Introduction
Purine nucleoside phosphorylase is a rare immunodeficiency disorder where the body loses the ability to fight against bacteria and viruses. It is inherited in an autosomal recessive (two copies of the abnormal gene) pattern. Individuals with this disease have a low number of T cells (a type of lymphocyte) responsible for identifying and attacking foreign substances that can cause infection. Few patients may also have a low number of B cells (a type of lymphocyte) responsible for producing proteins like antibodies. Individuals with both T and B cells are lacking develop a condition called severe combined immunodeficiency.
What Is Purine Nucleoside Phosphorylase Deficiency?
A shortage of immune cells in this disorder causes repeated and persistent infections. The infections develop during infancy or childhood. It can affect the sinuses or lungs. The infections are caused by opportunistic organisms which do not cause disease in healthy individuals. The disease may become life-threatening without treatment. Children who develop this disease do not survive past adulthood. The affected children tolerate the BCG (Bacille Calmette-Guerin) vaccine but develop fatal infections caused by the live viral vaccine or viruses like varicella (the virus causing skin blisters) or parainfluenza (which causes respiratory infections in young children).
What Are the Causes of Purine Nucleoside Phosphorylase Deficiency?
The disease results from PNP (purine nucleoside phosphorylase) gene mutations. The gene is responsible for producing purine nucleoside phosphorylase enzymes. The enzyme is found within the whole body but is most prominent in white blood cells like T and B. The enzyme nucleoside phosphorylase is a housekeeping enzyme that clears waste molecules formed by DNA (deoxyribonucleic acid) breakdown. In deficient conditions, the mutations reduce enzyme activity causing waste and deoxyguanosine triphosphate (dGTP) to build up to toxic levels. Neurological symptoms occur due to damage caused by dGTP accumulation in brain cells. Purine base accumulation intracellularly causes neuronal cell apoptosis (a mechanism where the cell programs its death).
What Are the Signs and Symptoms of Purine Nucleoside Phosphorylase?
The severity and number of symptoms can vary among people. Neurological involvement occurs before immune abnormalities.
-
T-cell deficiency is pronounced.
-
Failure to thrive.
-
Recurrent infections from viruses (varicella zoster), bacteria, fungi (Pneumocystis carinii), mycobacterial (a type of bacteria), or protozoal (single-celled parasites).
-
Infants with this disease tend to grow slower than average babies.
-
Most patients have neurological disorders, including:
-
Developmental delay.
-
Intellectual disability.
-
Ataxia (difficulty with balance or coordination).
-
Spasticity (muscle stiffness).
-
Motor system dysfunction, hyper or hypotonia (muscle tone), hyperactivity, tremors, and behavioral problems can occur.
-
-
The affected individuals have an increased risk of developing autoimmune diseases like autoimmune hemolytic anemia (red blood cells are damaged by immune response), idiopathic thrombocytopenic purpura (blood disorder with low platelet count), autoimmune neutropenia (reduced neutrophils in blood), thyroiditis (redness or swelling of thyroid), and lupus (an autoimmune disease of tissue or organ).
-
There is an increased incidence of lymphoma (cancer in the lymphatic system) development.
-
However, cerebrovascular accidents or sensorineural deafness (hearing loss caused by damage to the inner ear) occur less commonly.
How Is Purine Nucleoside Phosphorylase Deficiency Diagnosed?
The patients are examined for clinical symptoms of the disease. The laboratory investigation reveals leukopenia (low white blood count) and severe lymphopenia (low lymphocyte level), with lower levels of CD3 (cluster of differentiation 3, protein), CD4, and CD8 counts. The investigation also shows variable B cell function, immunoglobulin levels, and neutropenia (reduced neutrophil count). The characteristic diagnostic marker for the deficiency is hypouricemia (low serum uric acid level), complete or partial absence of PNP activity in red blood cell lysate (mixture formed by lysis of cell). There is an increase in urine or blood levels of inosine (a chemical found in ribonucleic acid) and guanosine (a chemical compound with neuroprotective properties). Genetic testing of the PNP gene is a confirmatory test. Newborn screening with liquid chromatography-tandem mass spectrometry (analytical test for separation and detection of compounds) helps with early detection.
What Is the Differential Diagnosis for Purine Nucleoside Phosphorylase Deficiency?
-
Aplastic Anemia- It is a disorder in which the body stops producing enough blood cells. The conditions cause fatigue (tiredness) and increase the risk of infection or uncontrolled bleeding. It is a severe condition that can develop at any age. The disease worsens with disease progression.
-
SCID (Severe Combined Immunodeficiency)- It is a rare genetic disorder that can cause life-threatening conditions in the immune system. It is a type of primary immune deficiency. It increases susceptibility to infections of the respiratory, ear, or sinus. The affected newborn can also develop oral thrush (fungal growth in the mouth), meningitis (redness or swelling in meninges), or pneumonia (an infection that causes redness or swelling of air sacs).
-
Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency- It is an inherited disorder that damages the immune system and causes SCID. Individuals with this disease lack immune protection against infections. The patients are susceptible to repeated infections that are life-threatening. The main symptoms include pneumonia, chronic diarrhea, and skin rashes.
-
Ataxia-Telangiectasia - It is a rare childhood disease that affects the brain and other parts of the body. Ataxia refers to uncoordinated movements like walking, and telangiectasia refers to enlarged blood vessels below the skin's surface. The patients may develop slurred speech, difficulty moving their eyes from side to side, and muscle cramps. The disease cannot be cured and requires symptomatic management. The affected individuals can survive up to early childhood.
-
Viral meningoencephalitis - It is an inflammatory disease of the meninges and brain. It causes stiff neck, fever, headache, and light sensitivity among affected individuals. Few patients develop serious complications such as confusion or seizures. The disease is considered a medical emergency. Herpes virus infection is a predominant factor in disease development.
What Is the Treatment for Purine Nucleoside Phosphorylase Deficiency?
Red blood cell transfusion that is rich in PNP provides temporary benefits. Hematopoietic stem cell transplantation is a recommended treatment for severe immune deficiency. The transplanted cells provide the PNP enzyme, improving purine homeostasis (maintaining the body's internal stability). Bone marrow transplantation can cure immunodeficiency but cannot reverse the neurological damage. Supportive care includes intravenous immunoglobulin therapy and treatment for pneumocystis carinii. Physical, occupational, and speech therapy reduces infection incidence and encourages optimal neurologic development.
There are ongoing studies on PNP inhibitors called immunities to be used as therapeutic agents. The inhibitors cause selective suppression of cellular immunity without altering humoral immunity. PNP inhibitors are currently used as a treatment for various autoimmune diseases. The alternate techniques that are being explored are injections of PNP enzyme replacement.
What Is the Prognosis for Purine Nucleoside Phosphorylase Deficiency?
Untreated patients have a poor prognosis for the disease. There is high mortality within the first decade of life. However, few patients live until the second or third decade of life. Patients after hematopoietic cell transplantation show improved immune function and prevent infection.
Conclusion
Purine nucleoside phosphorylase deficiency is an inherited immunodeficiency disorder. It is caused by PNP gene mutations resulting in a partial or complete reduction in enzyme activity. This causes several neurological anomalies, developmental delays, and intellectual disabilities. The disease is treated with bone marrow transplantation.
