How long do children with melas syndrome live? Rare diseases. Symptoms of the MELAS syndrome

02.07.2020

Keywords

MELAS SYNDROME / MELAS SYNDROME / EPILEPSY / EPILEPSY / CLINIC

annotation scientific article on clinical medicine, author of scientific work - Mukhin K.Yu., Mironov M.B., Nikiforova N.V., Mikhailova S.V., Chadaev V.A.

The MELAS syndrome is a genetically determined disease from the group of mitochondrial diseases, defined as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes). All organs and tissues are involved in the pathological process, but the muscular and nervous systems suffer to a greater extent. The disease most often develops between the ages of 6 and 10 years. The course of the disease is progressive. In most cases, the disease manifests with epileptic seizures, recurrent headaches, vomiting, and anorexia. Epilepsy is an important clinical manifestation of the MELAS syndrome. Epileptic seizures are the first recognizable symptom in mitochondrial encephalopathies (ME) in 53% of cases. In MELAS, occipital epilepsy is the most common. With the progression of the disease, resistance of epilepsy to therapy is noted, often with a status course. Cases of transformation into Kozhevnikov's epilepsy are described. We present the case history of a patient with a diagnosis of MELAS syndrome verified during his lifetime.

EPILEPSY IN MELAS SYNDROME

MELAS syndrome is a genetically determined disease of the mitochondrial group, defined as mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes. The pathologic process involves all organs and tissues, but it is mostly adversive for the muscular and nervous systems. The disease is most frequent in children aged 6 to 10. The clinical course is progressive. In most cases the disease is manifested by epileptic seizures, relapsing headaches, vomiting, anorexia. The important clinical presentation of MELAS syndrome is epilepsy. Epileptic seizures is the initial diagnosis symptom of mitochondrial encephalopathies (ME) in 53% of cases. Occipital epilepsy is the most frequent in MELAS syndrome. As the disease progresses, resistance of epilepsy to treatment is observed, often with the occurrence of status epilepticus. Some cases of transformation into Kozhevnikov's epilepsy are described. A history of a patient with a verified while alive diagnosis of MELAS syndrome is given.

The text of the scientific work on the topic "Epilepsy in melas syndrome"

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EPILEPSY WITH MELAS SYNDROME

K.Yu. Mukhin1, M.B. Mironov1, N.V. Nikiforova1, C.B. Mikhailova2, VA. Chadaev1, AA. Alikhanov1-2, B.N. Ryzhkov1, A.S. Petrukhin1

EPILEPSY IN MELAS SYNDROME

KYu. Mukhin1, M.B. Mironov1, N.V. Nikiforova1, S.V. Mikhailova2, UA. Chadaev1, AA. Alikhanov1-2, B.N. Ryzkov1 AS. Petrukhin1

1 - Department of Neurology and Neurosurgery, Faculty of Pediatrics, State Educational Institution of Higher Professional Education, Russian State Medical University of Roszdrav

2 - Russian Children's Clinical Hospital

MELAS syndrome is a genetically determined disease from the group of mitochondrial diseases, defined as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (mitochondrial encephalomyopathy, lactic acid with stroke-like episodes). All organs and tissues are involved in the pathological process, but the muscular and nervous systems suffer to a greater extent. The disease most often develops between the ages of 6 and 10 years. The course of the disease is progressive. In most cases, the disease manifests with epileptic seizures, recurrent headaches, vomiting, and anorexia. Epilepsy is an important clinical manifestation of the MELAs syndrome. Epileptic seizures are the first recognizable symptom in mitochondrial encephalopathies (ME) in 53% of cases. In MELAS, occipital epilepsy is the most common. With the progression of the disease, resistance of epilepsy to therapy is noted, often with a status course. Cases of transformation into Kozhevnikov's epilepsy are described. We present the case history of a patient with a diagnosis of MELAS syndrome verified during his lifetime.

Key words: MELAS syndrome, epilepsy, clinic, diagnostics, treatment.

Key words: MELAS syndrome, epilepsy, clinical picture, diagnostics, treatment.

The MELAS syndrome was first identified as an independent nosological form by S. Pavlakis et al. in 1984 . However, a number of authors suggest that the disease was described earlier under the name "familial polyodystrophy, mitochondrial myopathy, lactic acidemia."

The prevalence in the population has not been established. By 2000, more than 120 observations of the MELAS syndrome were published, including in the domestic press.

The MELAS syndrome in 25% of cases is maternally inherited with a high risk, but in 56-75% of patients the family history is not burdened. The disease is associated with mutations in mitochondrial DNA genes encoding subunits of respiratory chain complexes and transport RNA genes (MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV). In 80-90% of cases of MELAS syndrome, the disease is based on a point mutation in the MT-TL1 gene encoding leucine transfer RNA. With this mutation, the adenine nucleotide is replaced by guanine at position 3243 (A3243G), which disrupts the synthesis of all proteins in mitochondria.

All organs and tissues are involved in the pathological process, but the muscular and nervous systems suffer to a greater extent.

Mukhin K.Yu., Mironov M.B., Nikiforova N.V., Mikhailova C.V., Chadaev V.A., Alikhanov A.A., Ryzhkov BN., Petrukhin A.S.

Epilepsy in MELAS Syndrome Rus. zhur. det. Neur.: vol. IV, no. 3, 2009.

