Дефицит аденозиндеаминазы: генетика, симптомы и диагностика.

a metabolic disorder caused by ADA gene mutations

Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–20% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) after excluding disorders related to inbreeding. ADA deficiency can present in infancy, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known genotypes associated with the disorder. It occurs in fewer than one in 100,000 live births worldwide.

The main symptoms of ADA deficiency include pneumonia, chronic diarrhea, widespread skin rashes, jaundice (from hepatic infections), and candidiasis of the mouth and esophagus. Affected children also grow much more slowly than healthy children, commonly referred to as "failure to thrive," which may lead to other developmental delays. These symptoms are not due to the enzyme deficiency itself, but rather to the effects of frequent severe infections from viruses, bacteria, and certain fungi. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life. The large majority of cases of ADA deficiency are identified and diagnosed in children. However, a small minority have a less severe form of the disease and remain undiagnosed until childhood, adolescence, or adulthood.

The enzyme adenosine deaminase is encoded by the ADA gene on chromosome 20. Age of onset and severity is related to some 29 known genotypes associated with the disorder. which, in turn, leads to:
A buildup of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis, so cells are unable to divide. Since developing T cells and B cells are some of the most mitotically active cells, they are highly susceptible to this condition. An increase in S adenosylhomocysteine since the enzyme adenosine deaminase is important in the purine salvage pathway; both substances are toxic to immature lymphocytes, which thus fail to mature. Complete or near complete absence of T cells, B cells, and NK cells. As a result, the immune system is severely compromised or completely lacking.

Diagnosis in developed nations is usually done through standardized newborn screening tests for a range of congenital diseases, including ADA deficiency. Most newborns with SCID, including those with ADA deficiency as an underlying cause, can be identified before the onset of major infections due to their decreased levels of T cell receptor excision circles (TRECs). TRECs are a normal product of T cell development, and a deficit of them indicates a problem with lymphocyte maturation. In addition to antibiotics, intravenous immunoglobulin (IVIG) therapy is also provided when available. This treatment provides a layer of humoral immunity from healthy plasma donors.

Long term definitive treatment of ADA deficiency is typically achieved by transplantation of hematopoietic stem cells from a matched family member donor, preferably a sibling. Before transplantation, testing must be done to ensure that human leukocyte antigen (HLA) properties of the donor and the transplant recipient align, to avoid transplant rejection. In April 2016 the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed and recommended for approval a stem cell gene therapy called Strimvelis, for children with ADA SCID for whom no matching bone marrow donor is available.

ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the University of Washington. The ADA gene was used as a marker for bone marrow transplants. A lack of ADA activity was discovered by Giblett in an immunocompromised transplant candidate. After discovering a second case of ADA deficiency in an immunocompromised patient, ADA deficiency was recognized as the first immunodeficiency disorder.