MELAS patients usually don't seek medical attention before experiencing seizures or stroke-like episodes, events that often occur in late childhood or early adolescence. If queried, patients may report previously noted symptoms like intolerance of exercise, muscle weakness, myalgia and recurrent headaches.

Additional symptoms, e.g., lethargy, tachycardia, hypotension, dyspnea, nausea, vomiting and abdominal pain may be ascribed to lactic acidosis, a diagnosis that requires confirmation by laboratory analysis of blood samples. Severe lactic acidosis may even induce confusion, somnolence or stupor.

During later stages of the disease, these symptoms may overlap with neurological deficits caused by recurrent seizures and stroke-like episodes that provoke neuronal loss. MELAS patients generally suffer from prolonged focal seizures that may lead to status epilepticus, but generalized seizures may also occur [7]. Psychiatric manifestations (behavioral abnormalities, schizophrenia), progressive loss of motor and cognitive function (that may be recognized in dyspraxia, ataxia and aphasia) and eventually dementia result from neuronal cell death.

While the symptoms described above refer to a classical case of MELAS syndrome, a variety of other findings may indicate this disease. In fact, most MELAS patients present several of those pathologies:

• Cardiomyopathy
• Depression
• Bipolar disorder
• Hearing impairment
• Ophthalmoplegia
• Visual impairment or blindness
• Endocrine imbalances, particularly thyroid disorders
• Gastrointestinal problems
• Renal dysfunction [8]

A familial history of myopathy, encephalopathy, lactic acidosis and stroke-like episodes is highly suspicious for MELAS syndrome. However, because the age at symptom onset and the severity of the disease largely depend on the ratio of normal to mutated mtDNA, clinical presentation may vary largely even within one single family.

Thus, MELAS syndrome is rarely listed as a differential diagnosis after first presentation of an affected individual. A variety of diagnostic measures are usually applied to check for other diseases. In this context, magnetic resonance imaging or computed tomography scans may be realized to identify the extent of "cerebral infarction". In MELAS patients, multiple vascular territories are affected and findings may even be symmetrical. Further common results of brain imaging are cortical and cerebellar atrophy as well as basal ganglia calcification [9]. Magnetic resonance spectroscopy may reveal enhanced concentrations of lactic acid in brain parenchyma and cerebrospinal fluid.

Diagnosis of MELAS syndrome needs to be confirmed by genetic screens and determination of the underlying mutation. Molecular biological analysis of urinary sediment has been proven to be the most sensitive method to this end and false-negative results have to be expected when using other samples in heteroplasmic patients with low shares of mutated mtDNA.

Of note, even if patients don't present symptoms of cardiomyopathy, they should be submitted to a thorough cardiological examination since cardiac complications are a common cause of death in MELAS patients.

Causative treatment for MELAS syndrome is not available, although recent studies regarding dietary supplementation have yielded promising results:

• Rodriguez et al. suggested supplementation of creatine monohydrate, coenzyme Q10 and lipoic acid. The authors observed increased muscle strength and reduced serum lactate levels in three MELAS patients who partook in their study [10].
• Similar effects may be achieved by application of nicotinamide.
• L-arginine may be administered in an effort to improve cerebral blood flow and to diminish frequency and severity of stroke-like episodes in MELAS patients [11].

Little to no adverse effects have been reported for the above mentioned dietary supplements. Thus, although scientific evidence regarding the efficacy is still lacking, patients may benefit from those therapeutic approaches.

Otherwise, symptomatic treatment is indicated during episodes of acute decompensation.

Unfortunately, there is no causative treatment for MELAS syndrome; supportive treatment may merely relieve symptoms and improve life quality. Current research is focused on finding new therapeutic options and preliminary studies regarding dietary supplements have yielded promising results. However, clinical trials have yet to be conducted.

Despite all efforts, the disease takes a progressive course, leads to severe disability and is generally fatal before the age of 40. Early onset of severe symptoms corresponds to large shares of mutated mtDNA in heteroplasmic individuals and is associated with even lower life expectancy.

As has been indicated above, MELAS syndrome results from genetic disorders of the mtDNA. Human mtDNA measures about 17 kbp in length and encodes for a variety of proteins, primarily enzymes, but also for ribosomal and transfer RNA (rRNA and tRNA, respectively) [2]. Despite its small size, several mutations in the mitochondrial genome have been described. They may or may not cause specific clinical symptoms, and it is currently assumed that diseases like hypertension and diabetes mellitus may be related to mtDNA gene defects [3]. Besides MELAS syndrome, MIDD syndrome, Pearson syndrome and Kearns-Sayre syndrome shall be mentioned as examples for clinical disorders triggered by mtDNA mutations.

mtDNA is inherited maternally and consequently, a mother suffering from MELAS syndrome will pass the defect to all her children. Only her daughters will inherit the disease to their children, though. De novo mutations of mtDNA have been described and do indeed account for the majority of cases of Pearson syndrome or Kearns-Sayre syndrome, but are rarely related to MELAS syndrome.

