Pearson syndrome is a multisystem mitochondrial disease in which hematopoiesis disorders occur, insufficiency of pancreatic and liver functions. Pathology develops against the background of duplication (doubling) or sporadic deletion (loss of a site) of the maternal mDNA. The syndrome manifests itself in infancy with severe anemia, prolonged diarrhea, and a lag in psychomotor development. Diagnosis of the disease includes hematological and biochemical blood test, myelogram, genetic testing. Supportive treatment: enzyme replacement therapy, transfusion of blood components, metabolic agents.
64.0 Hereditary sideroblastic anemia
The syndrome is named after Professor Howard Pearson, who described its clinical symptoms in 1979. 10 years later, a link was established between pathology and molecular genetic defects of hereditary mitochondrial material. Previously, there were no more than 100 cases of Pearson syndrome in the world, but with the improvement of diagnostic criteria, the true incidence of the disease was established ‒ 1:5000-1:10000 newborns. The syndrome is characterized by a severe unfavorable course, the absence of etiopathogenetic therapy.
Pearson syndrome occurs when a fragment of mitochondrial DNA is duplicated or deleted. This mutation is transmitted only from the mother, since the paternal mitochondria do not enter the egg at conception, or are destroyed immediately after penetration. Specialists in the field of genetics have not yet been able to establish the pattern of development and provoking factors of the disease, therefore it is considered sporadic.
Mitochondria are organelles that are located in all cells of the body (except mature red blood cells) and produce up to 95% of energy. Energy in the form of ATP molecules is spent on maintaining vital processes. In each cell there are several thousand mitochondria containing 2-10 ring DNA molecules capable of replication, transcription, translation, regardless of the basic genetic information in the cell nucleus.
With mutation of mitochondrial DNA, the function of these organelles decreases, which affects all organs and tissues, therefore the syndrome belongs to organ-specific, has extremely severe manifestations. In patients with Pearson disease, electronic transport and oxidative phosphorylation are disrupted — key stages in the formation of ATP. The most energy-dependent tissues are the first to be damaged: the nervous system, muscles, including the myocardium, liver and pancreas.
In most cases, the syndrome debuts with sideroblastic anemia in the first months of the patient’s life. The child has pale skin with a bluish or greenish tinge, lethargy, constant drowsiness. The baby sucks the breast badly, eats little milk, slowly gains weight. Anemia cannot be treated with iron preparations, vitamin B12 or folic acid.
The second typical sign of Pearson syndrome is chronic diarrhea, which occurs due to pancreatic insufficiency. The frequency of stool in sick children reaches 10-20 times a day, the stool is liquid, fetid, usually there are curdled lumps of milk in it. Frequent regurgitation, intense colic, periodic vomiting attacks caused by metabolic crises are characteristic.
The syndrome may be supplemented by neurological disorders. The defeat of the neuromuscular system is manifested by persistent hypotension, ataxia, delay in the formation of large and small motor skills. Occasionally, subacute necrotizing encephalopathy begins in patients, which resembles Ley syndrome in the clinic and is accompanied by severe mental retardation.
With a “mild” variant of Pearson disease, with age, its transformation into another disease is possible — Kearns-Stace syndrome. In such children, there is a lag in growth, a delay in physical development, coordination disorders of the type of ataxia. The lesion of the eyes is represented by pigmented retinopathy, ophthalmoplegia. Generalized myopathies are characteristic, as well as myocardial damage with the appearance of arrhythmias.
Over time, the disease progresses with the involvement of other body systems. With kidney damage, tubulopathy, de Toni-Debre-Fanconi syndrome are detected. Liver pathology is characterized by fatty hepatosis, hepatomegaly, cytolysis. Fibrous changes in the pancreas cause a decrease in insulin synthesis, which is manifested by insulin-dependent diabetes mellitus.
