It is the most distinctive, although non-pathognomonic, disorder of MELAS syndrome, with an estimated prevalence between 31% and 90% of patients [7]. Its presentation is usually subacute, and the more commonly related symptoms are epileptic seizures, visual symptoms (especially cortical blindness) or a sensory-motor focal deficit. Brain MRI images show lesions that simulate an ischemic stroke, but do not have a distribution that corresponds to a defined vascular territory (Figure 1). The lesions predominate in the parietoccipital regions, can occur simultaneously in both hemispheres, are preferentially distributed in the cerebral cortex, and in some patients have an intermittent temporal pattern, disappearing withpout leaving sequelae [8].

Figure 1 Figure 1 Brain MRI in adult patient diagnosticated with MELAS Syndrome. 24 years old woman with confirmed mA3243G mutation and classical MELAS syndrome. Diffusion weighted brain MRI images show two SLE. A: right temporoparietal cortical hyperintensity corresponding to first SLE; B: the same patient, hospitalized two weeks after by another SLE, image shows cortical hyperintensity in the medial right frontal region. The previous lesion is not visible Figure 1 Brain MRI in adult patient diagnosticated with MELAS Syndrome. 24 years old woman with confirmed mA3243G mutation and classical MELAS syndrome. Diffusion weighted brain MRI images show two SLE. A: right temporoparietal cortical hyperintensity corresponding to first SLE; B: the same patient, hospitalized two weeks after by another SLE, image shows cortical hyperintensity in the medial right frontal region. The previous lesion is not visible

SLE are caused by endothelial dysfunction secondary to failure of the mitochondrial respiratory chain and an increase in regional anaerobic metabolism. The cerebral cortex is very sensitive to hypoxia, which explains its vulnerability to damage generated by SLEs. Moreover, seizures can also contribute to triggering SLE by increasing neuronal energy demand.

In the acute phase, brain CT shows hypodense cortical lesions, while MRI T2 and FLAIR weighted images show hyperintensities, and T1 weighted images show cortical edema, and post-contrast linear enhancement. In subacute phases, lesions may show gyri cerebral cortex hyperintensities in T1 weighted images and hypointensities in T2-FLAIR. The presence of hypointense cystic-like lesions inside the cerebral cortex suggests the diagnosis of MELAS syndrome ("black nail sign") [9]. In chronic phases of the disease, the lesions can leave sequelae as encephalomalacia, gliosis and cortical atrophy.

MR spectroscopy is very useful in helping to establish the diagnosis of MELAS syndrome. Typically, there is a decrease in the N-acetyl-aspartate peak and an increase in the lactate peak in acute lesions. In turn, in FDG-PET images the lesions usually show reduced metabolism.

There are few publications focused on the specific study of neuropsychological disorders in patients with MELAS, most of them correspond to clinical cases. The prevalence of cognitive impairment in people with a confirmed diagnosis varies between 40% and 90%, is generally progressive and worsens with each SLE [10]. The most severe forms of MELAS syndrome that begin in childhood occur with a delay or severe intellectual disabilities. Patients who have a late onset may have a normal cognitive level until the onset of the disease.

Mental functions can be globally altered with varying degrees of severity, including dementia. As SLE have a preferential distribution in posterior regions of the brain, it is common for patients to show alterations in tests assessing attention, visuospatial functions, and executive functions [11].

About 71-90% of patients with confirmed diagnosis of mitochondrial diseases have seizures during the course of the disease, with an estimated prevalence of epilepsy between 10-23% (versus ± 2-10/1.000 inhab. in the general population). Studies in Europe have shown that in patients suffering from epilepsy-related mitochondrial disease, the m.3243A>G mutation is the most found genotype. In a cohort in the United Kingdom, 34.9% of patients with this mutation developed epilepsy [12, 13].

Focal onset seizures are the most common, which can manifest in the context of an acute episode of SLE or as consequences to previous episodes. Myoclonic seizures are frequently described in different forms of mitochondrial diseases, including MELAS syndrome. Generalized seizures can also occur at any time during the disease. Cases of status epilepticus are also described, especially in relation to SLE. The electroencephalogram is generally altered with nonspecific findings, highlighting a slowing of the base rhythms and different types of epileptiform activity patterns [14].

The treatment of epilepsy in patients diagnosed with MELAS syndrome is not very different from that used in other etiologies, except that valproic acid should be avoided because it worsens mitochondrial function. Levetiracetam is a good alternative due to its clinical safety profile and its efficacy in the management of different types of seizures, especially myoclonus.