ORIGINAL ARTICLES

topics as the most volatile. The severity of clinical manifestations depends on the threshold effect (age, energy needs of tissues), on the control of nuclear genes over the synthesis of the respiratory chain, heteroplasmy (different content of mutant mtDNA molecules in tissues). It has been shown that in patients with the MELAS syndrome, the content of mutant mtDNA in various tissues is 93-96%. In proband family members, mutant mtDNA is also detected in the tissues, but its content is significantly lower: 62-89% in the erased form of the disease, from 28 to 89% in the absence of clinical signs of the syndrome.

The disease most often develops at the age of 6 to 10 years, but there are cases of an earlier (up to two years) or later debut - from 21 to 40 years. Before the onset of the disease, 90-100% of patients develop normally. The course of the disease is progressive, more malignant with an early onset.

In most cases, the disease manifests with epileptic seizures, recurrent headaches, vomiting, and anorexia. You should also pay attention to intolerance to physical activity in the form of deterioration of health and the appearance of muscle weakness. The myopathic symptom complex is manifested by exercise intolerance, muscle weakness, fatigue, and sometimes muscle hypotrophy.

As the disease progresses, dementia usually develops. Symptoms such as cerebellar ataxia, neurosensory deafness, and peripheral polyneuropathy are less common.

Stroke-like episodes are characteristic, which can be manifested by recurrent attacks of headache, dizziness, the development of focal neurological symptoms (paresis, hemianopsia), and coma. These acute episodes are often triggered by fever or intercurrent infections. These manifestations can have a fairly rapid regression (from several hours to several weeks), as well as a tendency to relapse.

Epilepsy is an important clinical manifestation often occurring in the early stages of MELAS. This is

often the most obvious neurological manifestation, especially in atypical mitochondrial encephalopathy (ME). Epileptic seizures are the first recognizable symptom in mitochondrial encephalopathies (ME) in 53% of cases.

In MELAS, occipital epilepsy (SE) is the most common. Characterized by focal seizures originating in the occipital lobes. Seizures are often associated with transient or persistent neurological symptoms such as visual field loss.

Seizures emanating from the occipital cortex are divided according to their manifestations into subjective sensations (aura) and into clinically detectable symptoms, as a rule, with a motor component. Epileptic auras emanating from the occipital lobe include simple and complex visual hallucinations, amaurosis. The most typical seizures characteristic of SE are simple visual hallucinations, which can manifest as positive (flashes, spots of light) and negative symptoms (scotoma, hemianopsia). Most often, visual hallucinations are described as a spot or spots of light, either steady or flashing. As a rule, the spot is white with a greenish tint. Also, hallucinations can be multi-colored or monochromatic. Hallucinations usually appear in the visual fields contralateral to the focus of excitation in the occipital cortex with subsequent spread. However, it should be noted that in the complaints of patients, the visual aura is not often detected.

Complex visual hallucinations are noted when epileptic excitation spreads to the occipito-temporal or occipito-parietal regions. Complex visual hallucinations may appear in the form of people, animal objects or scenes, be familiar or unfamiliar, pleasant or terrifying, frightening, simple or grotesque, may be static or move in a horizontal plane and disappear. As a rule, they are a terminal symptom before the development of a motor attack; may be the first ictal symptom, but more often occur following

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basic hallucinations.

Ictal ama vrosis is a special, extremely difficult to diagnose type of seizures emanating from the occipital cortex. According to many authors, this is the same frequent symptom of irritation of the occipital lobe, as well as visual hallucinations, but often remains unrecognized. Usually patients do not distinguish this symptom separately in the structure of the attack. Vision loss occurs bilaterally with loss of lateral fields. Possible homonymous hemianopia contralateral to the focus of the attack. The patients' sensations are described by them as darkening in the eyes, "white darkness", impaired color perception. Perhaps a status course with the formation of the so-called status epilepticus amauroticus.

Occipital seizures may present with autonomic symptoms. These include migraine headache, dizziness, nausea, and vomiting. A common symptom is post-attack migraine-like headache.

The clinical manifestations of seizures that occur limitedly in the occipital cortex are characterized by deviation of the eyes to the side. Deviation of the eyes can be noted together with the deviation of the head to the side. In most cases, deviation of the eyes towards the contralateral focus is noted. However, cases are described when abduction of the eyes is observed towards the focus. Also, one of the features of "occipital" seizures is the instantaneous distribution of the discharge to the anterior parts of the brain, while the clinical picture, as a rule, is dominated by a pronounced motor component. Tonic, tonic-clonic (both hemiconvulsive and secondary generalized), automotor seizures are possible. In this regard, it is important to identify the initial clinical symptoms - an unmotivated and sudden stop of the gaze, looking at non-existent objects, an unreasonable smile, vegetative manifestations, and necessarily documenting the primary ictogenic zone using the VEM method.

With the progression of the disease, resistance of epilepsy to therapy is noted, often with a status course. Cases of transformation into Kozhevnikov epilepsy are described. A number of auto-

Rov describes the possibility of status epilepticus as the first symptom in patients with MELAS without a history of previous epileptic seizures. Ribacoba R. et al. describe in their publication 4 cases of development of epilepsia partialis continua with focal motor seizures, which was preceded by a history of episodes of migraine headache. Miyazaki M. et al. showed the possibility of continued focal myoclonus within epilepsia partialis continua in patients with MELAS. Araki T. et al. observed a patient at the age of 37 years with epileptic status of focal seizures in the form of fluctuations of consciousness, homonymous hemianopsia in combination with paroxysmal episodes of eye deviation to the side. The EEG recorded continued EEG patterns of seizures localized in the occipital region. In adult patients with MELAS, there is a predominance of focal motor seizures, but the EEG shows a predominance of multiregional epileptiform activity in the occipital regions.

