APRT deficiency is a rare disease that causes kidney stones. The stones are unusual as they are made up of a substance called 2,8-dihydroxyadenine (DHA). This is unlike usual kidney stones which almost always contain calcium in one form or another. The lack of calcium is the reason why DHA stones do not show up on x-rays, although they can be seen on ultrasound and computed tomography (CT) scans.

In patients with APRT deficiency, DHA excretion increases very early in life. The first sign may be the presence of a reddish-brown material in a baby’s nappy. Otherwise the first symptoms relate to the kidney stones themselves. The first kidney stone can occur at any age and the symptoms include severe pain in the back, the side of the abdomen or the groin. There may also be episodes of pain and blood on passing urine. Patients with stones may also get urinary infections.

Some stones are very small and plug up the microscopic tubules of the kidney, causing local kidney damage. Obstruction or infection of the kidneys can lead to permanent damage and kidney failure can occur. A few patients will get kidney failure without having obvious stones picked up on a scan. Patients with poor kidney function may experience extreme tiredness, weight loss, poor appetite and increased thirst.

A crucial first step is to make the correct diagnosis as early as possible. The condition is very rare, and because kidney stones are quite common in the population, APRT deficiency may not be properly considered as a possible diagnosis. However the young age of patients is a clue.

The quickest way to make the diagnosis is to recover a stone and bring it to a kidney doctor who will have it analysed. Another way is to look for the distinctive DHA crystals in a urine sample (see Figure One below). If possible, all kidney stone formers should have the chemical composition of their stones analysed at least once.

Figure One: Crystals of 2,8-dihydroxyadenine (DHA) in a urine sample under a light microscope in normal light and in polarised light.

For patients with unexplained kidney failure an ultrasound examination, or a computed tomography (CT) scan of the kidneys, may identify kidney stones that are not detected on a regular x-ray.

The diagnosis can be confirmed with a blood test for APRT enzyme activity in red blood cells and by genetic testing.

Allopurinol is an effective treatment that blocks the production of DHA. It prevents new kidney stones being formed and protects against kidney failure. Some patients cannot tolerate allopurinol due to its side effects. These patients may be treated successfully with a medication called febuxostat. See Clinicians page for details.

Kidney stones may be spontaneously passed in the urine. Those that are not will need to be removed by a urologist, especially if they cause pain or blockages. There are various ways that stones can be removed. Lithotripsy uses sound waves to break the stones into smaller pieces that can then be passed in the urine. Endoscopy involves passing a flexible fibre optic ‘telescope’ up the urinary system to see the stone directly. Special tools built into the endoscope are used to capture or break up the stone. Open surgery for removal of stones is rarely required.

Patients whose disease has not been treated in time may progress to kidney failure. If so they will eventually need renal replacement therapy (RRT) in the form of dialysis or transplantation. There is a chance that APRT deficiency will re-develop in a transplanted kidney. This is because the underlying over production of DHA remains, so new deposits could begin again in the new kidney. It is therefore important that the diagnosis is made and that transplant patients are given the preventative treatments outlined above (allopurinol or febuxostat) to prevent this complication.

Patient 1

It was in April 2011 that my son was diagnosed with APRT Deficiency at 19 months of age. He had always been a healthy and active little boy with the exception of repeated ear infections.

One day he developed a fever and I noticed small red spots in his nappy, similar to the ones that had appeared when he was an infant. At the time I was advised not to worry as they were simply crystals that would disappear over time. The fever went down and he returned to daycare the morning after. It was later that same day that I received a call from the daycare provider, who was alarmed about the spots. I assured her that they were harmless, but was urged by a co-worker to seek medical attention. The physician at my local clinic wanted him to be taken to the Children‘s Medical Center for further testing which I did, and a urine sample was obtained.

A few days had passed when we were contacted by the hospital to inform us that they had found crystals in my son‘s urine. It was noted that they were caused by a rare condition affecting the kidney and we were invited to a meeting with a pediatrician the following morning. This news came as somewhat of a shock and as I had misunderstood the name of the disease, internet research proved unsuccessful and we had no idea what to expect.

The pediatrician quickly put our minds at ease and explained the nature of APRT Deficiency. We learned that the crystals had been observed during urine microscopic analysis which led to the diagnosis. This was a coincidence however, as children with APRT Deficiency usually present with reddish brown diaper spots.

Our son underwent further testing and enrolled in a group study of the disease. He was treated with Allopurinol which has agreed well with him. We found it a strange and sudden reality for our son to be put on medication for the rest of his life but thankfully the therapy is simple by nature and will stop kidney stone formation and prevents future development of kidney failure.