Mutation m.3243A>G is the most common cause of MELAS syndrome [4]. Additionally, mutations m.3244G>A, m.3258T>C, m.3271T>C and m.3291T>C have been associated with MELAS [5]. All of them affect the same gene, the one that encodes for tRNA-Leu(UUR). Loss of its function impedes correct mitochondrial protein biosynthesis and reduces the activity of respiratory chain complexes.

Of note, heteroplasmy, i.e., the presence of more than one type of mtDNA within the same organelle, can be observed in many people. In this situation, gene expression based on copies of normal DNA may partially compensate for defects present on mutated DNA circles. The ratio of normal to mutated DNA to be encountered in an individual patient presumably accounts for age of onset and severity of clinical symptoms.

Mutations of mtDNA are rather frequently observed [3]. Due to heteroplasmy, a precise assessment of disease prevalence is often difficult. Low shares of mutated mtDNA suffice to yield positive findings in molecular biological tests, but such results don't necessarily imply that affected individuals will develop symptoms at one point in their lifes.

With regards to MELAS syndrome, most reliable epidemiological data refer to mutation m.3243A>G, which is assumed to account for the majority of cases. Here, prevalence rates of up to 18 per 100,000 inhabitants have been reported [6]. These numbers are considered trustworthy because encephalomyopathic symptoms may be provoked even though large parts of a patient's mtDNA are unaltered.

Virtually all cells of the human body contain mitochondria and depend more or less on aerobic carbohydrate catabolism, with erythrocytes being the one important exception. Consequently, mtDNA mutations alter mitochondrial metabolism in a plethora of tissues and symptoms associated with MELAS syndrome vary widely. The most common complaints are triggered by the following pathophysiological events:

• Muscles and nerve tissue are most severely affected and functional impairment of these tissues typically dominates the clinical presentation. Myopathy and encephalopathy are direct results of mitochondrial function impairment, and it has been reported that even very low shares of mutated mtDNA in heteroplasmic individuals suffices to induce severe dysfunction of the respiratory chain [6]. Furthermore, cardiac myocytes and neurons are largely unable to sustain their metabolism by anaerobic glycolysis.
• Glycolysis is the transformation of glucose to pyruvate and under anaerobic conditions, i.e., if the respiratory chain is rendered ineffective due to defective mitochondrial protein biosynthesis, pyruvate is converted into lactic acid. This process is catalyzed by the enzyme lactate dehydrogenase and aims at recovering substrates required for continued anaerobic glycolysis. Subsequently, efflux of lactic acid is mediated by monocarboxylate transporter 1. These events lead to an abnormal accumulation of lactic acid in MELAS patients, a condition referred to as lactic acidosis.
• Stroke-like episodes resemble cerebral infarction only in terms of clinical symptoms. Indeed, MELAS-related stroke-like episodes are definitely not induced by thromboembolism, but their precise pathogenesis is incompletely understood. One hypothesis states that metabolic alterations and mitochondrial proliferation in smooth muscle cells of the tunica media of cerebral vessels lead to vasoconstriction and transient ischemia. Of note, such mitochondrial angiopathies may be visualized by means of diagnostic imaging.

Affected families may benefit from genetic counseling. Otherwise, no specific measures can be recommended to prevent MELAS syndrome and symptom onset.

Certain lifestyle decisions may delay disease progress: It is recommended to maintain a healthy diet and sufficient hydration, possibly ingest the above mentioned dietary supplements, realize light aerobic exercises to increase one's aerobic capacity and restrict vigorous exercise to avoid cardiac failure and rhabdomyolysis.

MELAS syndrome is an encephalomyopathic disease triggered by distinct mutations affecting the mitochondrial DNA (mtDNA). MELAS stands for myopathy, encephalopathy, lactic acidosis and stroke-like episodes, which are the main symptoms associated with this disease.

All mutations that have been associated with MELAS syndrome affect one single mitochondrial gene whose gene product is required for translation of distinct messenger RNAs. Loss of function mutations thus interfere with protein biosynthesis, particularly if certain codons account for significant shares of the sequence. This applies to proteins required for the assembly of respiratory chain complexes and consequently, aerobic glycolysis and oxidative phosphorylation are disturbed in MELAS patients. Because muscle cells and neurons largely depend on aerobic metabolism, they are most severely affected by the disease.