Epileptiform activity is recorded in 71% of cases after the onset of seizures. An electroencephalographic study of patients with MELAS syndrome is characterized by epileptiform activity in the occipital regions. A number of authors associate the appearance of regional epileptiform disorders with strokes. According to Fujimoto S.'s study, in the acute period (i.e., within 5 days after a stroke-like episode), the majority of examined patients with MELAS syndrome had regional high-amplitude delta waves in combination with polyspikes. The authors propose to consider this pattern as pathognomonic for stroke-like episodes. In addition to the occipital regions, epileptiform activity can spread to the temporal regions, bifrontally, and also bilaterally to the posterior regions with diffuse distribution. Perhaps the appearance of a photoparoxysmal response during rhythmic photostimulation.

The leading laboratory sign is an increase in the level of lactate in the blood.

ORIGINAL ARTICLES

wi over 2.0 mmol / l, which leads to the development of lactic acidosis.

An MRI of the brain in the early stages of the disease may be unremarkable, even if epilepsy occurs. Neuroimaging methods reveal infarct zones in the cerebral hemispheres (80%), less often in the cerebellum and basal ganglia. There may also be calcification of the basal ganglia, atrophy of the cerebral cortex. In a photon emission study, the accumulation of the isotope is detected 3-16 days before the appearance of the infarct zone (decrease in the isotope signal) on a computed tomogram of the brain. MRI of the brain shows lesions predominantly located in the occipital lobes, which may be transient. The occipital cortex is predominantly affected, the white matter is damaged to a lesser extent. On T2-weighted images, brain lesions in MELA appear as areas of increased signal intensity. Transient hyperintense areas are associated by a number of authors with reversible vascular edema.

Angiography usually does not reveal vascular abnormalities. Diffusion-weighted MRI demonstrates changes associated with vasogenic edema.

Histopathology: Muscle biopsy reveals fibers with torn "red edges". Autopsy of the brain is characterized by a combination of old and new foci of infarcts, as well as atrophy of the cortex with focal foci of necrosis.

Currently, therapy is supportive. The main direction of treatment is to improve the energy balance of mitochondria and the respiratory chain. Apply coenzyme p10 (80-300 mg / day), vitamins K1 and KZ (25 mg / day), succinic acid (up to 6 g / day), vitamin C (2-4 g / day), riboflavin (100 mg / day) and nicotinamide (up to 1 g/day). In connection with the developing secondary deficiency of carnitine, patients are prescribed L-carnitine (up to 100 mg/kg/day). Vitamin E (300-500 mg/day) and vitamin C (2-4 mg/day) are used as antioxidant therapy.

There are no generally accepted antiepileptic therapy regimens for MELA. A number of authors propose to exclude drugs that can inhibit energy metabolism (barbiturates, valproic acid drugs; as well as some drugs from other groups, for example, chloramphenicol). The literature describes several isolated cases of seizure aggravation with the use of valproic acid in the MELA syndrome with the A3243C mutation. The main AEDs in the treatment of epilepsy in the MELA syndrome are considered to be tegretol (or trileptal), topamax, keppra in average therapeutic doses. Properly selected therapy leads to a significant decrease in the frequency of secondary generalized convulsive seizures. However, seizures with impaired vegetative-visceral and visual functions are usually resistant to treatment. In the terminal stage of the disease, the frequency of epileptic seizures may decrease.

Here is the case history of a patient with a diagnosis of MELAY syndrome verified during his lifetime.

Patient Ch.A., aged 11, was observed at the Center for Pediatric Neurology and Epilepsy. At admission, complaints were made of a gradual loss of speech skills, a pronounced gait disorder with a refusal to walk, a significant decrease in vision, capriciousness, and negative behavior; daily serial attacks in the form of twitching of the muscles of the face, muscles of the upper and lower extremities, as well as short-term episodes of loss of vision.

The debut of the disease was noted at the age of 5 years 9 months. For the first time, against the background of full health, when falling asleep, a severe headache appeared, simple visual hallucinations ("yellow ray"), followed by a violent turn of the eyes and head to the side and the development of a generalized tonic-clonic convulsive seizure, after which vomiting was noted. After 9 months attacks with the same symptoms recurred and quickly acquired a serial character. After the appointment of tegretol at a dose of 400 mg per day, the frequency of attacks decreased to 1 time per month. Tegretol was replaced by Depakine Chrono at a dose of 900 mg/day, against which a clinical remission was noted for 6 months. Considering the clinical symptom

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tomatics, confinement of seizures to the period of falling asleep, normal intelligence of the patient, a positive reaction to valproate, idiopathic occipital epilepsy was diagnosed.

At the age of 7, focal versive seizures resumed with secondary generalization when falling asleep with the same frequency of 1 time per month. Increasing the dose of Depakine to 1500 mg/day did not lead to a decrease in the frequency of seizures. When lamiktal was added at a dose of 75 mg/day, the attacks stopped for 4 months, then resumed at the same frequency. At the age of 8, attacks with a short-term loss of vision joined. From 8 years 8 months before falling asleep, atypical absences began to appear: rapid blinking with closing of the eyelids and the institution of the eyeballs upwards; consciousness fluctuates.

