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 t ...

that causes immunodeficiency. 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 autosom ...

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 t ...

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 diffe ...

(SCID) among non-

inbred Inbreeding is the production of offspring from the mating or breeding of individuals or organisms that are closely related genetically. By analogy, the term is used in human reproduction, but more commonly refers to the genetic disorders and o ...

populations. ADA deficiency can present in infancy, 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 i ...

. 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 Carry or carrying may refer to: People *Carry (name) Finance * Carried interest (or carry), the share of profits in an investment fund paid to the fund manager * Carry (investment), a financial term: the carry of an asset is the gain or cost of h ...

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 substrates, and the enzyme converts the substrates into different molecules known as products. A ...

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 ...

. This deficiency results in an accumulation of

deoxyadenosine Deoxyadenosine (symbol dA or dAdo) is a deoxyribonucleoside. It is a derivative of the nucleoside adenosine, differing from the latter by the replacement of a hydroxyl group (-OH) by hydrogen (-H) at the 2′ position of its ribose sugar moiety. ...

, which, in turn, leads to: * a buildup of

dATP Deoxyadenosine triphosphate (dATP) is a nucleotide used in cells for DNA synthesis (or replication), as a substrate of DNA polymerase. It is classified as a purine nucleoside triphosphate, with its chemical structure consisting of a deoxyribose s ...

in all cells, which inhibits ribonucleotide reductase 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 occurs ...

, 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 r ...

s 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 A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides (purine and py ...

; 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 cancer cells and objects such as wood splinte ...

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 produce ...

* ADA enzyme in PEG vehicle

Gene therapy

In September 1990, the first gene therapy to combat this disease was performed by Dr. William French Anderson on a four-year-old girl, Ashanti DeSilva, 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 responsible for biomedical and public health research. It was founded in the late ...

, 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 responsible for elaborating the agency's opinions on all issues regardin ...

of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

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 DN ...

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 Eloise "Elo" R. Giblett (January 17, 1921 – September 16, 2009) was a pioneering genetic scientist and hematologist who discovered the first recognized immunodeficiency disease, adenosine deaminase deficiency. Giblett was a Professor of Medici ...

, 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 Seattle a ...

.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.