Pyruvate dehydrogenase deficiency is one of the forms of hereditary enzymopathies characterized by various disorders of the protein pyruvate dehydrogenase complex and abnormal carbohydrate metabolism. The main symptoms of this condition are various malformations, progressive damage to the central nervous system, convulsions, muscle weakness, ataxia and respiratory disorders. The diagnosis of pyruvate dehydrogenase deficiency is carried out on the basis of data from a biochemical blood test, the study of enzyme activity in tissues, genetic techniques and a comprehensive study of the nervous system. There is no specific treatment. The course of pathology in some cases is facilitated by a specially developed diet and the use of vitamin B1 preparations.
General information
Pyruvate dehydrogenase deficiency is a genetically heterogeneous group of hereditary pathologies that affect the structure and functions of proteins of a special pyruvate dehydrogenase complex. This condition was discovered and studied by geneticists in the 80-90s of the twentieth century, during the research the genetic heterogeneity of pathology was established and its main clinical forms were determined.
Pyruvate dehydrogenase deficiency is a fairly common condition compared to other types of enzymopathies. The most common type of disease is transmitted by an X-linked mechanism, but autosomal recessive variants of this pathology are also possible. The reason for such a high heterogeneity and diversity of clinical forms of pyruvate dehydrogenase deficiency is the complex complex structure of the pyruvate dehydrogenase complex. This enzyme is a combination of different proteins encoded by different genes, but united by one function.
Causes
The complexity of the structure of the pyruvate dehydrogenase complex makes it vulnerable to various genetic disorders. The pyruvate dehydrogenase enzyme itself is only one component of the complex (E-1), which, in turn, consists of four protein molecules – two alpha and beta chains each. The second component of the complex is represented by the enzyme dihydrolipoyl transacetylase (E-2), the third is dihydrolipoyl dehydrogenase (E-3). In addition, auxiliary proteins – pyruvate dehydrogenase phosphatase and lipoic acid synthetase – take an active part in the work of this system. Modern genetics has been able to prove that mutations of genes encoding all of the above proteins can lead to manifestations of pyruvate dehydrogenase deficiency. The functioning of the system also depends on the content of vitamin B1 (thiamine) and some other compounds in the body.
In the process of oxygen-free glucose cleavage (glycolysis process), which is especially active in muscles, hepatocytes and neurons (for the latter, glycolysis is the only way to process carbohydrates), pyruvic acid (pyruvate) is formed, which, through pyruvate dehydrogenase, turns into acetyl enzyme A and is further split into carbon dioxide and water. When pyruvate dehydrogenase is deficient, lactic acid (lactate) is formed from pyruvate, which is released into the blood and changes metabolic processes in tissues.
The accumulation of acidic products (pyruvate and lactate) in the blood and cytoplasm leads to a violation of the acid-base balance, which, in turn, changes the course of many biochemical processes. Since the processes of glycolysis and pyruvic acid processing occur even at the intrauterine stage of development, in severe cases of pyruvate dehydrogenase deficiency, violations are detected already at birth. The organs that suffer the most are those in which the largest amount of pyruvate is formed, primarily the brain and other nervous structures, as well as the muscular system. The development of pyruvate dehydrogenase deficiency is caused by mutations of various genes. At the same time, one of these genes is localized on the X chromosome, so it is inherited by a sex-linked mechanism, while the remaining mutations are autosomal recessive.
Classification
The previous classification of pyruvate dehydrogenase deficiency was based on the main clinical forms of the disease, which differed in the severity of symptoms, the age of their occurrence and the lethality of pathology. To date, the division of the state by genetic characteristics is recognized as more objective, that is, according to which specific gene and component of the complex has a defect. At the same time, there was no clear correlation between the genetics of pyruvate dehydrogenase deficiency and clinical forms of the disease.
- Type 1 is caused by a mutation of the PDHA1 gene, which encodes the alpha subunit of the pyruvate dehydrogenase enzyme. The gene is located on the X chromosome, so type 1 has the characteristics of a sex-linked disease. This form of pyruvate dehydrogenase deficiency is the classic and most common.
- Type 2 is caused by defects in the structure of the PDHB gene localized on the 3rd chromosome. The gene encodes the sequence of the beta subunit of the pyruvate dehydrogenase enzyme.
