Adenine Phosphoribosyltransferase Deficiency

A number sign (#) is used with this entry because adenine phosphoribosyltransferase deficiency (APRTD) is caused by homozygous or compound heterozygous mutation in the gene encoding adenine phosphoribosyltransferase (APRT; 102600) on chromosome 16q24.

Description

APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic (summary by Sahota et al., 2001).

Two types of APRT deficiency have been described based on the level of residual enzyme activity in in vitro studies of erythrocytes. Type I deficiency is characterized by complete enzyme deficiency in intact cells and in cell lysates, whereas type II deficiency is characterized by complete enzyme deficiency in intact cells, but only a partial deficiency in cell lysates. Type II alleles show reduced affinity for phosphoribosyl pyrophosphate (PRPP) compared to wildtype. In both types, APRT activity is not functional in vivo. Type II deficiency is most common among Japanese. Heterozygotes of either type do not appear to have any clinical or biochemical abnormalities (summary by Sahota et al., 2001).

Clinical Features

Mutant forms of adenine phosphoribosyltransferase were described by Kelley et al. (1968) and by Henderson et al. (1969) who found the inheritance to be autosomal. The heat-stable enzyme allele has a frequency of about 15% and the heat-labile enzyme allele a frequency of about 85%. Kelley et al. (1968) found apparent heterozygosity in 4 persons in 3 generations of a family. However, the level of enzyme activity in heterozygotes ranged from 21 to 37%, not 50%.

Fox et al. (1973) described a family with partial deficiency of red cell APRT, consistent with a heterozygous state, although enzyme activity was less than 50%. The partial deficiency of erythrocyte APRT was not associated with any detectable abnormality in purine metabolism. The proband had a normal concentration of PRPP and ATP in erythrocytes, a normal availability of purine nucleotides, a normal rate of purine biosynthesis de novo, a normal excretion of uric acid, and a normal response to adenine administration. Although the proband had both hyperuricemia and reduced erythrocyte APRT activity, these 2 traits segregated independently in the family.

Delbarre et al. (1974) found deficiency of APRT in persons with gout but recognized that purine overproduction was not necessarily caused by the APRT deficiency.

Emmerson et al. (1975) described a family with autosomal inheritance of APRT deficiency. The proband was a 24-year-old woman who had suffered from recurrent gouty arthritis since the age of 11 years. She also demonstrated considerable, although asymptomatic, renal impairment with a creatinine clearance of one-third normal. Eleven other asymptomatic members of the family also demonstrated a similar reduction in APRT activity in erythrocyte lysates. The partially purified APRT enzyme in the proband showed no difference in Michaelis constants, heat stability, or electrophoresis.

Debray et al. (1976) observed a child with urolithiasis and complete deficiency of APRT. Both parents had partial deficiency.

Van Acker et al. (1977) described brothers with complete deficiency of APRT. They were detected because one of them had from birth excreted gravel consisting of stones of 2,8-dihydroxyadenine in urine. Neither showed hyperuricemia or gout. Treatment with allopurinol and a low purine diet stopped stone formation. The authors concluded that homozygotes can be detected by raised urinary adenine levels and absence of detectable red cell APRT.

Barratt et al. (1979) reported a child, born of consanguineous Arab parents, who had 2,8-dihydroxyadenine stones resulting from a complete lack of APRT.

Gault et al. (1981) described 2,8-dihydroxyadenine urolithiasis in a white woman who lived in Newfoundland and first developed symptoms of urolithiasis at the age of 42. The authors noted that the use of infrared or x-ray diffraction analysis of calculi positive for uric acid with standard wet chemical tests can make the diagnosis. Affected adults may first present with renal failure. Renal biopsy shows changes similar to those of uric acid nephropathy.

Kishi et al. (1984) found only 10 reported cases of complete deficiency of APRT, beginning with the case of Cartier et al. (1974). Kishi et al. (1984) reported 3 cases in 2 families. Although APRT deficiency occurred in mononuclear cells and polymorphonuclear leukocytes as well as in red cells, no abnormality of immunologic or phagocytic function was detected. The sole clinical manifestation was urinary calculi composed of 2,8-DHA.

Manyak et al. (1987) found DHA-urolithiasis in a 50-year-old white woman who was homozygous for APRT deficiency.

Glicklich et al. (1988) reported the second case of homozygous APRT deficiency from the United States. The disorder was recognized 23 years after the patient, a black woman from Bermuda, had her initial episode of renal colic, and after 2,8-dihydroxyadenine stones had recurred after renal transplant.

APRT Deficiency in Japanese

Kamatani et al. (1987) examined samples from 19 Japanese families with DHA-urolithiasis. In 15 (79%) of the 19 families, the patients had only partial APRT deficiency, which contrasted with complete deficiency reported in all non-Japanese patients. All Japanese patients with DHA-urolithiasis were homozygotes regardless of whether the deficiency was complete or partial. However, family studies revealed 4 asymptomatic homozygous family members. The segregation pattern was consistent with an autosomal recessive mode of inheritance. Kamatani et al. (1987) estimated that about 1% of the Japanese population are carriers.

