominate the presentation [17]. MERRF epilepsy is classified as progressive myoclonus epilepsy (PME) with multisystem involvement [26]. In a study of adults with confirmed mitochondrial disease cited by Baysal and colleagues, 92.3% of m.8344A>G carriers had seizures and all had myoclonus; in the Italian registry, status epilepticus occurred in 2 of 24 patients (8%) [64]. The Mitochondrial Medicine Society (MMS) reports seizures in 35–60% of children and adolescents with confirmed mitochondrial disease and approximately 23% of adults, with the highest prevalences in the m.3243A>G and m.8344A>G genotypes [65]. Status epilepticus, rare but possible, may be convulsive, myoclonic or non-convulsive, and focal status alternating between hemispheres has been described as an atypical presentation [26, 64, 66].

Ataxia. Ataxia affects the trunk and limbs, with scanning speech; spastic paraparesis, hyperreflexia and a Babinski sign may coexist [17]. In adults, myoclonus is more closely associated with ataxia than with generalised seizures [25]. In the French series, sensory ganglionopathy contributed to ataxia in five patients [61].

Cognition, psychiatry and migraine. Dementia is slowly progressive in the classical presentation [17]. In the Newcastle study, patients with m.3243A>G or m.8344A>G had mild to moderate premorbid impairment and current deficits in verbal comprehension, perceptual reasoning, working memory, processing speed and recall; memory was intact after adjustment for premorbid ability, and decline was slow, with no expected short-term change [62]. Psychiatric disorders were recorded in 54% of the German cohort; GeneReviews refers predominantly to depressive disorder [1, 9]. Migraine is frequent (52% in the German cohort) and may be present from onset; Vollono and colleagues described seven patients with migraine with or without aura, most with one episode every two months [1, 9, 67].

Neuroimaging and neuropathology. MRI frequently shows cerebral atrophy and basal ganglia lesions; bilateral putaminal necrosis (in a childhood case) and brainstem and cerebellar atrophy have been described [1, 68, 69]. Stroke-like episodes are occasional and, when present, suggest overlap with MELAS [26].

3.3. Skeletal Muscle and Respiratory Function

Myopathy manifests as exercise intolerance, muscle weakness and elevated CK [1]. Muscle atrophy and proximal weakness are usual in advanced forms, and the Swedish boy illustrated in the Atlas had a stooped posture due to weakness at age 12 years [17]. Restrictive respiratory failure is a prognostic determinant: approximately half the patients in the Rome cohort required ventilation [58]. Blakely and colleagues described a middle-aged woman with distal weakness since childhood, ptosis, facial weakness and respiratory failure requiring nocturnal non-invasive ventilation, with more than 90% COX-deficient fibres, a presentation mimicking limb-girdle or distal muscular dystrophy [5]. In the four-generation Italian family described by Ripolone and colleagues, the variant manifested without central nervous system involvement: the 53-year-old proband had incidentally discovered hyperCKaemia, diabetes and a few lipomas, with many RRF and COX-negative fibres on biopsy; his mother had died aged 77 years with diabetes and lipomas, and two sisters aged 60 and 50 years were carriers without neurological symptoms [70].

3.4. Hearing and Vision

Sensorineural hearing loss occurs in 35–91% of patients depending on the series [1]. Optic atrophy is frequent in the classical series (39%); pigmentary retinopathy, ptosis, ophthalmoparesis and nystagmus occur in a minority [1, 40]. Visual evoked potentials may be reduced, and abnormal mitochondria and endomysial fibrosis have been described in the extraocular muscles [17].

3.5. Heart

Cardiac manifestations include hypertrophic and dilated cardiomyopathy and arrhythmias, with or without cardiomyopathy; the electrocardiogram (ECG) frequently shows ventricular pre-excitation, and conduction block has not been described in MERRF [1]. In the Paris series of 18 patients, 8 (44.4%) had cardiac abnormalities at diagnosis: dilated cardiomyopathy in 4, Wolff–Parkinson–White (WPW) syndrome in 3, incomplete left bundle branch block in 1 and ventricular ectopics in 1; during follow-up, another 2 developed left ventricular dysfunction and 2 died of heart failure, and early disease onset was the only factor associated with myocardial dysfunction [59]. In the Rome cohort, 53% had cardiac abnormalities, one patient had rapidly progressive cardiomyopathy and received an implantable cardioverter-defibrillator (ICD), and cardiac MRI showed non-ischaemic inferolateral left ventricular late enhancement as an early sign [58]. Clinical Cardiogenetics estimates cardiac involvement in 40% of patients with MERRF [71]. Vallance and colleagues described a sporadic infant with failure to thrive and sudden death at 11 months, with histiocytoid cardiomyopathy, diffuse hepatic steatosis and bilateral retinal hypoplasia at autopsy, and m.8344A>G in the liver and heart [54].

3.6. Multiple Symmetric Lipomatosis and Ekbom Syndrome

Lipomatosis is the most characteristic extraneurological manifestation of m.8344A>G. It develops in adulthood, with a mean onset at 45.2 years in the series by Chong and colleagues, predominantly in the cervical region, and lipomas may be infiltrative, progressive and bulky [1, 72, 73]. In the Italian network, 22 of 1300 patients with mitochondrial disease (1.7%) had lipomas; in 18%, multiple symmetric lipomatosis was the sole manifestation and in 54% it coexisted with classical MERRF, myopathy was present in 27%, lactate was elevated in all 12 patients tested, all 18 muscle biopsies showed mitochondrial abnormalities, and 86% of patients had a tRNA-Lys variant; distribution was cervicocraniothoracic in most and symmetric in 68% [74]. In the Canadian family of northern European ancestry described by Perera and colleagues, eight affected individuals had multiple symmetric lipomatosis and m.8344A>G, with complete cosegregation and without epilepsy, ataxia or myopathy [32]. Mitochondrial lipomatosis differs from the classical form of Madelung disease, typical of middle-aged men with chronic alcohol consumption, through absence of alcohol use and a maternal-line family history [32, 48]. Ekbom syndrome (photomyoclonus, cerebellar ataxia, skeletal deformities and cervical lipoma) was associated with m.8344A>G in 1995 [53].

3.7. Endocrine System, Gastrointestinal Tract and Other Organs

Short stature is frequent (57% in the classical series); diabetes occurs in 3–12% depending on the series [1]. Síndromes Genéticas: Reconhecer para Tratar lists possible endocrine manifestations in mitochondrial diseases (diabetes, adrenal insufficiency, hypoparathyroidism, thyroid dysfunction, ovarian or testicular insufficiency) and gastrointestinal manifestations (gastric and oesophageal dysmotility, anorexia, weight loss) [75]. In the German cohort, 38% had gastrointestinal symptoms and 35% dysphagia [9]. A 2026 systematic review of pancreatitis in mitochondrial disease brought together 24 individuals from 20 reports, predominantly with deletions and m.3243A>G, with 25% dying shortly after admission; it does not distinguish cases with m.8344A>G [76].

3.8. Age-Related Course and Treated Natural History

Most carriers are normal in childhood, and severity increases with age as declining oxidative capacity crosses each organ's threshold [17]. Saudubray describes usual onset in childhood or adolescence and GeneReviews from childhood to adulthood; adult onset predominates in genotype-based cohorts [1, 9, 40]. In a Finnish study of 52 patients with mitochondrial disease followed for a mean of nine years, functional capacity, measured using the modified Rankin scale and Karnofsky scale, declined in all genetic groups [77]. The sources consulted do not allow natural history to be separated from treated disease because no intervention alters progression and the series describe patients receiving symptomatic treatment.