Symptom onset typically occurs in childhood, but depending on the severity of mitochrondrial dysfunction, first symptoms may be detected at any age. Patients may report muscle weakness and myalgia, headaches and epileptic seizures. The latter may be related to increased serum levels of lactic acid. First stroke-like episodes are generally experienced in adolescence and rarely after the fourth decade of life. They are associated with hemiparesis, reduced consciousness, visual impairment and exacerbated headaches. During initial stroke-like episodes, these symptoms are generally transient. However, they may become permanent in subsequent fits. These events progressively destroy nerve tissue and cause patients to lose motor and cognitive abilities and to develop dementia [1].

There is no causative treatment for MELAS syndrome. Therapy is supportive and should involve a multidisciplinary team of physicians. Despite all efforts, MELAS syndrome significantly reduces the life expectancy of affected individuals.

MELAS syndrome is a genetic disorder triggered by mutations of mitochondrial DNA (mtDNA). MELAS is an abbreviation for myopathy, encephalopathy, lactic acidosis and stroke-like episodes. These are the main symptoms of the disease.

Causes

Mitochondria are cell organelles that can be found in virtually all cells of the human body, with red blood cells being the one important exception. Most cells depend on mitochondrial function since these organelles use oxygen to create ATP, the cellular currency of energy. If mitochondrial function is impaired - as is the case in MELAS patients - cellular metabolism is strongly disturbed. Muscle cells and neurons are most severely affected.

Of note, inheritance of mtDNA differs from that of nuclear DNA. In detail, a mother inherits her mtDNA to every child, but only her daughters will pass their mtDNA to the next generation.

Symptoms

Because so many different cell types depend on mitochondrial function, the clinical presentation of MELAS syndrome varies between individual patients, even if they pertain to the same family. Most patients experience intolerance of exercise, muscle weakness, muscle pain and recurrent headaches in childhood or adolescence. Before the age of 20, they may suffer epileptic seizures or stroke-like episodes that manifest in acute hemiparesis, reduced consciousness, visual impairment and exacerbated headaches. During initial stroke-like episodes, these symptoms are generally transient. However, the may become permanent in subsequent fits.

Diagnosis

Anamnesis, family history and clinical presentation may prompt a suspicion for MELAS syndrome. In order to confirm that diagnosis, genetic screens have to be performed. This way, the causative mutation in mtDNA can be identified.

Additionally, MELAS patients should undergo thorough cardiological examinations to evaluate if heart muscle involvement constitutes a vital risk.

Treatment

Unfortunately, no causative treatment is available. Dietary supplementation of creatine, coenzyme Q10, lipoic acid, nicotinamide and L-arginine have been recommended, but clinical trials have yet to be conducted.

Supportive treatment is provided during episodes of acute decompensation.

1. Isozumi K, Fukuuchi Y, Tanaka K, Nogawa S, Ishihara T, Sakuta R. A MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) mtDNA mutation that induces subacute dementia which mimicks Creutzfeldt-Jakob disease. Intern Med. 1994; 33(9):543-546.
2. Capt C, Passamonti M, Breton S. The human mitochondrial genome may code for more than 13 proteins. Mitochondrial DNA A DNA MappSeq Anal. 2016; 27(5):3098-3101.
3. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005; 6(5):389-402.
4. Karicheva OZ, Kolesnikova OA, Schirtz T, et al. Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria. Nucleic Acids Res. 2011; 39(18):8173-8186.
5. Kirino Y, Goto Y, Campos Y, Arenas J, Suzuki T. Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. Proc Natl Acad Sci U S A. 2005; 102(20):7127-7132.
6. 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(23):3697-3707.
7. Demarest ST, Whitehead MT, Turnacioglu S, Pearl PL, Gropman AL. Phenotypic analysis of epilepsy in the mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes-associated mitochondrial DNA A3243G mutation. J Child Neurol. 2014; 29(9):1249-1256.
8. Seidowsky A, Hoffmann M, Glowacki F, et al. Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature. Clin Nephrol. 2013; 80(6):456-463.
9. Kim IO, Kim JH, Kim WS, Hwang YS, Yeon KM, Han MC. Mitochondrial myopathy-encephalopathy-lactic acidosis-and strokelike episodes (MELAS) syndrome: CT and MR findings in seven children. AJR Am J Roentgenol. 1996; 166(3):641-645.
10. Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007; 35(2):235-242.
11. Koga Y, Akita Y, Nishioka J, et al. MELAS and L-arginine therapy. Mitochondrion. 2007; 7(1-2):133-139.