Purine nucleoside phosphorylase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Purine nucleoside phosphorylase deficiency is a disorder of the immune system called an immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses.

People with purine nucleoside phosphorylase deficiency have low numbers of immune system cells called T cells, which normally recognize and attack foreign invaders to prevent infection. Some affected individuals also have low numbers of other immune system cells called B cells, which normally help fight infections by producing immune proteins called antibodies (or immunoglobulins). These proteins target foreign invaders and mark them for destruction. The most severely affected individuals, who lack T cells and B cells, have a serious condition called severe combined immunodeficiency (SCID).

The shortage of immune system cells in people with purine nucleoside phosphorylase deficiency results in repeated and persistent infections typically beginning in infancy or early childhood. Infections most commonly affect the sinuses and lungs. These infections are often caused by "opportunistic" organisms that ordinarily do not cause illness in people with a normal immune system. The infections can be very serious or life-threatening, and without successful treatment to restore immune function, children with purine nucleoside phosphorylase deficiency usually do not survive past childhood.

Infants with purine nucleoside phosphorylase deficiency typically grow more slowly than healthy babies. About two-thirds of individuals with this condition also have neurological problems, which may include developmental delay, intellectual disability, difficulty with balance and coordination (ataxia), and muscle stiffness (spasticity). People with purine nucleoside phosphorylase deficiency are also at increased risk of developing autoimmune disorders, which occur when the immune system malfunctions and attacks the body's tissues and organs.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Purine nucleoside phosphorylase deficiency is caused by mutations in the PNP gene. The PNP gene provides instructions for making an enzyme called purine nucleoside phosphorylase. This enzyme is found throughout the body but is most active in specialized white blood cells called lymphocytes, which include T cells and B cells. Lymphocytes are produced in specialized lymphoid tissues, including the thymus and lymph nodes, and then released into the blood. The thymus is a gland located behind the breastbone; lymph nodes are found throughout the body. Lymphocytes in the blood and in lymphoid tissues are a major component of the immune system.

Purine nucleoside phosphorylase is known as a housekeeping enzyme because it clears away waste molecules that are generated when DNA is broken down. Mutations in the PNP gene reduce or eliminate the activity of purine nucleoside phosphorylase. The resulting excess of waste molecules and further reactions involving them lead to the buildup of a substance called deoxyguanosine triphosphate (dGTP) to levels that can be toxic to cells. Immature T cells in the thymus are particularly vulnerable to a toxic buildup of dGTP, which damages them and triggers their self-destruction (apoptosis). B cells and T cells in other lymphoid tissues can also be damaged. The shortage of T cells and sometimes B cells results in the immune problems characteristic of purine nucleoside phosphorylase deficiency. Damage to brain cells caused by buildup of dGTP is thought to underlie the neurological problems that occur in some people with purine nucleoside phosphorylase deficiency.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Purine nucleoside phosphorylase deficiency is rare; only about 70 affected individuals have been described in the medical literature. This disorder accounts for approximately 4 percent of all SCID cases.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal T cell morphology · Very frequent (99-80%)

Abnormal increase or decrease of total or subset T cell count. T cells are commonly characterized as CD3+ lymphocytes, or their subpopulations, in the blood, compared to a reference range for a given sex and age-group, measured ex vivo. These may include both TCR alpha/beta and gamma/delta T cells.

Decreased urinary urate · Very frequent (99-80%)

Decreased concentration of urate in the urine.

Abnormality of the nervous system · Frequent (79-30%)

An abnormality of the nervous system.

Autoimmune hemolytic anemia · Frequent (79-30%)

An autoimmune form of hemolytic anemia.

Autoimmunity · Frequent (79-30%)

The occurrence of an immune reaction against the organism's own cells or tissues.

Humoral immunodeficiency · Frequent (79-30%)

A general term referring to a defect in immunity resulting from impaired antibody production.

Hypouricemia · Frequent (79-30%)

The concentration of uric acid in the blood circulation is below the lower limit of normal.

Recurrent infections · Frequent (79-30%)

Increased susceptibility to infections as manifested by repeated bouts of infection.

Other findings in the same source

From: Orphanet

Additional reported features include Recurrent respiratory infections (Frequent (79-30%)); Severe combined immunodeficiency (Frequent (79-30%)); Unusual gastrointestinal infection (Frequent (79-30%)); Abnormality of central motor function (Occasional (29-5%)); Ataxia (Occasional (29-5%)); Atypical behavior (Occasional (29-5%)); Cerebral palsy (Occasional (29-5%)); Global developmental delay (Occasional (29-5%)); Hyperactivity (Occasional (29-5%)); Hypertonia (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Purine nucleoside phosphorylase deficiency is Allergy and Immunology, with a allergist / clinical immunologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the history suggest an allergy, an immune problem or another explanation?
• How would any proposed allergy or immune test change care?
• Is an individual emergency plan needed, and who should understand it?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.