MELAS …

Neuromuscular Disorders

Updated 06.05.2024
Released 09.06.1993
Expires For CME 06.05.2027

MELAS

Authors: Michelangelo Mancuso MD PhD, Adriana Meli MD

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Editor: Aravindhan Veerapandiyan MD

MELAS

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Introduction

Overview

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystem disorder characterized by (1) stroke-like episodes, typically before age 40; (2) encephalopathy, characterized by seizures, dementia, or both; and (3) evidence of a mitochondrial myopathy with lactic acidosis, ragged-red fibers, or both. Although at least 30 distinct mitochondrial DNA mutations have been associated with MELAS, about 80% of patients have the m.3243A> G tRNALeu(UUR) gene mutation. M.3243A>G heteroplasmy levels in blood, urine, and muscle are strongly associated with disease burden and progression. One study suggested that screening urinary epithelial cells for the m.3243A> G mutation may be the most sensitive noninvasive diagnostic test for MELAS. In this article, the authors discuss the clinical manifestations, pathogenesis, and diagnosis of this multisystem disorder, with particular emphasis on recent published works. Moreover, preclinical studies on newly evolving treatment concepts have been reported, including (1) L-citrulline and L-arginine to increase NO production, (2) L-cysteine to improve mitochondrial protein synthesis, (3) ketogenic diet to alleviate mitochondrial dysfunction, and (4) taurine supplementation for prevention of stroke-like episodes.

Key points

	• The clinical hallmark of MELAS is stroke-like episodes that usually affect young people (typically before age 40) and do not conform to large vessel territories.
	• Although 30 different mitochondrial DNA mutations have been associated with MELAS, about 80% of patients harbor the m.3243A> G mutation.
	• Although MELAS is generally maternally inherited, in most families, only one individual has MELAS, and the others are oligosymptomatic or asymptomatic.

Historical note and terminology

The first cases of MELAS were reported in 1975 by three different groups of investigators (34; 129; 71). Seven years later, Rowland and colleagues identified these and five additional cases with similar clinical syndromes and ragged-red fibers on muscle biopsy (119). They called this syndrome “mitochondrial myopathy, encephalopathy, and lactic acidosis.” Soon thereafter, Pavlakis identified stroke-like episodes as the distinctive clinical feature and renamed the syndrome “mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes” (112). The acronym MELAS is now widely accepted, although some clinicians prefer the name “mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.” In 1990, Goto and colleagues reported the first mitochondrial point mutation (A-to-G) associated with this syndrome at base pair 3243 (m.3243A> G) in a transfer RNA (tRNALeu(UUR)) (39). Since then, 30 additional point mutations and a four base-pair deletion mutation have been reported (Table 1).

Clinical manifestations

Presentation and course

Like other mitochondrial syndromes (ie, Kearns-Sayre syndrome and MERRF), MELAS is a multisystem disorder. To make a clinical diagnosis, the following features must be present: (1) stroke-like episodes typically—but not mandatory—before age 40; (2) encephalopathy, characterized by seizures, dementia, or both; and (3) evidence of a mitochondrial myopathy with lactic acidosis, ragged-red fibers, or both. In addition, to confirm the diagnosis, at least two of the following should be present: normal early development, recurrent headache, or recurrent vomiting (50).

A clinical diagnosis of MELAS can also be made in an individual with at least two category A and two category B criteria (150):

Table 1. Clinical Diagnostic Criteria of MELAS

Category A criteria	Category B criteria
• Headaches with vomiting • Seizures • Hemiplegia • Cortical blindness • Acute focal lesions on neuroimaging (see suggestive findings, brain imaging)	• High plasma or cerebrospinal fluid (CSF) lactate • Mitochondrial abnormalities on muscle biopsy (see suggestive findings, suggestive laboratory findings) • A MELAS-related pathogenic variant (see Table 2)

The diagnosis of MELAS is established in a proband who meets the clinical diagnostic criteria and who is a carrier of a pathogenic variant in one of the genes listed in Table 2 identified by molecular genetic testing.

Over 200 reported cases of MELAS support the validity of this clinical syndrome. Besides the obligatory cardinal manifestations, numerous additional symptoms and signs are associated with MELAS. Features reported in the majority of patients include exercise intolerance, limb weakness, short stature, hearing loss, and elevated cerebrospinal fluid protein. The headaches of MELAS have often been described as migrainous and are frequently severe during the acute phase of the strokes. Patients with mtDNA mutation m.3243A > G and with MELAS phenotype showed the highest prevalence of headache (88%, 86%, respectively) among patients affected by mitochondrial disorders in a cohort of a German cross-sectional study (75). The subjects described headaches as short-lasting and often mild or moderate intensity. The high prevalence of migraine in MELAS is independent of sex, phenotype, or genotype (82).

A stroke-like episode may occur not only in individuals with MELAS but also in patients with other forms of mitochondrial syndromes (105) and should be generally suspected if features of an ischemic stroke are accompanied by atypical central nervous system features. The most frequent onset symptoms of a stroke-like episode are migraine or migraine-like headache, seizures, drowsiness, vomiting, and visual field defects. Occasionally, strokes occur during a febrile illness. The strokes are called atypical because the lesions do not conform to the territories supplied by major cerebral arteries and are not caused by an occlusion of a vessel. The morphological equivalent of a stroke-like episode is the stroke-like lesion, which are most frequently located in an occipito-temporal distribution. The strokes usually affect the cortex and subjacent white matter and frequently affect posterior cerebral hemispheres. Acute strokes can be detected as increased signal on routine T2-weighted MRI scans. Elevated apparent diffusion coefficient was often reported during these episodes, mainly suggesting vasogenic edema in the acute phase and representing a different pattern than in classic stroke. However, there has been an increase in the number of reports of a decrease in apparent diffusion coefficient, compatibly with cytotoxic edema in acute phase, such as typical stroke. Thus, increased and decreased apparent diffusion coefficient portions are mixed in stroke-like lesions, supporting both cytopathy and vasogenic theories: mild energy failure should result in moderate cellular dysfunction, which is responsible for vasogenic edema (high apparent diffusion coefficient), and severe energy failure should relate to irreversible cellular failure, responsible for cytotoxic edema (low apparent diffusion coefficient) (55).

Features present in fewer than half of the patients are basal ganglia calcifications, myoclonus, ataxia, episodic coma, optic nerve atrophy, cardiomyopathy, pigmentary retinopathy, electrocardiographic evidence of pre-excitation, cardiac conduction block, ophthalmoplegia, diabetes mellitus, hirsutism, gastrointestinal dysmotility, and nephropathy. Cardiomyopathy affects about a third of patients with MELAS: the most common manifestation is hypertrophic cardiomyopathy, which may eventually progress to dilated cardiomyopathy. Individuals affected by MELAS syndrome may more easily run into serious cardiac complications such as malignant arrhythmias, heart failure, and sudden cardiac arrest (51).

Children with MELAS often have normal early psychomotor development until the onset of symptoms between 2 and 10 years of age. Though less common, infantile onset may occur and may present as failure to thrive, growth retardation, and progressive deafness. Onset in older children typically presents as recurrent attacks of a migraine-like headache, anorexia, vomiting, and seizures. Children with MELAS are also frequently found to have short stature (114).

Akinetic rigid parkinsonism/MELAS overlap syndrome was reported in a patient with a unique four base-pair deletion in the cytochrome b gene (21). Sandoval and colleagues reported a case of parkinsonism as initial symptom of MELAS syndrome, which is an unusual first manifestation of this disease (122). The association between movement disorders such as parkinsonism and MELAS syndrome is probably due to changes in basal ganglia resulting from stroke-like episodes. Peripheral neuropathy may be an under-recognized manifestation of MELAS; nerve conduction abnormalities were detected in 23 of 30 (77%) patients (63) and in 11 of 12 (92%) patients (84) with the m.3243A>G mtDNA mutation, mostly with a sensory axonal pattern. A 2012 review of the psychiatric manifestations of mitochondrial disorders included 26 cases of MELAS syndrome with one or more of the following symptoms: major depressive disorder (n=5), cognitive impairment (n=11), psychotic disorder (n=15), anxiety disorder (n=6), frontal lobe syndrome (n=3), or personality change (n=2) (03). A study reported how social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission, probably due to abnormalities in GABA signaling transmission (59). Rarely, catatonia may be observed in the acute phase of the disease (99).

Almost all reported cases of MELAS have a mitochondrial DNA point mutation. Maternal relatives, then, are likely to harbor the same mutation. Few families have more than one member with MELAS; more often oligosymptomatic maternally related individuals manifest only some of the features of MELAS. In addition, the MELAS point mutation may also be found in asymptomatic family members. Intriguingly, three families have been described where the m.3243A>G mutation has arisen de novo; this finding is of major relevance for both diagnostic investigations and genetic counselling (23).

Moraes and colleagues identified another clinical phenotype associated with the m.3243A>G mutation: progressive external ophthalmoplegia (PEO3243) (100). They identified 16 progressive external ophthalmoplegia patients with this mutation. Maternally inherited diabetes and deafness had been associated with the m.3243A>G mutation (118; 144). Mitochondrial patients may show features of both type 1 and type 2 diabetes. A progression to complete insulin dependency due to beta-cells failure is possible for these subjects, although most patients with mitochondrial diabetes do not require insulin therapy at diagnosis (151). In 770 Chinese patients with diabetes, the m.3243A>G mutation was found in 1.69% of patients (145). Patients with MELAS have also presented with a syndrome mimicking herpes simplex encephalitis, pulmonary artery hypertension, and cardiomyopathy (58; 133; 36).