It presents with different phenotypes. It is common to observe marked atrophy and generalized muscle weakness. The ocular muscles can also be affected, generating progressive external ophthalmoplegia. Muscle biopsy may be useful for the diagnosis of MELAS syndrome, specially if it shows ragged red fibers by abnormal mitochondrial deposits in the sarcolemma. Alterations in COX (cytochrome C oxidase) and SDH (succinate dehydrogenase) stains reveal abnormalities of oxidative phosphorylation.

It is another very common symptom in patients suffering from MELAS syndrome, with a higher prevalence than in the general population (40% to 50%). Migraine tends to present with visual or somesthetic auras and has a lower response to usual treatment [15].

Sensorineural hearing loss is a common disorder, often unnoticed by patients until an audiometric study is performed. Some patients with MELAS may present with the diabetes mellitus-deafness phenotype, described as another clinical pattern of mitochondrial diseases. Involuntary movements such as chorea, tremor, or parkinsonism are rare in patients with MELAS syndrome.

Hypertrophic cardiomyopathy is the most described disorder. Its prevalence is not well defined. Niedermayer et al. found that 8 out of 9 patients with MELAS syndrome, carriers of the classic mutation, had signs of hypertrophic cardiomyopathy. In addition, three patients had a shortening of the PR interval and one had an A-V conduction block [16]. Bambrilla et al., after a 16-year follow-up of 21 patients with MELAS syndrome, found eight patients with cardiac involvement, six of them (75%) were diagnosticated with hypertrophic cardiomyopathy, while one patient presented with dilated cardiomyopathy and another with persistent pulmonary artery hypertension [17]. Lioncino et al. suggest that hypertrophic cardiomyopathy is the most frequent cardiological disorder in MELAS syndrome, affecting about 40% of patients [18]. Hypertrophic cardiomyopathy is also described in patients with MELAS syndrome who carry mutations other than mA3243G, or in patients with this mutation but with atypical phenotypes [19, 20, 21, 22, 23].

The second most common cardiological condition in MELAS syndrome is Wolff-Parkinson-White syndrome [24]. Other studies show that patients with MELAS syndrome have higher prevalence of chronic hypertension compared to the general population, ranging from 41.5% to 58.9% of patients [25, 26]. Dilated cardiomyopathy is also described in a small number of patients with MELAS syndrome [27].

Chronic renal disease is probably the second most common non-neurological condition in MELAS syndrome. Clinically, the disease mimics Fanconi syndrome due to proximal tubular involvement, which presents with proteinuria, glycosuria and hyperphosphaturia. Kidney biopsy typically shows focal or segmental glomerulosclerosis [28] and renal perfusion abnormalities [29, 30, 31]. Chronic kidney disease occurs in patients with different phenotypes or genotypes [32, 33].

Patients with MELAS syndrome may also have acute renal failure. Fukutake et al. describe the case of a patient who died due to acute renal disease related to rhabdomyolysis, whose necropsy showed tubular necrosis with interstitial edema [34].

A high proportion of patients report gastrointestinal symptoms such as dysphagia, constipation, or diarrhea [35, 36]. The most described disorder is intestinal pseudo-obstruction syndrome, with an estimated prevalence of 40% of patients. It generally presents as an acute and severe complication in advanced stages of the disease, having a high lethality [37, 38].

Other rare disorders include recurrent superior mesenteric artery syndrome, which is characterized by postprandial vomiting, abdominal pain, and radiological images that show great dilation of the upper portion of the digestive tract [39]. Cases of sigmoid volvulus, intestinal perforation [40], and intestinal pneumatosis secondary to necrosis of the mucosa and lamina propria of the intestine have also been described, with the presence of antimitochondrial antibodies in the affected tissue [41].

The most observed disorder is diabetes mellitus, with an estimated prevalence of 31.9% [42]. It usually begins at an early age, and patients quickly require insulin. The "maternal diabetes-deafness" phenotype is observed in many patients carrying the A3243G mutation, usually several years before the onset of neurological manifestations [43]. Metformin is contraindicated in patients suffering from MELAS syndrome, as it increases the risk of SLE.

Autoimmune polyglandular syndrome has been described in very few cases of patients suffering from MELAS syndrome [44].

Although we did not find recent publications on this topic, it is well known that patients diagnosticated with MELAS syndrome generally have a short stature and a decreased body mass index, usually related to generalize muscle atrophy.

Lactic acidosis is an important marker for the diagnosis of the disease. However, it is not present in all patients.