MELAS syndrome is a genetic disease with damage to the central nervous system, muscle tissue and various organs. The pathology is based on a violation of tissue respiration and a defect in energy metabolism. The clinical picture is heterogeneous, includes acute episodes resembling a stroke, epileptic seizures, intolerance to physical exertion due to muscle weakness. MRI, EEG, ENMG and other studies are used for diagnosis. The final diagnosis is established when spot mutations in mitochondrial DNA are detected. Treatment consists in the appointment of metabolic drugs and symptomatic therapy.
ICD 10
E88.8 G71.3
General information
MELAS syndrome (mitochondrial encephalopathy with lactate acidosis and stroke-like episodes) refers to diseases caused by a genetic defect in mitochondrial DNA. In this syndrome, energy production in the mitochondrial respiratory chain is disrupted. The disease was first described in 1984. According to various data, pathology occurs with a frequency of 1:15,000 to 1:20,000 people. There are no gender differences. The average age of the debut is 6-10 years.
Reasons of MELAS syndrome
The cause of the pathology is point mutations of mitochondrial DNA. To date, about 10 genes are known, with the defect of which the manifestation of MELAS syndrome is observed. Mutations in genes encoding transport RNA are most often detected. Most often (80-90% of cases), the A3243G mutation is detected in the MTTL1 gene of the amino acid leucine transport RNA.
Due to the defect, the synthesis of mitochondrial proteins is disrupted. The presence of a mutation does not necessarily guarantee the phenotypic manifestation of the disease, which is associated with the phenomenon of heteroplasmia, that is, the simultaneous presence of normal and mutant mitochondrial DNA in a cell, organ or organism. A large number of defective DNA increases the likelihood of clinical manifestation of the syndrome.
Pathogenesis
A genetically determined defect in the synthesis of mitochondrial proteins (tissue respiration enzymes) leads to a violation of the processes of oxidative phosphorylation – the last stage of the breakdown of biological substrates: fatty acids, carbohydrates. Oxidative phosphorylation is considered the main link in energy metabolism, provides the formation of an overwhelming amount of energy carriers – ATP molecules.
Failure of these processes occurs in every mitochondria with defective DNA. Since mitochondria are present in almost all cells of the body, the lesion is multisystem in nature. Organs and tissues with high energy demand suffer the most: the central and peripheral nervous system, myocardium, skeletal muscles.
In muscles, energy deficiency (tissue hypoxia) leads to excessive formation of lactic acid. The genesis of acute cerebral disorders is a deficiency of nitric oxide due to the accumulation of cytochrome oxidase enzyme in vascular smooth muscles. When nitric oxide is insufficient, vasoconstriction occurs, platelet aggregation.
Classification
According to the severity of clinical manifestations, there are 3 forms of MELAS syndrome:
- Asymptomatic carriage is the presence of a genetic mutation and changes in muscle biopsy against the background of a complete absence of clinical signs of the disease.
- Oligosymptomatic – individual components of the syndrome are detected: muscle weakness, headaches, etc.
- Manifest – a vivid clinical picture with acute episodes.
Symptoms of MELAS syndrome
Usually, neurological symptoms manifest first, which occur as early as 6-15 years old. The most typical are considered to be stroke-like episodes (metabolic stroke). Frequent manifestations are hemianopia (loss of half of the visual field), imbalance, perception or reproduction of speech, changes in consciousness.
Half of the patients have focal or generalized tonic-clonic epileptic seizures, migraine-like headaches (unilateral, pulsating). The characteristic features of such attacks are the age of patients less than 40 years old, provoking an infectious disease, rapid regression of symptoms and frequent recurrence.
Acute psychoses and hemiparesis are less common. From other neurological manifestations, it is possible to distinguish a delay in neuropsychic development, inhibition, cognitive impairment. Due to the atrophy of the optic nerves, vision gradually deteriorates. Another specific sign of MELAS syndrome is pronounced muscle weakness and poor exercise tolerance.
Often there are pains, cramps in the muscles. Muscle spasms can also be caused by a decrease in the concentration of calcium in the blood due to hypoparathyroidism. Many patients have a gradual deterioration of hearing (sensorineural hearing loss), diabetes mellitus occurs. Cardiological signs of the disease include cardiomyopathy, arrhythmias, and chronic heart failure.
Complications
MELAS syndrome is a severe disease characterized by a wide range of adverse effects. The most frequent fatal complications are associated with mitochondrial encephalopathy. These include repeated “metabolic strokes” and epileptic statuses. A small proportion of patients fall into a coma.
Patients have an increased risk of developing life-threatening rhythm disturbances (ventricular tachycardia, fibrillation), cardiac arrest. Sensorineural hearing loss and optic nerve atrophy can lead to complete loss of hearing and vision. In isolated cases, intestinal obstruction, chronic renal and hepatic insufficiency occur.