4. Clinical Recognition and Warning Signs

4.1. When to Suspect the Disease

In an older child, adolescent or young adult, the combination of myoclonus, generalised seizures and ataxia after normal development should prompt consideration of PME, and MERRF is one of the non-recessive causes to exclude, alongside dentatorubral-pallidoluysian atrophy (DRPLA) [78, 79]. The probability increases with additional sensorineural hearing loss, short stature, ptosis, optic atrophy, neuropathy, exercise intolerance, cervical lipomas, ECG pre-excitation or a maternal-line family history, present in 81% of the classical series [1]. In an ataxic adult, ataxia with other organ involvement (hearing loss, diabetes) suggests MERRF or NARP (neuropathy, ataxia and retinitis pigmentosa) [80]. A historical diagnosis of “Ramsay Hunt syndrome” warrants investigation [1].

In adult epilepsy, Mochel and Sedel propose the following signs of inherited metabolic disease: atypical epilepsy with a mixture of generalised and partial seizures, PME, associated neurological deficits (cerebellar or pyramidal) or other organ involvement, meal- or fasting-related seizures, inefficacy or worsening with conventional antiseizure drugs, unexplained status epilepticus, increased lactate on MR spectroscopy, and EEG slowing with a photoparoxysmal response at 1–6 Hz [81]. Myoclonic epilepsy suggests lysosomal disease or respiratory chain disease such as MERRF [81]. In a child with seizures and developmental delay, lactic acidosis is a clue to mitochondrial disease [78].

Three frequent settings for diagnostic delay merit attention. The patient described by Baysal and colleagues was diagnosed with juvenile myoclonic epilepsy (JME) at age 16 years, and the genetic diagnosis was not made until age 26 years, when fatigue, weakness, ataxia and dysarthria appeared [64]. Multiple symmetric lipomatosis without alcohol consumption, particularly with maternal relatives sharing the same body habitus, should prompt testing for m.8344A>G [32, 48]. Indolent myopathy resembling limb-girdle or distal dystrophy, with negative testing of common genes, warrants biopsy and muscle mtDNA investigation [5]. Sensory ganglionopathy associated with myopathy, lipomatosis or epilepsy is another clue [61].

4.2. Warning Signs and Emergencies

Emergencies include status epilepticus (convulsive, myoclonic or non-convulsive), severe lactic acidosis, respiratory failure (due to myopathy or during seizures and sedation), heart failure and pre-excitation-associated tachyarrhythmias [26, 58, 59, 65]. In the Rome cohort, intractable lactic acidosis caused 5 deaths among 15 patients, and restrictive respiratory failure was the other critical prognostic factor [58]. Deterioration after introduction of an antiseizure drug (worsening myoclonus with lamotrigine, carbamazepine, phenytoin or gabapentin, or hepatic toxicity with valproate in a patient with undiagnosed POLG disease) is a warning sign relevant to this disease [15, 26].

4.3. Newborn Screening

There is no newborn screening for MERRF or mtDNA variants.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical Criteria

Classical clinical criteria require the four canonical features: myoclonus, generalised epilepsy, ataxia and RRF on muscle biopsy [1, 30, 75]. A molecular diagnosis is established in a patient with suggestive findings and a pathogenic or likely pathogenic variant in one of the associated genes; a VUS neither confirms nor excludes the diagnosis [1].

Absence of RRF does not exclude the disease; Mancuso and colleagues described MERRF without RRF and emphasised the need for molecular diagnosis [82].

5.2. Biochemistry

Lactate is elevated in blood and cerebrospinal fluid (CSF), often more in CSF than blood, and lactate and pyruvate rise excessively after moderate activity; normal lactate does not exclude the diagnosis, and recent seizures also elevate it [1, 17]. For mitochondrial disease in general, GeneReviews considers fasting blood lactate above 3 mmol/L and CSF lactate above 1.5 mmol/L supportive [3]. CSF protein may be elevated, rarely above 100 mg/dL [1]. Sampling requires care: crying and seizures elevate lactate, and pyruvate requires immediate deproteinisation with perchloric acid and cooling to avoid falsely low values [40]. First-line assessment includes full blood count, pH, bicarbonate, lactate, ketone bodies, plasma acylcarnitines and urinary organic acids (lactate, pyruvate and Krebs cycle intermediates) [3, 40]. Fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) correlate with mitochondrial dysfunction in myopathic patients [40]; a 2026 Food and Drug Administration (FDA) review emphasises the lack of robust treatment-response biomarkers in primary mitochondrial diseases [83].

5.3. Histology and Respiratory Chain

On muscle biopsy, modified Gomori trichrome staining shows RRF; SDH staining shows hyperreactive fibres, and RRF and some non-RRF fibres are COX-negative; sequential COX/SDH staining reveals “ragged-blue” fibres (COX-negative and SDH-positive) [1, 40]. Strongly SDH-reactive vessels with COX deficiency are another finding [30]. Respiratory chain investigation in muscle extracts shows reduced activity of complexes with mtDNA-encoded subunits, particularly COX, although activity may be normal [1].

5.4. Neurophysiology and Imaging

EEG shows generalised spike–wave discharges with background slowing, and focal epileptiform discharges may occur [1]; in a Swedish series, the Atlas describes bilateral bursts of high-voltage delta waves initially and synchronous bursts of slow spike–wave activity later [17]. Electromyography shows a myopathic pattern, and nerve conduction studies may show sensory or sensorimotor axonal neuropathy [1]. In neuroimaging, MMS considers the non-specific white matter lesions described in MERRF insufficiently sensitive to serve as a criterion [84]. Muscle MRI has a consistent pattern, cardiac MRI may show inferolateral late enhancement, and spectroscopy shows increased choline, reduced N-acetylaspartate and ventricular lactate [58]. In a Spanish study of 49 adults with primary mitochondrial myopathy, MRI-quantified muscle fat fraction correlated with strength (r=−0.567), the North Star Ambulatory Assessment (r=−0.731), the 100 m test (r=0.629), the 6-minute walk test (r=−0.311) and creatinine (r=−0.715), but not CK or GDF-15; the study is cross-sectional and does not distinguish patients with m.8344A>G [85].

5.5. Molecular Testing: Sample Selection and Algorithm

The 2023 British best practice guidelines recommend, for suspected mitochondrial myoclonic epilepsy (myoclonus, seizures, cerebellar ataxia, myopathy), targeted testing for m.8344A>G and m.3243A>G in any available sample, preferably muscle, followed by urine and finally blood; a normal blood result from age 18 years does not exclude presence in another tissue, and second-line testing is whole mtDNA sequencing after clinical examination or biopsy and, if appropriate, nuclear DNA analysis [11]. GeneReviews proposes two pathways: in a typical presentation, targeted m.8344A>G testing in leucocytes and, if negative, repeat testing in buccal mucosa, muscle or urinary sediment, or mitochondrial genome sequencing, which includes differential diagnosis genes and limits VUS unrelated to the presentation; in a presentation indistinguishable from other diseases with seizures and weakness, exome or genome sequencing, explicitly requesting inclusion of the mitochondrial genome because many laboratories analyse it only on request [1].

