Leigh syndrome is a genetically heterogeneous hereditary disease characterized by a variety of metabolic disorders and the formation of components of the central nervous system. Symptoms of this pathology, as a rule, manifest themselves in early childhood, they include muscle hypotension, problems with feeding and delayed psychomotor development. With further progression of the disease, epileptic seizures, hyperkinesis, respiratory disorders occur. Diagnosis is carried out on the basis of the data of the patient’s current status, magnetic resonance imaging, molecular genetic analyses. There is no specific treatment for this pathology, symptomatic therapy only slightly slows down the progression of the disease.
General information
Leigh syndrome (subacute necrotizing encephalomyelopathy) is a hereditary neurodegenerative disease of the central nervous system, which is characterized by early onset and steady progression of neurological disorders. This condition was first described in 1951 by the English psychiatrist Denis Leigh, who identified it as a hereditary variant of encephalomyelopathy. Further studies have shown that Leigh syndrome is an extremely heterogeneous condition from the point of view of etiology – it is caused by defects in many genes located on autosomes, the X chromosome and mitochondrial DNA. For this reason, the mechanism of inheritance of the disease may be (depending on the nature of the mutation) autosomal recessive, sex-linked or mitochondrial. Due to the variety of genetic defects that cause Leigh syndrome, the sexual distribution of this condition also differs, however, according to many geneticists, in general, it can be considered that it affects both boys and girls equally. The occurrence is approximately 1 case per 34-36 thousand newborns.
Causes and classification
The causes of the development can be mutations of a wide range of genes located on different chromosomes. However, the pathogenesis of this condition is approximately similar in various forms of pathology and is most often associated with a violation of the processes of cellular respiration and the functioning of the mitochondrial respiratory chain. In relation to some forms, a violation of the functioning of the pyruvate dehydrogenase complex has also been observed. Violation of the structure of proteins of the mitochondrial respiratory chain leads to insufficient synthesis of ATP, which is the main source of energy in all cells of the body. Neurons and neuroglial cells are particularly sensitive to a lack of energy, which causes the development of various disorders since childhood. Classification of all genetic defects in Leigh syndrome is based on which component of the respiratory chain (which is a protein complex) of mitochondria is disrupted as a result of mutation.
- Caused by the defeat of complex 1 (NADH-KoQ-reductase). This variant can be inherited both autosomal recessive and mitochondrial. The most common variants of this type of disease are caused by mutations of the nuclear genes NDUFA10 (located on the 19th chromosome), NDUFS4 and DUFAF2 (5th chromosome), NDUFS3 (11th chromosome). In addition, defects in the mitochondrial DNA genes MTND1, MTND2 and MTND3 can lead to the development of Leigh syndrome as a result of damage to mitochondrial complex 1. The result is a violation of the initial stage of electron and hydrogen transfer in the respiratory chain, which reduces the synthesis of ATP.
- Caused by defects in proteins included in the mitochondrial complex 2 (succinate-KoQ-reductase). The disease of this type is inherited only autosomal recessive, it was reliably possible to establish a relationship between Leigh syndrome and mutations of the SDHA gene localized on the 5th chromosome. This gene encodes subunit A of the succinate dehydrogenase complex, with genetic disorders of this type, the activity of the enzyme decreases, which leads to the development of the disease.
- Leigh syndrome, resulting from a violation of the structure of proteins of the mitochondrial complex 3 (KoQH2-cytochrome c-reductase). This variety includes the most common variant of the disease caused by a mutation of the BCS1L gene located on the 2nd chromosome. The development of Leigh syndrome is due to the reduced expression of the enzyme ubiquinone-c-reductase, which is part of the mitochondrial complex 3. Its release is regulated by a specific protein that is encoded by the BCS1L gene – as a result of mutation, the resulting defective protein is unable to fully perform its functions. This variant is characterized by autosomal recessive inheritance.
- Caused by damage to the mitochondrial complex 4 (cytochrome c oxidase). It can be caused by mutations of nuclear genes (COX10, SCO1), mainly located on the 17th chromosome, and damage to mitochondrial DNA – this was found out by the nature of inheritance of some forms, but the key genes have not yet been determined.
- Caused by a violation of the structure of the mitochondrial complex 5 (ATP synthase). This variant includes relatively rare mutations of the ATPAF2 gene localized on the 17th chromosome. As a result of the mutation, the work of ATP synthase is disrupted, the formation of ATP by oxidative means is sharply reduced.