In 82 m.3243A>G mutation carriers, the most prevalent symptoms were hearing loss (48%), gastrointestinal problems (42%), decreased vision (42%), exercise intolerance (38%), and glucose intolerance (37%), but only 4% had stroke-like episodes (24). Hearing loss may be of both cochlear and retrocochlear origin, and it may be subclinical. Therapeutic implications of early recognition include interventions in the form of hearing aids, cochlear implants, and cautioning the physicians for avoidance of aminoglycosides (143).

More than 50% of m.3243A > G mutation carriers were found to have some form of gait problems. It has been suggested that quantification of gait may be a suitable outcome parameter in the upcoming clinical trials in this patient group (116).

A study on a cohort of 129 English patients harboring the m.3243A>G mutation showed how only 10% of patients exhibited a classical MELAS phenotype (104). In general, the m.3243A>G mutation manifests far more often as mitochondrially inherited diabetes and deafness or as other oligosymptomatic forms than as full-blown MELAS. Patients with mitochondrially inherited diabetes and deafness have insulin-dependent diabetes associated to relatively low BMI; the onset of the diabetes, usually associated with progressive neurosensory deafness, is observed at 30- or 40-years-old (141).

A multicenter UK study identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes, with the possibility of analyzed postmortem cases in 26 cases (106). The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1, followed by recessive pathogenic POLG variants and other rarer pathogenic mtDNA variants. Clinicoradiological, electrophysiological, and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy, and significant radiological and pathological features of neurodegeneration were more evident in patients harboring pathogenic mtDNA variants compared with POLG.

A retrospective study comparing the clinical, myopathological, and brain MRI characteristics of patients with MELAS caused by mtDNA variants and MELAS patients carrying the m.3243A>G variant highlighted that MELAS caused by mtDNA mutations showed different features (146). Specifically, MELAS‐mtDNA related is characterized by lower mutation heteroplasmy in blood cells, lower frequency of migraine, lower multisystem involvement (hearing loss and diabetes) but higher stature, higher BMI, and smaller cortical stoke-like lesions in brain MRI. Moreover, it is characterized by lower presentation of ragged red fibers and COX‐deficient fibers/blue fibers.

In a retrospective study, several parameters have been identified as clinical biomarkers for distinguishing two subgroups of MELAS: classic MELAS and atypical MELAS (02). Classic MELAS was associated with later onset (after age 10), sensorineural hearing loss, vision loss at the stroke-like episodes onset, and large cerebral stroke-like lesions mainly involving the occipital and temporal lobes, and it was observed in in patients carrying mt-tRNA mutation, especially m.3243A>G. Atypical MELAS was associated with earlier onset (before age 10) and developmental delay in patients carrying respiratory chain subunit genes variants (complex I and complex V). It was also characterized by typical MRI pattern characterized by smaller lesions and lower frequency of posterolateral distribution, often involving the cerebellum (particularly association with MT-ATP6 variants).

Prognosis and complications

The disease progresses over years with episodic deterioration related to stroke-like events. The course varies from patient to patient. In a cohort of 33 adults with the m.3243A>G MELAS mutation followed for 3 years, deterioration of sensorineural function, cardiac left ventricular hypertrophy, EEG abnormalities, and overall severity were observed (85). In a natural history study in 31 patients with MELAS and 54 carrier relatives over a follow-up period of up to 10.6 years, neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. The death rate was more than 17-fold higher in fully symptomatic patients than in carrier relatives. The average observed age at death in the MELAS patient group was 34.5+/-19 years (range 10.2 to 81.8 years). Of the deaths, 22% occurred in patients younger than 18 years. The estimated overall median survival time based on fully symptomatic patients was 16.9 years from onset of focal neurologic disease (61). A Japanese prospective cohort study of 96 patients with MELAS confirmed a rapidly progressive course within a 5-year interval, with 20.8% of patients dying within a median time of 7.3 years from diagnosis (150). The studies mentioned above showed how the clinical severity of MELAS is linked to both the age of onset and the duration of the disease. A retrospective Chinese study in which 138 patients were enrolled reported how the main causes of death (observed in 42.2% of patients) were an acute stroke-like episode or status epilepticus. Stroke-like episodes were reported as the most common initial symptoms (154). Thus, a correct management of stroke-like episodes is primary to improve the prognosis.

The severity of the disease probably depends on the percent mutation and the tissue distribution of the mutation. Patients with a younger age of onset tend to have a more severe course. Yearly ECGs and echocardiograms to screen for cardiopathy, particularly in children with MELAS, may be prudent.

In a large prospective cohort study comprising 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers, proton magnetic resonance spectroscopic imaging ((1)H MRSI) showed promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype (148). Mutation carriers included 45 patients with MELAS, 11 participants who would develop the MELAS syndrome during follow-up (converters), and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). Higher lactate and total choline levels predicted the risk of individual mutation carriers to develop the MELAS phenotype.

Clinical vignette

The girl was born after a normal pregnancy and delivery. Early development was normal, but weakness of the legs was evident at age 2 when she was noted to have difficulty climbing stairs. At age 5 years, examination revealed short stature (92 cm) and low weight (15 kg), both below the third percentile. There was mild proximal muscle weakness with a Gowers sign. Her parents were nonconsanguineous and healthy. Her 4-year-old brother had mental retardation, short stature, and hearing loss. Her two sisters, 1 year and 11 years old, were clinically normal. At age 5.5 years, after strenuous exercise, she lost consciousness for 30 minutes. She subsequently had multiple episodes of dimmed vision, each lasting a few minutes. At age 6 years she had 30-minute to 60-minute periods of right body paresthesias followed by blindness after physical exertion. Following one episode, she had a generalized tonic-clonic seizure, and phenobarbital therapy was initiated. Postictally, she had a right hemiparesis that resolved after 3 days. A second right focal seizure was followed by hemiparesis for 5 days. Phenobarbital dosage was increased. Lactic acidosis was noted. After another generalized seizure she became blind. The loss of vision was thought to be cortical in origin because pupillary reactions to light and funduscopy were normal. A brain MRI revealed bilaterally increased T2-signal in the occipital cortex. Leukocyte DNA analysis revealed an A-to-G mutation at nucleotide 3243 of the mitochondrial DNA. L-carnitine (100 mg/kg per day) was initiated without clinical improvement; the disorder continued to progress. At age 9 years she was severely demented and deaf. Audiometry revealed neurosensory hearing loss. At age 10 years she died due to congestive heart failure.

Biological basis

Etiology and pathogenesis

Multiple mitochondrial DNA point mutations have been associated with the MELAS clinical phenotype (Table 2), and this list is still growing (MITOMAP). The most prevalent of these mutations is an A-to-G transition mutation at nucleotide 3243 (m.3243A> G) of the tRNALeu(UUR) (39). This mutation has been found in about 80% of cases of MELAS (39; 17). Five additional mutations in the tRNALeu(UUR), a hot-spot for mtDNA mutations, have been reported in patients with MELAS (Table 1). Eight other tRNA point mutations associated with MELAS have been described. In addition, mutations in polypeptide-encoding genes have been identified. The gene encoding subunit 5 of complex I (ND5) is a second hot spot for MELAS mutations as 6-point mutations in this gene have been associated with this phenotype, including the m.13513G>A, which may be the second most common cause of MELAS (123; 127). One patient with a MELAS phenotype had compound heterozygous mutations in the nuclear DNA encoded polymerase gamma (POLG1) gene (25). At least two mitochondrial DNA mutations have been associated with overlap MERRF-MELAS syndromes; one is at nucleotide 8356 in tRNA-Lys (153) and the other is at nucleotide 7512 in tRNA-Ser(UCN) (103). Several patients with features of both MELAS and Leigh syndrome have been reported with the m.13513G>A and a ND3 gene mutation (19; 77; 147). A case of stroke-like episodes/Leigh syndrome associated with a novel m.3482A>G mutation in MT-ND1 was reported (46). MELAS/Leigh syndrome was also described in 10 individuals of a four-generation family harboring the m.5537_5538insT mutation in MT-TW (134). A sporadic patient with a multisystem disorder with features of MELAS (stroke-like episodes), MERRF, Leber hereditary optic neuropathy, and Kearns-Sayre syndrome had a missense mutation in subunit 3 of complex I (140). In very rare cases, MERRF-like phenotypes have been described with the MELAS m.3243A> G mutation (11).