At the age of 9, multiple serial attacks appeared, lasting for several days, with simple visual hallucinations in the form of a flashing "ray" in front of the eyes, with a turn of the eyes and head to the right. Before falling asleep, such attacks sometimes turned into focal hemiclonic ones, which were manifested by reduction of the facial

musculature on the right, twitching of the head to the right, clonias of the right limbs (larger than the arm). Sometimes after the attack there was a severe headache and vomiting. At the same age, inhibitory attacks appeared: an aura in the form of goosebumps in the big toe of the right foot, followed by short-term weakness of the right leg and awkwardness of the right hand. Topamax was introduced into the treatment regimen at a dose of 100 mg/day - there were no epileptic seizures for 1 year.

Also, at the age of 9, paroxysmal conditions first appeared, accompanied by severe headache, vomiting, and the development of right-sided hemiparesis. In some cases, such conditions were accompanied by amaurosis lasting from several minutes to several days.

At the age of 10.5 years, attacks reappeared in the form of turning the head to the left, jerky movements of the eyeballs to the left, lasting up to 5 s, frequency up to 3 times per hour, daily, even during sleep. Topamax dose was increased to 150 mg/day without significant effect. At 10 years 10 months. after an intense headache, alternating

Rice. 1. Patient Ch.A. 10 years. Diagnosis: MEAE syndrome. Symptomatic focal epilepsy.

Video-EEG monitoring (2004): against the background of a diffuse slowdown in the main activity of the brain, continued epileptiform activity is recorded in the left occipital region. Subclinical EEG patterns of an attack were also registered in the left occipital region with spread to the left posterior temporal region.

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under the guidance of Professor K.Yu. Mukhina is engaged in the diagnosis and treatment of anxiety disorders of the nervous system in Aetei, specializes in Aetian forms of epilepsy.

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focal hemclonic and secondary generalized seizures that became serial and lasted 48 hours. Frizium was added to topamax at a dose of 10 mg/day with a temporary positive effect.

From the age of 8, difficulties with the assimilation of school material began to be noted; decreased memory. There was increased fatigue, exhaustion, inhibition of mental activity. The boy became capricious, irritable, negative; the background of mood has decreased. From the age of 9, there was an increase in this symptomatology.

From the anamnesis of life, it is known that the child was born from a second normal pregnancy, a second term delivery, birth weight 2800 g, length 53 cm. Early psychomotor and speech development was fully consistent with age. Past diseases: chicken pox at 6 years old, frequent acute respiratory viral infections (up to 4 times a year) from 6 years old. Heredity for epilepsy and other neurological diseases is not burdened.

At the time of examination (11 years old), the child's condition was severe; reacts negatively to inspection. Conscious, pro-oriented

space and time. He enters into contact extremely reluctantly, refuses to follow instructions. Spontaneous nystagmus to the left, head tilted to the left shoulder with a turn to the right. The tongue is in the midline, the pharyngeal reflex is reduced; Dysphagia and dysarthria are noted. Vision is reduced.

Moderate diffuse muscular hypotonia is determined. Tendon reflexes are evenly reduced. There was a slight decrease in muscle strength in the right limbs. Pathological foot reflexes were not detected. There are no objective data for violation of sensitivity. Not worth it in the Romberg test. Refuses to walk. When you try to put him on his feet, he cries, sits down on the floor. Missing when performing a finger-index test. Speaks slowly, in single words, reluctantly.

Additional methods of examination. Video-EEG monitoring (2004). Significant slowdown of the main background recording activity. During the study, continued epileptiform activity was recorded in the left occipital region with spread to the left posterior temporal region and with periodic formation of an EEG pattern

born in 1993 16/12/05

Rice. 2. Patient Ch.A. 11 years. Diagnosis: MELAS syndrome. Symptomatic focal epilepsy.

Video-EEG monitoring was carried out in dynamics after 1 year (2005): a significant slowdown in the background activity of the brain. During sleep recording, continued regional deceleration is recorded in the right fronto-central region, in the structure of which peak-wave activity is detected in the right fronto-central region.

ORIGINAL ARTICLES

stupa (Fig. 1). Also, continued regional deceleration in the right fronto-central region with the inclusion of single sharp waves is determined.

Video-EEG monitoring in dynamics (2005): Significant slowdown in the background activity of the brain. The study recorded continued regional slowdown in the right fronto-central region. In the structure of regional deceleration in the right fronto-central area, peak-wave activity is revealed (Fig. 2).

MRI of the brain. The first MRI (6 years) revealed a single hyperintense signal in T2 mode in the left hemisphere of the cerebellum. MRI study over time (10.5 years): a significant deterioration of the primary lesion was revealed with the spread of the pathological process widely to the left and right occipital-parietal regions of both hemispheres of the brain (Professor A.A. Alikhanov).

Visual evoked potentials: significant morphological and functional changes in the visual afferent system at the level of the optic nerve and the cortical part of the visual analyzer, more pronounced on the left.

Ophthalmologist's consultation: partial atrophy of the optic nerves. Elements of cortical agnosia.

Electrocardiogram: ectopic rhythm with acceleration up to 100 beats per minute.

Vertical position of the electrical axis of the heart. Changes in repolarization processes, which are more pronounced in orthostasis.

Electroneuromyography: revealed the primary muscular type of lesion. The conduction velocities along the peripheral nerves are not reduced.

The study of the level of lactate in the blood: the content of lactate in the blood is 3.0 mmol / l (the norm is up to 1.8).