5.6. Test Limitations

A negative blood result does not exclude the disease. Heteroplasmy may make the variant undetectable in leucocytes and detectable only in buccal mucosa, cultured fibroblasts, hair follicles, urinary sediment or, most reliably, skeletal muscle [1, 17]. Sequencing detects point variants and small insertions and deletions but usually does not detect partial, whole-gene or multigene deletions or duplications [1]. In genomic tests, false-negative rates vary by region, positive results are generally confirmed by a second method, and large deletions and duplications (above 8–10 base pairs), triplet expansions and epigenetic changes may escape detection [3]. mtDNA rearrangements and depletion require dedicated methods (long-range, real-time or digital polymerase chain reaction) and relevant tissue, generally muscle [40]. Fibroblasts do not always show the biochemical phenotype [71]. The proportion of variants detectable by a method is not equivalent to clinical sensitivity: sequencing detects all MT-TK point variants, but targeted m.8344A>G testing does not identify patients with another MT-TK variant, a variant in another mtDNA gene or a nuclear cause, together accounting for approximately 20% of cases [1].

5.7. Report Content and Interpretation

The report should state the gene, reference sequence (NC_012920.1), the m. description of the variant, quantified mutant load and tissue analysed, method and its detection limit, and classification according to the ACMG/AMP specifications for mtDNA [1, 33]. Load in one tissue does not predict phenotype or progression, and absence of the variant in blood does not guarantee absence from other tissues [1]. For a VUS (for example, m.8361G>A or m.8296A>G), maternal-line segregation, correlation between load and phenotype in several tissues, and single-fibre studies may contribute to reclassification but do not permit use of the variant for predictive testing before reclassification [4, 33]. Prenatal diagnosis and preimplantation genetic testing are addressed in section 8.3.

6. Differential Diagnosis

The differential diagnosis includes other mitochondrial diseases, hereditary ataxias and nuclear PMEs; multisystem involvement, lactic acidosis, maternal inheritance and RRF distinguish MERRF [1, 26]. Multiple lipomas prompt consideration of other causes of lipomatosis [1]. In the table, AR denotes autosomal recessive and AD autosomal dominant inheritance.

The distinction with the greatest practical consequences is between mitochondrial MERRF and the similar phenotype caused by POLG: both present with myoclonus, epilepsy, ataxia and neuropathy, but POLG disease is autosomal recessive, usually lacks RRF and absolutely contraindicates valproate because of the risk of liver failure [1, 12, 15]. For this reason, POLG investigation should precede any decision to use valproate in a patient with mitochondrial epilepsy without a molecular diagnosis. The second relevant distinction is from nuclear PMEs, particularly Unverricht–Lundborg and Lafora diseases, which lack myopathy, hearing loss, lipomatosis and maternal inheritance [26]. JME is a frequent initial diagnosis in patients with adolescent onset; subsequent development of weakness, ataxia, hearing loss or dysarthria should prompt reconsideration of the diagnosis [64]. Overlap with MELAS is recognised only when stroke-like episodes develop, which may be mistaken for paradoxical embolism, as in a 2026 report in which a patent foramen ovale initially diverted the investigation [86].

In Table 2.8 of chapter 2 of Saudubray and in Table 10.2, MERRF is listed among respiratory chain diseases causing PME, together with MELAS, NARP and POLG, while Niemann–Pick type C, Gaucher type 3, lipofuscinoses, sialidosis, SCARB2 disease and Lafora disease complete the metabolic group [40, 81]. Table 1 of the primary mitochondrial diseases GeneReviews distinguishes MERRF (myoclonus, seizures, cerebellar ataxia, myopathy; dementia, optic atrophy, hearing loss, neuropathy, spasticity and lipomas as additional findings) from MELAS, Kearns–Sayre syndrome, NARP, Leigh syndrome, Pearson syndrome, Leber hereditary optic neuropathy and chronic progressive external ophthalmoplegia [3].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no treatment that alters the course of MERRF or disease-specific guideline; reviews dedicated to MERRF epilepsy note the absence of specific pharmacological trials and guidelines [3, 10, 26]. Management relies on symptomatic treatment of myoclonus and seizures, prevention and treatment of cardiac, respiratory, auditory and endocrine complications, rehabilitation, and avoidance of drugs and circumstances that impair mitochondrial function, within a multidisciplinary team and ideally at a centre experienced in metabolic and cardiac disease [1, 65, 71]. Applicable general guidelines are the National Institute for Health and Care Excellence (NICE) NG217 guideline for epilepsies, endorsed for primary mitochondrial diseases by the InterERNs Mitochondrial Working Group, the 2020 drug safety Delphi consensus, and the 2015 and 2017 MMS consensus statements [12, 14, 15, 65, 84].

7.2. Myoclonus and Seizures: Recommendations and Divergences

GeneReviews recommends levetiracetam or clonazepam for myoclonus, conventional antiseizure drugs for seizures as directed by the neurologist, and avoidance of valproic acid [1, 82, 88]. Saudubray considers levetiracetam and clobazam the most effective drugs in mitochondrial epilepsy and recommends avoiding sodium valproate, particularly with POLG [40, 89]. The 2024 InterERN consensus (EpiCare, ERN EYE, ERN-RND, EURO-NMD and MetabERN) endorses NICE NG217 for adults and children with primary mitochondrial disease (“Strong” recommendation) and states that, from the perspective of mitochondrial toxicity, levetiracetam, perampanel, brivaracetam, lacosamide, lamotrigine, cannabidiol, cenobamate, gabapentin, pregabalin, vigabatrin, carbamazepine, benzodiazepines (including midazolam), phenytoin and oxcarbazepine in adults, topiramate (with caution if there is a risk of renal tubular acidosis or stone disease), the ketogenic diet and vagus nerve stimulation (VNS) are not contraindicated, and by consensus neither are zonisamide, ethosuximide and pregabalin in patients with myoclonus [12]. NICE NG217 (published April 2022 and updated 5 August 2026) offers levetiracetam or sodium valproate first line for myoclonic seizures, switching to the other as monotherapy or in combination if the first fails; second-line options are brivaracetam, clobazam, clonazepam, lamotrigine, phenobarbital, piracetam, topiramate or zonisamide; it warns that lamotrigine may worsen myoclonic seizures; and it directs that carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin should not be used because they may worsen myoclonic and absence seizures [14]. For children under 4 years with myoclonic seizures, NICE recommends advice from or referral to tertiary paediatric neurology [14].

Table sources: [10, 12, 14, 15, 26].

The divergence arises from two different questions. InterERN and the Delphi consensus assess mitochondrial toxicity in vivo and declare drugs such as carbamazepine, phenytoin, oxcarbazepine, gabapentin, pregabalin and vigabatrin “not contraindicated”; NICE, endorsed by InterERN itself, prohibits them in myoclonic seizures because they worsen seizures regardless of cause [12, 14]. Finsterer, from an expert perspective without a formal guideline, advises against valproate, carbamazepine, phenytoin and barbiturates because of mitochondrial toxicity demonstrated in preclinical studies, and lists carbamazepine, phenytoin, oxcarbazepine, tiagabine, vigabatrin, pregabalin and sometimes lamotrigine and gabapentin as aggravating myoclonus [26]. In practice, the two interpretations converge: in MERRF, drugs that worsen myoclonus should be avoided because of their effect on myoclonus, and levetiracetam, benzodiazepines, topiramate, zonisamide and piracetam are lower-risk options.

