Adenosine deaminase deficiency (ADA deficiency) is a

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...

that causes

immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...

. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

forms of

severe combined immunodeficiency Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in dif ...

(SCID) among non- inbred populations. ADA deficiency can present in

infancy An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

s associated with the disorder. It occurs in fewer than one in 100,000 live births worldwide.

Signs and symptoms

The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life. An association with polyarteritis nodosa has been reported.Liebowitz J, Hellmann DB1, Schnappauf O (2019) Thirty years of followup in 3 patients with familial polyarteritis nodosa due to adenosine deaminase 2 deficiency. J Rheumatol

Genetics

The enzyme adenosine deaminase is encoded by the ADA gene on

chromosome 20 Chromosome 20 is one of the 23 pairs of chromosomes in humans. Chromosome 20 spans around 66 million base pairs (the building material of DNA) and represents between 2 and 2.5 percent of the total DNA in cells. Chromosome 20 was fully sequenced ...

. ADA deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 20 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Age of onset and severity is related to some 29 known

s associated with the disorder.

Pathophysiology

ADA deficiency is due to a lack of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

adenosine deaminase Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) is an enzyme () involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. Its primary function i ...

. This deficiency results in an accumulation of deoxyadenosine, which, in turn, leads to: * a buildup of dATP in all cells, which inhibits

ribonucleotide reductase Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of t ...

and prevents

DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occur ...

, so cells are unable to divide. Since developing

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...

s and

B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

s 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. Because T cells undergo proliferation and development in the

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...

, affected individuals typically have a small, underdeveloped

. As a result, the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...

is severely compromised or completely lacking.

Diagnosis

The diagnosis is based on clinical features, with a concomitant decreased blood adenosine deaminase level supporting the diagnosis.

Treatment

Treatments include: *

bone marrow transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produ ...

* ADA enzyme in

PEG PEG or peg may refer to: Devices * Clothes peg, a fastener used to hang up clothes for drying * Tent peg, a spike driven into the ground for holding a tent to the ground * Tuning peg, used to hold a string in the pegbox of a stringed instru ...

vehicle

Gene therapy

In September 1990, the first gene therapy to combat this disease was performed by Dr.

William French Anderson William French Anderson (born December 31, 1936) is an American physician, geneticist and molecular biologist. He is known as the "father of gene therapy". He graduated from Harvard College in 1958, Trinity College, Cambridge University (England ...

on a four-year-old girl,

Ashanti DeSilva Ashanti may refer to: * Ashanti people, an ethnic group in West Africa ** Ashanti Empire, a pre-colonial West African state in what is now southern Ghana ** Ashanti dialect or Asante, a literary dialect of the Akan language of southern Ghana ** As ...

, at the

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government The federal government of the United States (U.S. federal government or U ...

, Bethesda, Maryland, U.S.A. In April 2016 the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee A committee or commission is a body of one or more persons subordin ...

of the European Medicines Agency endorsed and recommended for approval a stem cell

gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human D ...

called Strimvelis, for children with ADA-SCID for whom no matching bone marrow donor is available.House, Douglas W., (1 April 2016
European Ad Comm backs Glaxo's stem cell therapy Strimvelis for rare autoimmune disorder
Seeking Alpha, Retrieved 13 April 2016

History

ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the

University of Washington The University of Washington (UW, simply Washington, or informally U-Dub) is a public research university in Seattle, Washington. Founded in 1861, Washington is one of the oldest universities on the West Coast; it was established in Seat ...

.Motulsky A, Gartler S. "Biographical Memoirs: Eloise R. Giblett". ''National Academy of Sciences''. 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.