| Purine nucleoside phosphorylase deficiency | |
|---|---|
| Other names | PNP-deficiency |
 | |
| Purine nucleoside phosphorylase deficiency has an autosomal recessive pattern of inheritance. | |
| Treatment | Allegeneic hemotopoietic stem cell transplantation (HSCT) |
Purine nucleoside phosphorylase deficiency is a rare autosomal recessive [1] metabolic disorder which results in immunodeficiency.
In addition to the symptoms associated with immunodeficiency, such as depletion of T-cells, decline of lymphocyte activity, and an abrupt proliferation of both benign and opportunistic infections—PNP-deficiency is often characterized by the development of autoimmune disorders. lupus erythematosus, autoimmune hemolytic anemia, and idiopathic thrombocytopenic purpura have been reported with PNP-deficiency. [2] Neurological symptoms, such as developmental decline, hypotonia, and mental retardation have also been reported.[ citation needed ]
The disorder is caused by a mutation of the purine nucleoside phosphorylase (PNP) gene, located at chromosome 14q13.1. [3] [4] This mutation was first identified by Eloise Giblett, a professor at the University of Washington, in 1975. [5] PNP is a key enzyme in the purine catabolic [6] pathway, and is required for purine degradation. Specifically, it catalyzes the conversion of inosine to hypoxanthine and guanosine to guanine (both guanine and hypoxanthine will be made into xanthine which will then become uric acid). A deficiency of it leads to buildup of elevated deoxy-GTP (dGTP) levels resulting in T-cell toxicity and deficiency. [4] [7] In contrast to adenosine deaminase deficiency (another deficiency of purine metabolism), there is minimal disruption to B cells. [8]
PNP deficiency is inherited in an autosomal recessive manner. [1] This means the defective gene responsible for the disorder is located on an autosome (chromosome 14 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.[ citation needed ]
Diagnosis is based on the clinical examination and on laboratory findings showing leukopenia, severe lymphopenia with low CD3, CD4, and CD8 counts and variable B cell function and immunoglobulin levels. Neutropenia has also been reported. Hallmark diagnostic markers of PNP deficiency include hypouricemia, complete or near complete absence of PNP activity in red blood cell lysate and increased urine or blood levels of inosine, guanosine and their deoxy forms. Diagnosis is confirmed by genetic screening of PNP.[ citation needed ]
Differential diagnosis includes aplastic anemias, SCID, severe combined immunodeficiency due to adenosine deaminase deficiency, ataxia-telangiectasia, and viral meningoencephalitis.[ citation needed ]
Measurement of T cell receptor excision circles during newborn screening for SCID can detect some patients with PNP deficiency, although removal of metabolites by maternal PNP may delay the deleterious effects on PNP-deficient lymphocytes. Few newborn screening programs also measure purine metabolites in dried[ citation needed ]
Supportive treatment, including intravenous immunoglobulin therapy, prophylaxis for Pneumocystis carinii, and physical, occupational, and speech therapy, reduces the risk of infection and may encourage optimal neurologic development for patients.[ citation needed ]
PNP deficiency is extremely rare. Only 33 patients with the disorder in the United States have been documented. [2] In the United Kingdom only two children have been diagnosed with this disorder in 1994 and 2008. [9]
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 are synthesized from intermediates in their degradative pathway.
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Adenosine deaminase 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.
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Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA.
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Adenine phosphoribosyltransferase deficiency is an autosomal recessive metabolic disorder associated with a mutation in the enzyme adenine phosphoribosyltransferase.
Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.
Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction
Nezelof syndrome is an autosomal recessive congenital immunodeficiency condition due to underdevelopment of the thymus. The defect is a type of purine nucleoside phosphorylase deficiency with inactive phosphorylase, this results in an accumulation of deoxy-GTP which inhibits ribonucleotide reductase. Ribonucleotide reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides, thus, DNA replication is inhibited.
Nucleic acid metabolism is the process by which nucleic acids are synthesized and degraded. Nucleic acids are the polymers of nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Destruction of nucleic acid is a catabolic reaction. Additionally, parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.
Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and POLIP syndrome. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene.
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Galactose epimerase deficiency, also known as GALE deficiency, Galactosemia III and UDP-galactose-4-epimerase deficiency, is a rare, autosomal recessive form of galactosemia associated with a deficiency of the enzyme galactose epimerase.
Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.
Eloise "Elo" R. Giblett was a pioneering genetic scientist and hematologist who discovered the first recognized immunodeficiency disease, adenosine deaminase deficiency. Giblett was a Professor of Medicine at the University of Washington in Seattle and Executive Director of the Puget Sound Blood Center in Seattle. The author of over 200 research papers, she also wrote an esteemed textbook on genetic markers, Genetic Markers in Human Blood, published in 1969. She was elected to the National Academy of Sciences in 1980.
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