Purine nucleoside phosphorylase deficiency
Purine nucleoside phosphorylase (PNP) deficiency is a rare, inherited immunodeficiency disease that severely impacts the immune system by destroying T-cell lymphocytes. This autosomal recessive disorder occurs when individuals inherit mutated PNP genes from both parents, leading to a 25% chance of passing the genetic defect to offspring. Symptoms often include chronic infections that are resistant to treatment, as well as neurological issues like muscle spasticity and developmental delays. Diagnosis can be challenging due to overlapping symptoms with other conditions, but it typically involves blood tests and imaging.
While PNP deficiency is fatal, recent treatments, such as bone marrow transplants, can extend life expectancy and improve immune function. However, associated neurological and autoimmune issues may persist. Prophylactic measures, including good hygiene and low-dose antibiotics, are essential to manage infection risk. Prognosis remains poor, with an average life expectancy of around ten years, highlighting the importance of genetic counseling for affected families.
Purine nucleoside phosphorylase deficiency
ALSO KNOWN AS: PNP-deficiency
DEFINITION Purine nucleoside phosphorylase (PNP) deficiency is a rare and severe, inherited primary immunodeficiency disease. PNP-deficiency destroys T-cell lymphocytes in the immune system, severely weakening the immune system and decreasing life expectancy.
Risk Factors
Family history is the only known risk factor for this disease. It is an autosomal recessive disorder, and symptomatic individuals inherit a defective purine nucleoside phosphorylase gene (PNP) gene at chromosomal location 14q11.2 from each parent. Carrier parents have a 25 percent chance of passing this genetic defect to their offspring. Neurological symptoms often accompany this disease, but the route by which they develop is still undiscovered. Risk is evenly distributed between males and females.
Etiology and Genetics
This inherited genetic disease causes the absence or mutation of PNP. PNP deficiency is one of several severe combined immunodeficiency (SCID) diseases, which also include adenosine deaminase (ADA) deficiency and X-linked severe combined immunodeficiency (X-SCID). Individuals with X-SCID comprise the majority of SCID cases (Allenspach et al. 2013). PNP deficiency accounts for only about 4 percent of all combined immunodeficiency diseases (CID) and is differentiated by recurring symptoms of chronic and unusual infections resistant to drug therapies, neurological symptoms, lymphopenia, and increased incidences of lymphomas and autoimmune diseases at a young age.
Purines are components necessary in cellular energy systems and for the production of DNA and RNA. Purines are often recycled during catabolism using the purine salvage pathway. When the PNP is deficient along this pathway, elevated levels of deoxyguanosine triphosphate (dGTP) begins to accumulate in lymph tissues, whose primary function is immunity. Subsequently, the production of ribonucleotide reductase necessary for the synthesis of deoxynucleotides, which are used in the genetic code, and mitochondrial DNA repair is inhibited. As a result, T-cell lymphocyte and thymocyte sensitivity increases, leading to T-cell destruction and a decreased ability to fight infection. Unlike ADA deficiency, B-cell in the immune system are not affected.
Symptoms
PNP deficiency is often difficult to diagnosis because of recurring sinopulmonary and urinary tract infections that may also indicate other diseases, such as B-cell immunodeficiency, vitamin B12 deficiency, or interstitial cystitis. But PNP deficiency is distinguished from other diseases by neurological and autoimmune diseases coupled with unusual, recurring, and drug-resistant bacterial, fungal, mycobacterial, protozoal, and viral infections. Drug-resistant pneumonia and oral thrush before one year of age are usually the first indications of a PNP deficiency. Often, neurological symptoms precede infections because T-cell immunity declines gradually, thus delaying onset of infections. Ataxia, autoimmune hemolytic anemia, autoimmune neutropenia, behavioral issues, bronchiectasis, central nervous vasculitis, developmental and motor delays, diarrhea, failure to thrive, herpes infections, hypertonia, idiopathic thrombocytopenia, lupus, malabsorption, mental retardation, neurological symptoms, nodular lymphoid hyperplasia of the gastrointestinal tract, spasticity, recurrent sinopulmonary and urinary tract infections, thyroiditis, and tremors are all symptoms that have been associated with a PNP deficiency.
Screening and Diagnosis
When an immunodeficiency disease is suspected, family and patient history, physical exam, blood screening tests, and skin tests are used to make an accurate diagnosis. A physical exam usually finds absent or underdeveloped lymph glands and tissue. Blood screening tests include complete blood count and manual differential, quantitative serum immunoglobulin levels, response measurement, and complement response.
These blood tests usually show a marked decrease in circulating lymphocytes and serum antibodies. The US National Library of Medicine's Genetics Home Reference reported in 2014 that approximately two-thirds of PNP deficient individuals present with neurological symptoms, including muscle spasticity and intellectual disability. Autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia, thyroiditis, and lupus diseases are often found. Chest x-rays usually show an underdeveloped thymus gland. Average age of diagnosis is six and a half months.
Treatment and Therapy
PNP deficiency is fatal, but recent treatments can extend life span. Treatment first involves treating any infections with appropriate therapies. If failure to thrive is present, then appropriate nutrition interventions are also prescribed. In the case of anemia, red blood cell transfusions improve symptoms for a limited time. Successful bone marrow and stem cell transplantation from a compatible donor cure the underlying immunodeficiency and improve immune system function. However, accompanying neurological disorders or autoimmune diseases are not cured by bone marrow transplantation, and treatment of these disorders depends on the specific disease. Prophylactic precautions include avoiding situations where germs may spread and cause infections, use of good hygiene and nutrition practices, avoidance of live viral immunizations, and treatment with long-term, low-dose antibiotics to prevent and control infections. In vitro studies show gene and intracellular enzyme replacement therapies as well as infusing PNP fusion proteins may resolve PNP deficiency and offer promising treatments in the future. Transplants of stem cells from umbilical cord blood may also resolve neurological symptoms.
Prevention and Outcomes
Genetic counseling to assess risk is recommended when there is a family history of PNP deficiency. Prenatal diagnosis is possible in families with a previously affected child. However, prognosis is generally poor for PNP-deficiency, and life expectancy is usually not more than ten years of age at this time.
Bibliography
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