MELAS and the m.3243A>G Spectrum

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, maternally inherited diabetes and deafness, and other phenotypes of the MT-TL1 variant m.3243A>G

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

MELAS syndrome was delineated as a clinical entity by Pavlakis and colleagues in 1984, based on two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and recurrent cerebral insults resembling strokes, compared with nine published cases; their common presentation included ragged-red fibres (RRF) on muscle biopsy, normal early development, short stature, seizures and hemiparesis, hemianopia or cortical blindness, and the authors already distinguished it from Kearns–Sayre syndrome and MERRF, considering maternal transmission [23]. In 1990, Goto, Nonaka and Horai identified an A>G transition at nucleotide pair 3243 of the dihydrouridine loop of mitochondrial leucine (UUR) transfer RNA, present in 26 of 31 patients with MELAS and always heteroplasmic, absent from controls and patients with MERRF; the creation of an ApaI restriction site enabled the first simple molecular test [24]. In 1992, Hirano and colleagues described the complete history and post-mortem examination of one of the earliest cases and, based on 69 published cases, proposed the diagnostic criteria still cited today [12]. In the same year, van den Ouweland and colleagues found the same variant in a large pedigree with type 2 diabetes and sensorineural deafness transmitted through the maternal line, opening the chapter of mitochondrial diabetes [25].

Knowledge accumulated since then has shown that m.3243A>G does not define a single disease, but a continuous spectrum ranging from the asymptomatic carrier to MELAS, through MIDD, PEO, isolated cardiomyopathy and presentations without a syndromic label; in the British Medical Research Council (MRC) cohort, only 10% of symptomatic carriers had classical MELAS [2, 3]. This heterogeneity has led to two recent terminological developments. A 2026 European–American consensus, led by the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) with the Mitochondrial Medicine Society (MMS) and MetabERN, defined MELAS as a clinical syndrome requiring at least one stroke-like episode (SLE) in a context of mitochondrial dysfunction caused by a pathogenic mtDNA variant, discouraged the terms “MELAS-like” and “MELAS spectrum”, and requested that the acronym should not be used as a synonym for the m.3243A>G variant [13]. This article follows that convention: “MELAS” denotes the syndrome; “disease related to m.3243A>G” denotes the entire genotype spectrum.

Historically, the therapeutic approach has undergone distinct phases: enthusiasm for dichloroacetate ended in a randomised trial discontinued because of toxic neuropathy [26]; L-arginine, proposed on the basis of the nitric oxide deficiency hypothesis, was recommended by the MMS in 2016 [18], questioned by a systematic review in 2022 [27] and not recommended routinely in the 2019 and 2026 European consensus statements [13, 20]; taurine obtained authorisation in Japan in 2019 following an open-label phase III trial [28, 29]; and in 2026 controlled trials with sonlicromanol and zagociguat are ongoing, although no medicine is yet approved for MELAS in the United States or European Union [19, 30, 31]. The general principles of primary mitochondrial diseases (classification, nuclear genes, overarching laboratory approach) provide the background; the focus here is on what is specific to MELAS and m.3243A>G.

2. Molecular Genetics and Pathophysiology

2.1. The mitochondrial genome and the MT-TL1 gene

Human mtDNA is a circular double-stranded molecule of 16,569 bp encoding 13 polypeptides of the oxidative phosphorylation (OXPHOS) system, two ribosomal RNAs and 22 transfer RNAs; each somatic cell contains thousands of copies, the mature oocyte approximately 100,000 and the spermatozoon approximately 100 [8, 16]. The MT-TL1 gene encodes the leucine tRNA that decodes the UUA and UUG codons and is required for intramitochondrial synthesis of the 13 respiratory chain subunits; a variant in this gene compromises mitochondrial translation as a whole and therefore produces a combined deficiency of several complexes [1, 3]. Muscle biopsies in patients with MELAS usually show multiple partial deficiencies, particularly of complexes I and IV, but biochemistry may be normal [1]. The mtDNA mutation rate is 10 to 20 times higher than that of nuclear DNA [16].

2.2. Associated variants

Annex 4 of the French PNDS (French National Diagnosis and Care Protocol) reports similar frequencies (m.3243A>G in approximately 80%, m.3271T>C and m.13513G>A in fewer than 10% each, m.3252A>G in fewer than 5%) and adds to the list of rare variants, among others, m.3243A>T and m.3244G>A at the same or the adjacent nucleotide, m.3271delT and m.3258T>C in MT-TL1, m.1644G>A (MT-TV), m.5521G>A and m.5541C>T (MT-TW), m.12207G>A (MT-TS2), m.12146A>G and m.12299A>C (MT-TL2), m.8316T>C and m.8296A>G (MT-TK), variants of MT-ND1 (m.3376G>A, m.3380G>A, m.3481G>A, m.3697G>A, m.3946G>A, m.3949T>C, m.3959G>A) and of MT-ND5 (m.12770A>G, m.13042G>A, m.13084A>T, m.13514A>G, m.13528A>G), m.7023G>A (MT-CO2), m.9957T>C (MT-CO3), the deletion m.14787delTTAA and m.14864T>C (MT-CYB) and m.3093C>G (MT-RNR2); the list gives the first publication of each variant and not its current classification, so each requires confirmation in ClinVar or MITOMAP before being used to confirm a diagnosis [17]. The same document notes that predominant nephropathy or optic neuropathy should suggest a less common variant, such as m.13513G>A or other complex I subunit variants, which produce an overlap phenotype between Leber hereditary optic neuropathy and MELAS [17].

Historical nomenclature writes the variant as “A3243G”, “3243A>G” or “np3243”; the current HGVS (Human Genome Variation Society) form is NC_012920.1:m.3243A>G, on the revised Cambridge reference sequence. Mitochondrial genes do not have a MANE (Matched Annotation from NCBI and EMBL-EBI) transcript; the valid notation is genomic, on NC_012920.1. VariantValidator confirmed that the description is identical in GRCh37 and GRCh38, but that in the UCSC hg19 assembly, whose mitochondrial chromosome is NC_001807.4, the same variant corresponds to m.3244A>G; this discrepancy is a practical source of error when reanalysing older data [7]. The m.3243A>G variant has no direct protein consequence because the gene encodes a tRNA [1].

The book Atlas of Inherited Metabolic Diseases attributes approximately 80% of patients to m.3243A>G and approximately 8.5% to m.3271T>C, and describes other variants of the same tRNA (m.3250T>C, m.3256, m.3260A>G and m.3303C>T, the latter two with hypertrophic cardiomyopathy and myopathy) [33]. The same source also reports that variants in the nuclear POLG gene may produce a MELAS phenotype; GeneReviews adds MRM2 and FASTKD2 [1, 33]. The 2026 consensus restricts the term MELAS to mtDNA causes and treats SLEs of nuclear origin (for example POLG) as SLEs outside MELAS syndrome [13]. Correction note: the diabetes chapter of the Oxford Desk Reference describes the alteration as “3243-bp mitochondrial deletion”; it is a point substitution, as shown by the original publication and ClinVar [6, 24, 34].

2.3. Heteroplasmy, threshold and tissue segregation

Heteroplasmy is the coexistence of mutant and normal mtDNA within the same cell, tissue or individual; the mutant proportion varies between cells, tissues and relatives, and dysfunction only manifests above a threshold specific to each tissue and variant (threshold effect) [8, 35]. For m.3243A>G and MERRF variants, the biochemical threshold typically lies between 80% and 95% mutant load; for tRNA anticodon variants, a dominant-negative effect with pathogenic relevance below 20% has been described [3]. In cybrid studies, lines with more than 95% mutant mtDNA had reduced mitochondrial protein synthesis and respiratory chain deficiency [33].

Mutant load in blood decreases with age through negative selection in haematopoietic cells. The Oxford Desk Reference reports a decrease of approximately 1% per year [8]; the study by Grady and colleagues, with 231 blood samples, 235 urine samples and 77 muscle samples, estimated a compounded decrease of approximately 2.3% per year and proposed the correction “adjusted load = blood load / 0.977^(age+12)”, which improved correlation with muscle (R² from 0.38 to 0.48); blood, muscle and urine loads are correlated (R² 0.61–0.73), and in urine men have approximately 20% higher mutant load and more mtDNA copies, requiring adjustment for sex [15]. The two estimates of the decrease in blood differ because they derive from distinct sources and methods; Grady’s formula is the one with published validation against muscle. The French PNDS (French National Diagnosis and Care Protocol) stresses that the frequency of the most common signs of MELAS (SLE, dementia, epilepsy) correlates with the load in muscle and not with that in leucocytes, and that neither the severity of deafness nor that of nephropathy correlates with the load in blood or urinary sediment; the load in an accessible tissue therefore guides, but does not replace, the clinical assessment of each organ [17].

2.4. Mechanisms of injury

The pathogenesis of MELAS results from the interaction of three mechanisms: energy failure due to deficient mitochondrial translation, mitochondrial angiopathy (mitochondrial proliferation in the smooth muscle and endothelium of small vessels, visible as strongly succinate dehydrogenase-reactive vessels) and nitric oxide deficiency, with low plasma arginine and citrulline levels [1, 3, 33]. Citrulline and arginine deficiency described in MELAS, maternally inherited Leigh syndrome, NARP and Pearson syndrome underpinned the proposal to supplement nitric oxide precursors [3, 14]. A second line of clinical, electroencephalographic and neuropathological evidence brings SLEs closer to an epileptic encephalopathy: focal seizures at the onset of episodes, lesions that do not respect arterial territories, absence of demonstrated hypoperfusion in the acute phase, loss of inhibitory interneurons with severe complex I deficiency, and similarity between m.3243A>G SLEs and those in POLG disease [20, 36]. The 2026 consensus considers both models and adds cortical spreading depolarisation and a metabolic–vascular imbalance with regional hyperperfusion, without being able to rank their respective contributions [13]. The m.3243A>G variant also prevents taurine modification of uridine at the first anticodon position (taurinomethyluridine) of tRNA^Leu(UUR), disrupting codon decoding; this lesion underpinned the high-dose taurine trial [28, 29].

In variant-associated diabetes, the most recent hypothesis proposes a combination of insulin resistance and β-cell failure, more likely when heteroplasmy is high in skeletal muscle and moderate in the β-cell, with oxidative stress as the central mechanism [37]. Nuclear factors modulate the phenotype: in 238 adult carriers from the MRC cohort, age, age-adjusted blood load and sex explained little of the severity, and estimated heritability was high for psychiatric involvement (h² = 0.76) and moderate for cognition, ataxia, migraine and deafness (h² 0.40–0.46) [38].

2.5. Allelic diseases and overlaps

The same m.3243A>G variant is associated with PEO, maternally inherited diabetes with or without deafness, cardiomyopathy, isolated deafness and MERRF [1]. The Atlas describes a 20-year-old patient with sudden migraine, hemiparesis, homonymous hemianopia and seizures, considered to have MELAS, who developed myoclonus and ataxia at 25 years, constituting progression to MERRF, and a Sardinian family with MERRF/MELAS overlap associated with a tRNA^Lys variant [39]. MNGIE-like phenotypes (chronic intestinal pseudo-obstruction and neuropathy) may be caused by MT-TL1 variants [3]. Susceptibility to aminoglycoside-induced deafness belongs to MT-RNR1 (m.1555A>G), not MT-TL1; the Atlas presents MELAS disease as an important cause of aminoglycoside deafness while citing a study on m.1555A>G, an attribution not reproduced here [21, 33].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Distribution of m.3243A>G phenotypes

Among 129 patients from 83 families in the British MRC cohort, 10% had classical MELAS, 30% MIDD, 6% MELAS/MIDD overlap, 2% MELAS/chronic PEO (CPEO), 5% MIDD/CPEO, 6% PEO with other mitochondrial signs, 3% isolated sensorineural deafness, 28% unclassifiable combinations and 9% were asymptomatic [2]. Inborn Metabolic Diseases (Saudubray) reports that the complete MELAS presentation occurs in fewer than 10% of carriers and that the most frequent presentation is MIDD, with diabetes and deafness usually beginning in the fourth decade [3]. Among 238 adult carriers from the same cohort, seizures and SLEs affected 25% and 17%, respectively, whereas deafness, gastrointestinal complaints, psychiatric involvement and ataxia were more frequent [38]. In Slovakia, among carriers identified by screening 5,957 probands with deafness or diabetes, only 38% had both diabetes and deafness; symptoms usually began in the fourth decade in MIDD or isolated phenotypes and already in the second decade in probands with MELAS [40]. The French PNDS (French National Diagnosis and Care Protocol), drawing on the MRC cohort analysed by Pickett and colleagues, attributes approximately 15% of symptomatic patients to MELAS and approximately 30% to MIDD, with MELAS onset usually between 2 and 40 years of age [17, 38]; the difference from the 10% of Nesbitt and colleagues results from distinct samples and classification criteria within the same reference cohort, and neither value is a population proportion.

3.2. MELAS: age at onset and course

GeneReviews places onset between 2 and 40 years in the vast majority of patients, with 65–76% developing symptoms by 20 years; onset before 2 years (5–8%) or after 40 (1–6%) is rare [1]. More recent data challenge the 40-year limit: among 111 patients with SLEs of known genetic cause (United Kingdom, 1998–2018), mean age at the first SLE was 31.8 years and 32% had their first episode at 40 years or later; 43% had a recurrence in the following 12 months, with a median interval of 1.33 years between the first and second episodes [36]. In a Finnish cohort of 76 mitochondrial patients, 12 had SLEs (7 with m.3243A>G), with a mean age of 40 years at the first episode, a median duration of 14 days per episode and a need for intensive care in 10 patients [41]. The 2026 consensus accepts SLEs at any age, including after 40 years [13]. In the Japanese survey, SLEs, seizures and headaches were the most frequent symptoms in juvenile and adult forms; short stature predominated in the juvenile form and deafness, cortical blindness and diabetes in the adult form [11].

Sources: GeneReviews [1]; the book Síndromes Genéticas: Reconhecer para Tratar reproduces the same tables [42]. The “7–89%” range is printed in GeneReviews and in the Brazilian reproduction; the sequence of the other bands (≥90%, 50–74%) suggests a typographical error in the source, which could not be corrected using another primary source. These frequencies derive from series of patients with clinically defined MELAS and do not apply to m.3243A>G carriers in general.

3.3. Central nervous system

An SLE manifests as partially reversible aphasia, cortical visual loss, motor deficit, headache, altered mental state and seizures, with progressive accumulation of deficits [1]. The Atlas describes episodes that often begin with vomiting and headache, seizures or visual disturbances, sometimes triggered by infection or exercise, followed by transient hemiplegia or hemianopia lasting hours to weeks; lesions predominate in the posterior temporal, parietal and occipital lobes, and histology may show scattered infarcts in the brain, cerebellum and basal ganglia without inflammatory or atherosclerotic vessel changes [33]. The 2026 definition describes an SLE as an acute or subacute, evolving cerebral syndrome with neurological and/or psychiatric symptoms, usually associated with cortical/subcortical changes on magnetic resonance imaging (MRI), with or without electroencephalogram (EEG) abnormalities [13]. Seizures may be focal or generalised, occur as part of an SLE or independently, or precipitate an SLE; focal epilepsy often precedes episodes [1, 43]. Migraine-type, throbbing headache with frequent vomiting is typical and more intense during SLEs; in the family of patient NF in the Atlas, several members had migraine alone [1, 33].

Dementia results from the combined SLE lesions and a diffuse neurodegenerative process, documented by executive deficits with relative frontal preservation on imaging; the Atlas reports progression to dementia in 40–90% of patients [1, 33]. Other signs include ataxia, tremor, dystonia, myoclonus, cortical blindness, ptosis or ophthalmoplegia, pigmentary retinopathy and, rarely, Leigh-like presentations [3, 33]. Psychiatric manifestations (depression, bipolar disorder, anxiety, psychosis, personality changes) are recognised and may constitute the presentation of an SLE with frontal, temporal or limbic lesions [1, 20]. Peripheral neuropathy is distal sensorimotor, axonal or mixed; the Atlas reports abnormal nerve conduction in 77% of 23 variant carriers and autonomic symptoms in 80% of 35 carriers [1, 33].