Taking into account the presence of epileptic seizures emanating from the occipital regions of the cerebral cortex resistant to therapy, stroke-like episodes, periods of amaurosis, cognitive decline, the presence of hyperintense signals in the cerebellum and posterior regions of the cerebral cortex on MRI, an increase in the level of lactate in the blood, the patient had a diagnosis of MELAS syndrome was suggested. During a genetic examination, the A3243G mutation in the heteroplasmic state was found in the blood cells (the diagnosis was carried out at the State Research Center of the Russian Academy of Medical Sciences), and the diagnosis was verified.

Observation in follow-up showed a rapid progression of violations of higher mental functions, the development of cortical blindness, complete immobility of the patient, followed by the onset of death at the age of 12 years 10 months. (after 7 years from the onset of the disease).

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29. Williamson P.D., Thadani V.M., Darcey T.M., Spencer D.D., Spencer S.S., Mattson R.H. Occipital lobe epilepsy: clinical characteristics, seizure spread patterns, and results of surgery // Ann Neurol. - 1992. - V. 31. - P. 3-13.

30. Yi-Min Chen, Chih-Ming Lin, Peterus Thajeb. Paradoxical effect of sodium valproate that aggravates epilepsy of MELAS in a patient with A3243G mutation of the mitochondrial DNA // Central European Journal of Medicine. - 2007. - V. 2(1). - P.103-107.

31. Yoneda M., Maeda M., Kimura H., Fujii A., Katayama K., Kuriyama M. Vasogenic edema on MELAS: a serial study with diffusion-weighted MR imaging // Neurology. - 1999. - V. 53. - P. 2182-2184.

MELAS syndrome (MELAS) was first described in 1984 by S. Pavlakis and colleagues. But some researchers believe that the syndrome has already been designated earlier by such concepts as familial polyodystrophy, lactic acidemia.

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. The disease is caused by mutations in mitochondrial DNA (mtDNA). This disease has another name - mitochondrial encephalomyopathy.

General information

From 25 to 44% of cases of the disease are hereditary, transmitted through the maternal line. 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 transfer RNA. MELAS syndrome refers to mitochondrial diseases (MD) with an abnormal accumulation of mitochondria, resulting in disruption of the entire energy metabolism system of the cell.

Diseases of this group are transmitted only through the maternal line. With them, the most energy-dependent organs and tissues are affected in different combinations: skeletal muscles, heart, brain, eyesight, liver and kidneys.

Symptoms are polymorphic and can occur at any age. It includes manifestations of diabetes, hearing loss, seizures, endocrinopathies, short stature, cardiac pathologies, absolute inability to exercise, and psychomotor abnormalities.

Before it, psychomotor development is completely normal. No patients with the same symptoms were identified, since the mutation affects many genes: MTTL1, MTTQ, MTTH, MTTK, MTTS1, MTTS2, MTND1, 5, 6. Their number continues to increase.

In 80% of patients, MELAS syndrome is caused by a point substitution A3243G in the leucine tRNA gene (UUR).

The frequency has been studied unreliably. There are only a few data: for example, in Finland, the A3243G mutation rate was 16:100 thousand of the population; in England - 1 case per 13 thousand people.

Pathological changes

The characteristic pathological feature of MELAS syndrome is ragged red fibers (RRF), which can be seen in muscle tissue with a special Gomory tricolor. They are the result of mutated genes and the morphological substrate of mtDNA damage, formed as a result of the proliferation of these abnormal mitochondria.

What is a mitochondrion anyway

Mitochondria are a two-membrane organelle of a eukaryotic cell (a cell that has 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 throughout its life from a few to thousands. 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 freeze motionlessly or move inside the cytoplasm of the cell. They usually move to 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 cristae depends on the intensity of 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 proteins are synthesized by the mitochondria 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 take place 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. In other words, the mitochondrion 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, in MELAS syndrome, the condition resembles a post-stroke variant. But in fact, it is atypical: it occurs in young people, often provoked by infectious diseases, and can occur in the form of a malignant migraine-like headache, convulsions.

Angiography does not give any vascular pathologies. There may be normal vessels or increased calibers of some arteries, veins, 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.

In the 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 the white matter of the subcortex. But they can also occur in other parts of the brain. These areas resemble necrosis in a heart attack, but are located outside the basins of the central cerebral vessels.

Symptomatic manifestations

Usually, MELAS syndrome in children debuts at the age of 6-10 years (it can begin at 3 years and at 40 years). Early onset of the disease is more typical and affected 90% of patients. With an early onset, the disease flows more difficult. Patients are usually undersized, muscularly weak and absolutely not adapted to physical exertion.

Any tension or physical activity makes you feel worse. Of the internal organs, the heart is affected with malnutrition of the muscle and conduction, followed by the development of cardiovascular insufficiency. Nephropathy, diabetes, gastrointestinal disturbances with vomiting also occur, hearing is reduced. Characterized by muscle pain, lack of reflexes, paresis, convulsions, IPE, loss of consciousness. Muscle weakness (myopathic syndrome) and sensorineural hearing loss are also typical of this pathology.

Endocrinopathy is 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.

Seizures in MELAS syndrome are highly variable. They can be focal, generalized, tonic-clonic, and myoclonic. Absolute insensitivity of seizures to anticonvulsant therapy is characteristic. It often happens that doctors diagnose epilepsy and prescribe, for example, valproic acid. After it, the state of health deteriorates sharply and convulsions increase, because it depresses mitochondria. Although dementia develops, it rarely becomes a manifest symptom.