7.3. Valproate: Positions of the Sources

Síndromes Genéticas: Reconhecer para Tratar presents valproate as a first-line drug for generalised seizures and myoclonic abnormalities, to be used cautiously and with L-carnitine [75]. GeneReviews and Saudubray recommend avoiding it [1, 40]. The 2020 Delphi consensus restricts the absolute contraindication to POLG disease and known liver disease or signs suggestive of POLG (epilepsia partialis continua, explosive-onset focal epilepsy, high-amplitude rhythmic delta activity with spikes on EEG), allowing use in exceptional circumstances in other patients for refractory epilepsy or mood disorder [15]. The 2024 InterERN consensus adopts the same position: contraindicated in POLG and any mitochondrial liver disease gene, usable by consensus in patients without POLG or liver disease who have refractory epilepsy [12]. NICE offers it first line for myoclonic seizures in the general population, but subject to Medicines and Healthcare products Regulatory Agency (MHRA) measures: do not initiate sodium valproate in individuals of either sex under 55 years unless two specialists independently agree and document that no effective, tolerated alternative exists or that reproductive risks do not apply [14]. In clinical series, Su and colleagues recorded seizure progression in both patients treated with valproate monotherapy, and Chandra and colleagues reported visual, auditory and academic deterioration during valproate and zonisamide treatment that improved after switching to levetiracetam, although causality cannot be established from an isolated report [63, 90]. Conversely, Finsterer reports a 16-year-old boy with MERRF/Leigh overlap controlled with valproate without serious effects [26]. In MERRF, valproate is not a first-choice treatment; its use is admissible only after exclusion of POLG and liver disease, in refractory epilepsy and within current reproductive restrictions.

7.4. Drug and Supplement Dosing

Antiseizure drug doses come from labels approved for epilepsy in general; use in MERRF is outside the specific indication, although a myoclonic seizure indication exists for levetiracetam (adjunctive in JME) and clonazepam [91–93].

In the series by Su and colleagues, monotherapy doses were 6–12 mg/day for clonazepam, 1000–2000 mg/day for levetiracetam, 100–500 mg/day for topiramate and 16–60 mg/kg/day for valproate; these are observed doses, not recommendations [63]. The Atlas cites historical coenzyme Q doses of 4 mg/kg/day and riboflavin doses of 100 mg/day, without supporting trials [17]. MMS recommends offering coenzyme Q10 to most patients (ubiquinol is more bioavailable and requires dose adjustment), offering alpha-lipoic acid and riboflavin, considering folinic acid when central nervous system manifestations are present, and using L-carnitine only for documented deficiency, introducing supplements one at a time; doses are in online appendices that were not consulted [84]. No zonisamide medicine was returned by the openFDA search, and the piracetam label was not consulted; doses for these drugs are not included in the sources read.

7.5. Evidence on Antiseizure Drugs in MERRF

The only comparative therapeutic series specific to m.8344A>G is retrospective. At Qilu Hospital (China), 17 patients treated between 2003 and 2016 received monotherapy (clonazepam, valproate, levetiracetam or topiramate) for 82.9 ± 28.1 days: partial response in 4 (2 with clonazepam, 2 with levetiracetam), stable disease in 10 and progression in 3 (2 with valproate, 1 with topiramate); the 12 patients with an insufficient response switched to levetiracetam with clonazepam, with a positive effect and good tolerance in all 12 and improved cognition and coordination in 8, over 66.3 ± 45.3 months of follow-up (χ²=13.7; p<0.001 for the comparison between monotherapy and combination therapy) [63]. The study was neither randomised nor blinded, and the comparison is between sequential phases in the same patients. In an exploratory study of nine patients with PME of various causes, levetiracetam reduced myoclonus [88]. Finsterer considers levetiracetam combined with clonazepam, or topiramate, zonisamide or piracetam monotherapy, first line on the basis of expert opinion; describes a 71-year-old woman with m.8344A>G in whom piracetam was effective after failure of oxcarbazepine, levetiracetam and lamotrigine; and considers perampanel and rufinamide potentially effective based on non-mitochondrial myoclonus data [26, 29].

7.6. Status Epilepticus and Refractory Epilepsy

InterERN recommends treating generalised convulsive status epilepticus according to local protocols (NICE, Scottish Intercollegiate Guidelines Network, European Federation of Neurological Societies), with escalation to intensive care, except for sodium valproate in POLG disease; propofol is not contraindicated, but prolonged use in refractory status epilepticus requires monitoring, and ketamine, barbiturates and inhalational anaesthetics (desflurane, isoflurane, sevoflurane) are not contraindicated [12]. Doses in the InterERN status epilepticus algorithm (figure 4) were not read and are not reproduced. Finsterer proposes an intravenous benzodiazepine (lorazepam or midazolam) combined with levetiracetam; if ineffective, phenytoin, fosphenytoin or valproic acid (the latter contraindicated with POLG); in refractory status epilepticus, continuous infusion of midazolam, pentobarbital, thiopental or propofol, and advises against intravenous propofol in children because of the risk of propofol infusion syndrome, a more restrictive position than InterERN, which does not contraindicate it and requires only monitoring during prolonged use [12, 26].

In drug-resistant epilepsy, described options are the ketogenic diet (not contraindicated, “Strong” recommendation), the modified Atkins diet, cannabidiol, VNS and, without evidence in MERRF, glucocorticoids, N-acetylcysteine, surgery and deep brain stimulation [12, 26]. VNS terminated status epilepticus in a 16-year-old boy and a 38-year-old woman with super-refractory status epilepticus (section 10.1) [26, 64]. In a 2019 systematic review cited by Baysal and colleagues, acute VNS terminated status epilepticus in 28 of 38 patients with various causes (74%), with no response in 7, and 4 patients (11%) died from the underlying disease [64].

7.7. Supplements and Cofactors

GeneReviews reports benefit in some individuals with coenzyme Q10 and L-carnitine and lists ubiquinol, carnitine, alpha-lipoic acid, vitamin E, vitamin B complex and creatine as options that may benefit some patients [1]. In a small randomised, double-blind, placebo-controlled trial in heterogeneous mitochondrial diseases, the combination of creatine, coenzyme Q10 and lipoic acid reduced progression of ankle weakness and resting plasma lactate, with modest benefits [94]. The Cochrane review and Saudubray consider that there is no evidence to support or refute vitamin and cofactor use [40, 95]. Dichloroacetate lowers lactate but produced no clinical improvement in MERRF [17]. Patients with MERRF are not among the cofactor-treatable exceptions (coenzyme Q10 biosynthesis or ACAD9 deficiencies) [40].