The French PNDS (French National Diagnosis and Care Protocol) describes the SLE as typically beginning before 15 years of age and usually before 40, with late onset increasingly recognised; it may occur in a previously asymptomatic carrier or in a patient already severely affected [17]. In the history of the acute phase, attention is given to complex visual symptoms (elementary hallucinations such as phosphenes or coloured flashes, or formed hallucinations) and persistent auditory disturbances before the episode, the absence of signs of true stroke (abrupt focal deficit, particularly pure motor) and the triggers (infection, intestinal dysmotility, dehydration, prolonged fasting, non-adherence to antiepileptic treatment); the examination should assess the level of consciousness, visual field, language and apraxia [17]. Outside the acute phase, encephalopathy, hemiparesis, homonymous lateral hemianopia or cortical blindness, hemidystonia, aphasia and spasticity may persist [17].

The same document gathers the published frequencies for the remaining nervous system manifestations [17]. Cognitive disturbances are very frequent in MELAS, with a less favourable course in multisystem forms and severity correlated with CSF lactate; from the outset they may affect visuospatial functions, attention, abstraction and flexibility, and in children learning difficulties are found in approximately 50% and psychomotor delay in fewer than 10%; in MIDD, mild executive dysfunction and visual memory deficit are described. Seizures occur in approximately 25% of carriers, more often focal than generalised, with a risk of convulsive or non-convulsive status epilepticus (sometimes with psychiatric symptoms) and of drug resistance during SLEs or in encephalopathy. Cerebellar ataxia is late and more frequent in multisystem forms (66%) than in MELAS (25%), accompanied by dysarthria, dysphagia and nystagmus. Psychiatric disorders affect 69% of patients with MIDD or MELAS, generally begin between 20 and 40 years of age and are mainly depressive (half mild and reactive); moderate or severe forms account for 19% and include major depressive episodes (with suicidal ideation in 15%), anxiety, bipolar disorder, psychosis and personality changes with hallucinations. Myoclonus occurs in 10–30% of patients with MELAS and an extrapyramidal syndrome in approximately 5%, owing to lesions or calcifications of the basal ganglia, in which case ioflupane scintigraphy (DaTscan) may show dopaminergic denervation [17].

Peripheral neuropathy affects approximately 75% of patients, worsens with age, predominates in the lower limbs and is subclinical in half; there is an increased risk of carpal tunnel syndrome and of severe neuropathic pain; electromyography shows a predominantly axonal and sensory sensorimotor neuropathy, poorly controlled diabetes may add a demyelinating component and small-fibre involvement, probably underestimated, may be screened by Sudoscan; neurotoxic drugs and nutritional deficiency causes should be excluded [17]. Autonomic symptoms affect approximately 60% of carriers, may begin in childhood and manifest mainly as digestive dysmotility (ileus, diarrhoea, gastroparesis more rarely), neurogenic bladder and, less often, arrhythmias and orthostatic hypotension; lower urinary tract dysfunction (overactive bladder, urgency, weak stream, post-void residual, sexual dysfunction) is frequent and is confirmed by a bladder diary, questionnaires and urodynamic study [17]. Restrictive respiratory failure is rare and late; hypoventilation may be central (brainstem) or myopathic, is documented by pulmonary function tests, nocturnal oximetry or polysomnography, and sedatives may worsen the response to hypoxaemia and hypercapnia [17].

3.4. Skeletal muscle

Proximal myopathy, with exercise intolerance and fatigue, may precede SLEs; creatine kinase (CK) is normal or mildly elevated and electromyography may be myopathic [16, 33]. RRFs on modified Gomori trichrome staining and strongly succinate dehydrogenase-reactive vessels are characteristic; unlike MERRF, most MELAS RRFs are cytochrome c oxidase (COX)-positive [1]. Fatigue and pain are central complaints in recent studies; in a cross-sectional study of 17 carriers, patients with MELAS had a greater disease burden and lower exercise capacity than carriers without SLEs, but patient-reported measures did not reflect these objective differences [44]. The French PNDS (French National Diagnosis and Care Protocol) estimates muscle involvement in approximately 50% of patients, with peak incidence in the fifth decade: mild to moderate proximal weakness with amyotrophy, sometimes ptosis and PEO, myalgia and exercise intolerance with tachycardia and dyspnoea disproportionate to light exertion, reflecting low aerobic capacity (reduced maximal VO2) and aggravated by deconditioning [17]. Exercise testing (cycle ergometer or forearm contraction) shows a significant rise in lactate and in the lactate/pyruvate ratio in approximately two thirds of patients; CK, when elevated (171–650 IU/L), relates more to lactic acidosis, diabetes or central nervous system involvement than to myopathy; rhabdomyolysis is rare and moderate, after intense exertion, fever or a fall; muscle imaging is useful when symptoms have no correlate on examination or electromyography, but is often normal early on [17].

3.5. Diabetes and the endocrine system

Diabetes is the dominant endocrine manifestation. In GeneReviews, mean age at onset is 38 years and the phenotype may be type 1 or type 2; patients initially treated with diet or a sulfonylurea often progress to insulin deficiency and require insulin [1]. The Oxford Desk Reference describes onset in young adulthood, initial control with diet and rapid progression to insulin dependence, and notes that deafness usually precedes diabetes [16, 34]. MIDD affects up to 1% of patients with diabetes according to the review by Murphy and colleagues [45]; in the Slovak screening study, the variant was found in 0.14% of 4,158 patients in a general diabetes cohort and in 1.68% of 654 patients in a monogenic diabetes cohort, populations that are not comparable with each other [40]. Diabetes may present with a hyperglycaemic crisis or ketoacidosis [37, 46]. Other endocrine manifestations include short stature (sometimes with growth hormone deficiency), hypothyroidism, hypogonadotropic hypogonadism, hypoparathyroidism and, rarely, adrenal insufficiency [1, 47]. The Atlas reports a patient unsuccessfully treated with growth hormone [33].

The French PNDS (French National Diagnosis and Care Protocol) provides complementary figures [17]. Diabetes is part of the picture in at least a quarter of patients with MELAS and usually appears in the third or fourth decade; juvenile onset is rare and has only been observed from 10 years of age. In MIDD, the mean age at diagnosis of diabetes is 37 years, body mass index is normal or low (mean approximately 20 kg/m²), there is maternal diabetes in 80% of cases and the familial penetrance of diabetes has been estimated at 85%; deafness usually precedes diabetes. In 80% of cases the phenotype is that of type 2 diabetes, often discovered incidentally, with a lower body mass index and a faster need for insulin than in common type 2 diabetes; in 20% it mimics type 1 diabetes, insulin-dependent from the outset, with ketoacidosis at presentation in approximately one third of these. The mechanisms include declining insulin secretion through β-cell dysfunction and loss of mass, increased hepatic glucose production, absence of autoimmunity and, as a rule, little insulin resistance. Diagnosis uses the usual criteria (confirmed fasting venous glucose ≥1.26 g/L, ≥2 g/L with symptoms, or oral glucose tolerance test, performed when glycated haemoglobin is abnormal and fasting glucose values are insufficient); severity is assessed by glycated haemoglobin and by ketonaemia or ketonuria, with blood gas analysis if ketones are present, and C-peptide paired with glucose estimates insulin reserve. In a type 1 picture, negative anti-GAD, anti-IA2 and anti-ZnT8 antibodies support the mitochondrial diagnosis. Assessment includes complications (nephropathy, retinopathy, which is less frequent than in non-genetic diabetes, macrovascular disease, neuropathy and degree of podiatric risk) and the other cardiovascular risk factors [17].

As for the other glands, the PNDS describes hypoparathyroidism as rare, probably due to atrophy and not autoimmune, typical of early, severe and multisystem presentations, with hypocalcaemia, hyperphosphataemia and normal or low parathyroid hormone; peripheral hypothyroidism in approximately 10% of patients with MELAS, more frequent with age and in females, with a paediatric prevalence of 2.6% versus 0.1–1.6% in the general paediatric population, without established causality; growth delay in approximately half of patients with MELAS, the more frequent the earlier the onset, rarely due to growth hormone deficiency, which should be investigated by a stimulation test; and hypogonadotropic hypogonadism, in both sexes, with an estimated prevalence of approximately 2% in mitochondrial diseases [17].

3.6. Hearing and vision

Sensorineural deafness of cochlear origin is usually mild, insidiously progressive and early; it first affects high frequencies [1, 47]. In the Slovak study, the most frequent audiograms were downsloping (42% of affected ears) and flat (28%), and three patients with cochlear implants had stable functional outcomes [40]. Macular retinal dystrophy is frequent in disease related to m.3243A>G and is often detected at diabetic retinopathy screening appointments in patients with as yet undiagnosed MIDD [3]. Ptosis, PEO, optic atrophy and pigmentary retinopathy complete the ocular involvement [1, 33].

According to the French PNDS (French National Diagnosis and Care Protocol), the deafness of MIDD is sensorineural, bilateral, progressive and of endocochlear origin; it usually appears between 20 and 40 years of age, before diabetes, seems to progress faster in men and evolves in rapid steps in half of patients and gradually in the other half, starting with the high frequencies until all frequencies are affected [17]. By 40 years of age, 84–95% of patients have bilateral deafness and approximately 11% reach profound deafness with an indication for cochlear implantation; vertigo and vestibular deficit are rare. The initial assessment includes pure-tone audiometry (air and bone conduction, with contralateral masking if asymmetric), speech audiometry with headphones and, if there is a hearing aid or implant, in free field, tympanometry with stapedial reflexes and auditory evoked potentials or ASSR (auditory steady-state responses) to confirm the diagnosis or a deterioration, with language assessment to measure the impact [17].

In ophthalmology, the PNDS regards pattern macular dystrophy (pattern macular dystrophy), acquired, bilateral and progressive, described in up to 85% of patients with MIDD, as suggestive of m.3243A>G: pigmented or yellowish-white subretinal deposits, linear macular and peripapillary hyperpigmentation and possible progression to geographic chorioretinal atrophy, subtle on fundoscopy and better visualised on autofluorescence; initial foveal sparing preserves acuity, but progression may bring visual loss, photophobia and night blindness [17]. Diabetic retinopathy and macular oedema seem less frequent than in other forms of diabetes. Ptosis, PEO, early cataract, often posterior subcapsular, and patches of iris stromal atrophy should be sought; optic atrophy suggests less common complex I subunit variants, with rapid, profound and often sequential visual loss, central scotoma and papillary pseudo-oedema followed by pallor; central neuro-ophthalmological deficits (homonymous lateral hemianopia, bilateral occipital cortical blindness, nystagmus) complete the picture [17]. The recommended assessment includes visual acuity, slit-lamp biomicroscopy and fundoscopy, ocular motility, visual field, macular and papillary optical coherence tomography, autofluorescence and, if necessary, full-field and multifocal electroretinography [17].

3.7. Heart

The Atlas and the Oxford Desk Reference estimate cardiomyopathy in approximately 10% of patients; the mitochondrial cardiomyopathies chapter of Clinical Cardiogenetics reports cardiac involvement in 50% of patients with MELAS [16, 33, 48]. The chapter of the same book on cardiomyocyte models derived from induced pluripotent stem cells places cardiac dysfunction in approximately one third of patients, with abnormal mitochondria, mitochondrial inclusions and variable sarcomeric thickening, and reports that iPS cell lines with MT-TL1 variants already exist, but no cardiomyocyte model has yet been published [49]. None of the three sources gives the denominator or the definition used, so the estimates of 10%, approximately one third and 50% are not directly comparable. The typical form is non-obstructive concentric hypertrophy, which may progress to dilatation; left ventricular non-compaction and restrictive cardiomyopathy have been described [1, 48]. Patients with MELAS show pathological Q waves, left ventricular hypertrophy, left bundle branch block and ST/T changes, ventricular pre-excitation in approximately 15%, ventricular ectopic beats and diffuse focal intramural late enhancement on cardiac MRI [48]. In a cohort of 260 adults with mitochondrial disease (64 with m.3243A>G), followed for a median of 7 years, 10% had a major adverse cardiac event; single mtDNA deletions and m.3243A>G had the highest incidence, and intraventricular block (HR 16.9), diabetes (HR 7.0), ventricular ectopic beats (HR 3.6) and left ventricular hypertrophy (HR 2.5) were independent predictors; with zero, one, or two or more factors, incidence was 1.7%, 15% and 42% [50]. Sudden adult death may occur in young asymptomatic carriers: in the Newcastle cohort, incidence was 2.4 per 1,000 person-years, and analysis of two sudden deaths revealed severe respiratory chain deficiency and high variant loads in the myocardium [51]. End-stage heart failure is a frequent cause of death in patients with m.3243A>G [52].

The French PNDS (French National Diagnosis and Care Protocol), whose authors included the cardiologist Karim Wahbi (Cochin Hospital), describes exertional dyspnoea as the most frequent symptom, due to diastolic or systolic heart failure associated with hypertrophic cardiomyopathy, which may progress to pulmonary oedema or cardiogenic shock; palpitations due to ectopic beats, more rarely atrial fibrillation or accessory pathway tachycardia (Wolff–Parkinson–White syndrome), and exceptional presyncope or syncope, almost always with very advanced cardiomyopathy [17]. The hypertrophy is symmetrical and concentric, may exceed 25 mm wall thickness and have a granular myocardial appearance that leads to the mistaken suspicion of amyloidosis; systolic dysfunction (ejection fraction <50%) arises almost exclusively on prior hypertrophy and may fluctuate within a few days. The initial assessment includes at least an ECG (arrhythmias, bundle branch blocks or hemiblocks, short PR or pre-excitation) and echocardiography, the most important examination; if there are abnormalities, even minimal, 24-hour Holter monitoring, cardiac MRI (hypertrophy, late enhancement, T1 and extracellular volume, ejection fraction) and BNP or NT-proBNP, which may be elevated with a normal echocardiogram, are added. Electrophysiological study or an implantable loop recorder is reserved for syncope, severe presyncope or symptomatic pre-excitation. Carriers of m.3243A>G have a high risk of early or resistant arterial hypertension, so borderline office values warrant home self-measurement or ambulatory monitoring; in MIDD, cardiovascular risk stratification follows the recommendations of the Société Francophone du Diabète [17].

3.8. Kidney, digestive tract and other organs

Nephropathy associated with m.3243A>G is predominantly focal segmental glomerulosclerosis with proteinuria; Fanconi tubulopathy also occurs, and some patients have required dialysis or kidney transplantation [1, 3, 47]. Recurrent or cyclic vomiting is frequent; diarrhoea, constipation, gastric dysmotility, intestinal pseudo-obstruction and recurrent pancreatitis have been described, and pseudo-obstruction may herald a new SLE [1, 47]. Exocrine pancreatic insufficiency occurs in variant carriers [47]. Pulmonary hypertension, vitiligo, diffuse erythema with reticulate pigmentation, hypertrichosis and chronic anaemia have also been described [1]. The Atlas reports pancreatitis after valproate in one patient [33].

The French PNDS (French National Diagnosis and Care Protocol) describes nephropathy as frequent in adults with an oligosymptomatic form or MIDD, mainly glomerular, appearing in adolescence or young adulthood with isolated glomerular proteinuria of approximately 1–1.5 g/g, which may progress to nephrotic syndrome; biopsy shows non-specific focal segmental hyalinosis and has never revealed diabetic nephropathy lesions in published cases [17]. There are also proximal tubulopathies (up to complete Fanconi syndrome) and distal tubulopathies, chronic interstitial nephritis and cystic disease. According to the PNDS, chronic kidney disease progresses in most cases to stage 5, reached at a median age of 33 years (15–51 years), and its severity does not correlate with the load in leucocytes or urinary sediment [17].