It is also characteristic of the 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 the MELAS syndrome be suspected. Even such extensive symptoms do not give a correct diagnosis. The progression of the process occurs in different ways.

signs

The hallmark clinical feature of the MELAS syndrome is stroke-like episodes (IPE), in which neurological symptoms suddenly appear. IPE is characterized by asymmetry of lesions. They may be multiple.

The selectivity of such localization also gives certain focal symptoms:

hemianopsia (cortical blindness);
hemiparesis;
sensory aphasia (misunderstanding of words);
acalculia (violations of the account);
agraphia (spelling violations);
ataxia (impaired coordination of voluntary movements);
changes in consciousness.

It is not uncommon for these stroke-like symptoms to return every 1 to 3 months. The peculiarity of acute episodes in MELAS is that they have a rapid regression, but often recur, that is, as if they pass without a trace. In addition, in patients with this disease, calcifications are deposited in the basal ganglia (this is found on CT).

Stroke-like episodes often develop at the age of 5-15 years. They never become the result of thromboembolism. Angiopathy in MELAS is due to hyperproliferation of the same mitochondria.

IPE in symptoms is manifested by recurrent attacks of cephalalgia, dizziness, paresis, paralysis of the limbs, cranial nerves. The man is completely demoralized.

Lactic acidosis in MELAS syndrome

Its main culprit is an excess of lactic acid in the blood and tissues of the nervous system. This sharply reduces the acidity of the blood in the arteries. Such acidosis is a frequent companion of diabetes mellitus, which is present in MELAS syndrome.

At an early stage, manifestations are nonspecific. The following symptoms are observed: general weakness, chest pain, apathy, drowsiness. Myalgia after physical exertion and intermittent rapid breathing without any odor are very characteristic.

In the middle stage, lactic acid accumulates and hyperventilation syndrome (HVS) occurs. Carbon dioxide accumulates in the blood. Noisy breathing begins to form - Kussmaul. Pressure drops up to collapse, oliguria sets in. The patient becomes restless, delirious, 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 the mutation of a large number of genes, the diagnosis of MELAS syndrome is difficult. Held:

general and biochemical blood tests;
muscle biopsy;
genetic study with a comparative analysis among sick relatives;
CT of the brain: areas of infarcts more often in the hemispheres, less often in the cerebellum, basal ganglia;
an increase in the caliber of blood vessels (arteries, veins, capillaries);
DNA diagnostics: search for characteristic point mutations in mtDNA.

Therapy Methods

Treatment for MELAS syndrome has not been developed, and it is currently incurable. There are only attempts to slow down the defeat process. Treatment goes in two directions: post-syndromic therapy (epilepsy, diabetes mellitus) and pathogenetic. However, there is no effective pathogenetic therapy today.

There are symptomatic treatments: with hearing loss, hearing aids are actively used, with respiratory muscle weakness, respiratory therapy is provided. It was noted that with the MELAS syndrome in the patient's blood, the level of L-arginine is significantly reduced during IPE. Therefore, therapy is carried out 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 is being studied; L-carnitine, antioxidants (mexidol, mildronate), lactic acidosis correctors (dimephosphone) - all of them improve the cell's energy metabolism. In the treatment of seizures, valproates and barbiturates are not prescribed, since they depress mitochondria.

As a prevention of this syndrome, it is best to resort to the IVF method. If a woman knows that she has a case of manifestation of this disease in her family, then the cytoplasm for fertilization is taken from a healthy woman. The method is still at the stage of study, it is not mass.

Some Features

Diagnosis of mitochondrial disorders requires a very careful approach to therapy. Means of metabolic action must necessarily be included in it. They stabilize the processes of tissue respiration, oxidative phosphorylation in cells. Only the systematic implementation of such treatment can help maintain the condition of patients, preventing stroke episodes.

Forecast

The prognosis is unfavorable due to the lack of effective treatment. Life expectancy from the first onset of symptoms usually does not exceed five years. The lack of knowledge 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.

MELAS syndrome is a mitochondrial disorder characterized by muscle and CNS involvement.

MELAS (eng. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes - “mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes”) is a progressive neurodegenerative disease characterized by the manifestations listed in the title, and is accompanied by polymorphic symptoms - stroke, diabetes, seizures, decreased hearing loss, heart disease, short stature, endocrinopathies, exercise intolerance, and neuropsychiatric disorders.

Story.
The MELAS syndrome was first described in 1984 by Pavlakis and colleagues; ten years later, Pavlakis and Mizio Hirano published a review of 110 cases.

inheritance type:

maternal

Epidemiology:

The exact frequency of the disease is not known. There are few data in the literature on the incidence of the disease. In northern Finland, the A3243G mutation rate is 16.3:100,000.

Pathogenesis:

Mutations of mitochondral DNA, which control the respiratory chain of mitochondria, are accompanied by a disruption in the processes of oxidative phosphorylation, the most important source of energy for metabolic processes in the cell.

Clinical manifestations

At the age of 40 years, patients with MELAS are admitted with a clinic of transient ischemic attack, as well as with epilepsy, repeated vomiting, headache, and muscle weakness. These patients are often clinically diagnosed with dementia.
Young age and the absence of risk factors specific to stroke make MELAS more thoughtful.
Laboratory data
Lactate acidosis - increased levels of lactate and pyruvate.

