MELAS Syndrome was first described in 1984 by S. Pavlakis and colleagues. But some researchers believe that the syndrome has already been indicated previously by such concepts as family polyodystrophy, mitochondrial myopathy, lactacidemia.
The essence of pathology
In 1994, S. Pavlakis and Mizio Hirano described 110 cases of the disease. MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes) is a multisystem progressive neurodegenerative disease. It is polymorphic and is characterized by encephalopathy with convulsions and dementia, lactic acidosis. Mitochondrial DNA (mtDNA) mutations are the basis of the disease. This disease has another name - mitochondrial encephalomyopathy.
General information
From 25 to 44% of cases of the disease are hereditary, transmitted through the maternal side. In other cases, it occurs for the first time. Currently, more than 10 genes are known that mutate and lead to the development of this syndrome. These are genes encoding the functions of transport RNA. MELAS syndrome refers to mitochondrial diseases (MB) with an abnormal accumulation of mitochondria, as a result of which the whole system of energy metabolism of the cell is disrupted.
Diseases of this group are transmitted only through the maternal line. When they are affected in different combinations, the most energy-dependent organs and tissues: skeletal muscles, heart, brain, eyesight, liver and kidneys.
Symptoms are polymorphic and can manifest at any age. It includes manifestations of diabetes, hearing loss, seizures, endocrinopathies, short stature, cardiac pathologies, absolute inability to exercise and psychomotor abnormalities.
Before her, psychomotor development is completely normal. The same symptoms were not found in patients, since the mutation affects many genes: MTTL1, MTTQ, MTTH, MTTK, MTTS1, MTTS2, MTND1, 5, 6. Their number continues to increase.
In 80% of patients, the MELAS syndrome is caused by the point replacement of A3243G in the leucine tRNA gene (UUR).
The frequency is studied unreliably. There is only single data: for example, in Finland, the frequency of mutations A3243G was 16: 100 thousand of the population; in England - 1 case per 13 thousand
Pathomorphological changes
A characteristic pathomorphological sign of MELAS syndrome is torn red fibers (RRF), which can be seen in muscle tissue with a special tricolor color according to Gomori. They are the result of mutated genes and the morphological substrate of mtDNA damage; they are formed due to the proliferation of these abnormal mitochondria.
What is mitochondria in general
Mitochondria are a two-membrane organelle of a eukaryotic cell (a cell with a nucleus), the main function of which is to supply energy. That is, in fact, mitochondria are the energy base of cells, their energy stations.
The number of mitochondria in cells can vary from several to thousands in the course of her life. And more of them happen in cells associated with energy production.
The mitochondria themselves are most often round-elongated, ranging in size from 1 to 10 microns. They can still harden or move inside the cytoplasm of the cell. They usually move to places where more energy is needed.
On the inner membrane of the mitochondria there are outgrowths (cristae) on which there are whole systems of enzymes. Basically, these are protein compounds. The number of crystals depends on the intensity of the synthesizing processes. For example, in the mitochondria of muscle cells there are always a lot of them.
Mitochondria have an autonomous protein synthesis system - DNA, RNA and ribosomes. Some of the necessary mitochondrial proteins are synthesized by themselves - 5%, and some are obtained from the cytoplasm - 95%. Energy is extracted from organic compounds through a variety of enzymatic reactions.
Some of these reactions occur with the participation of oxygen, i.e., oxidation occurs, and after others, CO 2 is released with the transfer of hydrogen protons and the release of energy. To put it differently, mitochondria is an active participant in cellular respiration.
These reactions occur on the cristae or in the mitochondria itself, which is so important for the cell that if it is cured, the cell will be completely healthy.
Pathogenesis
At first glance, with MELAS syndrome, the condition resembles a post-stroke variant. But in fact, it is atypical: it occurs in young people, is often provoked by infectious diseases, can occur in the form of a malignant headache, similar to migraine, seizures.
Angiography does not give any vascular pathologies. Normal vessels may be enlarged or the caliber of some arteries or veins may be enlarged, or capillary hyperemia occurs.
MRI shows that acute brain damage in MELAS syndrome can migrate and even disappear. Some foci fluctuate. For a typical stroke, this is completely uncharacteristic.
With MELAS syndrome, there is the presence of multifocal necrosis. For the most part, this is noticeable in the occipital part (posterior localization) of the cerebral cortex and white matter of the subcortex. But they can occur in other parts of the brain. These sites resemble necrosis in a heart attack, but are located outside the basins of the central cerebral vessels.
Symptomatic manifestations
Usually, MELAS syndrome in children makes its debut at the age of 6-10 years (it can start at 3 years old and at 40 years old). The early onset of the disease is more typical and affected 90% of patients. With an early occurrence, the disease flows more difficult. Patients are usually undersized, muscularly weak, and absolutely not adapted to physical activity.
Any tension or physical activity impairs well-being. From the internal organs, the heart is affected with impaired muscle and conduction, followed by the development of cardiovascular failure. Nephropathy, diabetes, gastrointestinal disorders with vomiting also occur, hearing is reduced. Muscle pain, lack of reflexes, paresis, cramps, IPE, loss of consciousness are characteristic. Muscle weakness (myopathic syndrome) and sensorineural hearing loss are also typical of such a pathology.