The median of 33 years and the range of 15 to 51 years derive from a single pooled analysis, that of Guéry and colleagues (Necker Hospital and other French nephrology departments), which combined their series of 9 adults with 15 previously published adults (three series of 4 patients and three isolated cases), for a total of 24 patients [53]. In this group, 13 of the 24 were on kidney replacement therapy at last follow-up (mean follow-up 5 years, 1–17), two patients in the authors’ own series reached the sixth decade without end-stage kidney disease and mean proteinuria at presentation was 1.5 g/day (0.07–5 g/day), with nephrotic syndrome in only 2 of the 24 (approximately 8%), without haematuria and with normal blood pressure in 66% of cases, even at advanced stages; no adult had tubulopathy and 11 of the 20 assessable had creatinine clearance >60 mL/min at presentation [53]. The proportion of one third nephrotic syndromes that the PNDS attributes to this series does not match the published data (1 in 9 in the authors’ own series, 2 in 24 overall). There was a female predominance (19 women to 5 men, 79%); the first renal assessment took place at a median age of 32 years (14–50) and the kidney was the first manifestation in approximately one third of patients [53].

In the authors’ own series (9 patients from 6 families; inclusion criteria: proteinuria >1 g/24 h or creatinine clearance <80 mL/min, variant in blood or a tissue and absence of another cause), the median age at first renal assessment was 35 years and proteinuria appeared between 5 and 47 years of age [53]. Five patients reached end-stage kidney disease at 15, 36, 41, 42 and 51 years and four received a kidney transplant with good graft function. Mutant load in leucocytes, quantified in 6 patients, was 5–25%; one patient with an undetectable variant in blood had 60% in muscle; plasma lactate was elevated (2.3–4 mmol/L) in the 3 patients tested. Of the 5 biopsies, 2 showed focal segmental glomerulosclerosis (one of them with cortical cysts and enlarged kidneys, resembling polycystic disease) and 3 severe tubulointerstitial nephropathy without glomerulosclerosis, with arteriolar hyaline thickening in four; immunofluorescence was normal, none had diabetic glomerulopathy and electron microscopy showed enlarged mitochondria with abnormal cristae in podocytes, including the foot processes, or in proximal tubular cells in 3 of the 5 patients, with no change in mesangial, endothelial and smooth muscle cells. Cytochrome c oxidase activity in the renal tissue of one patient was normal, so normal renal COX/SDH histochemistry does not exclude the disease [53]. Across the published biopsies (19 of 24 patients), focal segmental glomerulosclerosis was the dominant lesion in 79%, with no difference on light microscopy from the primary form; the authors consider the abnormal mitochondria in podocyte foot processes possibly pathognomonic [53].

Extrarenal manifestations almost always accompany the nephropathy: bilateral sensorineural deafness preceded renal involvement in 8 of the 9 patients, 3 to 22 years earlier (20 of 24 overall), and many needed hearing aids before 35 years of age; diabetes appeared in all between 17 and 46 years of age, usually after the nephropathy (up to 12 years later), without excess weight, without anti-islet antibodies in the 3 tested and without diabetic retinopathy over 1 to 12 years of follow-up [53]. Five patients had hypertrophic cardiomyopathy (septum of 15 to 20 mm in the cases described), four macular dystrophy, four had SLEs or transient ischaemic attacks before 45 years of age, without sequelae, and two epileptic seizures; severe muscle atrophy was rare (1 in 9). One patient with 4 fetal losses before 25 weeks presented with pre-eclampsia at 23 weeks. In two patients without biopsy, the combination of deafness and familial nephropathy led to an initial diagnosis of Alport syndrome [53]. The load in urinary sediment (5% in three patients, one on dialysis and two transplanted) was similar to that in leucocytes and was present after transplantation, which shows that urinary cells derive mainly from the lower urinary tract and that urinary load does not measure renal involvement [53]. In the digestive tract, the PNDS distinguishes minor manifestations (occasional vomiting, constipation) and major ones (recurrent vomiting, gastroparesis and chronic intestinal pseudo-obstruction), due to smooth muscle energy deficiency, dysautonomia or, in recurrent vomiting, brainstem involvement; liver involvement is theoretically possible but is not documented for m.3243A>G [17].

3.9. Pregnancy

In a retrospective study of 60 female carriers from a national inventory (98 pregnancies in 46 women), 25.3% of deliveries were preterm (5.5% at 32 weeks or earlier), 12% of women had pre-eclampsia and 11% of pregnancies had gestational diabetes; urinary load did not differ between women with and without pre-eclampsia [54]. The French PNDS (French National Diagnosis and Care Protocol), citing the same study, reports 96 pregnancies and adds intrauterine growth restriction (below the 5th centile) in 13% and 4 fetal deaths; arterial hypertension increases the risk of pre-eclampsia [17]. The difference in denominator (96 in the PNDS, 98 in the original abstract) does not change the main proportions. Case reports describe premature rupture of membranes, worsening acidosis, status epilepticus, SLEs and magnesium sulphate toxicity [47, 48].

3.10. Paediatric features

The paediatric annex of the French PNDS (French National Diagnosis and Care Protocol) describes a mainly neurological initial presentation: learning and neurodevelopmental disorders in early childhood, rarely isolated, associated with failure to thrive, deafness, episodes of headache with vomiting of migraine type and exacerbations of lactic acidosis [17]. SLEs are often absent from the initial picture, appear mainly after 10 years of age, in adolescence or adulthood, with the same semiology as in adults (focal motor deficit, focal epilepsy with prolonged postictal deficit or epilepsia partialis continua, headache with vomiting), and should be considered in the face of any acute neurological manifestation. Epilepsy may occur outside SLEs, focal or myoclonic; psychiatric manifestations, ataxia and abnormal movements are rare; muscle weakness rarely predominates, but fatigability and exercise intolerance are frequent; neuropathy is rare and dysautonomia manifests as abdominal pain, alternating diarrhoea and constipation or pupillary changes. MIDD is rare or absent in young children and exceptional in older children and adolescents; diabetes is exceptional, as is cardiac involvement. Biochemically, there is no specific marker: lactate may be permanently elevated or only during exacerbations, Krebs cycle metabolites and alanine and proline may rise, but these changes fluctuate and occur in other causes of secondary mitochondrial dysfunction (severe sepsis, haemodynamic failure); glucose and CK are usually normal. MRI may be normal, electromyography is performed only if there are signs of neuropathy and muscle biopsy is justified only when the clinical picture and mtDNA testing are discordant [17]. Onset in childhood indicates more severe disease and a worse prognosis [11, 17].

4. Clinical Recognition and Warning Signs

Recognition rests on the combination of organs with high energy consumption and maternal genealogy. The Oxford Desk Reference emphasises that any mitochondrial sign associated with lactic acidosis is highly suggestive and that the combination of diabetes with sensorineural deafness strongly points to mitochondrial disease; it recommends a three-generation pedigree extended through the maternal line, with targeted questions about muscle weakness, vision, hearing and neurological signs [16]. The mitochondrial cardiomyopathies chapter suggests suspicion when two or more organs are involved and investigating exacerbations associated with infections, vaccines or exercise [48]. In the genealogy, maternal-line relatives may have diabetes alone, mild deafness or migraine, as in the pedigree of patient NF described in the Atlas and in the pedigree of the case in section 10 [33, 35, 46].

Persistent headache unresponsive to treatment should prompt neuroimaging to exclude an SLE [13]. Patients with a previous SLE should have an emergency care plan, and carriers an alert card [20, 47].

The French PNDS (French National Diagnosis and Care Protocol) organises suspicion around three entry points, which form the basis of its diagnostic decision tree [17]:

When the condition is suspected, the PNDS recommends seeking these supporting features and referring the patient to the organ specialist (neurologist, endocrinologist) or to the geneticist, preferably in a mitochondrial disease reference centre [17]. It assigns to the attending physician the detection of acute events (SLE, decompensation of diabetes, rhabdomyolysis), coordination of home care, informing relatives in the maternal line, monitoring of drug precautions and contact with the reference centre for any acute problem [17].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

GeneReviews establishes the diagnosis in a proband meeting the clinical criteria and having a pathogenic or likely pathogenic variant in one of the genes in table 1; a variant of uncertain significance neither confirms nor excludes the diagnosis [1]. Annex 6 of the French PNDS (French National Diagnosis and Care Protocol), which adopts the proposal of Ng and colleagues, lists five elements for the diagnosis of SLE: (1) compatible clinical features (acute or subacute onset, altered consciousness or encephalopathy, headache, nausea and vomiting, hemianopia or cortical blindness, visual hallucinations, focal motor seizures including epilepsia partialis continua, non-convulsive status including occipital seizures, focal motor deficit, neuropsychiatric symptoms, systematised sensory symptom, aphasia); (2) SLE lesion on MRI; (3) EEG with focal abnormalities, including epileptic discharges, with or without generalised abnormalities; (4) a pathogenic variant known to cause SLEs; (5) exclusion of differential diagnoses, such as stroke or viral encephalitis [17, 20].

5.2. Neuroimaging and neurophysiology

During an SLE, MRI shows asymmetric T2 hyperintensity, predominantly posterior (temporal, parietal, occipital), cortical with or without subcortical involvement, which does not respect vascular territories and may slowly expand over subsequent weeks; the apparent diffusion coefficient is increased, unlike in ischaemic infarction; MR angiography is usually normal and spectroscopy shows reduced N-acetylaspartate and lactate accumulation; computed tomography may show basal ganglia calcification [1]. Inborn Metabolic Diseases adds that lesions spare the deep white matter and are associated with generalised cerebral atrophy [3]. In patients with m.3243A>G or other mtDNA variants, cerebral atrophy was more frequent than in POLG disease (90% versus 44%) [36]. Ng’s consensus proposes a minimum MRI protocol with T1, T2, FLAIR, diffusion and an ADC map, and the 2026 consensus considers EEG an important early investigation [13, 20]. In the case in section 10, cortical areas showed restricted diffusion with subcortical vasogenic oedema, demonstrating that the diffusion pattern may vary according to the phase and epileptic component [46].

The French PNDS (French National Diagnosis and Care Protocol) details the signs of the acute phase: focal cortical lesion of variable extent, most often parieto-occipital and then temporal, with diffusion hyperintensity and variable ADC, T2 and FLAIR hyperintensity, T1 hypointensity, absence of microhaemorrhages on T2* or SWI, possible gyral enhancement after contrast, absent or minimal mass effect, possible extension to the adjacent subcortical white matter and possible multifocal lesions [17]. The non-contrast arterial spin labelling (ASL) perfusion sequence shows intense focal hyperperfusion, often more extensive than the morphological lesion, and is considered particularly useful in children. Outside the acute phase, the diagnosis is supported by SLE sequelae (focal cortical atrophy with laminar necrosis showing spontaneous T1 hyperintensity), symmetrical calcifications of the basal ganglia (CT is more sensitive than MRI), the inverted lactate doublet at 1.3 ppm on long echo time spectroscopy (144–288 ms), which may be the first detectable abnormality but is not always present, supratentorial and infratentorial atrophy, mainly cerebellar, and, very rarely, watershed leukoencephalopathy; a normal MRI does not exclude the diagnosis [17]. As poor prognostic factors for the SLE, the PNDS points to the duration and refractoriness of status epilepticus and, on MRI, a markedly reduced ADC in the white matter adjacent to the affected cortex, a sign of cytotoxic oedema [17]. The combination of myogenic tracings and predominantly sensory axonal neuropathy on electroneuromyography strengthens the mitochondrial hypothesis [17].

5.3. Biochemistry and muscle biopsy

Lactic acidaemia is very frequent, but may be absent in patients with extensive neurological involvement; CSF lactate may be elevated with normal blood lactate; CSF protein rarely exceeds 100 mg/dL [1, 33]. The mitochondrial diseases GeneReviews considers that fasting blood lactate above 3 mmol/L or CSF lactate above 1.5 mmol/L supports the diagnosis, although normal values do not exclude it [35]. Elevated lactate and anion gap may be the patient’s baseline values and do not always require treatment [13]. Plasma arginine and citrulline may be low [3, 33]. Fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF15) correlate with mitochondrial dysfunction in myopathic patients; in a study of m.3243A>G carriers, GDF15 correlated with baseline disease burden but did not detect changes over two years [3, 19]. Muscle biopsy shows COX-positive RRFs, succinate dehydrogenase-reactive vessels and combined deficiencies, but is no longer necessary when molecular testing is conclusive [1].

The French PNDS (French National Diagnosis and Care Protocol) recommends drawing venous lactate without a tourniquet and points out that hyperlactataemia also occurs in other metabolic diseases and after seizures or stroke; mitochondrial lactic acidosis is accompanied by a lactate/pyruvate ratio >20 and 3-hydroxybutyrate/acetoacetate >3, urinary excretion of Krebs cycle intermediates and increased plasma alanine and proline, and a fall in citrulline and arginine has been described during SLEs; CK is mildly to moderately elevated in approximately one third of patients, and an elevated fasting glucose or glycated haemoglobin without known diabetes also points to the spectrum [17]. On muscle biopsy, according to the data on 50 carriers gathered by Kärppä and colleagues and cited by the PNDS, RRFs are absent in 34% and the biopsy is normal in 28% of symptomatic patients; combined COX-SDH staining shows a mosaic of COX-negative and COX-positive fibres, there may be lipid accumulation and biochemistry may show multiple deficiencies (complexes I and/or IV) or be normal [17]. Since the introduction of next-generation sequencing, the PNDS reserves first-line biopsy for patients in intensive care or with rapid deterioration that does not allow waiting for the genetic result and for atypical presentations; it recommends performing it without propofol and, if functional study of the respiratory chain is requested, transporting the sample rapidly on dry ice [17].

5.4. Molecular tests, sample selection and limitations

GeneReviews proposes starting by testing for m.3243A>G in leucocyte DNA; if negative, test for m.3271T>C, m.3252A>G and m.13513G>A, or sequence the entire mitochondrial genome; when the phenotype is non-specific, exome or genome sequencing is preferable, checking whether the laboratory includes mtDNA [1]. The MMS recommends massively parallel mtDNA sequencing rather than testing a few variants, with detection of 1–2% heteroplasmy using the most sensitive techniques, and considers urine more informative and accurate than blood for m.3243A>G because of the high mtDNA content of renal epithelial cells [14]. Ng’s consensus recommends sending at least two samples (blood and urine, or blood and buccal mucosa) and quantifying heteroplasmy in each tissue [20]. The variant may be undetectable in blood and detectable in buccal mucosa, fibroblasts, hair follicles, urinary sediment or, more reliably, muscle [1, 42].

Test limitations should be stated in the report: the technique (PCR-RFLP, quantitative PCR, digital PCR, sequencing), heteroplasmy detection threshold, tissue analysed, measured percentage and NC_012920.1 reference [14, 40]. GeneReviews indicates that sequencing detects 100% of known point variants in the genes in table 1, which is not equivalent to clinical sensitivity: a negative blood result does not exclude disease if heteroplasmy is low in that tissue [1]. Large deletions require specific methods (long-range PCR, digital PCR or sequencing with adequate coverage), particularly in muscle [3, 14]. Exome and genome tests may have variable false-negative rates by region and may not detect large deletions [35]. Partial familial segregation does not convert a variant of uncertain significance into a pathogenic one.

The choice of initial sample differs between sources. GeneReviews starts with leucocytes [1]; the Ng consensus requires at least two samples [20]; the French PNDS (French National Diagnosis and Care Protocol) recommends, in the absence of a biopsy, DNA from urinary epithelial cells as the first sample, because the load approaches that of muscle, and considers buccal mucosa, hair follicles and above all blood less informative [17]. The PNDS confirms the diagnosis by identification of m.3243A>G or another pathogenic variant in heteroplasmy and stresses that a negative result does not exclude the diagnosis, because many variants are present only in the tissue expressing the deficiency, particularly muscle [17].