7.8. Heart

Cardiomyopathy is treated with standard therapy (diuretics, angiotensin-converting enzyme inhibitors, beta blockers) according to European Society of Cardiology guidelines [1, 71]. Clinical Cardiogenetics reports, based on in vitro rat muscle data, greater mitochondrial inhibition with propranolol (highly lipophilic) than with atenolol, which it proposes as a first-line option, and lists carvedilol, metoprolol, propranolol, amiodarone and statins as drugs to use cautiously [71]. Ablation should be considered for supraventricular tachycardias, WPW syndrome and other treatable arrhythmias; the threshold for a pacemaker is low; an ICD is indicated when there is a risk of sudden death, left ventricular wall thickness above 30 mm, or sustained or non-sustained ventricular tachycardia; the European hypertrophic cardiomyopathy sudden death risk calculator is not validated in individuals under 16 years or metabolic forms; and cardiac transplantation is considered in end-stage failure, taking comorbidities and natural history into account [65, 71]. Exercise testing should be monitored, weighing the risk of decompensation [71].

7.9. Respiratory Function, Muscle and Rehabilitation

Restrictive respiratory failure may require non-invasive ventilation, necessary in approximately half the Rome cohort and in the patient described by Blakely and colleagues [5, 58]. Motor impairment is treated with physiotherapy and aerobic exercise, based on evidence of training in patients with mtDNA defects [1, 96]. Physiotherapy, occupational therapy and speech and language therapy form part of the plan for patients with ataxia, dysarthria and dysphagia [1, 64].

7.10. Hearing, Vision, Endocrine System and Lipomas

Hearing loss is treated with hearing aids or cochlear implantation [1, 40]. Ptosis may be corrected surgically [40]. Diabetes follows standard treatment, but metformin may worsen lactic acidosis [1, 87]. Hormone deficiencies (growth hormone, thyroxine, insulin, hydrocortisone) are treated by replacement [40]. For lipomas, liposuction or excision may improve mobility and appearance, but recurrence is usual: in the man described by Kalaria and colleagues, the nuchal lipoma recurred after excision and bariatric surgery was abandoned because of extensive abdominal lipomatosis; in Chandra's family, the maternal aunt had recurrence after excision [44, 48, 90].

7.11. Agents and Circumstances to Avoid

GeneReviews recommends avoiding mitochondrial toxins (aminoglycosides, linezolid, tobacco and alcohol) and valproic acid [1]. The Oxford Desk Reference lists sodium valproate (caution), anaesthetic barbiturates, gentamicin (hearing loss), ciprofloxacin, chloramphenicol, tetracyclines, metformin and zidovudine for mitochondrial diseases [87]. Clinical Cardiogenetics adds topiramate, vigabatrin and lipophilic beta blockers [71]. The 2020 Delphi consensus concludes that, for most drugs, evidence is insufficient to prohibit them in primary mitochondrial diseases and decisions should be individualised, with clinical and lactate monitoring during the first days; InterERN endorses this rule [12, 15].

7.12. Anaesthesia and Perioperative Care

General recommendations are to minimise preoperative fasting, infuse glucose to maintain normoglycaemia, and use some inhalational anaesthetics, muscle relaxants and propofol cautiously [71]. InterERN declares propofol, ketamine, barbiturates and inhalational anaesthetics not contraindicated [12]. In a 2026 report, a 44-year-old woman with MERRF undergoing unilateral salpingo-oophorectomy received induction with low-dose midazolam, remifentanil and rocuronium and maintenance with desflurane and remifentanil, with normothermia, avoidance of lactate-containing solutions and close haemodynamic and respiratory monitoring, without complications [97].

7.13. Pregnancy, Lactation and Transition

In affected or at-risk women, pregnancy requires surveillance for diabetes and respiratory failure [1]. A systematic review of mitochondrial disease in pregnancy described increased risks of deterioration, preterm delivery, pre-eclampsia and magnesium sulphate toxicity [71, 98]. GeneReviews reports a high incidence of second- and third-trimester pregnancy loss in mitochondrial diseases generally [3]. NICE requires that valproate be used in women of childbearing potential only subject to MHRA measures and that topiramate not be used in these women outside the Pregnancy Prevention Programme; it describes a possible association between paternal valproate use near conception and neurodevelopmental disorders in offspring, and recommends referring men taking valproate who plan to have children within the following year for a treatment review [14]. In the patient reported by Baysal and colleagues, valproate discontinuation for pregnancy planning was followed by a tonic–clonic seizure [64]. The sources consulted do not address lactation or transition from paediatric to adult medicine specifically in MERRF; the general recommendations for mitochondrial diseases apply.

7.14. Regulatory Status

No medicine is authorised in the USA or EU for MERRF; of the four therapies authorised for primary mitochondrial diseases by 2026 (idebenone in Leber hereditary optic neuropathy, taurine in MELAS in Japan, doxecitine with doxribtimine, Kygevvi®, in thymidine kinase 2 (TK2) deficiency, and elamipretide, Forzinity®, in Barth syndrome), none is intended for MERRF [13]. Searches for orphan medicinal product designations for MERRF at the FDA and European Medicines Agency (EMA) found no results, but the official databases could not be consulted directly, preventing a conclusion that none exist.

7.15. Clinical Trials

MIT-E is the only randomised trial to have included patients with MERRF, and it was negative: the −8.31 percentage-point difference in median seizure change has a confidence interval including zero, and hospitalisation days had a median of zero in both arms [99]. The trial does not report results by genotype, so neither excludes nor demonstrates an effect in MERRF. The series by Su and colleagues compares sequential phases in the same patients without a control group and cannot estimate a causal effect [63]. There are no direct comparisons between antiseizure drugs in MERRF, and results from different series should not be compared with one another. Ongoing natural history registries, such as the global mitochondrial disease registry (NCT05554835, planned until 2040) and the NAMDC registry (NCT01694940), aim to provide the endpoints and baseline data needed for future trials [102, 103]. A 2026 review identified 159 primary mitochondrial disease studies on ClinicalTrials.gov between January 2010 and April 2026 (110 interventional), approximately half initiated since 2020, with 50 active or recruiting [13]. TRANSFORM, a trial of transcranial direct current stimulation in mitochondrial refractory focal epilepsy from age 2 years, is recruiting and is not MERRF-specific [102].

7.16. Developments over the Past 12 Months and Preclinical Research

Between October 2025 and October 2026, clinically relevant developments were the NICE NG217 update (5 August 2026), retaining the 2022 recommendations for myoclonic seizures (guideline) [14]; a Finnish observational drug safety study in mitochondrial disease, including 5 patients with m.8344A>G among 44 with mtDNA variants (descriptive cohort) [104]; case reports on anaesthesia, focal status epilepticus alternating between hemispheres, MERRF/MELAS overlap mimicking paradoxical embolism, and isolated lipomatosis [48, 66, 86, 97]; and reviews of biomarkers, clinical development and mtDNA therapeutic strategies [13, 83, 102, 105].