- Type 3 is caused by a mutation of the DLAT gene, which is located on the 11th chromosome. Since this gene encodes the E-2 component (dihydrolipoyl transacetylase), a mutation develops a deficiency of E-2, leading to the appearance of symptoms of pyruvate dehydrogenase deficiency.
- Type 4 – is associated with defects in the structure of the PDHX gene, which is also localized on the 11th chromosome. It has been established that the expression product of this gene is an auxiliary protein responsible for binding the E-3 component of the pyruvate dehydrogenase complex and its incorporation into the general system.
- Type 5 is caused by a mutation of the PDP1 gene, which encodes another auxiliary protein of the complex (pyruvate dehydrogenase phosphatase). This gene is located on the 8th chromosome.
- Type 6 – is caused by defects in the structure of the LIAS gene localized on the 4th chromosome. The gene encodes the structure of the enzyme lipoic acid synthetase, which plays an auxiliary role in the structure of the pyruvate dehydrogenase complex.
For each type of pyruvate dehydrogenase deficiency, several dozen varieties of mutations have been found, which together gives hundreds of variants of this condition. This is why a wide range of clinical manifestations of the disease and differences in the severity of symptoms are associated with it – from lethal forms leading to stillbirth or death at an early age to a relatively benign course. Different types of pyruvate dehydrogenase deficiency react differently to therapeutic measures, in particular, to the use of high doses of thiamine.
Symptoms
Clinically, there are two main forms of pyruvate dehydrogenase deficiency: metabolic, which is characterized by an increase in symptoms of general acidosis, and neurological, which is accompanied by damage to the brain and nerves. However, “pure” isolated types of the disease are rare enough, a spectrum of transitional forms can be determined between them, therefore, both metabolic and neurological disorders are registered in all patients to varying degrees.
Metabolic manifestations of pyruvate dehydrogenase deficiency include frequent vomiting, weakness, muscle pain and hyperventilation of the lungs, in some cases the development of coma is observed. Neurological manifestations are reduced to seizures, mental retardation and cerebellar ataxia, sometimes to atrophy of the optic nerves.
According to another clinical classification, neonatal, infantile and benign forms of pyruvate dehydrogenase deficiency are distinguished.
- The neonatal type is characterized by an early, often congenital onset of the disease, often combined with other malformations (micrognathia, anterior location of the anus). The course of this form of pyruvate dehydrogenase deficiency is rapid, often leading to death in the first weeks or months of life.
- The infantile form of pathology is more common, develops at 4-8 months, rarely combines with other congenital malformations and leads to death before the age of 2.
- A benign type of pyruvate dehydrogenase deficiency occurs at the age of 3-12 years, sometimes in adults, accompanied by moderate ataxia and muscle weakness, may be aggravated by conditions leading to an increase in pyruvate release (for example, during exercise).
Diagnostics
Pyruvate dehydrogenase deficiency is diagnosed by biochemical blood and urine tests, determination of enzyme activity in fibroblasts and genetic and molecular analyses. Auxiliary diagnostic methods are examination by a neurologist and MRI of the brain. A sharp decrease in the pH level, high concentrations of pyruvic and lactic acids are found in the blood and urine. Pyruvate dehydrogenase deficiency can also be established by determining the activity of this enzyme in skin fibroblasts. In the presence of a disease, the activity of the enzyme decreases sharply.
Magnetic resonance imaging and neurological examination indicate the presence of cerebellar ataxia, seizures and optic nerve atrophy. MRI of the brain can detect foci of necrosis and demyelination, as well as a variety of cysts of various localization in the cerebral cortex, midbrain and cerebellum. Similar changes are often detected in the study of the spinal cord. Genetic diagnosis is currently performed only for the first type of pyruvate dehydrogenase deficiency by sequencing the PDHA1 gene. For other forms of the disease, the methods of molecular genetic diagnosis are almost not used.
Treatment and prognosis
There is no specific treatment for pyruvate dehydrogenase deficiency, the course of the first type of disease can be facilitated by taking increased doses of vitamin B1 (thiamine). Among other therapeutic measures, a diet with a reduced carbohydrate content is relatively effective to reduce the synthesis of pyruvate. It is necessary to limit physical activity. With mental retardation, the help of psychologists and defectologists is required, children are taught in specialized institutions. The prognosis of pyruvate dehydrogenase deficiency is uncertain, but often unfavorable. The course and outcome depend on the severity of symptoms, the severity of metabolic and neurological disorders.