As a separate variant of Leigh syndrome, the form of the disease is often indicated due to mutations of the PDHA1 gene, which is located on the X chromosome. As a result, the inheritance of this type of pathology is linked to gender – almost exclusively boys are ill, while women are carriers of pathological genes. The mitochondrial type of inheritance also has many features. The transmission of pathological genes occurs from mother to offspring and continues only through the female line. Since each mitochondria has its own DNA molecule, both “healthy” and “sick” organelles are present in the cell at the same time, and during cell division (including during meiosis during egg formation), the distribution of diseased genes turns out to be unequal. Women with a relatively small percentage of “sick” mitochondria in their cells may be phenotypically healthy, but pass them on to their offspring. It is impossible to predict exactly how many pathological mitochondria a child of such carriers will receive, so the probability of developing Leigh syndrome in the children of these women is uncertain.
Symptoms
Manifestations of Leigh syndrome usually occur during the first year of a child’s life, sometimes they can be registered at the age of 2-5 years, in rare cases, the development of the disease begins in adolescence. Usually, the first manifestation of the pathology is drowsiness or, conversely, increased excitability of the child, in infants there is a violation of nutrition, a shortage of body weight. In the future, Leigh syndrome leads to a delay in psychophysical development, and in older children – to a gradual loss of already acquired skills. Among other neurological symptoms of the disease, paresis, tremor of the extremities, impaired coordination of movement, peripheral nerve damage, and decreased tendon reflexes are most often noted. In the future, clonic seizures and epileptic seizures may be recorded.
Due to the lack of energy caused by Leigh syndrome, not only the nervous system suffers, but also other organs with high ATP consumption. In most cases, muscle hypotension and weakness are noted in sick children. The disease also affects the liver, an organ with a very high energy consumption. In patients with Leigh syndrome, liver enlargement, jaundice, and sometimes hepatolienal syndrome are often detected. As the pathology progresses, breathing disorders occur – it becomes difficult, sometimes acquires the character of Cheyne-Stokes breathing. A number of patients develop myocardiodystrophy over time.
Leigh syndrome has a progressive course. At the terminal stages, there is a lesion of the visual organs, which is manifested by nystagmus, color perception disorder, strabismus. Eventually, optic nerve atrophy and complete blindness may occur. Muscle hypotension and hyporeflexia are replaced by spastic muscle tension and increased tendon reflexes. 2-7 years after the appearance of the first symptoms of Leigh syndrome, a sharp drop in body weight occurs, the above manifestations increase sharply, a fatal outcome occurs due to respiratory or cardiovascular insufficiency.
Diagnosis and treatment
To determine the presence of Leigh syndrome, brain MRI, electroneuromyography, the study of hereditary history, molecular genetic analyses are used. During the examination, characteristic neurological symptoms, tremor of the limbs, lag in psychophysical development are revealed, in infants – a shortage of body weight. Magnetic resonance imaging of the brain reveals symmetrical changes in the area of the medulla oblongata, thalamus and bridge, sometimes similar changes can be recorded in the spinal cord. The best results of the diagnosis of Leigh syndrome using MRI are obtained when using T2W and FLAIR modes.
In cases where there are signs of damage to peripheral nerves and muscles, electroneuromyography is performed to diagnose Leigh syndrome. In this disease, the main and most frequent result of ENMR is a slowdown in the rate of passage of the nerve impulse, which indicates the demyelination of nerves. The study of hereditary anamnesis is informative in the case of autosomal recessive forms of the disease, with mutation of mitochondrial DNA genes, it is difficult to clearly determine the familial nature of the pathology. Molecular genetic diagnostics is massively used only in relation to certain forms of Leigh syndrome (caused by mutations of the BCS1L, SURF1 and some others genes).
There is no specific treatment for this pathology, symptomatic therapy is used: anticonvulsants and nootropic drugs, drugs to improve cerebral circulation. An important role in the treatment of Leigh syndrome is played by the appointment of vitamins that serve as cofactors of enzymes of the mitochondrial respiratory chain – B1, B6, Q10. Their regular intake allows you to slow down the progression of the disease somewhat and reduce the severity of symptoms. However, despite all the therapeutic measures taken, 80% of patients die 2-7 years after the registration of the first manifestations of pathology.
Prognosis and prevention
The prognosis of Leigh syndrome is extremely unfavorable, since most patients die a few years after the onset of the disease. Symptomatic treatment can somewhat slow down the progression of pathology and weaken the severity of manifestations, but it does not provide a full-fledged improvement. In most cases, a year or two before the fatal outcome, complete disability of the patient occurs due to neurological, respiratory and metabolic disorders. The cause of death in Leigh syndrome is most often cardiovascular or respiratory failure. Prevention of this disease is carried out within the framework of medical and genetic counseling of parents before conception of a child.