Diagnostics
Patients with MELAS syndrome are supervised by neurologists, pediatricians. During a general examination, attention is drawn to low growth, pronounced hypotension, muscle hypotrophy. The combination of myopathy with acute neurological disorders in a young patient makes it possible to suspect the disease. Additional examination aimed at clarifying the diagnosis includes:
- Laboratory tests. The biochemical analysis of blood determines a high level of lactic acid, glucose and glycated hemoglobin, a decrease in the concentration of calcium. When analyzing blood for hormones, a decrease in the content of somatotropic and parathyroid hormones is detected. In the general analysis of urine, proteinuria is often detected.
- MRI of the brain. Brain damage is visualized as irregularly shaped foci with clear contours and slightly increased intensity of the MR signal. There are signs of volumetric impact on the subarachnoid space. Calcifications are often detected in the basal ganglia with predominant localization in the occipital and parietal regions. With repeated MRI, fluctuation or disappearance of foci is detected.
- MR spectroscopy. Magnetic resonance spectroscopy of the brain shows a significant decrease in high-energy phosphorus compounds and an increase in lactate concentration.
- EEG. The electroencephalogram shows a slowdown in the main activity, diffuse disturbances of bioelectric processes of the brain, signs of island-wave activity, increasing against the background of hyperventilation.
- ENMG. Electroneuromyography confirms the presence of non-specific signs – a reduction in the duration of the potential and amplitude of motor units, a block and a slowdown in the conduction of a nerve impulse.
- Muscle biopsy. The most typical morphological changes are the phenomenon of “torn red fibers” (myofibrils with a large number of proliferating altered mitochondria), perimysium sclerosis, regional necrosis. There is a positive histochemical staining for cytochrome oxidase and succinate dehydrogenase.
- DNA research. A crucial diagnostic test for the verification of MELAS syndrome. In peripheral blood lymphocytes, the A3243G mutation of the MTTL1 gene is detected more often than others.
Differential diagnosis of acute episodes is carried out with ischemic strokes, subarachnoid hemorrhage, acute infectious meningoencephalitis. Myopathic syndrome should be distinguished from hereditary muscular dystrophy, polymyositis. Pathology also needs to be differentiated from other mitochondrial diseases.
Treatment of MELAS syndrome
Radical treatment has not been developed. All methods of therapy are aimed at improving the patient’s condition and are only palliative in nature. A diet with a limited carbohydrate content is necessary. Dietary nutrition is required to reduce the level of glucose, which negatively affects the parameters of energy metabolism, and to correct diabetes mellitus. The following medications are used:
- Metabolic drugs. To improve oxidative phosphorylation in mitochondria, a complex energotropic treatment is prescribed, including drugs that promote electron transfer in the respiratory chain (coenzyme Q10, succinic acid), cofactors of energy metabolism enzymes (riboflavin, nicotinamide), antioxidants (ascorbic acid, tocopherol).
- Precursors and donors of nitric oxide. During a stroke-like episode, medications that increase the level of nitric oxide in the blood (L-arginine, citrulline), promote vasodilation and improve microcirculation were effective.
- Preparations for the correction of CSCR. Drugs that reduce the level of lactate in the blood (lactate acidosis correctors) are used only in the acute period in patients with a very high content of lactic acid in the blood. Their appointment requires great caution because of the ability to have a toxic effect on nerve tissue. Intravenous administration of sodium bicarbonate is possible.
- Glucocorticosteroids. The use of adrenal cortex hormones (prednisone) leads to a significant regression of neurological symptoms.
- Means for the correction of hormonal disorders. With the development of diabetes mellitus, hypoglycemic drugs (metformin, glibenclamide) are recommended, and if they are ineffective, insulin therapy is recommended. When hypoparathyroidism occurs, calcium and vitamin D are added to the treatment regimen .
- Antiepileptic drugs. Valproic acid derivatives widely used in epileptology are strictly contraindicated, since they inhibit energy metabolism. Preference is given to clonazepam, lamotrigine, topiramate.
Depending on the clinical picture, cardiotropic agents (beta-blockers, antiarrhythmics, ACE inhibitors), correctors of liver failure (albumin and medications that suppress the formation of ammonia), hemodialysis sessions are prescribed. The use of drugs that inhibit mitochondrial function (barbiturates, chloramphenicol, statins) should be avoided as much as possible, since this leads to a deterioration of the patient’s condition.
Prognosis and prevention
MELAS syndrome is a severe progressive disease with a high frequency of deaths. The life expectancy of people with asymptomatic carrier and oligosymptomatic form does not differ from that in the general population. With manifest form, according to various data, the life span is from 7 to 40 years from the moment of the onset of the disease.
Methods of primary prevention have not been developed. Since neurological attacks are often provoked by acute infection, it is recommended to get flu vaccinations and general preventive measures aimed at increasing the body’s resistance (regular exercise, hardening) to prevent them.