5.5. Practical algorithm

1. Clinical suspicion (SLE, MIDD, cardiomyopathy or multisystem combination) → three-generation maternal genealogy and multisystem assessment [3, 16].
2. Quantitative testing for m.3243A>G in blood and urine (or buccal mucosa), with heteroplasmy in each tissue; urgent request in the context of an SLE [14, 20].
3. Negative with a suggestive phenotype → complete mtDNA sequencing in urine or muscle; consider POLG and exome/genome if the presentation is compatible with a nuclear cause [1, 20].
4. Persistent uncertainty → muscle biopsy with histology, respiratory chain assessment and muscle mtDNA [3, 20].
5. Confirmed diagnosis → classify the phenotype (MELAS only if an SLE has occurred) and begin baseline assessment (section 11) [1, 13].

The decision tree of the French PNDS (French National Diagnosis and Care Protocol) (annex 3) follows the same logic with two practical differences: targeted testing for m.3243A>G is preferably performed on urinary epithelial cells (or buccal mucosa; blood is the least informative) and, if the patient is at risk of rapid deterioration or the presentation is atypical, one proceeds directly to muscle biopsy, which then allows complete mtDNA sequencing in muscle; the diagnosis is confirmed by the variant in heteroplasmy [17].

5.6. Assessment of extent after diagnosis

The French PNDS (French National Diagnosis and Care Protocol) defines a systematic multidisciplinary initial assessment, to estimate extent and severity and to serve as a baseline for follow-up (annexes 8 and 8 bis) [17]:

According to the PNDS, the diagnosis is disclosed in a dedicated consultation, by an experienced physician, as double news (serious chronic disease and genetic origin), with explanation of the natural history, follow-up, social support and the patient association, the possibility of being accompanied by a relative and a second consultation for further questions; genetic counselling takes place in a separate consultation [17]. In children, the diagnosis should be disclosed to both parents and then to the child in age-appropriate words, without forgetting siblings [17].

6. Differential Diagnosis

7. Treatments and Risk Management Strategies

7.1. Principles

There is no curative treatment or medicine approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA) for MELAS or disease related to m.3243A>G; treatment is supportive, multidisciplinary and guided by monitoring for complications [1, 19, 35]. The MMS recommends care at a tertiary centre with metabolic and cardiological expertise, a summary document for emergencies and attention to precipitating factors (infection, fasting, dehydration, surgery) [47, 48]. The 2026 consensus emphasises that recommendations are level IV (expert opinion) and decisions should be individualised [13]. The French PNDS (French National Diagnosis and Care Protocol) starts from the same premise — no treatment has been shown to reduce disability — and organises care around early detection of complications, preventive and symptomatic medicines, genetic counselling, rehabilitation and medico-social and psychological support, coordinated by a physician from a reference or competence centre for mitochondrial diseases (or inherited metabolic diseases) together with the attending physician, and systematically involving a geneticist, neurologist, cardiologist, otorhinolaryngologist and ophthalmologist and, if necessary, a gastroenterologist, nephrologist and physical medicine and rehabilitation physician [17]. The supplements used in practice (coenzyme Q10, idebenone, L-carnitine, riboflavin, arginine, taurine) rest on pathophysiological arguments, case reports and small open-label trials; none has shown efficacy in a randomised double-blind trial, particularly in m.3243A>G carriers, and their use is left to the clinician’s judgement [17].

7.2. Stroke-like episode: acute approach and disagreement between consensus statements

This disagreement reflects the hierarchy of evidence. Japanese L-arginine studies were open-label and uncontrolled: in the 2005 study, infusion improved SLE symptoms and oral administration reduced episode frequency and severity [60]; in the two open-label phase 3 trials integrated into a 9-year follow-up (15 patients with oral arginine, 10 with IV arginine), primary endpoints did not reach statistical significance (prolongation of the interictal period with p = 0.0625), there were no deaths or bedridden patients during the 2-year trial and no adverse effects attributed to treatment were recorded; the placebo-controlled design was abandoned for ethical reasons [61]. The 2022 systematic review gathered 37 publications (0 randomised trials, 3 open-label trials, 1 retrospective cohort and 33 reports or series; 91 patients, 86% with m.3243A>G): 54% of reports described a response to acute arginine, 40% of them with concomitant antiseizure medicines; in the open-label trials, improvement in headache at 24 hours was the most frequently reported benefit (31/39, 79%); 12% of patients died during follow-up or while receiving prophylaxis; the evidence was classified as level 5, with no demonstrable benefit [27]. A 2026 review from the Newcastle group observes that practice still varies between North America and Europe and between paediatrics and adult medicine [19].

Beyond seizure treatment, an SLE requires multisystem assessment on admission: consensus statements recommend full blood count, urea, creatinine and electrolytes, liver function tests, glucose, lactate without a tourniquet, C-reactive protein, urine, CK, blood gas analysis, ECG and chest or abdominal radiographs if aspiration or pseudo-obstruction is suspected; early hydration and nutrition, through a nasogastric or nasojejunal tube at a continuous low volume and parenteral nutrition if fasting is prolonged; treatment of pseudo-obstruction with gastric decompression and, rarely, surgery; antipsychotics (haloperidol, quetiapine, benzodiazepines) for psychotic symptoms, with arrhythmia monitoring in m.3243A>G carriers; and bicarbonate only for severe lactic acidosis (pH < 7.1 according to the 2019 consensus), avoiding highly concentrated dextrose solutions according to the 2026 consensus [13, 20]. Acute kidney injury, rhabdomyolysis (rare), heart failure and infections should be actively sought [13]. Serum lactate is not a reliable marker of sepsis or ischaemia in these patients [20].

The 2021 French PNDS (French National Diagnosis and Care Protocol) adopts the protocol of Ng and colleagues for the acute phase and adds organisational elements [17, 20]. Patients and carers should be trained to recognise early signs; all patients with a previous SLE should have a written emergency care plan and patients at risk an emergency card; when an SLE is suspected, the patient should be directed to a reference centre or to a hospital with intensive care (paediatric, in the case of a child). Before hospitalisation, in a patient with a previous SLE and symptoms suggestive of a new episode, a benzodiazepine is administered early; in hospital, the IV antiepileptic of choice is levetiracetam (20–40 mg/kg, maximum 4,500 mg), with phenytoin (15–20 mg/kg, with cardiac monitoring), phenobarbital (10–15 mg/kg, with respiratory monitoring) or lacosamide (200–400 mg) as alternatives, maintaining the usual antiepileptic (by nasogastric tube if the oral route is impossible) and without waiting for EEG or MRI if they are not available [17]. The levetiracetam range of 20–40 mg/kg comes from the consensus of Ng and colleagues; the accompanying maximum of 4,500 mg corresponds to the 60 mg/kg dose used in the ESETT trial in children and adults with benzodiazepine-resistant status epilepticus (fosphenytoin 20 mg PE/kg, maximum 1,500 mg PE, in the same trial), which is the regimen of the general convulsive status epilepticus protocols [20, 62]. Indications for intensive care are generalised convulsive status epilepticus, frequent focal seizures with generalisation not responding to IV antiepileptics, severe encephalopathy with a high risk of aspiration and focal status with impaired consciousness refractory to benzodiazepines and two IV antiepileptics; in refractory status, midazolam is the anaesthetic of first choice, propofol is decided case by case because of the risk of propofol infusion syndrome with prolonged use (particularly in children), with glucose supply and lactate monitoring, under continuous or at least daily EEG, aiming for burst suppression for at least 48 hours; at intubation suxamethonium should be avoided, because of the risk of rhabdomyolysis [17]. The same annex recommends considering venous thromboembolism prophylaxis, assessing swallowing in the presence of encephalopathy, cerebellar signs or focal deficits, monitoring cardiac conduction and ventricular function in the presence of acidosis, electrolyte disturbances, antiepileptics or volume replacement, giving IV hydration to patients at risk of dehydration (with monitoring of fluid balance and electrolytes in patients of low weight, with cardiomyopathy or nephropathy) and treating mild lactic acidaemia mainly by rehydration, reserving bicarbonate with caution for pH <7.1 and excluding dichloroacetate; lactate should not be interpreted as a marker of sepsis or ischaemia [17]. The PNDS table defines acidaemia responding to rehydration as lactate of 2.2–5.0 mmol/L “with pH <7.30”; the consensus of Ng and colleagues, which the PNDS reproduces, states lactate of 2.2–5.0 mmol/L with pH >7.30, that is, hyperlactataemia without acidaemia, and this is the criterion to apply [20].

Regarding specific therapies, the PNDS records the MMS recommendation (IV arginine in the acute phase in m.3243A>G carriers and oral arginine for prevention) and the discussion on the ketogenic diet and corticosteroids, but concludes that the evidence does not allow them to be formally recommended and leaves their use to the clinician’s judgement; it also records the position of the European centres that regard seizures as the immediate cause of the SLE and place seizure control and supportive care at the centre of treatment, and states that no prophylactic antiepileptic has shown efficacy [17]. On corticosteroids, the therapeutic annex reports partial or complete efficacy of IV corticosteroid therapy combined with antiepileptics in isolated cases of MELAS and in a series of mitochondrial encephalopathies of nuclear origin, with the hypothesis of repair of the blood–brain barrier and reduction of vasogenic oedema [17]. In the acute phase and in advanced disease, enteral nutrition by nasogastric tube or gastrostomy may be necessary to meet requirements in a catabolic state and to protect the airway [17].

7.3. Published L-arginine, taurine and citrulline regimens (off-label use in the USA and EU)

The only IV arginine product with an FDA label, R-Gene® 10 (10% injectable arginine hydrochloride, Pharmacia & Upjohn, NDA 016931, label dated 2 April 2024), is indicated solely as a growth hormone stimulus in diagnostic tests; the labelled paediatric dose is 0.5 g/kg over 30 minutes, not exceeding 30 g, and the label warns that overdose in children has caused hyperchloraemic metabolic acidosis, cerebral oedema and death, that hypersensitivity reactions including anaphylaxis have been recorded, and that the product “is not intended for therapeutic use”; adverse effects described in 1,670 infusions were nausea, vomiting, headache, flushing, paraesthesia and venous irritation in approximately 3% [65]. Use in MELAS is therefore off-label. Taurine in the Japanese trial had no serious adverse effects and reduced the annual SLE rate from 2.22 to 0.72, but cerebral atrophy continued to progress [28, 29].

The French PNDS (French National Diagnosis and Care Protocol) is the only one of the guidelines consulted that tabulates dosages of cofactors and antioxidants for children and adults (annex 10a), always with the caveat that prescription is left to the clinician’s judgement and that none has shown efficacy in a randomised trial in m.3243A>G [17]:

For coenzyme Q10, the PNDS cites improvements in fatigability, strength and quality of life in a randomised double-blind trial in 24 patients with mitochondrial disease (NCT00432744), which the trial review reproduced in its annex 10c describes only as a favourable trend, and, for idebenone, lower scores on the fatigue severity scale in a MELAS trial whose primary endpoint was cerebral lactate (NCT00887562), and recommends, like the MMS, introducing supplements one at a time and avoiding “cocktails” at the outset; the North American Mitochondrial Disease Consortium describes overall subjective improvements, but warns of adverse effects and costs when more than four supplements are combined [17]. Folinic acid is justified only in the presence of CSF folate deficiency, which has never been described in MELAS [17]. The 2026 consensus found no evidence for these supplements in the acute phase or in the prevention of SLEs [13].

7.4. Epilepsy and medicine selection

Epilepsy is treated with the usual medicines; levetiracetam, perampanel, lacosamide, lamotrigine, cenobamate, cannabidiol, gabapentin, pregabalin, benzodiazepines, barbiturates, ketamine and the ketogenic diet are not contraindicated, and the 2024 InterERN consensus endorses NICE NG217 guidelines with adaptations [59]. Topiramate should be used cautiously when there is a risk of renal tubular acidosis [47, 59]. The Atlas reports the use of lamotrigine for myoclonus [33]. The dose of renally eliminated medicines, such as levetiracetam, should be adjusted in nephropathy [21].

The French PNDS (French National Diagnosis and Care Protocol) follows the national recommendations for epilepsy, with particular features: it considers valproate contraindicated (hepatotoxicity and inhibition of the respiratory chain), but, if it was started before the diagnosis and the epilepsy is controlled, it should not be withdrawn because of the risk of decompensation, including status epilepticus; it advises against prolonged phenytoin because of the risk of cerebellar atrophy; it warns of metabolic acidosis with carbonic anhydrase inhibitors (topiramate, zonisamide); and it favours drugs with low mitochondrial toxic potential — gabapentin, lamotrigine and levetiracetam [17]. It cites an Italian multicentre study in which levetiracetam was the most widely used antiepileptic, particularly in adults, and prefers levetiracetam for myoclonus [17]. The original study is a retrospective cross-sectional survey of the Italian mitochondrial disease network (98 patients with mitochondrial epilepsy of various aetiologies, 42% with m.3243A>G): levetiracetam was effective in 81% of cases of adult-onset epilepsy, and phenobarbital and vigabatrin, more widely used in early-onset epilepsy (up to 3 years of age), in 75% and 66%, respectively; efficacy corresponds to the response rate with seizure reduction greater than 50%, and not to complete control [66]. The ketogenic diet is an alternative in drug-resistant epilepsy, particularly in children, started in hospital with a specialised medical and dietetic team; there is no evidence for vagus nerve stimulation or epilepsy surgery, and there is no indication for EEG or preventive treatment in carriers without seizures [17]. When a seizure occurs, triggers should be sought and treated (infection, dehydration, hypoglycaemia in diabetic patients, hyponatraemia due to inappropriate antidiuretic hormone secretion, nephropathy or carbamazepine and oxcarbazepine, significant lactic acidosis relative to previous values, treated only if severe), the heart (cardiomyopathy and arrhythmia), respiratory and bulbar function (risk of aspiration) and the bowel (ileus) monitored, non-convulsive status epilepticus excluded by urgent EEG in the presence of obtundation or a prolonged postictal state, and SLE suspected in the presence of new focal deficits with headache and obtundation, with brain MRI [17]. In status epilepticus, it adds to the measures of annex 6 caution with benzodiazepines if there is respiratory weakness, discussion of the ketogenic diet and corticosteroids, measurement of CK in convulsive status epilepticus and monitoring of the left ventricle and of pseudo-ileus, which may compromise enteral absorption of antiepileptics [17].

For dystonia and spasticity, which are less frequent, the PNDS uses the usual treatments (annex 11) [17]. Oral baclofen (Lioresal®) is the most widely used maintenance treatment for spasticity, at the usual doses, with sedation as the main adverse effect; diazepam (Valium®) and clonazepam (Rivotril®) are used mainly in dystonic storm; trihexyphenidyl (Artane®) is the first choice in focal and generalised dystonia, with progressive dose increase in children, and frequent adverse effects (blurred vision, dry mouth, confusion, memory loss and possible worsening of hyperkinetic dystonia). Tetrabenazine (Xenazine®) is more effective in mobile dystonias than in fixed postures; it is started at 0.5 mg/kg/day and increased weekly by 0.5 mg/kg/day according to efficacy and tolerance, in 3 daily doses (half-life 5 to 7 hours), with doses between 1 and 20 mg/kg/day (mean approximately 4 mg/kg/day) and not exceeding 200 mg/day; sedation affects up to 50% of patients and behavioural changes, depressive symptoms, oculogyric crises, hypersalivation, nausea and vomiting should be monitored [17]. The labels differ from these paediatric doses: in the US label safety and efficacy in children are not established, doses above 50 mg/day require CYP2D6 genotyping, the maximum is 100 mg/day (37.5 mg per dose) in extensive and intermediate metabolisers and 50 mg/day (25 mg per dose) in poor metabolisers, and there is a boxed warning on depression and suicidal ideation; the UK SmPC allows up to 200 mg/day in adults, with increases of 12.5 mg every 3–4 days, and does not define a paediatric dosage [67, 68]. Botulinum toxin type A is an adjunctive focal treatment for permanent spasticity or focal dystonia; in France, onabotulinumtoxinA and abobotulinumtoxinA have paediatric authorisation, and repetition of injections is decided by clinical response and the injector’s experience [17].

