MELAS syndrome is an encephalomyopathy triggered by genetic disorders of the mitochondrial DNA. In this line, MELAS is the abbreviation for the most common symptoms: myopathy, encephalopathy, lactic acidosis and stroke-like episodes.
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 . 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:
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 . 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:
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) . 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 . 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 . Additionally, mutations m.3244G>A, m.3258T>C, m.3271T>C and m.3291T>C have been associated with MELAS . 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 . 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 . 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:
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 .
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.
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.
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.
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.
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.