Preclinical research targeting m.8344A>G follows three avenues. The first is mutant load reduction: mitoTALENs (mitochondria-targeted transcription activator-like effector nucleases) reduced load and restored respiratory capacity in hybrid cells with m.8344A>G, with shortened versions for viral packaging, and the review by Chujo and Tomizawa reports a normal load of 60–80% with restoration of oxygen consumption (cellular studies) [39, 106]. Mitochondrial zinc-finger nucleases delivered by an adeno-associated viral vector, cited by GeneReviews, were tested in a mouse model of the alanine tRNA variant m.5024C>T, not a MERRF model [1, 107]. Mitochondrial base editors (DdCBE) have been applied to other tRNA variants but not to m.8344A>G in humans [105]. The second avenue is compensation for the modification defect: MTO1 or TRMT61B overexpression in homoplasmic myoblasts restored mitochondrial translation (cellular study) [39]. The third is modulation of biogenesis and mitophagy: rapamycin for four weeks completely rescued bioenergetics in fibroblasts with intermediate loads and mildly rescued it at high loads, through mTORC1 inhibition and TFEB activation, whereas PGC-1α overexpression and nicotinic acid were ineffective at high loads [108]; in fibroblasts and induced pluripotent stem cell-derived neurons with m.8344A>G, PINK1-mediated mitophagy was more pronounced, and N-acetylcysteine suppressed PINK1 accumulation and removal of damaged mitochondria, leading the authors to propose restoration of mitophagic flux (2026, cellular study) [109]. In cardiomyocytes derived from induced pluripotent stem cells of patients with m.8344A>G, Clinical Cardiogenetics describes reduced mitochondrial respiration, increased reactive oxygen species, overexpression of antioxidant genes, fragmented mitochondria and increased levels of the fission protein Drp1 (cellular study) [110]. A 2025 letter on the microbiome in MERRF is speculative and presents no data [111]. Saudubray and Clinical Cardiogenetics list other experimental approaches in mitochondrial diseases (coenzyme Q10 analogues, bezafibrate, vitamin B3 analogues, elamipretide, epicatechin, RTA 408, arginine and citrulline), none studied specifically in MERRF [40, 71].

8. Reproductive Options and Family Counselling

8.1. Risks to Relatives

MERRF due to mtDNA variants is maternally transmitted. A proband's father is not at risk; the mother is generally a carrier, with or without symptoms, although the variant may be undetectable in her leucocytes and detectable only in buccal mucosa, fibroblasts, hair follicles, urinary sediment or muscle [1]. Apparently isolated cases usually result from an incomplete family history and, rarely, a de novo variant [1]. If the mother is a carrier, all siblings inherit the variant in different proportions, and clinical expression depends on load and its distribution; the mother and the mother's siblings are also at risk [1]. All children of a carrier woman inherit the variant, and the children of a carrier man are not at risk [1, 71]. Síndromes Genéticas: Reconhecer para Tratar states that approximately 80% of cases have a family history consistent with maternal inheritance [75].

8.2. Maternal Load and Risk of Affected Offspring

Offspring risk estimation is based on small, older datasets. In the Swedish and Norwegian study by Larsson and colleagues, four women with 10–33% lymphocyte load had 7 of 14 children without a detectable mutation (detection limit 3 in 1000), whereas five women with 43–73% transmitted the variant to all 12 children; the authors concluded that, above a maternal load of 35–40%, transmission to all children is highly likely [41]. The Oxford Desk Reference presents empirical risks derived from 47 women carrying m.8344A>G: fewer than 5% affected offspring with maternal blood load below 35%, 15% with 40–59%, 20% with 60–79% and 80% with 80–100% [87]. The source article for these figures is Chinnery and colleagues' 1998 paper, which analysed lineages with m.3243A>G or m.8344A>G and found that a higher maternal blood load is associated with a higher frequency of affected children and that, at the same load, the affected frequency is higher with m.3243A>G than with m.8344A>G; the authors caution that the results should not be used as absolute risks [112]. The article's full text was not among the sources consulted, so denominators by stratum could not be confirmed. The mtDNA genetic bottleneck during oogenesis produces large deviations between maternal and offspring loads, varying between variants, and prevents exact risk estimates [40]. GeneReviews adds that women with higher blood loads may be more likely to have affected offspring, but individual phenotypic prediction is impossible [1].

8.3. Prenatal Diagnosis, Preimplantation Genetic Testing and Mitochondrial Donation

Prenatal diagnosis (chorionic villus sampling at 10–12 weeks, amniocentesis at 15–18 weeks) and preimplantation genetic testing (PGT) are technically possible once the family variant has been identified [1, 3]. Their utility is uncertain: load in villi or amniocytes may not correspond to other fetal tissues, may change in utero or after birth through mitotic segregation, and cannot predict phenotype, age at onset, severity or progression [1, 3]. The Oxford Desk Reference, based predominantly on m.8993T>G data, is more favourable: fetal tissues show little variation, and load in the prenatal sample appears to predict that in most tissues at birth; it proposes prenatal diagnosis for low-risk women, in vitro fertilisation with a donated oocyte for moderate or high loads, and nuclear transfer using a donor oocyte [87]. The Atlas considers prenatal diagnosis generally unreliable [17]. The divergence reflects the variant from which the data derive: m.8993T>G has a more uniform and stable tissue distribution than tRNA variants [3].

In the Newcastle programme (United Kingdom), where PGT and pronuclear transfer are offered according to load, four women with m.8344A>G and high load underwent pronuclear transfer without achieving a clinical pregnancy, and two of the 16 women achieving a clinical pregnancy after PGT carried m.8344A>G [113]. Of the 32 mitochondrial donation applications approved by the Human Fertilisation and Embryology Authority (HFEA), four concerned m.8344A>G; the programme recorded eight live births in total, without a breakdown by variant in the passage consulted, and one child developed self-limited myoclonic epilepsy of infancy, which should not be confused with MERRF [114]. The 243rd European Neuromuscular Centre (ENMC) workshop, in 2019, developed guidance on reproductive options in families with maternally inherited mtDNA disease [115]. In vitro fertilisation with a donated oocyte prevents transmission [40].

8.4. Cascade Testing, Predictive Testing and Minors

Cascade screening is confined to the maternal line when the variant is in mtDNA [71]. Once the family variant is known, at-risk relatives can undergo molecular testing; without it, neurological, ophthalmological and audiological assessment, ECG, echocardiography and lactate measurement are recommended [1]. Interpreting a result in an asymptomatic relative is difficult: load in one tissue does not predict phenotype, and absence of the variant in blood does not guarantee absence from other tissues [1]. The Atlas proposes blood testing in asymptomatic individuals and muscle testing in symptomatic individuals [17]. Genetic counselling should be offered before pregnancy to affected or at-risk young adults, and DNA banking is indicated when the molecular diagnosis is unconfirmed [1]. The sources consulted contain no specific recommendations for predictive testing in minors with regard to MERRF; surveillance of at-risk relatives (section 11.3) has clinical value independently of the test result.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence

All available population studies are from northern Europe and measure m.8344A>G variant prevalence in defined populations, rather than clinical syndrome prevalence.

For Finland, GeneReviews cites a 2005 article on mtDNA deletions; the northern Finland m.8344A>G study is that of Remes and colleagues (2003), whose text was inaccessible, and the value of 0–1.5/100,000 is presented as transcribed by GeneReviews [1, 117, 120]. GeneGuidance adopts 0.39/100,000 as the reference value and emphasises that it applies to the recurrent variant and populations of European ancestry [116]. For comparison, in the same north-eastern England population, the minimum prevalence of individuals affected by m.3243A>G was 3.5/100,000, and by m.14709T>C, 0.8/100,000 [8]. Síndromes Genéticas: Reconhecer para Tratar gives 0.9/100,000 in Europe and 1/100,000 worldwide, without an identifiable primary source [75]. Orphanet has no European point prevalence estimate [2]. mtDNA variants explain only 15–30% of oxidative phosphorylation defects in childhood and more than half of adult-onset mitochondrial diseases, consistent with the predominance of adult onset in MERRF [40].