Table 2. MtDNA Mutations causing MELAS

mtDNA nucleotide change	Gene symbol	Protein Change	Reference
m.3243A> G	MT-TL1	No protein translated	(39)
m.3271T>C			(40)
m.3252A>G			(101)
m.3291T>C			(41)
m.3256C>T			(125)
m.3260A>G			(107)
m.583G>A	MT-TF		(45)
m.1642G>A	MT-TV		(139)
m.1644G>A			(137)
m.4332G>A	MT-TQ		(05)
m.5521G>A	MT-TW		(49)
m.5541C>T			(57)
m.5537_5538insT			(134)
m.5814A>G	MT-TC		(89)
m.7512T>C	MT-TS1		(78)
m.8316T>C	MT-TK		(14)
m.8296A>G			(121)
m.12146 A>G	MT-TH		(13)
m.12158A>G			(76)
m.12299A>C	MT-TL2		(01)
m.12315G>A			(130)
m.3481G>A	MT-ND1	p.Gln59Lys	(86)
m.3697G>A		p.Gly131Ser	(67)
m.3946G>A		p.Gln214Lys	(67)
m.3949T>C		p.Tyr215His	(67)
m.3571_3572insC			(81)
m.7023G>A	MT-CO2	p.Val374Met	(136)
m.9957T>C	MT-CO3	p.Phe251Leu	(90)
m.12770A>G	MT-ND5	p.Glu145Gly	(79)
m.13042G>A		p.Ala236Thr	(102)
m.13084A>T		p.Ser250Cys	(19)
m.13513G>A		p.Asp393Asn	(123)
m.13514A>G		p.Asp393Gly	(18)
m.13528A>G		p.Thr398Ala	(94)
m.14453G>A	MT-ND6	p.Ala74Val	(117)
m.14787_14790del		p.Ile14Thr+fs	(21)
m.14864T>C	MT-CYB	p.Cys40Arg	(31)
m.15092G>A	MT-CYB	p.G116S	(88)
m.3482A>G	MT-ND1	p.E59G	(46)

The origin of the mtDNA mutations is uncertain, but nucleotide substitutions occur about 10 times more frequently in mtDNA than in nDNA (12), and the repair mechanisms for mtDNA may not be as efficient as for nDNA (80). In support of this concept is the high frequency (one in 200 live births) of de novo m.3243A> G and other common mtDNA mutations detected in a survey of umbilical cord blood samples in the Northeast of England (29). The m.3243A> G mutation is clearly transmitted in a maternal inheritance pattern (17).

Even in the first stages of embryogenesis, there is a compensatory cellular response to the respiratory chain defect. MELAS embryos have been shown to harbor approximately 3-fold higher amounts of mtDNA, suggesting that mtDNA can replicate in early embryos and emphasizing the need for sufficient amount of wild-type mtDNA to sustain embryonic development in humans (98).

Clinical expression of the mutation depends on three factors: (1) mtDNA heteroplasmy, (2) mtDNA tissue distribution, and (3) tissue threshold. Each mitochondrion contains multiple copies of mtDNA, and each cell contains multiple mitochondria. Therefore, each cell can contain a variable proportion of normal and mutant mtDNA molecules (heteroplasmy). The tissue distribution of mutant mtDNA is also heterogeneous. In addition, the most metabolically active tissues are most susceptible to the deleterious effect of the mtDNA mutations (tissue threshold). The tissue threshold probably does not vary significantly among individuals, but mtDNA heteroplasmy and variable tissue distribution may account for the clinical diversity of patients with MELAS. As yet undefined nuclear DNA factors may also modify the phenotypic expression of the mtDNA mutations (100).

Analyses of respiratory chain enzymes have demonstrated complex I deficiency or combined defects of multiple complexes (50).

Skeletal muscle biopsies demonstrate mitochondrial abnormalities. Modified Gomori trichrome stain shows ragged-red fibers; the red stain in the subsarcolemmal regions of muscle fibers is due to accumulations of mitochondria. Similarly, the succinate dehydrogenase histochemical stain reveals darker than normal fibers, which are equivalent to ragged-red fibers. Ultrastructural studies have confirmed the increased number of mitochondria, as well as morphologically abnormal mitochondria that sometimes contain paracrystalline inclusions. MELAS may be distinguished from other mitochondrial diseases thanks to the identification of a large proportion of ragged-red fibers, with variable activity of COX and the presence of strongly succinate dehydrogenase-stained vessels. Ragged-red fibers are commonly seen in patients with MELAS, myoclonus epilepsy with ragged-red fibers (MERRF), Kearn-Sayre syndrome, and chronic progressive external ophthalmoplegia, and are absent in patients with Leber hereditary optic neuropathy, neuropathy, ataxia, and retinitis pigmentosa, and some nuclear defects associated mitochondrial diseases. Exceptionally, in a Chinese study, patients negative for ragged-red fibers were identified with similar disease course, clinical symptoms, and neuroimaging results to ragged-red fibers-positive patients with MELAS, suggesting that in cases of highly suspected MELAS, yet without positive myopathological findings, combined immunofluorescence and genetic studies should be used to achieve final diagnosis (83).

Pathological studies have demonstrated a spongiform encephalopathy predominantly in the cerebral cortex (131). These cortical lesions are characterized by necrosis, loss of neurons, gliosis, and microcystic formations (status spongiosus). Subcortical white matter may be involved, but deep white matter is usually spared. Other regions of the brain that can be affected include the cerebellum, pontine nuclei, and inferior olives. Mineral deposits of calcium and iron have been noted in and around blood vessel walls in the basal ganglia and thalamus. Immunohistochemical staining for mtDNA-encoded subunits of the respiratory chain enzymes revealed decreased staining in multiple focal areas of the brain, predominantly in the cerebral cortex (132). Abnormal and excessive mitochondria were observed in smooth muscle and endothelial cells of small arterioles (less than 250 microns in diameter) and capillaries of MELAS brains (108); this vasculopathy may contribute to the pathogenesis of stroke-like episodes. In addition to endothelial dysfunction, diseased endothelial cells were found to be proatherogenic and proinflammation due to high levels of reactive oxygen species and Ox-LDLs, and high basal expressions of VCAM-1, in particular isoform b, respectively. Consistently, more monocytes were found to adhere to MELAS endothelial cells as compared to the isogenic control, suggesting the presence of an atherosclerosis-like pathology in MELAS (113).

Autopsy studies of brains from two patients with MELAS provided further evidence of vasculopathy as it revealed cytochrome c oxidase-deficiency with high levels (95% or higher) of the m.3243A> G mtDNA mutation in leptomeningeal and cortical blood vessels (07). An in vitro study suggests that the m.3243A> G mutation impairs integrity of the blood-brain barrier (20). Large extracranial blood vessels may also be affected in patients with MELAS as demonstrated in a patient with the common m.3243A> G mutation who had a fatal aortic dissection and whose mother also died of large vessel rupture (138).

Postmortem brain tissues from four patients with MELAS showed reduced hippocampal expression of calbindin D, a high affinity calcium-binding protein. As similar reductions have been associated with aging and neurodegenerative disorders, including Alzheimer disease, this may play a role in the cognitive abnormalities associated with MELAS (30).

The pathogenesis of MELAS is not fully understood and believed to result from several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, nitric oxide (NO) deficiency, and neuronal hyperexcitability. Nitric oxide deficiency in MELAS syndrome is likely to be multifactorial in origin, with the decreased availability of the nitric oxide precursors, arginine and citrulline, playing a major role. When compared to control subjects, children with MELAS syndrome were found to have lower nitric oxide production, arginine flux, plasma arginine, and citrulline flux. Arginine supplementation and more so citrulline supplementation resulted in increased nitric oxide production, arginine flux, and arginine concentration. The greater effect of citrulline in increasing nitric oxide production is due to its greater ability to increase arginine availability, particularly in the intracellular compartment in which nitric oxide synthesis happens. Controlled clinical trials to assess the therapeutic effects of arginine and citrulline on clinical complications of MELAS syndrome are needed (27). In addition, neuronal hyperexcitability may play a crucial role in the acute stroke-like lesions (53). According to this, Sakai and colleagues reported a case of a patient in which treatment with the anticonvulsant levetiracetam was effective against the stroke-like episodes (120). The neuronal hyperexcitability theory primarily supposes the astrocytic dysfunction due to ATP deficiency as the underlying mechanism: astrocytic dysfunction impairs glutamatergic neurotransmission causing defective uptake of glutamate through glutamate transporters and of potassium through Na+/ K+ ATPase into astrocytes. This determines the elevation of glutamate and potassium concentration in the synaptic clefts that can induce not only vasodilatation in small vessels but also neuronal death by excitotoxicity. Therefore, it is possible that mitochondrial dysfunction in MELAS syndrome could contribute to neuron-astrocyte metabolic uncoupling, altering the glutamate–glutamine cycle. A prospective observational case-control study found CSF glutamate levels were significantly higher in patients with MELAS than in control (43).

In addition, neuronal hyperexcitability may play a role in the acute stroke-like lesions (53), even if the exact pathophysiology of acute cortical lesions in MELAS remains unclear. According to the cytopathic theory, defects in oxidative phosphorylation resulting from the mitochondrial mutation cause neuronal and glial cellular dysfunction, which may result in cell death during periods of higher metabolic activity. This theory is also supported by the higher baseline metabolic activity in the occipital cortex, the area in which the presence of lesions is more frequent. Otherwise, the angiopathic theory proposes that abnormal mitochondrial function in the arteriolar endothelium results in impaired autoregulation and subsequent ischemia (08). A detailed histopathological study of the temporal bone of a MELAS patient indicated that degeneration of the stria vascularis and spiral ganglion cells cause sensorineural hearing loss (135).