Visualization data
Changes in the brain are similar to changes in a stroke.
Differences from a stroke
1) the affected areas do not coincide with the boundaries of the arterial vascular pools.
2) with repeated attacks, the foci are visualized in a different localization.
+ clinical data (young age, no risk factors for stroke).

CT
Multiple hypodense areas inconsistent with the vascular bed.
Calcification of the basal ganglia (most common in older patients).

Atrophy occurs against the background of regression and clinical improvement.

MRI
Acute infarction
For differentiation with stroke, ADC and DWI are used (diffusion restriction in strokes (cytotoxic edema), and in MELAS, diffusion is slightly limited or unchanged (vasogenic edema).
Involvement in the pathological process of the subcortical white matter of the brain.
Deterioration in the visualization of the clarity of the contours of the convolutions and an increase in the signal from them on T2-weighted images.

Chronic infarction
Changes can be symmetrical or asymmetrical.
Focal atrophy occurs against the background of regression and clinical improvement.
The parietal, occipital, and temporal lobes of the brain are most commonly affected.

MR spectroscopy
Increased lactate levels.

The materials are intended for neurologists, therapists, and general practitioners.

Sergey Likhachev, head, MD. sciences, professor;

Inessa Pleshko, Leading Researcher, Ph.D. Sciences, Neurological Department of the Republican Scientific and Practical Center for Neurology and Neurosurgery.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a progressive autosomal dominant disease, the clinical manifestations of which include recurrent subcortical ischemic strokes, migraine, subcortical dementia, and affective disorders. Current prevalence - 1 case
per 100,000 population.

The Republican Scientific and Practical Center for Neurology and Neurosurgery sees 7 patients (including 4 women) with CADASIL; age - from 32 to 68 years. They were examined by neurological, molecular genetic methods. There were characteristic symptoms; in history - migraine, recurrent lacunar strokes and affective disorders. Brain MRI revealed subcortical infarcts and leukoencephalopathy characteristic of CADASIL.

As a result of molecular genetic diagnostics, 2 people had a heterozygous mutation in the Notch3 gene on the 19th chromosome, which causes CADASIL. Notch genes encode transmembrane receptors involved in cell ontogeny. With CADASIL, in most cases, missense mutations are determined, due to which the structure of the transmembrane protein changes and its functions are impaired.

The pathogenesis of CADASIL is not completely clear. It is believed that the main factor is arteriopathy with progressive occlusion of small perforating vessels of the white matter of the brain (leading to chronic hypoperfusion). At the same time, characteristic granular osmiophilic inclusions are found, causing proliferation of basement membrane components, thickening of the middle membrane and mechanical compression of small arteries. As a result, the blood-brain barrier is damaged - edema develops.

An additional pathological factor is the activation of astrocytes near the vascular wall. They release endothelium-1, causing vasoconstriction and impaired blood flow.

The composition of granular osmiophilic inclusions is unknown. It is assumed that the Notch3 protein is one of their components. In skin biopsies of patients with a Notch3 mutation, osmiophilic granules and degeneration of smooth muscle cells can be detected even before the age of 20 years.

Clinical diagnostics of CADASIL:

burdened family history;
the development of the first symptoms of the disease before the age of 50;
the presence of two of the following symptoms - migraine, recurrent strokes, mood disturbances, subcortical dementia.

Vascular risk factors etiologically associated with neurological symptoms should be excluded. MRI shows damage to the white matter of the cerebral hemispheres and the absence of cortical infarcts.

A reliable diagnosis of "CADASIL" is confirmed by a positive result of molecular genetic diagnosis or the detection of arteriopathy with characteristic granular osmiophilic inclusions in skin or muscle biopsy.

The most common symptoms of CADASIL are transient ischemic attacks and ischemic strokes, observed in almost 85% of patients.

They are characterized by a recurrent course, manifested by classic syndromes of lacunar strokes and complete clinical remission after a few days or weeks.

The second most common are cognitive impairments (noted in 60% of patients). May begin at age 35, sometimes even before ischemic episodes. Approximately 75% of CADASIL patients develop dementia. The first symptom is usually a migraine; often occurs before the age of 20 and usually precedes strokes.

Data on the involvement of the heart in the pathological process in CADASIL are contradictory. L. Oberstein et al. (2003) found that 25% of patients diagnosed with CADASIL had a history of acute myocardial infarction or Q-wave pathology on the electrocardiogram. In another study, Cumurciuc et al. (2006) found no positive cardiac history in 23 people with a Notch3 mutation.

Clinical manifestations of CADASIL and cerebral microangiopathy of a different etiology are similar - differential diagnosis is required.

In order to timely determine CADASIL in patients and their families, it is necessary to resort to molecular genetic methods and / or histological studies.

MELAS syndrome

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare hereditary disease caused by pathology of the mitochondrial genome, impaired energy metabolism and functioning of the most energy-dependent organs and tissues (CNS, cardiac and skeletal muscles, eyes, kidneys, liver, bone marrow, endocrine system). The wide variability of clinical manifestations of the MELAS syndrome and the rare occurrence predetermine the difficulties in diagnosis for the practitioner.

In the Republican Scientific and Practical Center for Neurology and Neurosurgery, 3 patients (a 46-year-old woman and her sons, aged 24 and 23) are observed with a diagnosed MELAS syndrome. They underwent clinical and neurological examination, molecular genetic diagnostics, MRI of the brain.