7.5. Diabetes (MIDD and MELAS diabetes)

There are no randomised trials in mitochondrial diabetes [37]. GeneReviews recommends dietary modification (especially in lean patients), oral antidiabetic medicines (typically sulfonylureas), avoiding metformin, and insulin when needed [1]. The MMS indicates that combination therapy, including insulin, may be necessary because insulin resistance and deficiency coexist [47]. The 2026 review by Chaudhry and colleagues, which proposes an algorithm based on pathophysiology rather than trials, suggests glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors as first-line treatment for their cardiorenal and oxidative stress-related properties, insulin in the presence of insulin deficiency, and caution with SGLT2 if baseline C-peptide is low because of the risk of ketoacidosis; it also summarises Newcastle guidance, which proposes a dipeptidyl peptidase 4 (DPP-4) inhibitor first-line when weight loss is undesirable [37]. The same review warns that diabetic ketoacidosis may be the first manifestation and that rapid correction of hyperglycaemia may worsen lactic acidosis, recommending repeated lactate measurement [37]. GLP-1 agents should be used cautiously in underweight patients or those with dysmotility [37]. A 2025 report describes metformin use without lactic acidosis in a patient with m.3243A>G; this is an isolated case that does not change recommendations [69].

The 2021 French PNDS (French National Diagnosis and Care Protocol), which also draws on the Newcastle guidance, recommends diet, oral antidiabetic agents and insulin without restriction, except metformin; it proposes sulfonylureas and DPP-4 inhibitors as first line, preferring the latter because they do not cause hypoglycaemia; it accepts GLP-1 receptor agonists for their cardiovascular benefit and SGLT2 inhibitors for their cardiorenal benefit, both with caution because of weight loss in patients who are already lean and, in the case of SGLT2 inhibitors, because of the risk of euglycaemic ketoacidosis, which makes them inadvisable in insulinopenia [17]. The need for insulin, when not present from the outset, usually arises within a few years, the sooner the lower the body mass index and the higher the glycated haemoglobin at diagnosis; involuntary weight loss and the presence of ketones indicate insulinopenia and require treatment to be reviewed, which may be combined (insulin with oral antidiabetic agents) or insulin alone; glucose self-monitoring and therapeutic education are part of treatment [17]. The other endocrinopathies are treated as those of other causes: calcium and vitamin D supplementation in hypoparathyroidism, levothyroxine in hypothyroidism, testosterone or oestrogens in hypogonadotropic hypogonadism and growth hormone in proven deficiency, the latter with caution and close monitoring because of variable efficacy and the risk of adverse effects; some teams do not recommend it because of the risk of worsening the disease [17]. First-line treatment thus differs between sources: sulfonylureas in GeneReviews, sulfonylureas or DPP-4 inhibitors in the PNDS and in Newcastle, GLP-1 agonists and SGLT2 inhibitors in the review by Chaudhry and colleagues; none is based on trials in mitochondrial diabetes [1, 17, 37].

7.6. Hearing, vision, heart, kidney and muscle

Audiometry is recommended at baseline assessment and then every 1–2 years, hearing aids for moderate to severe deafness and cochlear implantation for profound deafness, with outcomes described as good [1, 40, 47]. For vision, neuro-ophthalmological assessment with optical coherence tomography and electroretinography at diagnosis and an annual examination; ptosis may be corrected by an experienced surgeon [1, 47]. Cardiomyopathy is treated according to general guidelines, with diuretics, an angiotensin-converting enzyme inhibitor and a beta-blocker; the Clinical Cardiogenetics chapter reports, based on in vitro data, that carvedilol, metoprolol and propranolol inhibit mitochondrial function and identifies atenolol as first choice, a recommendation derived from laboratory data rather than clinical trials [48]. The Newcastle group advocates early introduction of an angiotensin-converting enzyme inhibitor and beta-blocker in confirmed cardiomyopathy, electrophysiological study for pre-excitation or conduction abnormalities and, since 2016, an implantable event recorder for arrhythmia surveillance in selected patients; an implantable cardioverter-defibrillator is indicated in patients at risk of sudden death, with wall thickness >30 mm or ventricular tachycardia [48, 51]. Heart transplantation is possible following multisystem assessment [1, 48]. For nephropathy, the MMS recommends a nephrologist with mitochondrial expertise and considers kidney transplantation, with good outcomes in most reported cases [47]. Supervised aerobic exercise improves oxidative capacity without reported adverse effects [1, 14].

Heart according to the French PNDS (French National Diagnosis and Care Protocol). There is no treatment targeting myocardial energy metabolism with demonstrated clinical benefit [17]. With left ventricular ejection fraction <45%, all validated heart failure treatments are applied (angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, beta-blockers and the others); with an ejection fraction of 45–50%, fibrosis on MRI without systolic dysfunction or elevated biomarkers, angiotensin-converting enzyme inhibitors are sometimes used without proof of efficacy, an option considered reasonable given the frequent progression to systolic dysfunction and good tolerance. Arrhythmias are treated as in the general population (antiarrhythmics and antithrombotics); there is no indication for a prophylactic pacemaker in “moderate” conduction disturbances (first-degree atrioventricular block, bundle branch blocks, hemiblocks), unlike Kearns–Sayre syndrome; a cardioverter-defibrillator for primary prevention should be considered only in systolic dysfunction and/or marked hypertrophy (thickness >20 mm) and/or non-sustained ventricular tachycardia, in patients with a good neurological and general prognosis and after multidisciplinary discussion, because the risk of sudden death appears lower than in other genetic hypertrophic cardiomyopathies; pre-excitation with re-entrant tachycardia warrants ablation of the accessory pathway [17]. Heart transplantation is discussed in end-stage failure after multidisciplinary assessment of extracardiac complications, mainly neurological, with no data suggesting a specific post-transplant risk [17]. In MIDD, cardiovascular risk assessment may justify antiplatelet therapy and a low-dose statin with monitoring for myalgia and CK [17]. The thickness threshold for the defibrillator (>20 mm in the PNDS, >30 mm in the Newcastle sources and Clinical Cardiogenetics) is one of the divergences between guidelines (section 7.11).

Kidney. Chronic kidney disease follows the usual rules of nephroprotection: referral to nephrology if albuminuria exceeds 300 mg/g, proteinuria 0.5 g/g or filtration rate is <60 mL/min/1.73 m²; early blockade of the renin–angiotensin system with an angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist; targets of proteinuria <0.5 g/g and blood pressure <130/80 mmHg (KDIGO 2012) [17]. The 2021 KDIGO guideline on blood pressure in chronic kidney disease replaced that target with systolic pressure <120 mmHg, measured in a standardised way in the office, when tolerated [70]. At stage 5 (GFR <15 mL/min), haemodialysis, peritoneal dialysis or transplantation may be proposed, after multidisciplinary assessment of extrarenal complications, and sometimes conservative treatment; in transplantation, kidney donation by a living mother should be excluded (the mother is usually a carrier) and mTOR inhibitors appear preferable for immunosuppression; recurrence of focal segmental glomerulosclerosis in the graft has not been described [17]. Guéry and colleagues add that the father may be a donor without specific contraindication, but that the variant should be excluded in the mother and siblings before donation [53]. In the same analysis, corticosteroid therapy did not change proteinuria in any of the 6 patients with glomerulosclerosis treated, and the authors advise against it in this glomerulosclerosis; in the 10 kidney transplants described there was no recurrence, but the 6 non-diabetic patients developed diabetes soon after transplantation (attributed in part to corticosteroids) and 2 had SLEs in the following 3 years, which justifies glycaemic and neurological monitoring after transplantation [53].

Hearing. No drug prevents or halts deafness [17]. A conventional hearing aid, unilateral or bilateral depending on the deafness, is recommended in permanent bilateral deafness with a mean threshold above 30 dB (criteria of the Bureau International d'Audiophonologie), a speech intelligibility threshold in quiet above 30 dB or significant degradation of intelligibility in noise, and may be proposed in mild deafness depending on its impact; it should be fitted by audiologists experienced in severe deafness [17]. Cochlear implantation follows the 2012 HAS criteria: bilateral profound deafness; severe deafness with disyllabic word discrimination <50% at 60 dB in binaural conditions with a well-fitted hearing aid; severe to profound unilateral deafness with disabling tinnitus and failure of a CROS or bone-conduction aid, or with fluctuating contralateral hearing; the indication results from multidisciplinary assessment in a specialised centre, the implant may be unilateral or bilateral, simultaneous or sequential, and a second implant is proposed if contralateral hearing deteriorates [17]. In cochlear implant users, in a neurological emergency, contrast-enhanced CT is preferred; if MRI is essential, 1.5 T is preferably used, with a tight head bandage over the implant and confirmation of the model’s compatibility [17].

Vision. Diplopia may be compensated with prisms or monocular occlusion with a filter; ptosis with an eyelid crutch mounted on spectacles or with surgery by a specialised team, preferably frontalis suspension (autologous fascia lata or silicone band, the latter adjustable postoperatively) when levator function is impaired; cataract is operated on by the usual technique under local anaesthesia; diabetic retinopathy and maculopathy follow the general recommendations [17]. Visual loss from retinopathy and optic atrophy does not recover; low-vision rehabilitation (oculomotor strategies, technical and optical aids) and reassessment of fitness to drive are part of treatment [17].

Digestive tract and dysautonomia. Only symptomatic treatment exists: ondansetron for recurrent vomiting, a proton pump inhibitor for vomiting and gastroparesis, erythromycin as second line, enteral nutrition and, in severe pseudo-obstruction with nutritional impact, parenteral nutrition [17]. Surgery for pseudo-obstruction appears contraindicated because of the risk of worsening lactic acidosis and decompensating the disease, without demonstrated efficacy; a venting gastrostomy is sometimes proposed [17]. For dysautonomia, in the absence of specific recommendations, the PNDS refers to the treatment of other causes (annex 12): in gastroparesis, dietary measures (splitting meals, limiting fats and poorly digestible fibre, avoiding tobacco, alcohol and carbonated drinks) and, if these fail, metoclopramide or domperidone, with erythromycin as second line (IV in exacerbations, oral in chronic treatment, with attention to cardiac risk and interactions); in constipation, fibre and polyethylene glycol osmotic laxatives; in alternating diarrhoea and constipation, ispaghula bulk-forming laxatives; in refractory diarrhoea, loperamide and, if this fails, a somatostatin analogue [17]. In urinary disorders: intermittent self-catheterisation or catheterisation by a carer in chronic retention, retraining and continence products in incontinence, hygiene measures and sequential antiseptic or antibiotic in recurrent infections (more than 3 per year), antimuscarinics with caution in storage dysfunction (risk of retention), intradetrusor botulinum toxin in neurogenic overactivity and neuromodulation [17]. In symptomatic orthostatic hypotension: eliminate aggravating factors (antihypertensives, anaemia, dehydration), stand up slowly, avoid large meals and hot environments, increase salt if possible, compression stockings or tights and, if these fail, midodrine (risk of supine hypertension) and, as second line and with caution, fludrocortisone (hypertension, weight gain, electrolyte disturbances and risk of adrenal insufficiency on abrupt withdrawal) [17].

Breathing, neuropathy and muscle. Respiratory failure is treated as in chronic neuromuscular diseases with hypercapnic decompensations (PaCO2 ≥45 mmHg) [17]. Neuropathy follows the treatment of non-mitochondrial neuropathies, with no demonstrated benefit from drugs or vitamins; it requires optimal glycaemic control, active treatment of neuropathic pain with antiepileptics or antidepressants (taking ataxia and other comorbidities into account), sometimes in a pain clinic, early non-pharmacological and psychological approaches and, for orthopaedic deformities, preference for conservative treatment [17]. Coenzyme Q10 may sometimes reduce fatigability or myalgia, without robust proof, and L-carnitine is given in proven deficiency [17]. In acute rhabdomyolysis: prevent or treat kidney injury with hyperhydration with potassium-free crystalloids (sometimes with vasoconstrictors used with caution), correct any hyperkalaemia above 5 mmol/L and hypocalcaemia only if severe, do not correct hyperphosphataemia and monitor fluid balance in intermediate care in severe forms [17].

7.7. Anaesthesia, intercurrent illness and prevention

The MMS recommends minimising preoperative fasting, adding glucose to intravenous fluids (except with a ketogenic diet or pyruvate defects), caution with volatile anaesthetics and muscle relaxants, and repeating neuroimaging when neurological changes occur [47]. GeneReviews recommends routine, influenza and pneumococcal vaccination because febrile illnesses may trigger decompensation [1]. The 2026 consensus recommends multidomain cognitive assessment, cognitive rehabilitation, selective serotonin or serotonin–noradrenaline reuptake inhibitors for depression and anxiety, psychological support for patients and caregivers, and standard migraine treatment, including triptans, gepants, ditans and monoclonal antibodies for migraine prevention (the latter with monitoring because data are lacking) [13].

The French PNDS (French National Diagnosis and Care Protocol) adds the following anaesthetic precautions (annex 16), without trials comparing them [17]. There is no association with malignant hyperthermia, but postoperative central hyperthermia (24–48 h) has been described; spinal anaesthesia with bupivacaine or tetracaine and epidural anaesthesia may be used, and regional anaesthesia is avoided only in the presence of axonopathy or sensorimotor lesions. Almost all anaesthetics depress the respiratory chain in vitro (barbiturates and etomidate complex I; propofol and benzodiazepines complexes I, II and III; halogenated agents complex I and coenzyme Q; bupivacaine acylcarnitine translocase; fentanyl and remifentanil minimal effect; dexmedetomidine no effect described), but general anaesthesia with IV or volatile agents and non-depolarising neuromuscular blockers has been used without complications. Prolonged propofol infusion above 4 mg/kg/h (66 µg/kg/min) increases the risk of propofol infusion syndrome and requires lactate monitoring; a single propofol bolus at induction is acceptable, except in recent deterioration or metabolic crisis. There is greater sensitivity to sedatives, hypnotics and opioids (prefer remifentanil), ketamine is an alternative for minor surgery, and elective surgery should be postponed during fever or metabolic crisis. In the preoperative assessment: neurological status, ECG and echocardiogram, glucose, transaminases, renal function, endocrinopathies, baseline lactate, swallowing and reflux, sleep apnoea and treatments. During anaesthesia: short fast (sugary fluids up to 1 h before) or glucose infusion from the start of the fast (except on a ketogenic diet), carnitine and usual antiepileptics in the morning, maintenance with a balanced electrolyte solution with 5% or 10% glucose (avoid lactate), monitoring of glucose and lactate, avoid hypoventilation or hyperventilation and hypothermia or hyperthermia, avoid suxamethonium (rhabdomyolysis, hyperkalaemia) and use non-depolarising neuromuscular blockers (rocuronium, atracurium, cisatracurium) with monitoring, avoid prolonged tourniquet use; in recovery, monitoring in intermediate care because of the reduced response to hypoxia and hypercapnia, with glucose and lactate. On a ketogenic diet: avoid prolonged fasting and carbohydrate-containing solutions (including syrups, glycerol, mannitol and the hidden intake from transfusions), target glucose of 50–80 mg/dL at induction, propofol only at induction, avoid corticosteroids, prefer Plasmalyte®, correct hypoglycaemia with 0.25 g/kg of glucose, resume the diet as soon as possible with ketonuria between 40 and 160 mg/dL [17]. It also refers to the Orphanesthesia guidance on mitochondrial diseases [17].

