Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) is a rare genetic disorder that primarily affects the nervous system and muscles. It is one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000. Both genders are equally affected but only women can pass the condition on as mitochondria are carried in the tails of sperm cells and therefore shed outside the zygote during fertilization. MELAS is characterized by recurrent episodes of encephalopathy, myopathy, headache and focal neurological deficits. The condition is relentlessly progressive, resulting in neurological impairment by adolescence or early adulthood. The neurological symptoms of MELAS are believed to result from a combination of impaired mitochondrial energy production, microvascular angiopathy and nitric oxide deficiency which may cause impaired cerebral vasodilation. The syndrome is caused by mutations in the genetic material (DNA) in the mitochondria. While most of our DNA is in the chromosomes in the cell nucleus some of our DNA is in another important structure called the mitochondrion (plural: mitochondria). The mitochondria are located outside the nucleus in the cell’s cytoplasm. Each mitochondrion has a chromosome made of DNA that is quite different from the better-known chromosomes in the nucleus. The mitochondrial chromosome is much smaller; it is round (whereas the chromosomes in the nucleus are normally shaped like rods); there are many copies of the mitochondrial chromosome in every cell; and no matter whether we are male or female, we inherit our entire mitochondrial chromosome from our mother. The most common mutation causing MELAS is in the MTTL1 mitochondrial gene. A single base pair mutation, m.3243A>G, is found in 80% patients and a second common mutation, m.3271T>C, is found in 10%. However, many other genes are being identified with similar phenotypic syndromes such as POLG and BCS1L. These mutations impair the ability of mitochondria to manufacture proteins involved in the key function of mitochondria — to produce energy and power the cells in our body. The symptoms of MELAS usually appear in childhood following a period of normal development, although they can begin at any age. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement and a loss of intellectual function (dementia). Most people with MELAS have a buildup of lactic acid in their bodies, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes and hormonal imbalances. The diagnosis of MELAS is usually suspected on clinical grounds. However, confirmation of the diagnosis usually requires a muscle or brain biopsy. The muscle biopsy shows characteristic ragged red fibers; a brain biopsy shows stroke-like changes. Unfortunately there is as yet no treatment to stop the damage done by MELAS syndrome and the outcome for individuals with the syndrome is usually poor. MELAS is progressive and patients are managed according to what areas of the body are affected at a particular time. In other words, treatment is tailored to the symptoms. Moderate treadmill trainingcan help improve the endurance of individuals with myopathy. Metabolic therapies, including dietary supplements, have shown benefits for some individuals. These treatments include coenzyme Q10, phylloquinone, menadione but these are not definitive cures. The relentless progression of MELAS syndrome and the lack of a definitive cure highlight the urgent need for advanced research and new treatments. Despite the knowledge we have gained about the genetic mutations causing MELAS the exact mechanisms by which these mutations lead to the diverse symptoms of the syndrome are not fully understood. For instance, it is not clear why the same genetic mutation can lead to a wide range of symptoms, from muscle weakness to stroke-like episodes and dementia. Understanding these mechanisms could open the door to targeted treatments that can halt or even reverse the progression of the disease. Moreover the current approach to managing MELAS is largely reactive, focusing on treating the symptoms as they appear. This approach does not prevent the progression of the disease and the repeated stroke-like episodes can lead to irreversible damage over time. Developing treatments that can prevent these episodes or reduce their severity could significantly improve the quality of life for individuals with MELAS. The diagnosis of MELAS also presents challenges. The syndrome is currently diagnosed through muscle or brain biopsies, invasive procedures that carry risks. Furthermore the diagnosis often comes after the onset of severe symptoms such as stroke-like episodes. Earlier diagnosis could allow for earlier intervention, potentially delaying the onset of severe symptoms. Research into safer and more effective diagnostic methods is therefore another critical need. In conclusion, MELAS syndrome is a severe and progressive condition that affects multiple systems in the body. Despite advances in our understanding of the genetic basis of the syndrome, we still lack effective treatments that can halt or reverse its progression. The development of such treatments depends on further research into the mechanisms of the disease as well as improved methods for diagnosis. The funding of this research is an urgent need, given the severity of MELAS syndrome and the lack of a cure. By supporting this research, we can bring hope to individuals with MELAS and their families and potentially contribute to our understanding of a broad range of mitochondrial diseases.