9.2. Portugal, Brazil and Other Populations

In a Portuguese cohort of 450 patients with suspected mitochondrial disease investigated by next-generation sequencing, 38 (9%) had mtDNA point variants or deletions, and m.8344A>G was identified in one patient [121]. In Brazil, the Curitiba series described six patients with MERRF, five with m.8344A>G [60], and the same group's 2014 review discusses diagnostic criteria [30]. Neither study measures prevalence. Other cohorts come from Italy, Germany, France, Denmark, the United Kingdom, the USA, China and Japan (sections 2 and 3); the Canadian family with lipomatosis had northern European ancestry [32]. The sources consulted describe no founder effect or differences in frequency between populations; the variant arose independently in several lineages [20, 21]. Absence of data outside northern Europe reflects a lack of studies and does not demonstrate lower frequency.

9.3. Special Populations

Children under 4 years with myoclonic seizures should be referred to tertiary paediatric neurology [14]. Women of childbearing age require antiseizure medication and pregnancy planning (sections 7.13 and 8). The infant with histiocytoid cardiomyopathy, forms without central nervous system involvement and isolated lipomatosis show that the diagnosis should be considered outside the classical neurological presentation [32, 54, 70].

9.4. Reference Networks and Patient Associations

In the EU, patients with MERRF are followed within the European Reference Networks (ERNs) EURO-NMD (neuromuscular diseases, https://ern-euro-nmd.eu/) and MetabERN (inherited metabolic diseases, https://metab.ern-net.eu/); the 2024 consensus on seizures in mitochondrial diseases was produced by the joint mitochondrial working group of ERN EpiCare, ERN EYE, ERN-RND, EURO-NMD and MetabERN [12]. Patient associations include The Lily Foundation (United Kingdom), United Mitochondrial Disease Foundation (USA), International Mito Patients, Mito Foundation (Australia), MitoAction and Mitochondrial Care Network, and the North American Mitochondrial Disease Consortium maintains a patient contact registry [1]. The German mitoNET network (https://www.mitonet.org/) maintains the registry from which the German cohort derives [9], and MitoCanada (https://www.mitocanada.org/) is the Canadian association. The Children's Mitochondrial Disease Network and ENMC are additional British and European resources [87].

10. Illustrative Clinical Case

10.1. Super-Refractory Status Epilepticus in a Woman with m.8344A>G Treated with Vagus Nerve Stimulation (Baysal et al., 2025)

Baysal and colleagues, from Kiel University Hospital (Germany), described a 38-year-old woman with MERRF due to m.8344A>G [64]. Development had been normal, and a maternal aunt had mild muscle weakness and developmental delay without a diagnosis. At age 14 years she developed progressive myoclonus, predominantly in the lower limbs, and fatigue; at age 16 years she had her first unprovoked bilateral tonic–clonic seizure in a nightclub and received a presumptive diagnosis of JME. Valproate controlled seizures for two and a half years; discontinuation for pregnancy planning was followed by another tonic–clonic seizure, lamotrigine worsened myoclonus, and levetiracetam provided partial relief, with persistent daily myoclonus and absence-like seizures. At age 26 years, progressive fatigue, weakness, ataxia and dysarthria developed; MRI, laboratory tests and lumbar puncture showed no abnormalities, and genetic testing identified m.8344A>G.

Over subsequent years, the patient received polytherapy (levetiracetam, zonisamide, clobazam, topiramate and subsequently perampanel, lacosamide, clonazepam, brivaracetam and lorazepam) and experienced eight episodes of status epilepticus over four years, convulsive, myoclonic and non-convulsive, predominantly after deliberate dose reductions because of adverse effects, with several intensive care admissions under burst-suppression coma (propofol, isoflurane, midazolam, sufentanil). At the admission in question, she was taking clonazepam 2.5 mg/day, lacosamide 300 mg/day, perampanel 6 mg/day, brivaracetam 100 mg/day, coenzyme Q10 100 mg/day, thiamine 100 mg/day and levocarnitine 1000 mg/day. She was admitted for her second convulsive status epilepticus that month, unresponsive to intravenous lorazepam, levetiracetam and lacosamide, midazolam and propofol; she was intubated and maintained in burst suppression with propofol, followed by isoflurane and sufentanil, with vasopressors, and developed aspiration pneumonia. MRI showed global frontal atrophy and T2 hyperintensities in the right middle cerebral artery territory, interpreted as postictal changes. She was extubated on the fifth day, but nine days later returned to intensive care with focal seizures and multifocal myoclonus requiring ten days of burst suppression (isoflurane, midazolam, propofol, sufentanil, ketamine) with levetiracetam, topiramate and clobazam, and reintubation; in accordance with her previously expressed wishes, she refused gastrostomy and tracheostomy. EEG showed moderate encephalopathy with generalised epileptiform potentials predominantly bifrontally and artefacts from periorbital myoclonus.

On day 36, a vagus nerve stimulator (VNS Therapy, Sentiva M1000) was implanted, activated that day and titrated from 0.125 mA to 2 mA over six days (20 Hz, 250 µs, 30 s on; off period reduced from 5 to 1.8 minutes; duty cycle from 10% to 25%). Propofol was withdrawn over one week, the patient was extubated seven days after implantation, myoclonus improved from day seven, and there were no tonic–clonic seizures from day 21, apart from two focal to bilateral seizures during the first three weeks, attributed to dexmedetomidine reduction and infection. Stimulation adverse effects during the first two months were hoarseness, coughing bouts and asymptomatic bradycardia recorded by the stimulator, which improved, with an unremarkable Holter. After two years, she had experienced no tonic–clonic seizures or status epilepticus, myoclonus had decreased but persisted, focal impaired-awareness seizures were very rare, and she used a wheelchair and depended on others for physical care, with physiotherapy, speech and language therapy and occupational therapy. Video-EEG 18 months after the last status epilepticus recorded no seizures or interictal epileptiform activity and showed moderate encephalopathy; neuropsychological assessment revealed verbal, non-verbal and working memory deficits. The authors acknowledge that the data are retrospective and seizure frequency was not quantified. According to the captions, the article's figures show postictal MRI (figure 1), the intensive care treatment timeline (figure 2) and EEG (figure 3); the full text is openly available in PubMed Central (PMC12023898).

The case illustrates diagnostic delay when disease begins with a JME-like presentation, worsening myoclonus with lamotrigine, recurrence associated with valproate discontinuation and dose reductions, and the severity of status epilepticus in MERRF. VNS used as acute treatment for super-refractory status epilepticus is an approach described in reports and a systematic review of cases of various causes, rather than routine treatment; InterERN considers VNS not contraindicated in mitochondrial diseases without specifically recommending it for status epilepticus [12, 64]. Initial valproate use without prior POLG investigation occurred before the molecular diagnosis and does not follow current recommendations for patients with suspected mitochondrial disease (section 7.3).