The PNDS recommends the usual vaccines, including influenza, pneumococcal and SARS-CoV-2, based on the conclusion of the WHO Global Advisory Committee on Vaccine Safety that there is no evidence of an association between vaccination and worsening of mitochondrial diseases, whereas febrile infections may trigger decompensations [17]. For migraine it accepts the usual analgesics and triptans, with caution with acetylsalicylic acid and non-steroidal anti-inflammatory drugs and noting that topiramate may worsen acidosis; for cognitive disorders no drug is recommended and anticholinesterases have insufficient data, cognitive remediation with a speech therapist being useful; psychiatric symptoms are treated with the usual drugs and depression with antidepressants [17].

7.8. Regulatory status

An orphan or Fast Track designation is not a marketing authorisation, and authorisation in one country does not imply reimbursement or access elsewhere. No information on access to these products in Portugal (INFARMED) or Brazil (ANVISA/CONITEC) was found in the sources consulted. In France, the 2021 PNDS (French National Diagnosis and Care Protocol) lists coenzyme Q10 (ubiquinone) and idebenone (Mnesis®) as available under temporary authorisations for use (ATU) and ubiquinol only as a food supplement; the same document serves as the reference for the care protocol under the long-term condition scheme (ALD), with exemption from patient co-payment, and for identifying products used outside their marketing authorisation [17].

7.9. Clinical trials and developments over the past 12 months

Trials in this disease are small, often open-label and uncontrolled, with primary endpoints not met or still unpublished. Positive results in secondary analyses or after post hoc stratification of sonlicromanol do not demonstrate efficacy; the 60% proportion of complete prevention with taurine derives from 10 patients without a comparison group and the confidence interval is wide; the absence of statistical significance in the Japanese arginine trials does not prove inefficacy, but prevents benefit being asserted. Indirect comparison between these studies does not allow the interventions to be ranked. The 2025 study by Stefanetti and colleagues showed that, in MELAS, patient-reported measures may not align with objective measures, which has implications for endpoint selection in trials [44].

Over the past 12 months (October 2025 to October 2026), verified developments were: publication of the European–American consensus on the definition and treatment of MELAS and SLEs (peer-reviewed article, March 2026) [13]; the start of dosing in the phase 3 KHENERFIN trial (sponsor press release and registry, April 2026) [30, 72]; completion of PRIZM recruitment (January 2026 press release) and completion of the trial in the registry, without released results [31, 75]; the review by Chaudhry and colleagues with an algorithm for MIDD diabetes (review article, 2026) [37]; and the Slovak screening study in 5,957 probands (2026) [40]. European orphan designations for KL1333 (2017) and sonlicromanol (July 2025) remain active in the Union register consulted on 6 October 2026 [73]. The search found no new medicine authorisation for MELAS in the USA or EU during that period, which does not prove the absence of non-public regulatory processes.

7.10. Rehabilitation, nutrition, psychological support and particular situations

The French PNDS (French National Diagnosis and Care Protocol) gives rehabilitation a central place [17]. A physical medicine and rehabilitation consultation is recommended in the presence of hemiparesis, ataxia or neuromuscular involvement, particularly after an SLE. Physiotherapy, regular and tailored to an initial assessment, distinguishes three presentations: SLE sequelae (techniques validated in stroke), myopathic symptoms (exercise reconditioning, muscle strengthening, adapted physical activity) and the ataxic form (proprioception, balance, gait, coordination, fall prevention), with a playful dimension in children; isolated passive techniques bring no lasting benefit. Occupational therapy intervenes as soon as there is an impact on independence (hygiene, dressing, eating, writing, keyboard), in technical aids, home adaptation and wheelchair prescription. Speech therapy should start early in the presence of deafness (lip reading and strengthening of cognitive skills in severe postlingual deafness, maintained after cochlear implantation), aphasia, dysarthria, swallowing disorder (texture modification, cold and carbonated drinks, straw, forward head flexion, buccofacial praxis, pneumophonic coordination, elimination of distractors) or cognitive disorder [17].

Aerobic training programmes are supported by two small trials with m.3243A>G carriers, cited in annex 13 of the PNDS [17]. In the first, 20 patients (13 with m.3243A>G) underwent 14 weeks of cycling (50 sessions, approximately 4 per week) at a heart rate of 70–80% of that reached at peak VO2: maximal power increased by 29% and maximal VO2 by 26%, without histological changes, with stable heteroplasmy and an 81% ± 124% increase in mtDNA quantity. In the second, 10 adults with m.3243A>G trained for 16 weeks, 3 times a week, at the same relative intensity: maximal power increased by 12% and maximal VO2 by 16%, with unchanged CK. The level of evidence is low, but there were no signs of muscle injury. The PNDS requires prior cardiological assessment and stepwise progression, changing only one parameter at a time (duration, intensity or frequency), only after several stable weeks and if all tolerance criteria are met: absence of muscle pain on the following days, of new or worsening pain during sessions, of unusual fatigue not resolving within a few hours and of cardiac, neurological or sensory symptoms (which require stopping immediately and seeking medical advice); in case of deterioration, training is interrupted and resumed at a lower level with medical authorisation [17].

In nutrition, the aim is to ensure sufficient energy intake, particularly for growth [17]. The ketogenic or high-fat diet controls seizures in respiratory chain deficiencies and, in cell and animal models, stimulates mitochondrial biogenesis, reduces oxidative stress and slightly lowers the proportion of mutant mtDNA, supplying ketone bodies to complex II and bypassing complex I; in patients, results in SLEs are contradictory. In children, a less restrictive high-fat diet is usually started first and the strict ketogenic diet (3:1 or 4:1) is reserved for worsening of the disease or onset of epilepsy; lipid proportions range from 70% of energy at the 1:1 ratio to 90% at 4:1, with protein according to nutritional references for growth, energy at least equal to requirements for age, sugars almost eliminated and starches controlled; ketosis is checked daily by urine dipstick at the start; a 4:1 ketogenic powdered formula (Ketocal®, Nutricia) exists that can be used in bottles, meals and tube feeding [17].

Psychological support should begin at diagnosis and continue throughout life, including the parents when the patient is a child, with attention to the risk of depression and isolation [17]. Therapeutic education, in individual and group sessions, aims at knowledge of the disease and treatments, prevention of decompensations and first measures at home, with progressive involvement of the child to strengthen adherence in adolescence [17]. Transition to adult services should be planned, explained and carried out during a period of metabolic stability, ideally with a joint consultation of the paediatrician, adult physician, psychologist and social worker, and with supervision by a specialised centre throughout life [17]. For travel, symptomatic patients should carry a certificate with a summary of the disease, risk situations, actions to take and contact details of the reference centre, which also allows medicines and special products (such as the ketogenic formula) to be carried in the aircraft cabin [17]. In advanced disease with multiple disability, severe dystonia or infectious complications, or when life is at risk during an exacerbation, palliative care and end-of-life support may be instituted by shared ethical decision between teams, ethics committees and families; in paediatrics, the PNDS suggests recording the goals in a certificate for patients with special care needs [17]. Organ retrieval for donation from a deceased patient with mitochondrial disease is, according to the PNDS, absolutely contraindicated [17].

7.11. Divergences between the French PNDS and the other guidelines

8. Reproductive Options and Family Counselling

8.1. Risk to relatives

Transmission is maternal: the father of a proband does not have the variant; the mother usually has it, with or without symptoms, although it may be undetectable in leucocytes and detectable in other tissues; the proband may have a somatic de novo variant; if the mother is a carrier, all siblings inherit the variant, with unpredictable loads; all children of a female carrier inherit the variant and no child of a male carrier inherits it; the siblings and mother of a carrier mother are also at risk [1, 35, 42]. Paternal transmission is exceptional and, for counselling purposes, the risk is considered essentially zero [8]. Families with apparently de novo m.3243A>G have been described; in an umbilical cord study, the rate of variants not detected in maternal blood was estimated at 0.00107% of live births [78, 79].

Individual phenotype prediction from the load is very imprecise [1, 16]. The Oxford Desk Reference proposes empirical estimates for offspring: low load (<30% in muscle, <10% in blood), asymptomatic woman or diabetes alone, probable risk of affected offspring approximately 15–25%; moderate load (>50% in muscle) or symptoms beyond diabetes and/or deafness, probable risk above 60%; the entire maternal line has increased risk of diabetes, deafness and cardiomyopathy [16]. GeneReviews adds that women with higher blood loads may be more likely to have affected children [1]. These values are approximations without prospective validation and should be presented as such. The mitochondrial genetic bottleneck during oogenesis explains large load variations between siblings [3, 8].

Predictive testing may be offered to maternal-line relatives, but interpretation in asymptomatic individuals is very difficult [1, 16]. Its clinical utility lies mainly in surveillance: diabetes, hearing, ECG and echocardiography, because sudden death may occur in young asymptomatic carriers, leading the Newcastle group to recommend extensive family screening [1, 51]. The UK SLE prediction model (body mass index, age-adjusted blood load, deafness severity and serum lactate; area under the curve 0.87) may support stratification and counselling [36].

The French PNDS (French National Diagnosis and Care Protocol) adds rules for the organisation of counselling [17]. The genetic counselling consultation, separate from the diagnostic consultation, is the responsibility of a trained physician or a genetic counsellor, preferably in a reference or competence centre, and addresses the mode of transmission, variability of expression, monitoring of treatable complications, the risk of having an affected child and the alternatives (oocyte donation, prenatal and preimplantation diagnosis). The patient, or the parents of a minor, should be informed of the French legal obligation to inform at-risk relatives (decree no. 2013-527), and may ask the physician to do so. To distinguish an inherited variant from a de novo one, the variant is sought in the mother in blood, urine and buccal mucosa, because the blood load decreases with age and may become undetectable; absence in several maternal tissues favours a de novo variant, with a very low recurrence risk and reassuring counselling for the mother’s maternal line, but does not exclude a low load in the oocytes, which is why prenatal diagnosis is offered. In carriers with a low load, prenatal or preimplantation diagnosis may be offered; with a very high load, or if the woman does not wish to undergo these procedures, oocyte donation is the only way to prevent transmission with certainty [17].

For asymptomatic relatives in the maternal line, the PNDS specifies that the test be prescribed in an individual consultation by a physician from a dedicated multidisciplinary team (article R.1131-5 of the French Public Health Code) and performed on two independent samples, at least one of urine; testing is not a condition for surveillance, which may be offered to those who prefer not to know their status, and only allows surveillance to be discontinued if the variant is undetectable in tissues of different origins by a sensitive technique [17]. Presymptomatic diagnosis in minors is discussed case by case: it is not usually authorised in the absence of preventive or curative treatment, but may be justified by early screening for treatable complications (diabetes, heart, deafness), weighing the psychosocial consequences of a result that does not predict the age of onset and the fact that surveillance can be offered to any child at risk [17]. The incidental finding of a very low m.3243A>G load may, depending on the context, lead to the person being considered presymptomatic and offered the same follow-up [17].

8.2. Prenatal diagnosis, preimplantation genetic testing and mitochondrial donation

Preconception counselling is recommended for women with MELAS and young adult women at risk, ideally before pregnancy [1]. Pregnancy should be supervised by an obstetrician with monitoring for diabetes, respiratory failure, pre-eclampsia and preterm delivery [1, 47, 54]. Premature ovarian insufficiency may require assisted reproductive techniques [47].

8.3. Pregnancy: surveillance according to the French PNDS

The PNDS (French National Diagnosis and Care Protocol) recommends follow-up by an obstetrician aware of the disease and informing asymptomatic carriers of the increased risk of gestational diabetes (approximately 10%), whose screening and treatment (diet and insulin) are the usual ones, with reassessment of glucose tolerance postpartum [17]. In pre-existing diabetes, pregnancy should be planned with glycated haemoglobin <6.5% in the periconceptional period and a switch to insulin alone if the patient is taking oral antidiabetic agents, then following the rules for diabetic pregnancy (monthly glycated haemoglobin, quarterly fundoscopy, fetal echocardiography); if there is pre-existing diabetes, fundoscopy and macular optical coherence tomography in the first trimester. In hypothyroidism, levothyroxine doses are increased with monthly TSH. Neurologically, the antiepileptic is maintained and adjusted; myopathy, neuropathy and SLEs may worsen, respiratory failure, which is rare, may require preventive non-invasive ventilation at the end of pregnancy, and in the presence of acute focal deficit MRI may be performed at any gestational age, preferably at 1.5 T and without contrast. For the heart, ECG and echocardiography before conception and early in pregnancy; hypertrophic cardiomyopathy or systolic dysfunction justify assessment in a specialised centre and periodic surveillance according to severity, with a second assessment by the third trimester in less severe forms, because of the risk of heart failure or potentially fatal arrhythmias; angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists should be stopped as soon as pregnancy is planned, with proteinuria at least monthly in nephropathy [17].

9. Special Considerations: Population Diversity and Epidemiology

Estimates should distinguish variant carriers, symptomatic patients and patients with MELAS. For carriers: in Finland, a study of 245,201 adults with phenotype-directed screening found a frequency ≥16.3/100,000 (95% CI 11.3–21.4) [1, 9], and the variant arose independently at least nine times in that population, excluding a single founder effect [9]; in Australia, in a population cohort of 2,954 people (99% of European ancestry, mean age 66 years), frequency was 236/100,000 (0.24%; 95% CI 0.10–0.49%), all with mild to moderate deafness [10]; in the United Kingdom, approximately 1 in 400 people [2, 51]; in 3,168 cord blood samples from sequential births, at least 1 in 200 newborns had one of ten pathogenic mtDNA variants, with m.3243A>G the most common [79]; Inborn Metabolic Diseases reports low load in 0.2% of the European population [3]. For disease: in north-east England, the minimum prevalence of disease-causing pathogenic mtDNA variants (symptomatic and asymptomatic) was 1 in 5,000 adults, and that of all adult mitochondrial disease approximately 1 in 4,300 [82]. For MELAS: 0.18/100,000 in Japan [11]. The Orphanet record for MELAS brings together values of differing nature (0.18/100,000 in Japan; 1.63/100,000 in Finland; 236/100,000 in a specific population, corresponding to carriers; 0.6/100,000 in Europe, according to the EMA in 2015) [83]. The Oxford Desk Reference cites MELAS as one of the most common mitochondrial diseases (1/10,000), an estimate that does not distinguish carriers from patients [16]. The French PNDS (French National Diagnosis and Care Protocol) summarises the variant frequencies as 0.95/100,000 in England (epidemiological study by Chinnery and colleagues, 2000), 18/100,000 in Finland (paediatric study by Uusimaa and colleagues, 2007) and 236/100,000 in Australia, the prevalence of MELAS at approximately 0.2/100,000 in Japan and that of mitochondrial diseases at 1/5,000; it presents no French data [17]. The English estimate of 2000 is far lower than the frequency of approximately 1 in 400 cited for the United Kingdom and than that obtained in cord blood (at least 1 in 200 newborns with one of ten variants, m.3243A>G being the most common), which illustrates the weight of the ascertainment method in these estimates [2, 17, 79].

The discrepancy between carrier and disease frequencies reflects incomplete penetrance and threshold effects [71]. Hospital series data (for example, the MRC cohort or Finnish SLE cohort) describe phenotype distribution among referred patients and are not population prevalences [2, 41]. In diabetes, frequency depends on the population screened: 0.14% in a general diabetes cohort and 1.68% in a monogenic diabetes cohort in Slovakia [40]. Sex data suggest differences in urinary loads, requiring adjustment [15].

The most frequently cited prospective natural history data come from the cohort of 35 families of Kaufmann and colleagues (31 patients with MELAS and 54 carrier relatives) [84]; in Europe, from British and Finnish cohorts and other reference centre series [2, 38, 41, 50, 54]; in Japan, from the national survey [11]. The Brazilian book Síndromes Genéticas: Reconhecer para Tratar reports that no MELAS epidemiological data exist in Brazil [42]; no Portuguese population data were found in the sources consulted, which does not demonstrate their absence.