The pathomechanism whereby defects in mitochondrial DNA cause the histological and clinical features of MELAS is not known. Muscle cells with the m.3243A> G mutation grown in tissue culture demonstrate respiratory deficiency (69). King and Attardi developed a cell line called rho-0 that grows in the absence of mtDNA (65). The rho-0 cells can be fused with cytoplasts harboring mutant mtDNA forming cybrids. Cybrids with greater than 95% m.3243A> G mtDNA showed decreased rates of protein synthesis, lower levels of steady-state mitochondrial translational products, reduced oxygen consumption, and increased amounts of an unprocessed RNA fragment containing the mutant gene (designated RNA-19) (66). Kaufmann and colleagues confirmed the presence of elevated levels of RNA-19 in vivo by studying tissues from patients with MELAS (62). Other investigators have demonstrated that high levels of the mutant tRNA decreased aminoacylation (covalent attachment of leucine to the tRNA) and were associated with hypomodification of the D-stem; these alterations may contribute to the decreased protein synthesis (48; 10; 16). An alternative theory, also based on cybrid work, is that the mutant tRNALeu (UUR) is less efficiently modified at the base corresponding to the wobble base of the codon, thereby leading to misreading of leucine codons as phenylalanine codons due to lack of a post-transcriptional methyl-taurine modification of the anticodon wobble base (68). Cultured myoblasts from a patient with the m.3243A> G mutation revealed evidence of both amino acid misincorporation and moderate reduction of protein synthesis (124).

Obviously, the mitochondrial dysfunction in MELAS leads to complex mitochondria-to-nucleus signaling pathways whose components are, however, mostly unknown. It was demonstrated that oxidative stress mediates an NFkB-dependent induction of microRNA-9/9*, which acts as a post-transcriptional negative regulator of the mt-tRNA-modification enzymes GTPBP3, MTO1, and TRMU (96). Down-regulation of these enzymes affects the modification status of non-mutant tRNAs and contributes to the MELAS phenotype. Importantly, anti-microRNA-9 treatments of MELAS cybrids reverse the phenotype. These data represent the first evidence that an mt-DNA disease can directly affect microRNA expression and that cells respond to stress by modulating the expression of mt-tRNA-modifying enzymes. Hence, microRNA-9/9* is a crucial player in mitochondria-to-nucleus signaling as it regulates expression of nuclear genes in response to changes in the functional state of mitochondria (95).

A cybrid model of MELAS demonstrated that the m.3243A> G mutation in the mitochondrial tRNALeu(UUR) significantly changes the expression pattern of several mitochondrial tRNA-derived small RNAs (mt tsRNAs or mt tRFs), which are generated constitutively under certain conditions including cellular stress. Particularly mt tRFs derived from mt tRNA LeuUUR containing the m.3243A> G mutation (mt 5'-tRF LeuUUR-m.3243A> G and mt 5'-tRF LeuUUR) or not are respectively increased and decreased in both MELAS cybrids and fibroblasts. Moreover, it seems that miRNA pathway components, specifically Dicer and Ago2, are involved in the biogenesis and action of mt tRFs. Their immunoprecipitation in cytoplasm and mitochondria fractions increases the amount of mt tRFs in MELAS condition compared to wild type. Increased levels of mt tRFs were detected in urine and blood samples from MELAS patients; therefore, mt tRFs may be noninvasive biomarkers for MELAS. mt 5′-tRF LeuUUR-m.3243A> G antagonist oligonucleotides increased expression of mitochondrial transcripts, particularly those encoding complex I subunits and improved mitochondrial respiration in MELAS cybrids (97).

By using a multiomic approach, in a cybrid model of MELAS of neurons carrying different mutation loads of the m.3243A> G mitochondrial DNA variant, a metabolic dysregulation of the glutamate pathway was detected, along with a direct correlation glutamate concentration, mitochondrial complex I inhibition, and the m.3243G>A heteroplasmy level in cells with the MELAS mutation (06). These findings were confirmed by the transcriptomic analysis and postmortem brain tissue analysis from a MELAS patient, confirming the glutamate dysregulation.

Tissue- and cell-type-specific manifestations of heteroplasmic mtDNA 3243A>G mutation can be reproduced in human induced pluripotent stem cells (44). Of note, complex I was specifically sequestered in perinuclear PTEN-induced putative kinase 1 (PINK1) and Parkin-positive autophagosomes on neuronal differentiation, suggesting active degradation through mitophagy. These data show that cellular context actively modifies respiratory chain deficiency in MELAS and that autophagy is a significant component of neuronal MELAS pathogenesis.

Diagnostic workup

Screening patients for MELAS should begin with routine blood tests including complete blood count, serum electrolytes, liver function tests, blood urea nitrogen, creatinine, lactate, and pyruvate. These tests may reveal kidney or liver dysfunction. Lactate and pyruvate at rest are commonly elevated in patients with MELAS; these values may increase dramatically after moderate exercise. The blood leukocyte DNA may be screened for an mtDNA point mutation. The m.3243A>G mutation is detectable in about 80% of patients with MELAS. Age-adjusted blood heteroplasmy may be the most convenient heteroplasmy measure to use routinely within the clinical setting (42). Urine heteroplasmy levels should be adjusted for sex and are highly variable, and thus, must be interpreted with caution, even if urinary epithelial cells show m.3243A>G mutation levels that are comparable to levels in skeletal muscle and higher than in leukocytes (128). Therefore, urinary epithelial cells may be the tissue of choice to confirm the diagnosis of MELAS without an invasive procedure (24).

MELAS has a higher prevalence of ECG abnormalities compared with other mitochondrial clinical syndromes, and the m.3243A>G mutation is associated with a higher prevalence of electrocardiogram abnormalities than other genetic defects (115). Electrocardiogram may reveal pre-excitation or incomplete heart block. The latter is much less common than in Kearns-Sayre syndrome; there are no reports of complete heart block in MELAS. Lumbar puncture may show elevated cerebrospinal fluid protein, but only one case was reported to have a protein greater than 100 mg/dL. Electromyography and nerve conduction studies are typically consistent with a myogenic process, although a neuropathy may also be present.

Brain imaging with CT or MRI scans often reveals lesions compatible with strokes, frequently affecting the posterior cerebrum, and not conforming to the distribution of major arteries; in addition, basal ganglia calcification and atrophy are commonly seen (92). A brain magnetic resonance spectroscopy study of MELAS patients and their relatives demonstrated a direct correlation between the neurologic impairment and cerebral lactic acidosis (64). Moreover, abnormal cortical vein T2/FLAIR signal has been observed in patients with MELAS, correlating with cumulative brain lesion severity but not acuity. As venous hyperintensity was present prior to, during, and after lesion onset, it may even be predictive of lesion development. Possible mechanisms of brain injury include cortical venous stenosis, congestion, and venous ischemia (149).

By 7T magnetic resonance spectroscopy (MRS), it was possible to noninvasively quantify intramyocellular lipid accumulation (38). This may serve as a novel biomarker in the future.

In case of suspicion of stroke-like episode, physicians should obtain a detailed history from the patient or caregiver. Focal neurologic deficit that shows which hyper-acute onset, especially pure motor weakness (facial weakness or hemiparesis) that evolves rapidly within minutes, is unusual for a mitochondrial stroke-like episode and more suggestive of a vascular stroke. Otherwise, complex visual symptoms, perceptive problems, and hearing disturbances persisting for hours or days are features more suggestive of mitochondrial stroke-like episode. It is also important to try to identify potential triggers such as infection, gut dysmotility, dehydration, prolonged fasting, and nonadherence to the antiepileptic drug(s). For any suspected stroke-like episodes in patients who are known to harbor primary mtDNA or recessive POLG pathogenic variants, physicians should perform MRI head scan (proposed protocol: T1, T2, FLAIR, DWI, and ADC; if MRI head is contraindicated, CT head can be performed), electroencephalogram (EEG), blood and laboratory tests, chest radiograph (if aspiration pneumonia suspected), abdominal radiography (if intestinal pseudo-obstruction is suspected), and electrocardiogram (105).

Finally, skeletal muscle biopsy can be performed to confirm the diagnosis. Ragged-red fibers on modified Gomori trichrome stain are the hallmark histological feature. The ragged-red fibers often show positive histochemical staining for cytochrome c oxidase activity. In addition, other features characteristic of abnormal mitochondria may be found. Mitochondrial enzyme activities can be measured in whole muscle homogenate, or in isolated mitochondria. The muscle mtDNA should be screened for the mutations associated with MELAS.

Management

No treatment for the genetic defect is currently available. Coenzyme Q10 (50 to 100 mg three times a day) and L-carnitine (330 mg three times a day) have been used to improve mitochondrial function. Idebenone, another quinone compound similar to coenzyme Q10, has the theoretical advantage of crossing the blood-brain barrier and has been reported to be beneficial in isolated patients with MELAS; a study suggested that the benefit use of idebenone is due to one of its longer-lasting metabolites, QS-10, QS-6, and QS-4 (37). Beta-Lapachone, a natural quinone compound, was found to attenuate mitochondrial dysfunction in MELAS cybrid cells more efficiently than the quinones idebenone and CoQ10 that are already in clinical use (56). β-Lapachone restored energy production and mitochondrial membrane potential, normalized the elevated ROS level, reduced lactic acidosis, and activated Sirt1 by increasing the intracellular NAD(+)/NADH ratio, which was accompanied by increased mtDNA content. Further studies are needed to establish the efficacy of this compound in vivo.

Dichloroacetate inhibits the pyruvate dehydrogenase-specific kinase, thereby activating pyruvate dehydrogenase complex and reducing lactate levels. Unfortunately, a double-blind randomized placebo-controlled trial of DCA showed no treatment benefit and the trial was terminated due to frequent peripheral nerve toxicity (60).

Supplementation with L-cysteine (which is required for the 2-thiomodification of mitochondrial tRNAs) partially rescued the mitochondrial translation defect in vitro in fibroblasts of patients carrying the m.3243A>G and m.8344A>G mutations (04). Clinical studies on L-cysteine have not yet been performed.