Endocrinopathies are represented not only by diabetes mellitus, but also by growth hormone deficiency. Cardiac and renal disorders are rare in the development of the disease in question.
Cramps in MELAS syndrome are very variable. They can be focal, generalized, tonic-clonic and myoclonic. The absolute insensitivity of seizures to anticonvulsant therapy is characteristic. It often happens that doctors diagnose epilepsy and prescribe, for example, valproic acid. After it, her health deteriorates sharply and convulsions increase because she depresses the mitochondria. Dementia, although it has developed, but it rarely becomes a manifest symptom.
Myopathic syndrome is also characteristic of a disease, but it also occurs in many other pathologies, and therefore it cannot serve as a basis for diagnosis. Only when combined with migraines, convulsions and / or stroke-like phenomena can the onset of MELAS syndrome be suspected. Even such an extensive symptomatology does not give a correct diagnosis. The progression of the process occurs in different ways.
Signs
A distinctive clinical sign of MELAS syndrome is stroke-like episodes (IPE), in which neurological symptoms suddenly occur. IPE is characterized by asymmetry of lesions. They can be multiple.
The selectivity of this localization gives certain focal symptoms:
- hemianopsia (cortical blindness);
- hemiparesis;
- sensory aphasia (misunderstanding of words);
- acalculia (violation of the account);
- agraphy (spelling violations);
- ataxia (impaired coordination of voluntary movements);
- changes in consciousness.
Such symptoms, similar to strokes, often return every 1-3 months. The peculiarity of acute episodes in MELAS is that they have a quick regression, but they often recur, that is, as if they pass without a trace. In addition, in patients with such a disease, calcifications are deposited in the basal ganglia (this is detected on CT).
Stroke-like episodes often develop between the ages of 5-15. They never result from thromboembolism. Angiopathy with MELAS is due to hyperproliferation of the same mitochondria.
IPE in symptoms is manifested by recurrent attacks of cephalalgia, dizziness, paresis, paralysis of limbs, cranial nerves. A person is completely demoralized.
Lactic acidosis with MELAS syndrome
Its main culprit is an excess in the blood and tissues of the nervous system of lactic acid. In this case, the acidity of the blood in the arteries decreases sharply. Such acidosis is a frequent companion of diabetes mellitus that is present with MELAS syndrome.
At an early stage, manifestations are nonspecific. The following symptoms are observed: general weakness, pain behind the sternum, apathy, drowsiness. Myalgia after physical exertion and intermittent rapid breathing without any smell are very characteristic.
At the middle stage, lactic acid accumulates and hyperventilation syndrome (DHW) occurs. Carbon dioxide accumulates in the blood. Noisy breathing begins to form - Kussmaul. Pressure drops until collapse, oliguria sets in. The patient becomes restless, raves, and then loses consciousness with the subsequent development of a coma - this is the last stage. Symptoms of lactic acidosis develop rapidly, namely, within a few hours. Then comes death.
Diagnostic measures
As already noted, due to the polymorphism of symptoms and mutations of a large number of genes, the diagnosis of MELAS syndrome is difficult. Held:
- general and biochemical blood tests;
- muscle biopsy;
- a genetic study with a comparative analysis among sick relatives;
- CT of the brain: zones of heart attacks more often in the hemispheres, less often in the cerebellum, basal ganglia;
- cerebral angiography: an increase in the caliber of blood vessels (arteries, veins, capillaries);
- DNA diagnostics: the search for characteristic point mutations in mtDNA.
Therapies
The treatment of MELAS syndrome has not been developed, and today it is incurable. There are only attempts to slow down the defeat process. Treatment is carried out in two directions: syndromic therapy (epilepsy, diabetes mellitus) and pathogenetic. However, there is no effective pathogenetic therapy today.
There are symptomatic treatments: with hearing impairment, hearing aids are actively used, with respiratory muscle weakness, respiratory therapy is provided. It was noted that with MELAS syndrome, the level of L-arginine in the patient's blood significantly decreases with IPE. Therefore, they are treated with arginine preparations and vitamins. The positive effect of coenzyme Q or idebinone (noben), succinic acid preparations, vitamins K 1 and K 3 , B 2 , B 3 , E, C; L-carnitine, antioxidants (mexidol, mildronate), correctors of lactic acidosis (dimephosphon) - all of them improve the energy metabolism of the cell. In the treatment of seizures, valproates and barbiturates are not prescribed, since they inhibit mitochondria.
As a prevention of this syndrome, it is best to resort to the IVF method. If a woman knows that a case of manifestation of this disease has been recorded in her family, then the cytoplasm for fertilization is taken from a healthy woman. The method is still under study, it is not massive.
Some features
Diagnosing mitochondrial disorders requires a very thorough approach to therapy. It must necessarily include metabolic agents. They stabilize the processes of tissue respiration, oxidative phosphorylation in cells. Only the systematic conduct of such treatment can help in maintaining the condition of patients by preventing stroke episodes.
Forecast
The prognosis is poor due to the lack of effective treatment. Life expectancy from the first onset of symptoms usually does not exceed five years. The lack of study of the causes of the disease leads to the fact that the optimal treatment regimen has not yet been found. All this makes the chances of a cure minimal.