10. Illustrative Clinical Case

10.1. MELAS with diabetes presenting as a hyperglycaemic crisis and rapid cognitive decline (Tran et al., 2023)

A 36-year-old woman with a family history of diabetes (Figure 1 of the original article: mother, aunt and uncle treated with oral antidiabetic medicines in adulthood; sister and cousin receiving insulin since their twenties, all in the maternal line) was admitted at 27 years, in 2013, with altered consciousness and seizures, without a diagnosis; in 2018 she was admitted again with the same symptoms, followed by progressive dementia and deafness [46]. In 2020, aged 34 years, she presented with vomiting and headaches, with glucose 4.5 mmol/L and lactate 3 mmol/L; genetic testing confirmed m.3243A>G and MELAS was diagnosed, with coenzyme Q10, thiamine, folic acid and acetyl-L-carnitine prescribed [46]. In March 2022 she was admitted in a coma with seizures, dehydration and deep breathing; her body mass index was 16.9 kg/m² and, in the preceding month, she had polyuria, weight loss and frequent consumption of sugary drinks. Tests showed glucose 33.8 mmol/L, glycated haemoglobin 10.4%, lactate 10.2 mmol/L, pH 7.35, bicarbonate 16 mmol/L, β-hydroxybutyrate 0.93 mmol/L and estimated glomerular filtration rate 53 mL/min/1.73 m²; MRI showed left frontal hyperintense oedema and old lesions (Figure 2A–C of the article) [46].

Metabolic abnormalities resolved in 2 days with an insulin infusion and fluids, and lactate fell to 2.5 mmol/L; the patient regained consciousness on day 7 and was discharged on day 10 with basal–bolus insulin (glargine 18 U and glulisine 6 U before meals), later reduced to glargine 12 U with a DPP-4 inhibitor [46]. She was readmitted in April and May 2022 with seizures and loss of consciousness; in April, after two days of transient visual loss, MRI showed a new left occipital lesion with cortical diffusion restriction and subcortical vasogenic oedema (Figure 2D–F) [46]. Despite improved glycaemia (glycated haemoglobin 7.6%), cognition, communication, vision and hearing deteriorated and, from July 2022, the patient became dependent for daily activities [46].

Links to the figures consulted: Figure 1 — pedigree and Figure 2 — MRI in March and April 2022.

The case brings together several elements of the spectrum: maternal transmission of diabetes with type 2 and type 1 phenotypes in the same family, absence of systematic diabetes screening after MELAS diagnosis, diabetes presenting as a hyperglycaemic crisis with marked lactic acidosis, and recurrent SLEs with rapid decline. The authors speculate that acute diabetes onset contributed to cognitive decline, a hypothesis that an isolated case cannot confirm; they recommend patient education and diabetes screening with glycated haemoglobin or a glucose tolerance test, consistent with recommendations for annual glucose surveillance [1, 46, 47]. The supplement combination used in this case has no demonstrated efficacy according to the 2026 consensus, and the transition to a DPP-4 inhibitor corresponds to one of the options described in Newcastle guidance summarised by Chaudhry and colleagues [13, 37].

10.2. Sudden death in young asymptomatic carriers (Ng et al., 2016)

A 30-year-old man was assessed following family screening: his mother had developed MELAS at 54 years (load 66% in muscle, 53% in urine and 20% in blood). He worked, exercised regularly and was asymptomatic apart from mild deafness and occasional bowel complaints; ECG, 24-hour Holter and echocardiography were normal; load was 92% in urine and 39% in blood. He died suddenly during sleep after an evening in which he had consumed 10 units of alcohol [51]. A teacher whose sister had had an SLE in adolescence, with a normal ECG and mild non-progressive left ventricular hypertrophy, and loads of 68% in urine and 30% in blood, was found dead in bed after a night out [51]. In both, post-mortem studies showed severe respiratory chain deficiency and high variant loads in the heart, without myocardial fibre disarray; the hypertrophic cardiomyopathy sudden death risk tool would not have identified them [51]. These cases underpin cardiovascular assessment of all carriers, family screening and inclusion of m.3243A>G in the molecular autopsy of unexplained sudden adult death [51].

11. Prognosis and Long-Term Follow-Up

11.1. Natural history and mortality

MELAS progresses over years, with episodic deterioration related to SLEs and a variable course between patients [1]. In the prospective cohort of Kaufmann and colleagues (85 relatives from 35 families, follow-up to 10.6 years), neurological examination, neuropsychological tests and daily living scales declined in all patients with MELAS, without significant deterioration in carrier relatives; ventricular lactate on spectroscopy increased and was associated with greater mortality, and childhood onset was associated with a worse course [84]. According to GeneReviews, in this cohort mortality was more than 17 times higher in fully symptomatic patients than in carriers, mean observed age at death was 34.5 ± 19 years (10.2–81.8), 22% of deaths occurred before 18 years and estimated median survival was 16.9 years after focal neurological disease onset [1]. In Japan, 96 patients showed rapid progression over 5 years; 20.8% died at a median of 7.3 years after diagnosis, and the juvenile form had a greater risk of death than the adult form (HR 3.29; 95% CI 1.32–8.20) [1, 11]. In 33 adults with m.3243A>G followed for 3 years, neurosensory function, left ventricular hypertrophy, EEG abnormalities and overall severity worsened [1]. In the Finnish SLE cohort, mean time between the first SLE and death was 3.6 years (0–16) [41]. POLG disease with SLEs had a more fulminant course than m.3243A>G, but neurodegeneration (atrophy and lower brain weight) was more marked with mtDNA variants [36]. The Brazilian textbook reports that SLE deficits tend to improve over months, whereas dementia and seizures may progressively worsen [42]. The French PNDS (French National Diagnosis and Care Protocol) adds that, in the cohort of 151 carriers of de Laat and colleagues (82% symptomatic, only 5% with MELAS) followed for 6 years, the Newcastle Mitochondrial Disease Adult Scale (NMDAS) score increased on average by approximately 0.5 points per year, mainly through hearing loss, speech disturbances, exercise intolerance, imbalance, and psychiatric and gastrointestinal symptoms; that in the Japanese survey 60% of the 96 patients had the juvenile form (onset before 18 years) and 17 of the 20 who died had that form (in the original publication, 58 of the 96 patients had the juvenile form, with 29.3% deaths over the 5-year follow-up, versus 7.9% in the adult form) [11]; and that progression is slow in MIDD and oligosymptomatic forms and marked by episodic deterioration in MELAS, with carriers who never become ill [17]. As severity factors it points to onset before 18 years of age, the duration and refractoriness of status epilepticus in the SLE and a very low ADC in the white matter adjacent to the cortical lesion [17].

Reported causes of death include end-stage heart failure, frequent in patients with m.3243A>G, and sudden arrhythmic death, including in asymptomatic carriers [51, 52]. In adults with mitochondrial disease, intraventricular block, diabetes, ventricular ectopic beats and left ventricular hypertrophy predict major cardiac events [50, 52]; in m.3243A>G carriers, age-adjusted blood load is associated with overall disease severity [15, 40].

11.2. Recommended surveillance

The Brazilian textbook recommends annual ophthalmological, audiological, cardiological (ECG and echocardiography) and endocrine (fasting glucose and TSH) assessments [42]. For daily living, the MMS recommends planning travel to high altitude and monitoring oxygen saturation during flights in patients with cardiomyopathy or respiratory weakness [47].

The French PNDS (French National Diagnosis and Care Protocol) recommends, in the absence of intercurrent events, at least one annual consultation in a reference or competence centre, with systematic search for the signs of each organ, and intervals by specialty according to whether or not there is known involvement; in advanced stages, involving a palliative care team is justified [17]:

For asymptomatic carriers and at-risk relatives who do not wish to be tested, the PNDS proposes a multidisciplinary initial assessment (genetics, neurology, hearing, ophthalmology, cardiology, endocrinology, digestive tract and kidney) that demonstrates the absence of signs and serves as a baseline, followed by surveillance adapted to age, comorbidities, the phenotype of affected relatives and the patient’s understanding, vigilant enough not to miss diabetes, cardiac involvement or SLE, but without a burden that compromises adherence [17]:

In the symptomatic child, the paediatric annex of the PNDS proposes a paediatric neurology consultation 3 times a year (neurological and neuromuscular signs, growth and head circumference), annual otorhinolaryngology, ophthalmology and paediatric cardiology (ECG and echocardiography), paediatric endocrinology, gastroenterology and nephrology in the presence of warning signs, tests (liver function tests, lactate, calcium, phosphate, vitamin D, TSH) annually or at decompensation, brain MRI at diagnosis and then according to the clinical picture, neuropsychological assessment at diagnosis from 6 years of age and then every 2–3 years, Holter every 2–5 years if there are abnormalities and cardiac MRI every 5 years in hypertrophic cardiomyopathy [17]. The ophthalmological examination is performed with the child awake: slit-lamp biomicroscopy and fundoscopy from very early on, visual acuity with the acquisition of language, optical coherence tomography and autofluorescence from 3–4 years of age and kinetic perimetry from 5–6 years (before that, confrontation visual field); systematic cardiac assessment begins at 10 years, the age from which the first complications appear in genetic cardiomyopathies [17].

The main differences from the other sources are the longer cardiac intervals in patients without cardiac involvement (2–3 years, versus annual in GeneReviews) and in asymptomatic carriers (3 years and then every 5 years), audiometry every 3 years in asymptomatic adults and the PNDS’s internal inconsistency regarding Holter and cardiac MRI (section 7.11) [1, 17, 48].

11.3. Networks and resources

In Europe, adult and paediatric patients are followed within ERN EURO-NMD (mitochondrial diseases working group) and MetabERN, which coordinated the 2026 consensus with the North American MMS [13]. Patient associations: United Mitochondrial Disease Foundation (USA), International Mito Patients, The Lily Foundation (United Kingdom), Mito Foundation (Australia) and MITOCON (Italy); the North American Mitochondrial Disease Consortium patient contact registry is available in the USA [1, 13, 16].

In France, the PNDS (French National Diagnosis and Care Protocol) organises care around two reference centres for mitochondrial diseases in children and adults, integrated into the FILNEMUS rare neuromuscular disease health network: CALISSON, with its coordinating centre in the medical genetics department of Nice University Hospital and a constituent centre in the paediatric neurology department of La Timone Hospital (Marseille), and competence centres in Lyon, Montpellier and Toulouse; and CARAMMEL, with its coordinating centre in the molecular genetics department of Necker-Enfants Malades Hospital (Paris), constituent centres in Angers, Bordeaux, Le Kremlin-Bicêtre and Strasbourg and competence centres in Caen, Dijon, Paris (Lariboisière and Henri Mondor), Rouen and Tours [17]. The reference centre for genetic deafness (Necker, with constituent centres at Pitié-Salpêtrière and in Lille), the network of cochlear implant centres and the reference centre for inherited metabolic diseases in adults (Pitié-Salpêtrière) collaborate [17]. The associations listed are AMMi (Association contre les Maladies Mitochondriales), Alliance Maladies Rares, AFM-Téléthon and associations of deaf people and of cochlear implant users; general information refers to Orphanet [17].

The PNDS also describes the French social framework, useful as a model of organisation [17]: exemption from patient co-payment with 100% coverage of disease-related expenses under the long-term condition scheme (ALD), without dispensing with basic social coverage, because it does not include the daily hospital fee (forfait hospitalier); transport to reference centres more than 150 km away subject to prior approval; at school, a personalised schooling plan (PPS) defined with the Maison Départementale des Personnes Handicapées (MDPH), a classroom assistant (AESH), extra time in examinations and an individualised reception plan (PAI) for medication, ketogenic diet or emergency procedures; before 6 years of age, early medico-social action centres (CAMSP) and, if necessary, medico-educational institutes and home-based special education services; for parents, parental presence leave and daily allowance (continuous maximum of 28 months) and the supplement to the disabled child education allowance; for adults, recognition of disabled worker status, sheltered or adapted employment, the disabled adult allowance, the disability compensation benefit, an invalidity card from 80% disability, a parking card and respite stays for carers.

12. Summary and Final Considerations

m.3243A>G in MT-TL1 is the most frequent pathogenic mtDNA variant and defines a spectrum ranging from the asymptomatic carrier to MELAS, through MIDD, PEO, cardiomyopathy and nephropathy; classical MELAS accounts for approximately 10% of symptomatic patients in the largest European cohort [2]. Carrier frequency (16 to 236 per 100,000, depending on the study) is much higher than disease frequency, explained by heteroplasmy, the threshold effect, tissue segregation and nuclear factors [9, 10, 38]. Molecular diagnosis should use urine and/or muscle in addition to blood, with heteroplasmy quantification and age correction of blood load, and variant description should use NC_012920.1, taking account of the different numbering in the hg19 assembly [7, 14, 15].

The 2026 consensus restricted MELAS diagnosis to mtDNA variant carriers with at least one SLE and shifted acute treatment towards early seizure control and multisystem support, with a negative consensus on routine L-arginine and taurine, whereas the 2015–2017 North American recommendations and GeneReviews retain IV and oral L-arginine [1, 13, 47]. No medicine is approved in the USA or EU; taurine is authorised in Japan; sonlicromanol, zagociguat and KL1333 are in controlled trials, without efficacy results enabling clinical use [29–31, 74]. Diabetes, deafness and cardiac risk — including sudden death in asymptomatic carriers — justify maternal-line screening and structured annual surveillance [1, 50, 51]. In reproduction, PGT and, in the United Kingdom, mitochondrial donation offer alternatives, but phenotype prediction from the load remains imprecise [1, 80, 81]. The 2021 French national protocol adds a complete model of organisation: systematic initial assessment by organ, differentiated surveillance for patients and asymptomatic carriers, paediatric and adult dosages of supplements and arginine, rules for rehabilitation and aerobic training, anaesthetic and obstetric precautions and prenatal diagnosis by amniotic fluid with load thresholds; it diverges from the other sources on the initial sample (urine), the choice of antidiabetic agents, the threshold for the defibrillator and the intervals for cardiac and auditory surveillance [17].