In cybrid cells with almost homoplasmic m.3243A>G mutation, the addition of ketone bodies for 4 weeks significantly restored complex I activity and ATP synthesis, and it increased mtDNA copy number. Hence, ketogenic diet may be a promising therapy for MELAS (32).

L-arginine, a nitric oxide precursor, has been used to stimulate vasodilation in MELAS (73; 72). In open-label studies, intravenous L-arginine administered shortly after the onset of stroke-like episode seemed to improve outcomes whereas oral administration during interictal phases appeared to decrease the frequency and severity of stroke-like events (73; 72). Maintaining plasma arginine concentration at least 168 mmol/l has been reported to prevent the ictuses through the putative pathophysiologic mechanism and optimal normalization of endothelial dysfunction (54). There is even more improvement in nitric oxide production with arginine and citrulline supplementation (27; 26). Interestingly, NO production seems to become measurable now by use of a stable isotope tracer infusion technique (28). Controlled studies assessing the potential beneficial effects of arginine or citrulline supplementation, their optimum dosing, and safety ranges in stroke-like episodes of MELAS syndrome are urgently required.

In the meantime, recommendations for the treatment of stroke-like episodes have been published by the Mitochondrial Medicine Society (110; 70):

	• Patients with known MELAS who present with any symptoms suggestive of a metabolic stroke should receive a loading dose of intravenous arginine hydrochloride. Although the optimal dose has not been defined, a bolus of 0.5 g/kg given within 3 hours of symptom onset is recommended.
	• After the initial arginine bolus, an additional 0.5 g/kg should be administered as a continuous infusion for 24 hours for the next 3 to 5 days.
	• Patients may be transitioned to oral L-arginine at a 1-to-1 dose once swallowing safety is ensured and they are able to tolerate oral intake.
	• Prophylaxis: Once a patient with MELAS has experienced a first stroke, arginine should be administered prophylactically to reduce the risk of recurrent stroke-like episodes. A daily dose of 0.15 to 0.30 g/kg administered orally in three divided doses is recommended.
	• Moreover, in the acute episode, the patient should be given dextrose-containing fluids as soon as possible to reverse ongoing or impending catabolism (even in the setting of euglycemia). In the acute stroke-like episode, patients should immediately undergo electroencephalography to assess for subclinical status epilepticus.
	• Seizures respond to conventional anticonvulsant therapy; there is no known drug regimen of choice.

A clinical trial demonstrated that oral supplementation with high-dose taurine was effective in preventing stroke-like episodes and was able to ameliorate taurine modification defect in mitochondrial tRNALeu(UUR) in peripheral blood leucocytes in vivo (109). However, as for arginine, no adequately controlled clinical studies determining the efficacy of these compounds in treating or preventing stroke-like episodes have been published.

In 2018, in Newcastle, a European group of experts met to develop a consensus-based guidance for the management of mitochondrial stroke-like episodes (105). The consensus recommends managing patients with stroke-like episodes at the intensive care unit in the following circumstances:

	• Generalized, convulsive status epilepticus
	• Focal motor seizures with breakthrough generalized seizures, which fail to respond to intravenous AEDs
	• Severe encephalopathy with a high risk of aspiration
	• Focal motor status epilepticus with retained consciousness failing to respond to benzodiazepine and other intravenous AEDs

Possible manifestations that may be observed during a stroke-like episode are focal seizures (including nonmotor seizures such as occipital seizures) with or without evolution to bilateral convulsive seizures. In case of first episode, an early administration of benzodiazepine if the patient is not in hospital should be considered. Once in hospital patients should be treated urgently with an intravenous antiepileptic drug such as intravenous levetiracetam (20-40 mg/kg, max 4500 mg), phenytoin (15-20 mg/kg with cardiac monitoring), phenobarbitone (10-15 mg/kg with respiratory monitoring), or lacosamide (200-400 mg).

Midazolam is the first choice of general anesthetics agent for treating refractory status epilepticus associated with stroke-like episodes.

Sodium valproate is contraindicated for patients with POLG mutations and should also be avoided in patients with MELAS epilepsy caused by other genotypes if an alternative drug is available and efficient.

Maintenance intravenous fluid should be administered for patients who are at risk of dehydration, especially in those with encephalopathy or those presenting with vomiting due to intestinal pseudo-obstruction. A better response to rehydration may be observed in subjects with elevated plasma lactate.

Sodium bicarbonate can be used with care in severe lactic acidosis (pH < 7.1). However, the management of severe metabolic acidosis needs a multidisciplinary approach (ie, with intensivist or nephrologist). As mentioned above, the use of dichloroacetate on lowering lactic acid is not recommended because it may cause toxic neuropathy in patients with MELAS.

Hearing loss caused by isolated cochlear dysfunction has been successfully treated with cochlear implantation (126). Aminoglycosides and platinum-based anticancer drugs, due to the increase of reactive oxygen species levels following their administration, may precipitate the development of hearing loss and should be used with caution. Consequently, mitochondria-targeted antioxidants could be useful for the prevention and treatment of diseases associated with mitochondrial dysfunction, although clinical trials are necessary to confirm the otoprotective role of these supplements in patients (33).

Special considerations

Pregnancy

Infertility may preclude this issue in some patients. Women with mtDNA point mutations are at risk of passing the mutation to their children. Prenatal testing of the fetus is of uncertain utility. In a small study of nine pregnancies in five women from families with the m.3243A>G mtDNA mutation, mutation loads in amniocytes and chorionic villi were stable at two to three stages of pregnancy (09). Eight pregnancies with fetal mutation levels 35% or lower mutation produced healthy children who have been followed for 3 months to 6 years, whereas the pregnancy with 63% mutation in the fetus was terminated. Additional studies are necessary to establish the value of prenatal testing.

In a retrospective cohort study on obstetric complications in carriers of the m.3243A>G mutation, 98 pregnancies in 46 women were reported. Of those, 25.3% had premature delivery (including 5.5% with gestation ≤ 32 weeks), 12% suffered from preeclampsia, and 11% were complicated by gestational diabetes. Hence, proper guidance during pregnancies and early detection of possible obstetric complications are needed in patients with MELAS and carriers. As techniques to prevent transmission of mitochondrial mutations are studied, it is important to know the possible complications patients may experience from the ensuing pregnancy (22).

Anesthesia

In theory, drugs that lower seizure threshold should be avoided. Because propofol can inhibit the mitochondrial respiratory chain, some authors have advocated avoidance of this anesthetic agent in patients with mitochondrial diseases (93); however, patients with MELAS have received propofol without complications (111). We recommend midazolam as the first choice of general anesthetics agent for treating refractory status epilepticus associated with stroke-like episodes.

The greater susceptibility of patients affected by mitochondrial diseases to developing lactic acidosis should be considered by physicians during surgical procedures and perioperative fasting, which may be possible metabolic stress factors and exacerbate this condition. Routine, perioperative use of lactate-free intravenous fluids (such as 5% dextrose-0.9% saline) is recommended in all patients with mitochondrial diseases undergoing general anesthesia, including those affected by MELAS.