All are short; in history - symptoms of mitochondrial pathology: sensorineural hearing loss, migraine-like headaches, poor exercise tolerance. The debut of the disease is generalized convulsive seizures. In 2 patients, the first symptoms appeared before the age of 20; there were epileptic seizures following one after another, episodes of visual impairment with the presence of foci in neuroimaging in the occipital and temporal regions, an increase in the level of lactate in the blood and cerebrospinal fluid. 1 person had a moderate decrease in cognitive functions; according to ultrasound of the heart - hypertrophic cardiomyopathy; diabetes.

A molecular genetic study revealed multisystem lesions typical of MELAS, wide variability and varying degrees of clinical manifestations, corresponding to the number of A3243G mutant copies in the tRNA Leu(UUR) gene.

MELAS is characterized by a maternal type of inheritance, the presence of sporadic cases when a de novo mutation occurs; accumulation in cells - both normal and mutant types - of mitochondrial DNA (heteroplasmy) and random distribution during division between daughter cells (mitotic segregation). At the genetic level, the cause of MELAS syndrome is the heteroplasmic rearrangement 3243A>G in the tRNALeu(UUR) gene (80% of cases are detected).

The pathogenesis of the disease has not yet been studied. There are 2 main theories - "mitochondrial angiopathy" and "mitochondrial cytopathy". It is known that the stroke-like lesion does not correspond to the vascular zones and extends to the surrounding areas due to concomitant vasogenic edema caused by prolonged epileptic activity. As suggested, stroke-like episodes are due to neural hyperexcitability in a limited area of the brain. It arises from mitochondrial dysfunction in capillary endothelial cells, or in neurons, or in astrocytes; depolarizes adjacent neurons, leading to the spread of epileptic activity.

In addition, in the intervals between stroke-like episodes, according to single photon emission computed tomography (SPECT), patients with MELAS have hypoperfusion of the posterior cingulate cortex, which indicates a disorder of cerebral hemodynamics.

Violation of oxidative phosphorylation, rupture of the mitochondrial respiratory chain contribute to the predominance of catabolic metabolism and changes from the Krebs cycle to anaerobic glycosis with lactate accumulation. A high level of the latter in the CNS usually correlates with periods of neurological symptoms.

The main clinical signs of MELAS are stroke-like episodes, lactic acidosis, and the presence of "torn red fibers" in muscle biopsy specimens. Additional manifestations may be dementia, psychosis, epileptic seizures, migraine-like headaches, ataxia, myopathy, calcification of the basal ganglia on neuroimaging, optical atrophy, retinopathy, deafness, diabetes, intestinal pseudo-obstruction, cardiomyopathy.

The early age of MELAS debut is from 5 to 20 years, however, there are observations of a late onset - in the 5th–6th decades of life. There are cases when the syndrome started after cardiac disorders.

The multisystem nature of lesions in MELAS complicates clinical diagnosis.

The hereditary nature of the disease obliges to conduct molecular genetic studies in order to make an accurate diagnosis.
and identify other patients - from among the relatives of the patient.

The materials are intended for neurologists, therapists, and general practitioners.

Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes

Basal ganglia calcification, cerebellar atrophy, increased lactate; CT image of a person diagnosed with MELAS
Speciality	neurology

genetics

Muscle biopsy of a person diagnosed with MELAS, but not carrying a known mutation. (a) Gomori's modified tricolor dye shows some ragged red fibers (arrows). (b) Cytochrome c oxidase stain, showing type-1, slightly stained and type II fibers, dark fibers and a few fibers with abnormal mitochondrial collections (arrows). Note cytochrome c oxidase negative fibers are usually seen in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). (c) Succinate dehydrogenase staining shows several ragged blue fibers and intense staining in blood vessel mitochondria (arrow). (d) Electron microscopy shows an abnormal collection of mitochondria with paracrystalline inclusions (arrows), osmiophilic inclusions (large arrows), and mitochondrial vacuoles (small arrows).

MELAS is caused by mutations in genes in mitochondrial DNA.

NADH dehydrogenases

Mutations in MT-TL1 cause over 80 percent of all MELAS cases. They reduce the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in various tissues, especially in the brain.

inheritance

This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance and heteroplasmy. This pattern of inheritance refers to genes contained in mitochondrial DNA. Because eggs, but not sperm, contribute mitochondria to the developing embryo, only females go through mitochondrial conditions for their babies. Mitochondrial disorders can appear in every generation of a family and can affect both men and women, but fathers do not pass on the mitochondrial traits of their children. In most cases, people with MELAS inherit the altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in the mitochondrial gene and occurs in people without a family history of MELAS.

diagnostics

Treatment / prognosis

Patients are managed according to what areas of the body are affected at a particular point in time.

How long do children with melas syndrome live? Rare diseases. Symptoms of the MELAS syndrome

annotation scientific article on clinical medicine, author of scientific work - Mukhin K.Yu., Mironov M.B., Nikiforova N.V., Mikhailova S.V., Chadaev V.A.

Related Topics scientific papers in clinical medicine, author of scientific work - Mukhin K.Yu., Mironov M.B., Nikiforova N.V., Mikhailova S.V., Chadaev V.A.

EPILEPSY IN MELAS SYNDROME

The text of the scientific work on the topic "Epilepsy in melas syndrome"

Essence of pathology

General information

Pathological changes

What is a mitochondrion anyway

Pathogenesis

Symptomatic manifestations

signs

Lactic acidosis in MELAS syndrome

Diagnostic measures

Therapy Methods

Some Features

Forecast

genetics

NADH dehydrogenases

inheritance

diagnostics

Treatment / prognosis

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