Purine nucleoside phosphorylase (PNP) deficiency

Purine nucleoside phosphorylase, or PNP, is an enzyme that helps the body break down and recycle purines, which are building blocks of DNA. When PNP is missing, some of these building blocks pile up. They are especially toxic to T cells and to some brain cells.

PNP deficiency causes a combined immunodeficiency. T-cell numbers fall, often to very low levels, and B cells and natural killer cells can also be affected. By one estimate, it accounts for about 4% of cases of severe combined immunodeficiency (SCID).

Doctors diagnose it by measuring PNP enzyme activity in the blood and testing the PNP gene. Newborn screening for SCID, which looks for low T-cell numbers, finds only some babies with PNP deficiency. A more sensitive newborn test that measures purine waste in the blood spot exists but is not used everywhere.

It is caused by changes in both copies of the PNP gene, one inherited from each parent. Parents who each carry one changed copy usually have no symptoms. Each of their children has a one-in-four chance of being affected.

It is very rare. About 100 people with PNP deficiency have been described in the medical literature, mostly in single case reports. How it affects the nervous system can vary a lot, even within one family.

Symptoms usually start between infancy and preschool age, often later than in classic SCID. Children get repeated or severe infections, most often of the lungs and sinuses, and chickenpox and other viruses can be dangerous. A few first come to attention because of autoimmune problems, where the immune system attacks the body’s own red blood cells or platelets. Less often, blood cancers develop.

About two-thirds of people have problems with the nervous system. These can include developmental delay, trouble with balance and coordination (ataxia), stiff muscles (spasticity) and intellectual disability. In a large European study, most children already had some of these signs by the time of transplant.

Timing matters. The toxic waste keeps building up until the enzyme is replaced. In the same study, children transplanted within two years of their first symptoms had better survival, and children whose nerve symptoms began before 11 months of age did less well.

Families often face infections and developmental worries at the same time. Care may involve immunologists, neurologists, physical and occupational therapists and developmental specialists. Therapy for movement and learning may continue for years, including after transplant.

A transplant means conditioning treatment, a long hospital stay and months of follow-up for infection, graft failure and graft-versus-host disease. In the European study, a few children whose first graft did not last needed a second transplant. The small group of babies diagnosed at birth because of a family history, and transplanted early, all survived.

Parents may want genetic counseling before another pregnancy. When a family’s gene change is known, a new baby can be tested soon after birth.

The transplant gives the child donor stem cells that make working PNP enzyme and healthy T cells. Matched family donors, matched unrelated donors, unrelated cord blood and partly matched (haploidentical) family donors have all been used. In the European study, 25 of 46 first transplants came from unrelated adult donors or unrelated cord blood.

Relatives are tested before they donate. In that study, healthy family members who carried one changed copy of the gene were allowed to donate. When no family donor matches, a registry search is a real and common route.

Because the toxins can keep harming the nervous system until the enzyme is replaced, teams try to move to transplant quickly. That can make an unrelated donor search urgent. Joining a registry cannot promise a match for any one child, but more volunteers mean more children may find one in time.