References

01: Abu-Amero KK, Ozand PT, Al-Dhalaan H. Novel mitochondrial DNA transversion mutation in transfer ribonucleic acid for leucine 2 (CUN) in a patient with the clinical features of MELAS. J Child Neurol 2006;21:971-2. PMID 17092464
02: Alves CAPF, Zandifar A, Peterson JT, et al. MELAS: phenotype classification into classic-versus-atypical presentations. AJNR Am J Neuroradiol 2023;44(5):602-10. PMID 37024306
03: Anglin RE, Garside SL, Tarnopolsky MA, Mazurek MF, Rosebush PI. The psychiatric manifestations of mitochondrial disorders: a case and review of the literature. J Clin Psychiatry 2012;73:506-12. PMID 22579150
04: Bartsakoulia M, Mϋller JS, Gomez-Duran A, Yu-Wai-Man P, Boczonadi V, Horvath R. Cysteine supplementation may be beneficial in a subgroup of mitochondrial translation deficiencies. J Neuromuscul Dis 2016;3(3):363-79. PMID 27854233
05: Bataillard M, Chatzoglou E, Rumbach L, et al. Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation. Neurology 2001;56:405-7. PMID 11171912
06: Belal S, Goudenège D, Bocca C, et al. Glutamate-induced deregulation of Krebs cycle in mitochondrial encephalopathy lactic acidosis syndrome stroke-like episodes (MELAS) syndrome is alleviated by ketone body exposure. Biomedicines 2022;10(7):1665. PMID 35884972
07: Betts J, Jaros E, Perry RH, et al. Molecular neuropathology of MELAS: level of heteroplasmy in individual neurons and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol 2006;32:359-73. PMID 16866982
08: Bhatia KD, Krishnan P, Kortman H, Klostranec J, Krings T. Acute cortical lesions in MELAS syndrome: anatomic distribution, symmetry, and evolution. AJNR Am J Neuroradiol 2020;41(1):167-73. PMID 31806591
09: Bouchet C, Steffann J, Corcos J, et al. Prenatal diagnosis of myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome: contribution to understanding mitochondrial DNA segregation during human embryofetal development. J Med Genet 2006;43:788-92. PMID 16690729
10: Borner GV, Zeviani M, Tiranti V, et al. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet 2000;9(4):467-75. PMID 10699170
11: Brackmann F, Abicht A, Ahting U, Schröder R, Trollmann R. Classical MERRF phenotype associated with mitochondrial tRNA(Leu) (m.3243A>G) mutation. Eur J Pediatr 2012;171:859-62. PMID 22270878
12: Brown WM, Prager EM, Wang A, Wilson AC. Mitochondrial DNA sequences of primates: tempo and mode of evolution. J Mol Evol 1982;18:225-39. PMID 6284948
13: Calvaruso MA, Willemsen MA, Rodenburg RJ, van den Brand M, Smeitink JA, Nijtmans L. New mitochondrial tRNA HIS mutation in a family with lactic acidosis and stroke-like episodes (MELAS). Mitochondrion 2011;11:778-82. PMID 21704194
14: Campos Y, Lorenzo G, Martin MA, et al. A mitochondrial tRNA(Lys) gene mutation (T8316C) in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes. Neuromuscul Disord 2000;10:493-6. PMID 10996780
15: Cheldi A, Ronchi D, Bordoni A, et al. POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndrome. BMC Neurol 2013;13:8. PMID 23324391
16: Chomyn A, Enriquez JA, Micol V, Fernandez-Silva P, Attardi G. The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke- like episode syndrome-associated human mitochondrial tRNALeu(UUR) mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes. J Biol Chem 2000;275(25):19198-209. PMID 10858457
17: Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 1992;31:391-8. PMID 1586140
18: Corona P, Antozzi C, Carrara F, et al. A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients. Ann Neurol 2001;49(1):106-10. PMID 11198278
19: Crimi M, Galbiati S, Moroni I, et al. A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome. Neurology 2003;60(11):1857-61. PMID 12796552
20: Davidson MM, Walker WF, Hernandez-Rosa E. The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier. Mitochondrion 2009;9:463-70. PMID 19682606
21: de Coo IF, Renier WO, Ruitenbeek W, et al. A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann Neurol 1999;45(1):130-3. PMID 9894888
22: 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. PMID 26455484
23: 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. PMID 27331024
24: de Laat P, Koene S, van den Heuvel LP, Rodenburg RJ, Janssen MC, Smeitink JA. Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A > G mutation. J Inherit Metab Dis 2012;35(6):1059-69. PMID 22403016
25: Deschauer M, Tennant S, Rokicka A, et al. MELAS associated with mutations in the POLG1 gene. Neurology 2007;68:1741-2. PMID 17502560
26: El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen 2017;5:10. PMID 28736735
27: El-Hattab AW, Emrick LT, Hsu JW, et al. Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation. Mol Genet Metab 2016;117(4):407-12. PMID 26851065
28: El-Hattab AW, Jahoor F. Assessment of nitric oxide production in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome with the use of a stable isotope tracer infusion technique. J Nutr 2017;147(7):1251-7. PMID 28515163
29: 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;83:254-60. PMID 18674747
30: Emmanuele V, Garcia-Cazorla A, Huang HB, et al. Decreased hippocampal expression of calbindin D(28K) and cognitive impairment in MELAS. J Neurol Sci 2012;317:29-34. PMID 22483853
31: Emmanuele V, Sotiriou E, Rios PG, et al. A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome. J Child Neurol 2013;28(2):236-42. PMID 22638077
32: Frey S, Geffroy G, Desquiret-Dumas V, et al. The addition of ketone bodies alleviates mitochondrial dysfunction by restoring complex I assembly in a MELAS cellular model. Biochim Biophys Acta 2017;1863(1):284-91. PMID 27815040
33: Fujimoto C, Yamasoba T. Mitochondria-targeted antioxidants for treatment of hearing loss: a systematic review. Antioxidants (Basel) 2019;8(4):109. PMID 31022870
34: Gardner-Medwin D, Dale G, Parker J. Lactic acidosis with mitochondrial myopathy and recurrent coma. First International Congress of Child Neurology 1975:47.
35: Garone C, D'Souza AR, Dallabona C, et al. Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome. Hum Mol Genet 2017;26:4257-66. PMID 28973171
36: Gieraerts C, Demaerel P, Van Damme P, Wilms G. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome mimicking herpes simplex encephalitis on imaging studies. J Comput Assist Tomogr 2013;37(2):279-81. PMID 23493219
37: Giorgio V, Petronilli V, Ghelli A, et al. The effects of idebenone on mitochondrial bioenergetics. Biochim Biophys Acta 2012;1817(2):363-9. PMID 22086148
38: Golla S, Ren J, Malloy CR, Pascual JM. Intramyocellular lipid excess in the mitochondrial disorder MELAS: MRS determination at 7T. Neurol Genet 2017;3(3):e160. PMID 28589178
39: Goto YI, Nonaka I, Horai S. A mutation in the tRNALeu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348(6302):651-3. PMID 2102678
40: Goto Y, Nonaka I, Horai S. A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta 1991;1097(3):238-40. PMID 1932147
41: Goto Y, Tsugane K, Tanabe Y, Nonaka I, Horai S. A new point mutation at nucleotide 3291 of the mitochondrial tRNA(Leu(UUR)) gene in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochim Biophys Res Commun 1994;202(3):1624-30. PMID 7520241
42: Grady JP, Pickett SJ, Ng YS, et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol Med 2018;10(6). PMID 29735722
43: Guerrero-Molina MP, Morales-Conejo M, Delmiro A, et al. Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome. J Neurol 2022;269(6):3238-48. PMID 35088140
44: Hamalainen RH, Manninen T, Koivumäki H, Kislin M, Otonkoski T, Suomalainen A. Tissue- and cell-type-specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model. Proc Natl Acad Sci U S A 2013;110(38):E3622-30. PMID 24003133
45: Hanna MG, Nelson IP, Morgan-Hughes JA, Wood NW. MELAS: a new disease associated mitochondrial DNA mutation and evidence for further genetic heterogeneity. J Neurol Neurosurg Psychiatry 1998;65(4):512-7. PMID 9771776
46: Hayashi Y, Iwasaki Y, Yoshikura N, et al. Clinicopathological findings of a mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT-ND1. Neuropathology 2021;41(1):84-90. PMID 33300189
47: Heindryckx B, Neupane J, Vandewoestyne M, et al. Mutation-free baby born from a mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome carrier after blastocyst trophectoderm preimplantation genetic diagnosis. Mitochondrion 2014;18:12-7. PMID 25159128
48: Helm M, Florentz C, Chomyn A, Attardi G. Search for differences in post-transcriptional modification patterns of mitochondrial DNA-encoded wild-type and mutant human tRNALys and tRNALeu(UUR). Nucleic Acids Res 1999;27(3):756-63. PMID 9889270
49: Herrero-Martin MD, Ayuso T, Tunon MT, Martin MA, Ruiz-Pesini E, Montoya J. A MELAS/MERRF phenotype associated with the mitochondrial DNA 5521G>A mutation. J Neurol Neurosurg Psychiatry 2010;81:471-2. PMID 20360171
50: Hirano M, Ricci E, Koenigsberger MR, et al. MELAS: an original case and clinical criteria for diagnosis. Neuromusc Disord 1992;2:125-35. PMID 1422200
51: Hsu YR, Yogasundaram H, Parajuli N, Valtuille L, Sergi C, Oudit GY. MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis. Heart Fail Rev 2016;21(1):103-16. PMID 26712328
52: Hyslop LA, Blakeley P, Craven L, et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 2016;534(7607):383-6. PMID 27281217
53: Iizuka T, Sakai F. Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms. Curr Neurovasc Res 2005;2(1):29-45. PMID 16181098
54: Ikawa M, Povalko N, Koga Y. Arginine therapy in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Curr Opin Clin Nutr Metab Care 2020;23(1):17-22. PMID 31693521
55: Ito H, Mori K, Kagami S. Neuroimaging of stroke-like episodes in MELAS. Brain Dev 2011;33(4):283-8. PMID 20609541
56: Jeong MH, Kim JH, Seo KS, Kwak TH, Park WJ. β-Lapachone attenuates mitochondrial dysfunction in MELAS cybrid cells. Biochem Biophys Res Commun 2014;454(3):417-22. PMID 25451262
57: Ji K, Lin Y, Xu X, et al. MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNATrpand remarkable mitochondrial dysfunction. J Med Genet 2022;59(1):79-87. PMID 33208382
58: Johns DR, Stein AG, Wityk R. MELAS syndrome masquerading as Herpes simplex encephalitis. Neurology 1993;43:2471-3. PMID 8255441
59: Kanellopoulos AK, Mariano V, Spinazzi M, et al. Aralar sequesters GABA into hyperactive mitochondria, causing social behavior deficits. Cell 2020;180(6):1178-97.e20. PMID 32200800
60: Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized controlled clinical trial. Neurology 2006a;66:324-30. PMID 16476929
61: Kaufmann P, Engelstad K, Wei Y, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology 2011;77:1965-71. PMID 22094475
62: Kaufmann P, Koga Y, Shanske S, et al. Mitochondrial DNA and RNA processing in MELAS. Ann Neurol 1996;40:172-80. PMID 8773598
63: Kaufmann P, Pascual JM, Anziska Y, et al. Nerve conduction abnormalities in patients with MELAS and the A3243G mutation. Arch Neurol 2006b;63:746-8. PMID 16682545
64: Kaufmann P, Shungu DC, Sano MC, et al. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology 2004;62(8):1297-302. PMID 15111665
65: King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 1989;246:500-3. PMID 2814477
66: King MP, Koga Y, Davidson M, Schon EA. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu (UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol Cell Biol 1992;12:480-90. PMID 1732728
67: Kirby DM, McFarland R, Ohtake A, et al. Mutations of the mitochondrial ND1 gene as a cause of MELAS. J Med Genet 2004;41:784-9. PMID 15466014
68: Kirino Y, Yasukawa T, Ohta S, et al. Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. Proc Natl Acad Sci U S A 2004;101(42):15070-5. PMID 15477592
69: Kobayashi Y, Momoi M, Tominaga K, et al. A point mutation in the mitochondrial tRNALeu (UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). Biochem Biophys Res Commun 1990;173:816-22. PMID 2268345
70: Koenig MK, Emrick L, Karaa A, 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. PMID 26954033
71: Koenigsberger MR, Pellock JM, DiMauro S, Eastwood AB. Juvenile mitochondrial myopathy, short stature and lactic acidosis: a clinical, biochemical, and ultrastructural study. Fifth Annual Meeting of the Child Neurology Society 1976.
72: Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 2005;64(4):710-2. PMID 15728297
73: Koga Y, Ishibashi M, Ueki I, et al. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology 2002;58(5):827-8. PMID 11889254
74: Kotagal S, Peterson P, Martens M, Lee CP, Nigro M, Archer C. Impaired NADH-CoQ reductase activity in a child with moyamoya syndrome. Pediatr Neurol 1988;4(4):241-4. PMID 3149483
75: Kraya T, Deschauer M, Joshi PR, Zierz S, Gaul C. Prevalence of headache in patients with mitochondrial disease: a cross-sectional study. Headache 2018;58(1):45-52. PMID 29139113
76: Lee H, Na JH, Lee YM. Mitochondrial tRNAHismutation (m.12158A > G) associated with MELAS syndrome. Clin Genet 2022;101(4):474-5. PMID 35092007
77: Lim BC, Park JD, Hwang H, et al. Mutations in ND subunits of complex I are an important genetic cause of childhood mitochondrial encephalopathies. J Child Neurol 2009;24:828-32. PMID 19617458