13. References

1. El-Hattab AW, Almannai M, Scaglia F. MELAS. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. Published 27 February 2001; last updated 29 November 2018. PMID: 20301411. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1233/
2. Nesbitt V, Pitceathly RD, Turnbull DM, Taylor RW, Sweeney MG, Mudanohwo EE, et al. The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation—implications for diagnosis and management. J Neurol Neurosurg Psychiatry. 2013;84(8):936-8. doi:10.1136/jnnp-2012-303528. PMID: 23355809.
3. Rahman S, Mayr JA. Disorders of Oxidative Phosphorylation. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 10 (sections 10.1–10.5). doi:10.1007/978-3-662-63123-2_10
4. Orphanet. MELAS (ORPHA:550). Version of 02/07/2026. Available from: https://www.orpha.net/en/disease/detail/550 (accessed 6 Oct 2026).
5. Orphanet. Maternally-inherited diabetes and deafness (ORPHA:225). Version of 02/07/2026. Available from: https://www.orpha.net/en/disease/detail/225 (accessed 6 Oct 2026).
6. National Center for Biotechnology Information. ClinVar. VCV000009589: NC_012920.1(MT-TL1):m.3243A>G — Pathogenic (reviewed by expert panel; last evaluation 20 August 2020). Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/9589/ (accessed 6 October 2026).
7. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-8. doi:10.1002/humu.23348. PMID: 28967166. Query for NC_012920.1:m.3243A>G (VariantValidator 4.0.1, vvdb_2025_3) on 6 October 2026: https://rest.variantvalidator.org
8. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Mitochondrial inheritance; p. 34–5.
9. Majamaa K, Moilanen JS, Uimonen S, Remes AM, Salmela PI, Kärppä M, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet. 1998;63(2):447-54. doi:10.1086/301959. PMID: 9683591.
10. Manwaring N, Jones MM, Wang JJ, Rochtchina E, Howard C, Mitchell P, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007;7(3):230-3. doi:10.1016/j.mito.2006.12.004. PMID: 17300999.
11. Yatsuga S, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T, et al. MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta. 2012;1820(5):619-24. doi:10.1016/j.bbagen.2011.03.015. PMID: 21443929.
12. Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, et al. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord. 1992;2(2):125-35. doi:10.1016/0960-8966(92)90045-8. PMID: 1422200.
13. Mancuso M, Bellusci M, Carelli V, de Coo I, Diodato D, Distelmaier F, et al. Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements. Eur J Neurol. 2026;33(4):e70588. doi:10.1111/ene.70588. PMID: 41999163.
14. Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701. doi:10.1038/gim.2014.177. PMID: 25503498.
15. Grady JP, Pickett SJ, Ng YS, Alston CL, Blakely EL, Hardy SA, et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol Med. 2018;10(6):e8262. doi:10.15252/emmm.201708262. PMID: 29735722.
16. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Mitochondrial DNA diseases; p. 490–4.
17. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Maladies mitochondriales apparentées au MELAS. Centres de référence CALISSON et CARAMMEL, filière FILNEMUS; text of September 2021. Saint-Denis La Plaine: HAS; published 27 Dec 2021. Available from: https://www.has-sante.fr/jcms/p_3289846
18. Koenig MK, Emrick L, Karaa A, Korson M, Scaglia F, Parikh S, et al. Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes. JAMA Neurol. 2016;73(5):591-4. doi:10.1001/jamaneurol.2015.5072. PMID: 26954033.
19. Lim AZ, Moe AM, Stefanetti RJ, Ng YS. Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials. Genes (Basel). 2026;17(8):850. doi:10.3390/genes17080850. PMID: 42650043.
20. Ng YS, Bindoff LA, Gorman GS, Horvath R, Klopstock T, Mancuso M, et al. Consensus-based statements for the management of mitochondrial stroke-like episodes. Wellcome Open Res. 2019;4:201. doi:10.12688/wellcomeopenres.15599.1. PMID: 32090171.
21. De Vries MC, Brown DA, Allen ME, Bindoff L, Gorman GS, Karaa A, 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. doi:10.1002/jimd.12196. PMID: 32030781.
22. AbbVie Inc. Depakote® (divalproex sodium) delayed-release tablets — prescribing information (NDA 018723), effective version of 31 Mar 2026. U.S. Food and Drug Administration/openFDA. Available from: https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22DEPAKOTE%22 (accessed 6 Oct 2026).
23. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol. 1984;16(4):481-8. doi:10.1002/ana.410160409. PMID: 6093682.
24. Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348(6302):651-3. doi:10.1038/348651a0. PMID: 2102678.
25. van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992;1(5):368-71. doi:10.1038/ng0892-368. PMID: 1284550.
26. Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006;66(3):324-30. doi:10.1212/01.wnl.0000196641.05913.27. PMID: 16476929.
27. Stefanetti RJ, Ng YS, Errington L, Blain AP, McFarland R, Gorman GS. l-Arginine in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes: A Systematic Review. Neurology. 2022;98(23):e2318-28. doi:10.1212/WNL.0000000000200299. PMID: 35428733.
28. Ohsawa Y, Hagiwara H, Nishimatsu SI, Hirakawa A, Kamimura N, Ohtsubo H, et al. Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial. J Neurol Neurosurg Psychiatry. 2019;90(5):529-36. doi:10.1136/jnnp-2018-317964. PMID: 29666206.
29. Chujo T, Tomizawa K. Mitochondrial tRNA modifications: functions, diseases caused by their loss, and treatment strategies. RNA. 2025;31(3):382-94. doi:10.1261/rna.080257.124. PMID: 39719325.
30. ClinicalTrials.gov. NCT06451757 — KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases (Khondrion BV). Last updated 29 Jun 2026. Available from: https://clinicaltrials.gov/study/NCT06451757 (accessed 6 Oct 2026).
31. ClinicalTrials.gov. NCT06402123 — A Phase 2b Study of Zagociguat in Patients With MELAS (Tisento Therapeutics). Last updated 6 Oct 2026. Available from: https://clinicaltrials.gov/study/NCT06402123 (accessed 6 Oct 2026).
32. National Center for Biotechnology Information. ClinVar. VCV000009590 (m.3271T>C, Pathogenic, 25 Apr 2023), VCV000009594 (m.3252A>G, Likely pathogenic, 9 Sep 2024) and VCV000009702 (MT-ND5 m.13513G>A, Pathogenic, 26 Oct 2021), all reviewed by an expert panel. Available from: https://www.ncbi.nlm.nih.gov/clinvar/ (accessed 6 Oct 2026).
33. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like episodes (MELAS); p. 385–92.
34. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Diabetes mellitus; p. 390–1.
35. Chinnery PF. Primary Mitochondrial Disorders Overview. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. First published 8 Jun 2000; last updated 29 Jul 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1224/
36. Ng YS, Lax NZ, Blain AP, Erskine D, Baker MR, Polvikoski T, et al. Forecasting stroke-like episodes and outcomes in mitochondrial disease. Brain. 2022;145(2):542-54. doi:10.1093/brain/awab353. PMID: 34927673.
37. Chaudhry A, Thompson DM, Chanoine JP. Diabetes management in maternally inherited diabetes and deafness (MIDD): A review and a proposed treatment algorithm. Diabetes Obes Metab. 2026;28(2):826-39. doi:10.1111/dom.70240. PMID: 41145374.
38. Pickett SJ, Grady JP, Ng YS, Gorman GS, Schaefer AM, Wilson IJ, et al. Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors. Ann Clin Transl Neurol. 2018;5(3):333-45. doi:10.1002/acn3.532. PMID: 29560378.
39. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Myoclonic epilepsy and ragged red fiber (MERRF) disease; p. 393–8.
40. Varga L, Borecka S, Skopkova M, Rambani V, Sklenar M, Cipkova K, et al. Screening for Maternally Inherited Diabetes and Deafness in Large Cohorts of Hearing Impaired and Diabetic Patients. Ear Hear. 2026;47(3):863-76. doi:10.1097/AUD.0000000000001780. PMID: 41664274.
41. Mickelsson N, Hirvonen J, Martikainen MH. Clinical features and treatment of stroke-like episodes in mitochondrial disease: a cohort-based study. J Neurol. 2024;272(1):47. doi:10.1007/s00415-024-12745-y. PMID: 39666093.
42. Ribeiro HPB, Mont'Alverne AG, Ribeiro EM. MELAS (miopatia mitocondrial, encefalopatia, acidose lática e episódios semelhantes a acidente vascular cerebral). In: Ribeiro EM, coordinator. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 137–41.
43. Saudubray JM, García-Cazorla Á. Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1. doi:10.1007/978-3-662-63123-2_1
44. Stefanetti RJ, Charman SJ, Newman J, Hallsworth K, Blain AP, Ng YS, et al. Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design. Brain Commun. 2025;7(5):fcaf342. doi:10.1093/braincomms/fcaf342. PMID: 41048545.
45. Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med. 2008;25(4):383-99. doi:10.1111/j.1464-5491.2008.02359.x. PMID: 18294221.
46. Tran NQ, Phan CC, Vuong TB, Tran TV, Ma PT. Acute onset of diabetes and rapid cognitive decline in a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome. Endocrinol Diabetes Metab Case Rep. 2023;2023(2):22-0416. doi:10.1530/EDM-22-0416. PMID: 37073829.
47. Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19(12). doi:10.1038/gim.2017.107. PMID: 28749475.
48. Blank AC, Breur JMPJ, Fuchs SA, Koop K, Baas AF. Mitochondrial Cardiomyopathies. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 179–91. doi:10.1007/978-3-030-45457-9_11
49. van Mil A, Neef K, Balk GM, Buikema JW, Sluijter JPG, Doevendans PAF. Induced Pluripotent Stem Cells. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 439–48. doi:10.1007/978-3-030-45457-9_26.
50. Wahbi K, Bougouin W, Béhin A, Stojkovic T, Bécane HM, Jardel C, et al. Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. Eur Heart J. 2015;36(42):2886-93. doi:10.1093/eurheartj/ehv307. PMID: 26224072.
51. Ng YS, Grady JP, Lax NZ, Bourke JP, Alston CL, Hardy SA, et al. Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults. Eur Heart J. 2016;37(32):2552-9. doi:10.1093/eurheartj/ehv306. PMID: 26188002.
52. Schade van Westrum SM, Wahbi K, Bonne G, van der Kooi AJ. Hereditary Neuromuscular Diseases and Cardiac Involvement. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 378–9. doi:10.1007/978-3-030-45457-9_22
53. Guéry B, Choukroun G, Noël LH, Clavel P, Rötig A, Lebon S, et al. The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol. 2003;14(8):2099-108. doi:10.1097/01.asn.0000080180.51098.02. PMID: 12874464.
54. de Laat P, Fleuren LH, Bekker MN, Smeitink JA, Janssen MC. Obstetric complications in carriers of the m.3243A>G mutation, a retrospective cohort study on maternal and fetal outcome. Mitochondrion. 2015;25:98-103. doi:10.1016/j.mito.2015.10.005. PMID: 26455484.
55. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Deafness in early childhood; p. 122–5.
56. Whittaker RG, Blackwood JK, Alston CL, Blakely EL, Elson JL, McFarland R, et al. Urine heteroplasmy is the best predictor of clinical outcome in the m.3243A>G mtDNA mutation. Neurology. 2009;72(6):568-9. doi:10.1212/01.wnl.0000342121.91336.4d. PMID: 19204268.
57. Mochel F, Sedel F. Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 2. doi:10.1007/978-3-662-63123-2_2
58. Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. Chapter 4, Hypertrophic Cardiomyopathy — 4.6 Differential Diagnosis (table 4.1); p. 67.
59. Mancuso M, Papadopoulou MT, Ng YS, Ardissone A, Bellusci M, Bertini E, et al. Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group. Eur J Neurol. 2024;31(7):e16275. doi:10.1111/ene.16275. PMID: 38576261.
60. Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Tanabe Y, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64(4):710-2. doi:10.1212/01.WNL.0000151976.60624.01. PMID: 15728297.
61. Koga Y, Povalko N, Inoue E, Nakamura H, Ishii A, Suzuki Y, et al. Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research. J Neurol. 2018;265(12):2861-74. doi:10.1007/s00415-018-9057-7. PMID: 30269300.
62. Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019;381(22):2103-13. doi:10.1056/NEJMoa1905795. PMID: 31774955.
63. Morris AAM, Jones S. Medications Used in the Treatment of Inborn Errors of Metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 45 (quadro 45.1, Arginine). doi:10.1007/978-3-662-63123-2_45
64. ClinicalTrials.gov. NCT03952234 — L-Citrulline Dose Finding Safety Study in MELAS (Baylor College of Medicine). Completed; last updated 26 Jun 2024. Available from: https://clinicaltrials.gov/study/NCT03952234 (accessed 6 Oct 2026).
65. Pharmacia & Upjohn Company LLC. R-Gene® 10 (Arginine Hydrochloride Injection, USP) — prescribing information (NDA 016931), effective version of 2 Apr 2024. U.S. Food and Drug Administration/openFDA. Available from: https://api.fda.gov/drug/label.json?search=openfda.generic_name:%22arginine+hydrochloride%22 (accessed 6 Oct 2026).
66. Ticci C, Sicca F, Ardissone A, Bertini E, Carelli V, Diodato D, et al. Mitochondrial epilepsy: a cross-sectional nationwide Italian survey. Neurogenetics. 2020;21(2):87-96. doi:10.1007/s10048-019-00601-5. PMID: 31900734.
67. Tetrabenazine tablets — prescribing information (ANDA 213316), effective version of 22 Oct 2020. U.S. Food and Drug Administration/openFDA. Available from: https://api.fda.gov/drug/label.json?search=openfda.generic_name:tetrabenazine (accessed 2026-11-07).
68. Tetrabenazine 25 mg tablets — Summary of Product Characteristics. electronic Medicines Compendium (emc), updated 15 Sep 2026. Available from: https://www.medicines.org.uk/emc/product/2668/smpc (accessed 2026-11-07).
69. Santhosh T, Ramamurthy P, Simha V. Safe Use of Metformin in Mitochondrial Diabetes in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes: Insights From a Patient With m.3243A>G Mutation. AACE Endocrinol Diabetes. 2025;12(3):150-2. doi:10.1016/j.aed.2025.07.001. PMID: 41048693.
70. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021;99(3S):S1-S87. doi:10.1016/j.kint.2020.11.003. PMID: 33637192.
71. GeneGuidance. Gene record for MT-TL1 (clinical curation, experimental treatment and frequency). Project reference database, version of 26 Sep 2026 (local query).
72. Khondrion BV. Khondrion Announces First Patient Dosed in Pivotal Phase 3 KHENERFIN Study of Sonlicromanol in Mitochondrial DNA 3243A>G Primary Mitochondrial Disease [press release]. 16 Apr 2026. Available from: https://www.khondrion.com/news/ (accessed 6 Oct 2026).
73. European Commission. Union Register of medicinal products — Orphan designations (active): EU/3/17/1947 (2-isopropyl-3H-naphtho[1,2-d]imidazole-4,5-dione, MELAS, 12 Dec 2017) and EU/3/25/3083 (sonlicromanol hydrochloride, inherited defects of oxidative phosphorylation, 18 Jul 2025). Available from: https://ec.europa.eu/health/documents/community-register/html/reg_od_act.htm (accessed 6 Oct 2026).
74. ClinicalTrials.gov. NCT05650229 — Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease (Pharming Technologies B.V.). Last updated 26 Jun 2026. Available from: https://clinicaltrials.gov/study/NCT05650229 (accessed 6 Oct 2026).
75. Tisento Therapeutics. News: “Tisento Therapeutics Receives U.S. FDA Fast Track Designation for Zagociguat for the Treatment of MELAS” (17 Jun 2025) and “Tisento Therapeutics Completes Enrollment in PRIZM, a Global Phase 2b Study of Zagociguat for the Treatment of MELAS” (8 Jan 2026) [press releases]. Available from: https://www.tisentotx.com/news (accessed 6 Oct 2026).
76. Smeitink J, van Es J, Bosman B, Janssen MCH, Klopstock T, Gorman G, et al. Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation. Brain. 2025;148(3):896-907. doi:10.1093/brain/awae277. PMID: 39501914.
77. van Tienen FHJ, Hoeijmakers JGJ, van der Leij C, Timmer E, Wanders N, Lindsey PJ, et al. Intra-arterial transplantation of autologous mesoangioblasts in m.3243A>G mutation carriers is safe: First phase 1/2 human clinical study. Mol Ther. 2025;33(10):5061-72. doi:10.1016/j.ymthe.2025.07.005. PMID: 40682269.
78. de Laat P, Janssen MC, Alston CL, Taylor RW, Rodenburg RJ, Smeitink JA. Three families with 'de novo' m.3243A>G mutation. BBA Clin. 2016;6:19-24. doi:10.1016/j.bbacli.2016.04.007. PMID: 27331024.
79. Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. 2008;83(2):254-60. doi:10.1016/j.ajhg.2008.07.004. PMID: 18674747.
80. Hyslop LA, Blakely EL, Aushev M, Marley J, Takeda Y, Pyle A, et al. Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease. N Engl J Med. 2025;393(5):438-49. doi:10.1056/NEJMoa2415539. PMID: 40673696.
81. McFarland R, Hyslop LA, Feeney C, Pillai RN, Blakely EL, Moody E, et al. Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease. N Engl J Med. 2025;393(5):461-8. doi:10.1056/NEJMoa2503658. PMID: 40689593.
82. Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015;77(5):753-9. doi:10.1002/ana.24362. PMID: 25652200.
83. Orphanet/Orphadata. Epidemiological data of rare diseases (en_product9_prev.xml): MELAS (ORPHA:550). Available from: https://www.orphadata.com/data/xml/en_product9_prev.xml (accessed 6 Oct 2026).
84. Kaufmann P, Engelstad K, Wei Y, Kulikova R, Oskoui M, Sproule DM, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology. 2011;77(22):1965-71. doi:10.1212/WNL.0b013e31823a0c7f. PMID: 22094475.