It has now been a year since his diagnosis and we take him in for check-ups regularly, though the therapy has proven very successful. His urine has to be checked for crystals to assess whether the dosages should be increased. We find it very comforting that our doctors are in the forefront of international research of the disease and its nature. Meanwhile, our little boy leads a very normal life, happy and energetic as ever!

Patient 2

At the age of 21, after numerous urinary tract infections, I ended up in A&E and was diagnosed with kidney stones. The doctors were unable to determine what type of stone they were and I found myself back in A&E a few months later, blocked with stones. I was told that only one of my kidneys was functional as the other one was shriveled up. Doctors suggested everything from lithotripsy to medication to removal of the stones. I was finally introduced to a urologist at Massachusetts General Hospital, who gave me an ileal ureter as other measures did not work and surgery was not viable at that point. I finally passed a fragment of a stone which was identified as a 2.8 dihydroxyadenine stone. My urologist explained to me that I had APRT Deficiency which was caused by a genetic anomaly in my parents, with a 25% chance of their offspring getting this type of kidney stone. I was put on Allopurinol but had a strong allergic reaction with gradual loss of hair and sight over a couple of months. Fortunately I regained my sight but my hair was damaged.

We tried Allopurinol again some years later with a different dosage but my reactions were the same. For years I waited for Febuxostat to come to America to see if that would do what Allopurinol could not. When it came out I went on it immediately but crystals formed over my eyes causing me to lose my vision again. However, the crystals cleared and I regained my sight eventually. Currently there are no viable drugs for me and I have approximately 11 stones in my functioning kidney and 5 in my non-functioning kidney.

The stones continue to grow and congregate but tend to stay in the lower pole of my kidneys. I have not passed any stones since the 90s and removal is not an option until the kidney shows signs of distress (urea and creatinine are presently good). Transplant is obviously not an option unless my kidneys fail. I take a preventative antibiotic for infections as I had nine infections last year. I have been doing great since going back on the preventative; infection free!

Patient 3

Despite having APRT Deficiency I did not experience any symptoms until at the age of 41 when I developed a kidney stone. Two years later my right kidney was removed as it had stopped working. In the following years I had repeated urinary tract infections which led to the other kidney also stopping working. At that point I had to be treated with dialysis. I was not diagnosed however until 1998 when doctors were looking for the condition in my siblings as one of my brothers had been diagnosed with APRT Deficiency. Several years later I received a very successful deceased donor kidney transplant in Copenhagen. Since then I have been treated with Allopurinol; my course has been uneventful and my kidney is working well.

Pending.

APRT (adenine phosphoribosyltransferase) is an enzyme, a type of protein that converts one substance into another in a single step. For many of the body’s processes several different steps are needed. APRT breaks down a chemical called adenine ready for disposal. This can be seen in Figure Two below:

Figure Two: The role of APRT in the break-down of adenine

If there is a deficiency of APRT, adenine cannot be converted to the next step in the pathway. This causes DHA to accumulate. It is filtered from the blood stream by the kidneys and enters the urinary system. Because DHA cannot easily be dissolved it forms minute crystals, which can build up to become larger kidney stones. Crystals and stones cause local damage wherever they form in the kidneys. Blockage to the flow of urine or any urinary infection makes this kidney damage worse.

Genetics

At present approximately 50 genetic mutations are known to affect the APRT gene and lead to APRT deficiency.

Everyone has 2 copies of the APRT gene, one from each parent:

• Healthy people have two normal copies.
• Carriers have one copy that works normally and one that doesn’t. Carriers are usually perfectly healthy because the normal copy can still do its job but they can still pass the condition on to their child.
• In patients with the condition, neither copy works normally. The gene can’t do its job properly and so the not enough APRT is produced.
• When both parents are carriers, a child could be healthy with two normal genes, or a healthy carrier like their parents with one healthy and one faulty gene, or affected with both genes being faulty. This pattern is called autosomal recessive inheritance (Figure Three).

a = gene with mutation A = gene without mutation

Figure Three: Autosomal recessive inheritance in APRT deficiency

The APRT Deficiency Rare Disease Group (RDG) is working with international partners with the aim of finding new and improved treatments, and to empower patients. A first step is to compare the symptoms and genetic markers of APRT deficiency. To do this the RDG is registering patients with these conditions in the National Renal Rare Disease Registry (RaDaR).The registry will be used to find suitable participants for future research trials into the effectiveness of new treatments.

If you are interested in finding out more about the registry RaDaR or the activity of the RDG please visit the APRT deficiency RDG page.