Adenine phosphoribosyltransferase deficiency

Adenine phosphoribosyltransferase deficiency is an autosomal recessive metabolic disorder associated with a mutation in the enzyme adenine phosphoribosyltransferase.

Signs and symptoms

Most patients with APRT deficiency have repeated episodes of kidney stones that are not detected by a conventional x-ray study. However, all stones are easily detected by other medical imaging methods such as ultrasound or computerized tomography (CT) scan. A minority of patients develop symptoms of kidney failure. Kidney stones are often associated with severe loin or abdominal pain. Symptoms associated with kidney failure are largely nonspecific such as increased fatigue and weakness, poor appetite, and weight loss. Children with the disease may have similar symptoms as adults. In young children, APRT deficiency can cause reddish-brown diaper spots.

Genetics

Adenine phosphoribosyltransferase deficiency has an autosomal recessive pattern of inheritance.

APRT deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Characteristics

The disorder results in accumulation of the insoluble purine 2,8-dihydroxyadenine. It can result in nephrolithiasis (kidney stones), acute renal failure and permanent kidney damage.

More than 300 individuals with this disease have been reported world-wide but it is not known how common this medical problem truly is. Patients with the disease deficiency lack the enzyme adenine phosphoribosyltransferase and therefore have difficulties breaking down dietary substances called purines, resulting in accumulation of a compound called 2,8-dihydroxyadenine (2,8-DHA) that is excreted by the kidneys. Up to 70% of affected patients, have red hair or relatives with this hair color.

Diagnosis

Adenine phosphoribosyltransferase (APRT) deficiency (also known as 2,8-dihydroxyadeninuria) should be suspected in individuals with the following clinical, radiographic, laboratory, and pathology findings.

Clinical manifestations

• Kidney stone disease and renal colic
• Chronic kidney disease (CKD)
• Crystal nephropathy (confirmed by kidney biopsy)
• Reddish-brown diaper stain in infants and young children
• Allograft dysfunction following kidney transplantation

Radiographic findings

• Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray.
• Ultrasound examination frequently demonstrates increased echogenicity of the kidneys.

Laboratory findings

• Urine microscopy. The round and brown DHA crystals can usually be detected by urine microscopy . Small and medium-sized DHA crystals display a central Maltese cross pattern when viewed by polarized light microscopy , while larger crystal aggregates do not as they are impermeable to light.

Kidney stone analysis. Analysis of DHA crystals and kidney stone material using infrared or ultraviolet spectrophotometry (at both acidic and alkaline pH) and/or x-ray crystallography differentiates DHA from uric acid and xanthine, which also form radiolucent stones. Although stones in persons with APRT deficiency are predominantly composed of DHA, they may contain trace amounts of other minerals.

• Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency .
• Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended.

The diagnosis of APRT deficiency is established in a proband with absent APRT enzyme activity in red cell lysates or biallelic pathogenic variants in APRT identified by molecular genetic testing.

Treatment

Treatment with the xanthine oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase) allopurinol or febuxostat can improve kidney function, even in individuals with advanced CKD. The prescribed dose of allopurinol and febuxostat should not routinely be reduced in affected individuals who have impaired kidney function. Ample fluid intake is advised. Surgical management of DHA nephrolithiasis is the same as for other types of kidney stones. ESRD is treated with dialysis and kidney transplantation. Even after kidney transplantation, treatment with an XOR is recommended.

Agents/circumstances to avoid: Azathioprine and mercaptopurine should not be given to individuals taking either allopurinol or febuxostat.

External links

Classification	ICD-10: E79 ICD-9-CM: 277.2 OMIM: 102600 DiseasesDB: 32632
External resources	Orphanet: 976

• Adenine phosphoribosyltransferase deficiency at NIH's Office of Rare Diseases