78: Lindberg C, Moslemi AR, Oldfors A. MELAS syndrome in a patient with a point mutation in MTTS1. Acta Neurol Scand 2008;117:128-32. PMID 17894844
79: Liolitsa D, Rahman S, Benton S, Carr LJ, Hanna MG. Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations. Ann Neurol 2003;53(1):128-32. PMID 12509858
80: Liu P, Demple B. DNA repair in mammalian mitochondria: Much more than we thought. Environ Mol Mutagen 2010;51:417-26. PMID 20544882
81: Lou X, Zhou Y, Liu Z, et al. De novo frameshift variant in MT-ND1 causes a mitochondrial complex I deficiency associated with MELAS syndrome. Gene 2023;860:147229. PMID 36717040
82: Lu J, Liu W, Zhao H. Headache in cerebrovascular diseases. Stroke Vasc Neurol 2020a;5(2):205-10. PMID 32606088
83: Lu Y, Deng J, Zhao Y, et al. Patients with MELAS with negative myopathology for characteristic ragged-red fibers. J Neurol Sci 2020b;408:116499. PMID 31726383
84: Luigetti M, Sauchelli D, Primiano G, et al. Peripheral neuropathy is a common manifestation of mitochondrial diseases: a single-centre experience. Eur J Neurol 2016;23(6):1020-7. PMID 26822221
85: Majamma-Voltti KA, Winqvist S, Remes AM, et al. A 3-year clinical follow-up of adult patients with 3243A>G in mitochondrial DNA. Neurology 2006;66(10):1470-5. PMID 16717204
86: Malfatti E, Bugiani M, Invernizzi F, et al. Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy. Brain 2007;130:1894-904. PMID 17535832
87: Mancuso M, Orsucci D, Angelini C, et al. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol 2014a;261(3):504-10. PMID 24375076
88: Mancuso M, Nesti C, Ienco EC, et al. Novel MTCYB mutation in a young patient with recurrent stroke-like episodes and status epilepticus. Am J Med Genet A 2014b;164A(11):2922-5. PMID 25125337
89: Manfredi G, Schon EA, Bonilla E, Moraes CT, Shanske S, DiMauro S. Identification of a mutation in the mitochondrial tRNACys gene associated with mitochondrial encephalopathy. Hum Mutat 1996;7:158-63. PMID 8829635
90: Manfredi G, Schon EA, Moraes CT, et al. A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. Neuromusc Disord 1995;5:391-8. PMID 7496173
91: Manwaring N, Jones MM, Wang JJ, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion 2007;7:230-3. PMID 17300999
92: Matthews P, Tampieri D, Berkovic S, et al. Magnetic resonance imaging shows specific abnormalities in the MELAS syndrome. Neurology 1991;41:1043-6. PMID 2067632
93: Maurtua M, Torres A, Ibarra V, DeBoer G, Dolak J. Anesthetic management of an obstetric patient with MELAS syndrome: case report and literature review. Int J Obstet Anesth 2008;17:370-3. PMID 18691868
94: McKenzie M, Liolitsa D, Akinshina N, et al. Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption. J Biol Chem 2007;282:36845-52. PMID 17940288
95: Meseguer S, Boix O, Navarro-González C, et al. microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases. Sci Rep 2017;7(1):6209. PMID 28740091
96: Meseguer S, Martínez-Zamora A, García-Arumí E, Andreu AL, Armengod ME. The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum Mol Genet 2015;24(1):167-84. PMID 25149473
97: Meseguer S, Rubio MP. mt tRFs, new players in MELAS disease. Front Physiol 2022;13:800171. PMID 35273517
98: Monnot S, Samuels DC, Hesters L, et al. Mutation dependance of the mitochondrial DNA copy number in the first stages of human embryogenesis. Hum Mol Genet 2013;22(9):1867-72. PMID 23390135
99: Montano V, Simoncini C, LoGerfo A, Siciliano G, Mancuso M. Catatonia as prominent feature of stroke-like episode in MELAS. Neurol Sci 2021;42(1):383-5. PMID 32761397
100: Moraes CT, Ciacci F, Silvestri G, et al. Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA. Neuromuscul Disord 1993;3:43-50. PMID 8392410
101: Morten KJ, Cooper JM, Brown GK, Lake BD, Pike D, Poulton J. A new point mutation associated with mitochondrial encephalomyopathy. Hum Mol Genet 1993;2:2081-7. PMID 8111377
102: Naini AB, Lu J, Kaufmann P, et al. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF. Arch Neurol 2005;62(3):473-6. PMID 15767514
103: Nakamura M, Nakano S, Goto Y, et al. A novel point mutation in the mitochondrial tRNA(Ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome. Biochem Biophys Res Commun 1995;214(1):86-93. PMID 7669057
104: Nesbitt V, Pitceathly RD, Turnbull DM, 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. PMID 23355809
105: Ng YS, Bindoff LA, Gorman GS, et al. Consensus-based statements for the management of mitochondrial stroke-like episodes [version 1; peer review: awaiting peer review]. Wellcome Open Res 2019;4:201. PMID 32090171
106: Ng YS, Lax NZ, Blain AP, et al. Forecasting stroke-like episodes and outcomes in mitochondrial disease. Brain 2022;145(2):542-54. PMID 34927673
107: Nishino I, Komatsu M, Kodama S, Horai S, Nonaka I, Goto YI. The 3260 mutation in mitochondrial DNA can cause mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Muscle Nerve 1996;19:1603-4. PMID 8941275
108: Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol 1987;74(3):226-33. PMID 3673514
109: Ohsawa Y, Hagiwara H, Nishimatsu SI, 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. PMID 29666206
110: Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med 2015;17(9):689-701. PMID 25503498
111: Park JS, Baek CW, Kang H, et al. Total intravenous anesthesia with propofol and remifentanil in a patient with MELAS syndrome: a case report. Korean J Anesthesiol 2010;58:409-12. PMID 20508802
112: Pavlakis SG, Phillips PC, DiMauro S, DeVivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481-8. PMID 6093682
113: Pek NMQ, Phua QH, Ho BX, et al. Mitochondrial 3243A >G mutation confers proatherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells. Cell Death Dis 2019;10(11):802. PMID 31641105
114: Pia S, Lui F. MELAS Syndrome. StatPearls In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. PMID 30422554
115: Quadir A, Pontifex CS, Lee Robertson H, Labos C, Pfeffer G. Systematic review and meta-analysis of cardiac involvement in mitochondrial myopathy. Neurol Genet 2019;5(4):e339. PMID 31403078
116: Ramakers R, Koene S, Groothuis JT, de Laat P, Janssen MC, Smeitink J. Quantification of gait in mitochondrial m.3243A > G patients: a validation study. Orphanet J Rare Dis 2017;12(1):91. PMID 28506302
117: Ravn K, Wibrand F, Hansen FJ, Horn N, Rosenberg T, Schwartz M. An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome. Eur J Hum Genet 2001;9(10):805-9. PMID 11781695
118: Reardon W, Ross RJ, Sweeney MG, et al. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 1992;340:1376-9. PMID 1360090
119: Rowland LP, Hays AP, DiMauro S, DeVivo DC, Behrens MT. Diverse clinical disorders associated with morphological abnormalities of mitochondria. In: Cerri C, Scarlato G, editors. Mitochondrial pathology in muscle diseases. Padua: Piccin Editore, 1983.
120: Sakai S, Osaki M, Hidaka M, et al. Association between stroke-like episodes and neuronal hyperexcitability in MELAS with m.3243A>G: a case report. eNeurologicalSci 2018;12:39-41. PMID 30229135
121: Sakuta R, Honzawa S, Murakami N, Goto Y, Nagai T. Atypical MELAS associated with mitochondrial tRNA(Lys) gene A8296G mutation. Pediatr Neurol 2002;27(5):397-400. PMID 12504210
122: Sandoval AR, Zamora R, Santizo JO, Alegría RA, Gutiérrez JR, et al. Parkinsonism as a clinical manifestation of MELAS syndrome. Clin Case Rep Rev 2015.
123: Santorelli FM, Tanji K, Kulikova R, et al. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun 1997;238:326-8. PMID 9299505
124: Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet 2008;17:3697-707. PMID 18753147
125: Sato W, Hayasaka K, Shoji Y, et al. A mitochondrial tRNA(Leu)(UUR) mutation at 3,256 associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke- like episodes (MELAS). Biochem Mol Biol Int 1994;33:1055-61. PMID 7804130
126: Scarpelli M, Zappini F, Filosto M, Russignan A, Tonin P, Tomelleri G. Mitochondrial sensorineural hearing loss: a retrospective study and a description of cochlear implantation in a MELAS patient. Genet Res Int 2012;2012:287432. PMID 22567382
127: Shanske S, Coku J, Lu J, et al. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. Arch Neurol 2008;65:368-72. PMID 18332249
128: Shanske S, Pancrudo J, Kaufmann P, et al. Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet A 2004;130A:134-7. PMID 15372523
129: Shapira Y, Cederbaum S, Cancilla P. Familial poliodystrophy, mitochondrial myopathy, and lactate acidemia. Neurology 1975;25:614-21. PMID 1171391
130: Snyder MT, Manor J, Gijavanekar C, et al. Heteroplasmic pathogenic m.12315G>A variant in MT-TL2 presenting with MELAS syndrome and depletion of nitric oxide donors. Am J Med Genet A 2024;194(3):e63461. PMID 37953071
131: Sparaco M, Bonilla E, DiMauro S, Powers J. Neuropathology of mitochondrial encephalomyopathies due to mitochondrial DNA defects. J Neuropathol Exp Neurol 1993;52:1-10. PMID 8426185
132: Sparaco M, Simonati A, Cavallaro T, et al. MELAS: clinical phenotype and morphological brain abnormalities. Acta Neuropathol 2003;106(3):202-12. PMID 12910362
133: Sproule DM, Dyme J, Coku J, et al. Pulmonary artery hypertension in a child with MELAS due to a point mutation of the mitochondrial tRNA(Leu) gene (m.3243A>G). J Inherit Metab Dis 2008. PMID 18181029
134: Strasser L, Doja A, Davila J, Chakraborty P, Bourque DK. The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability. Am J Med Genet A 2023;191(12):2890-7. PMID 37654102
135: Takahashi K, Merchant SN, Miyazawa T, et al. Temporal bone histopathological and quantitative analysis of mitochondrial DNA in MELAS. Laryngoscope 2003;113(8):1362-8. PMID 12897560
136: Tam EW, Feigenbaum A, Addis JB, et al. A novel mitochondrial DNA mutation in COX1 leads to strokes, seizures, and lactic acidosis. Neuropediatrics 2008;39:328-34. PMID 19568996
137: Tanji K, Kaufmann P, Naini AB, et al. A novel tRNA(Val) mitochondrial DNA mutation causing MELAS. J Neurol Sci 2008;270:23-7. PMID 18314141
138: Tay S, Nordli DR Jr, Bonilla E, et al. Aortic rupture in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Arch Neurol 2006;63:281-3. PMID 16476819
139: Taylor RW, Chinnery PF, Haldane F, et al. MELAS associated with a mutation in the valine transfer RNA gene of mitochondrial DNA. Ann Neurol 1996;40:459-62. PMID 8797538
140: Taylor RW, Singh-Kler R, Hayes CM, et al. Progressive mitochondrial disease resulting from a novel missense mutation in the mitochondrial DNA ND3 gene. Ann Neurol 2001;50:104-7. PMID 11456298
141: Tsang SH, Aycinena ARP, Sharma T. Mitochondrial disorder: maternally inherited diabetes and deafness. Adv Exp Med Biol 2018;1085:163-5. PMID 30578504
142: Uusimaa J, Moilanen JS, Vainionpaa L, et al. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children. Ann Neurol 2007;62:278-87. PMID 17823937
143: Vandana VP, Bindu PS, Sonam K, et al. Audiological manifestations in mitochondrial encephalomyopathy lactic acidosis and stroke like episodes (MELAS) syndrome. Clin Neurol Neurosurg 2016;148:17-21. PMID 27359089
144: van den Ouweland J, Lemkes H, Ruitenbeck W, et al. Mutation in mitochondrial tRNALeu (UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet 1992;1:368-71. PMID 1284550
145: Wang S, Wu S, Zheng T, et al. Mitochondrial DNA mutations in diabetes mellitus patients in Chinese Han population. Gene 2013;531(2):472-5. PMID 24055484
146: Wang W, Zhao Y, Xu X, et al. A different pattern of clinical, muscle pathology and brain MRI findings in MELAS with mt-ND variants. Ann Clin Transl Neurol 2023;10(6):1035-45. PMID 37221696
147: Wang Z, Qi XK, Yao S, et al. Phenotypic patterns of MELAS/LS overlap syndrome associated with m.13513G>A mutation, and neuropathological findings in one autopsy case. Neuropathology 2010;30(6):606-14. PMID 20408961
148: Weiduschat N, Kaufmann P, Mao X, et al. Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. Neurology 2014;82(9):798-805. PMID 24477106
149: Whitehead MT, Wien M, Lee B, Bass N, Gropman A. Cortical venous disease severity in MELAS syndrome correlates with brain lesion development. Neuroradiology 2017;59(8):813-8. PMID 28667360
150: Yatsuga S, Povalko N, Nishioka J, et al. MELAS: A nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta 2012;1820:619-24. PMID 21443929
151: Yeung RO, Al Jundi M, Gubbi S, et al. Management of mitochondrial diabetes in the era of novel therapies. J Diabetes Complications 2021;35(1):107584. PMID 32331977
152: Yoo DH, Choi YC, Nam DE, et al. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome. Mitochondrion 2017;35:54-8. PMID 28499982
153: Zeviani M, Muntoni F, Savarese N, et al. A MERRF/MELAS overlap syndrome with a new point mutation in the mitochondrial DNA tRNALys gene. Eur J Hum Genet 1993;1:80-7. PMID 8069654
154: Zhang Z, Zhao D, Zhang X, et al. Survival analysis of a cohort of Chinese patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) based on clinical features. J Neurol Sci 2018;385:151-5. PMID 29406897