The most dangerous complication in children with Pearson disease is lactic acidosis, in which the contractility of the heart is progressively impaired, neurological symptoms increase, gastrointestinal disorders worsen. Then there is collapse, hypothermia, acute renal failure. Lactic acidosis ends in a deep coma. Death occurs in 60-70% of patients even during intensive therapy.
During the examination, exhaustion, pallor of the skin, delay in psychomotor development attracts attention. Clinical signs are similar to other mitochondrial diseases, which requires pediatricians to be highly professional and carry out comprehensive diagnostic measures. To verify the diagnosis of Pearson syndrome, the following laboratory and instrumental studies are prescribed:
- Hematological tests. The hemogram shows signs of macrocytic anemia, reticulocytopenia, with severe thrombocytopenia, neutropenia. When studying the indicators of iron metabolism, a typical manifestation is an increase in ferritin levels with a normal amount of iron in the blood.
- Biochemical research. The concentration of pancreatic amylase in the blood serum decreases, as a rule, cytolysis syndrome develops with an increase in ALT, AST, and alkaline phosphatase levels. Lactic acidosis is indicated by a sharp increase in the level of lactic acid in the blood, a decrease in the level of bicarbonate, a drop in pH less than 7.3.
- Bone marrow biopsy. A myelogram is necessary to differentiate different variants of hematopoiesis disorders. Pearson disease is characterized by vacuolization of the cytoplasm of erythrocyte precursors, the presence of ring-shaped sideroblasts after staining with Prussian blue.
- Molecular genetic research. To confirm the diagnosis, DNA is isolated from the mitochondria of leukocytes with its subsequent genetic testing. In this case, a large deletion or duplication of mDNA will be determined, often there are signs of heteroplasmia.
Taking into account the main clinical manifestations, instrumental imaging methods are additionally used. Ultrasound of the abdominal organs reveals hepatomegaly, enlargement and diffuse changes of the pancreas. With neurological symptoms, a CT scan of the brain is shown, confirming focal atrophic lesions. To exclude concomitant congenital malformations, EchoCG and chest x-ray are performed.
Assistance to patients with Pearson syndrome requires a multi-system approach with the participation of pediatricians, pediatric hematologists, gastroenterologists, according to indications, geneticists, neurologists, nephrologists are involved in therapy. Patients need lifelong supportive treatment, including:
- Transfusion of blood components. This is the only way to correct severe anemia, to make up for the lack of platelets to improve coagulation, to increase the level of white blood cells to activate the immune system.
- Stimulation of granulocytopoiesis. With a critical decrease in the number of neutrophils, preparations of granulocyte colony-stimulating factor are used, which increase the formation of leukocytes in the bone marrow.
- Enzyme therapy. Preparations of pancreatic enzymes and bile acids are used to improve the digestion of food in the small intestine, reduce the manifestations of maldigestion, normalize stool.
- Metabolic drugs. To stimulate electron transfer in the respiratory chain of mitochondria, activation of ATP production, the intake of coenzyme Q10, levocarnitine is recommended. Vitamins B2, PP, E are usually prescribed.
- Correction of blood pH. To eliminate lactic acidosis, solutions of sodium bicarbonate, methylene blue, and trisamine are administered. In severe cases, treatment is supplemented with hemodialysis or peritoneal dialysis with lactate-free dialysis.
Clinical studies on the use of cell therapy for Pearson syndrome have been launched in Israel. The experiment involves the transplantation of maternal cells with healthy mitochondria into the child’s body. Researchers expect an improvement in the quality of life of patients, a reduction in the need for transfusions, the intake of enzymes. If successful, this method will be the key to the etiopathogenetic treatment of other mitochondrial pathologies.
Prognosis and prevention
The life span of patients whose manifestation of the disease occurred during the first months after birth is no more than 2-3 years. Despite the achievements of modern medicine, the prognosis remains unfavorable, most deaths occur as a result of increasing lactic acidosis. Given the sporadic nature of the pathology, genetic counseling of couples and prenatal diagnostics do not show effectiveness as preventive measures.