10.2. Classical MERRF with a Maternal Family History (Chandra et al., 2015)

Chandra and colleagues described a 13-year-old Indian girl born to consanguineous parents and the dizygotic twin of a brother who died in the neonatal period, normal until age 10 years [90]. After a systemic infection, she developed myoclonus three to four times daily, lasting approximately 4 seconds, treated with valproate 500 mg 2×/day and zonisamide 50 mg 2×/day; within one year she developed progressive visual loss to counting fingers at 1 m, progressive hearing loss, academic decline, mild gait instability and throbbing headache. Her mother and maternal aunt had similar disease from age 17 years, both treated with valproate 1200 mg/day, both with large midline cervical lipomas, and the aunt had undergone surgery with recurrence. Examination showed short stature, bilateral primary optic atrophy, sensorineural hearing loss and a slightly unsteady gait. Serum lactate was 53.3 mg/dL (reference 4.5–20), ammonia 52 µmol/L and CK 61 IU; EEG showed spike–wave activity at 2–3 Hz, brainstem auditory evoked potentials were absent and visual evoked potentials had prolonged latencies; MRI was normal except for prominent cerebellar folia; muscle biopsy showed RRF and COX-deficient fibres, and m.8344A>G was identified in blood. The patient and her mother switched to levetiracetam, benzodiazepines and a combination of supplements (coenzyme Q10, levocarnitine, vitamins B1, B6, C, E and K, and lipoic acid); four months later, the patient's vision and cognition had improved and she had no myoclonus. The article's figures (the mother's cervical lipoma, pedigree and muscle histochemistry with RRF, COX-deficient fibres and “ragged-blue” fibres) are described in the captions and available in PubMed Central (PMC4943405). Improvement after valproate discontinuation in an isolated report does not establish causality.

10.3. Natural Course in a Childhood Form (Atlas of Inherited Metabolic Diseases)

The Atlas illustrates a Swedish boy, the proband of one of Larsson and colleagues' families, whose relatives had cervical lipomas: at age 12 years he could still walk, with a stooped posture due to weakness; at age 16 years he depended on a wheelchair and died aged 18 years; at autopsy, the brain tissues studied had 91–99% mutant mtDNA [17, 41, 45].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis is highly variable, even within a family with the same genetic defect [40]. The disease is progressive, worsening as organ oxidative capacity falls below the threshold [17]. Síndromes Genéticas: Reconhecer para Tratar associates myopathy and neuropathy with a poorer prognosis, without numerical data [75]. Documented causes of death in cohorts are intractable lactic acidosis (5 of 15 patients in the Rome cohort), respiratory failure and heart failure (2 of 18 patients in the Paris series, with a mean follow-up of 5 years) [58, 59]. In the Paris series, early disease onset was the only factor associated with myocardial dysfunction [59]. In paediatric-onset mitochondrial diseases generally, cardiomyopathy is associated with higher mortality (71% with cardiomyopathy and 26% without in one series; survival at age 16 years of 16% with cardiomyopathy and 95% without in another), but these data are not MERRF-specific [71]. Cognition declines slowly, and functional capacity decreases over years in all genetic groups of mitochondrial disease [62, 77]. The sources consulted contain no MERRF survival curves or life expectancy estimates.

11.2. Initial Assessment after Diagnosis

GeneReviews recommends height and weight measurement; neurological assessment; baseline brain MRI with spectroscopy; EEG if seizures are suspected; neuropsychological assessment; audiological assessment; ophthalmological assessment (ptosis, optic atrophy, pigmentary retinopathy, ophthalmoplegia); physiotherapy and occupational therapy for neurological impairment; echocardiography and ECG; fasting blood glucose and glucose tolerance testing; genetics consultation; and family support through community resources and social services [1]. For baseline cardiac assessment, MMS adds a 12-lead ECG and echocardiography with ventricular mass and function, and 24-hour Holter monitoring if there are palpitations, paroxysmal events or high risk [65]. Respiratory function (forced vital capacity) should be assessed at diagnosis [58, 59].

11.3. Surveillance

Sources differ regarding cardiac intervals. GeneReviews recommends annual ECG and echocardiography; MMS allows ECG and echocardiography intervals to be extended to every 2–3 years after three stable years but calls for more frequent surveillance in m.8344A>G carriers because of pre-excitation risk; the Paris series proposes neurological and cardiac assessment (ECG, echocardiography and Holter) at least every 2 years [1, 59, 65]. In MERRF, these data together justify maintaining annual ECG, extending only echocardiography intervals when stable, and reserving regular Holter monitoring for at-risk patients. Quarterly surveillance proposed by Finsterer is one author's opinion and is not included in a guideline [26]. Follow-up should be provided by a neurologist or paediatric neurologist and a metabolic physician, with cardiology, and the Oxford Desk Reference recommends periodic ECG and blood glucose measurement [87].

12. Summary and Final Considerations

MERRF is a maternally inherited mitochondrial disease classically defined by myoclonus, generalised epilepsy, ataxia and ragged red fibres, caused in approximately 80% of cases by the m.8344A>G variant in MT-TK and in approximately 10% by other variants in the same gene, with smaller contributions from other mitochondrial tRNA genes and, in similar phenotypes, POLG. The variant impairs lysine tRNA anticodon modification and consequently mitochondrial translation; the clinical effect depends on mutant load in each tissue, which in muscle must exceed approximately 90–95% to produce a biochemical defect, and blood load underestimates muscle load without decreasing with age, unlike m.3243A>G.

Genotype-ascertained cohorts have shown that the complete syndrome is the exception: many carriers have only myopathy, hearing loss, lipomatosis, respiratory failure or cardiac disease, and some are asymptomatic. Onset is generally in young adulthood, myoclonus is more closely associated with ataxia than seizures, and ventricular pre-excitation, cardiomyopathy, restrictive respiratory failure and lactic acidosis determine prognosis. Multiple symmetric lipomatosis without alcohol consumption and with a maternal history, and epilepsy diagnosed as JME subsequently accompanied by weakness, ataxia or hearing loss, are clues that shorten the diagnostic journey.

Diagnosis begins with targeted m.8344A>G and m.3243A>G testing, preferably in urine or muscle, and proceeds with mitochondrial genome sequencing and, if necessary, exome or genome sequencing and muscle biopsy; a negative blood result does not exclude the disease, and m.8361G>A and m.8296A>G, previously accepted as causal, are now variants of uncertain significance. Biopsy is no longer mandatory in the North American consensus definition.

There is no disease-modifying treatment, and the only randomised trial including patients with MERRF, using vatiquinone, was negative. Myoclonus treatment relies on levetiracetam and benzodiazepines, with topiramate, zonisamide, piracetam, perampanel and brivaracetam as alternatives; drugs that worsen myoclonus should be avoided, and valproate, offered first line by NICE in the general population and permitted by consensus in patients without POLG or liver disease, is not a first choice in MERRF and requires prior exclusion of POLG and compliance with reproductive restrictions. Supplements are used empirically, without demonstrated efficacy. Annual cardiac surveillance, auditory, ophthalmological, endocrine, respiratory and cognitive assessment, rehabilitation, and perioperative and pregnancy planning complete management.

Genetic counselling is constrained by heteroplasmy: all children of a carrier woman inherit the variant, but in unpredictable proportions, the relationship between maternal load and risk of affected offspring is based on small datasets, and prenatal diagnosis has limited predictive value. Fertilisation with a donated oocyte, preimplantation genetic testing and mitochondrial donation are options, and initial British results in m.8344A>G carriers show that pronuclear transfer has not yet produced pregnancies in this group. Preclinical research focuses on mutant load reduction using mitochondria-targeted nucleases, compensation for the tRNA modification defect, and modulation of mitophagy, without clinical translation to date.

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