Contributors

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

Authors

Michelangelo Mancuso MD PhD

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

Dr. Meli had no relevant financial relationships to disclose.
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Editor

Aravindhan Veerapandiyan MD

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

Michio Hirano MD
Thomas Klopstock MD
Francesco Gruosso MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor (matrilinear or -in case of POLG- autosomal recessive)
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Mitochondrial myopathy, not elsewhere classified: G71.3
ICD-11: Mitochondrial protein translation defects: 5C53.23

Mitochondrial DNA depletion syndromes: 5C53.20

Other specified disorders of mitochondrial oxidative phosphorylation: 5C53.2Y

Epilepsy due to genetic syndromes with widespread or progressive effects: 8A60.A

Other specified mitochondrial myopathies: 8C73.Y
OMIM: MELAS: #540000

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MELAS

Associated Disorders

Ataxia
Basal ganglia calcifications
Cardiac conduction block
Cardiomyopathy
Diabetes mellitus
- Elevated CSF protein
- Episodic coma
- Exercise intolerance
- Headaches
- Hearing loss
- Hirsutism
- Limb weakness
- Mitochondrial encephalomyopathy
- Mitochondrial myopathy
- Myoclonus
- Nephropathy
- Ophthalmoplegia
- Optic nerve atrophy
- Pigmentary retinopathy
- Progressive external ophthalmoplegia
- Seizures
- Stroke-like episodes

Differential Diagnosis

heart disease
carotid artery disorders
vertebral artery disorders
sickle cell anemia
vasculopathies
- ischemic stroke
- lipoprotein disorders
- cancer
- venous thrombosis
- moyamoya disease
- complicated migraine
- homocystinuria
- migraine with prolonged aura
- basilar migraine
- hemiplegic migraine
- herpes simplex encephalitis
- other mitochondrial diseases
- Kearns-Sayre syndrome
- myoclonus epilepsy associated with ragged-red fibers (MERRF)
- Leigh syndrome

Also Relevant

Drug-induced myopathies
Epilepsy in mitochondrial disorders
Kearns-Sayre syndrome
Myoclonus epilepsy with ragged-red fibers
Stroke in young adults

Clinical Categories

Patient Handouts

Web References

Testing

Guidelines

NORD: Mitochondrial Myopathy

MELAS …

MELAS

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical Diagnostic Criteria of MELAS

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 2. MtDNA Mutations causing MELAS

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Carnitine palmitoyltransferase II deficiency

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Pyruvate carboxylase deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Chronic progressive external ophthalmoplegia

MELAS

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical Diagnostic Criteria of MELAS

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 2. MtDNA Mutations causing MELAS

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Carnitine palmitoyltransferase II deficiency

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Pyruvate carboxylase deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Chronic progressive external ophthalmoplegia

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