Biochemical Features

Rappaport and DeMars (1973) identified clones of cells resistant to 2,6-diaminopurine (DAP) in skin fibroblast cultures derived from 13 of 21 normal humans. In some of the mutant cultures adenine phosphoribosyltransferase was normal. Two mutants from unrelated boys had little or no detectable APRT activity, and resistance to DAP resulted from reduced ability to convert DAP to its toxic ribonucleotide via APRT. The authors reasoned that mutant-yielding cultures were heterozygous to begin with, and suggested that DAP resistance has a heterozygote frequency as high as 0.2. This contrasted with the very low frequency of electrophoretic variants of APRT. There may be other mechanisms for DAP-resistance: for example, azaguanine resistance is determined by mutation at the X-linked HPRT locus.

Diagnosis

Maddocks and Al-Safi (1988) used identification of adenine in the urine by thin-layer chromatography to diagnose APRT deficiency.

Simmonds et al. (1992) pointed out that patients who are mistakenly diagnosed as having uric acid lithiasis will be treated successfully with allopurinol despite the incorrect diagnosis. This may be responsible for underdiagnosis of the disorder. Families carrying the mutant APRT gene need to be aware of it since acute renal failure may be the presenting symptom and this may be reversible, though some patients progress to chronic renal failure requiring dialysis and transplantation. Maddocks (1992) described a simple test for distinguishing uric acid calculi from 2,8-DHA calculi. Ward and Addison (1992) indicated that even visual examination can distinguish the two: 2,8-DHA stones are reddish-brown when wet and grayish when dry; they are also very soft and friable. Stones composed mainly of uric acid are very rare in children.

Laxdal and Jonasson (1988) found 2 children and 2 adults in 4 unrelated families with 2,8-dihydroxyadenine crystalluria. They suggested that the presence of round, brownish urine crystals, even without radiolucent kidney stones, should alert the physician to the diagnosis. Thirteen heterozygotes were identified by study of the families.

Laxdal (1992) pointed out that Iceland contributed 8 of the 62 APRT-deficient type I homozygotes. The 8 cases were from 8 different families. Although remote ancestral connections were identified, all 8 cases were detected by the finding of typical round reddish-brown crystals in the urine on light microscopy. The importance of alert laboratory technicians in making the diagnosis was emphasized.

Terai et al. (1995) detected homozygous APRT deficiency by the finding of 2,8-dihydroxyadenine-like spherical crystals in the urinary sediment. The molecular diagnosis was established using PCR-SSCP with the demonstration of the APRT*J allele (102600.0003).

Inheritance

APRT deficiency is usually inherited in an autosomal recessive pattern (Kamatani et al., 1987).

Ishidate et al. (1991) reported father and daughter with DHA-urolithiasis. The father and his wife were first cousins; thus, this was an example of pseudodominance.

Molecular Genetics

In a lymphoblastoid cell line from a Caucasian patient in Belgium with complete APRT deficiency, Hidaka et al. (1987) identified compound heterozygosity for 2 mutations in the APRT gene (102600.0001 and 102600.0002). Gathof et al. (1991) identified homozygosity for an APRT mutation (102600.0002) in identical twin brothers born to nonconsanguineous German parents with APRT deficiency.

In 5 patients from Iceland with complete APRT deficiency, Chen et al. (1990) identified a homozygous mutation in the APRT gene (D65V; 102600.0004).

In Japanese, partial deficiency of APRT leads to 2,8-dihydroxyadenine urolithiasis (type II), whereas all Caucasian patients with 2,8-DHA urolithiasis have been completely deficient (type I). Fujimori et al. (1985) found that partially purified enzyme from Japanese families has a reduced affinity for phosphoribosylpyrophosphate (PRPP), as well as increased resistance to heat and reduced sensitivity to the stabilizing effect of PRPP. They referred to this common Japanese mutant allele as APRT*J. In Japanese patients with APRT deficiency, Hidaka et al. (1988) identified the molecular basis for the APRT*J allele: an M136T (102600.0003) substitution in the putative PRPP-binding site. The mutant enzyme showed abnormal kinetics and activity that was less than 10.3% of normal. By a specific cleavage method using cyanogen bromide (BrCN) to identify the M136T allele, Kamatani et al. (1989) found that 79% of all Japanese patients with APRT deficiency and more than half of the world's patients have this particular mutation.

Kamatani et al. (1990) reported a 2-year-old Japanese boy with DHA urolithiasis due to compound heterozygosity for a null APRT allele (APRT*Q0) and the APRT*J allele.

In 2 sisters from Newfoundland with APRT deficiency, Sahota et al. (1994) identified a homozygous mutation in the APRT gene (L110P; 102600.0007). One of the sisters exhibited 2,8-dihydroxyadenine urolithiasis, whereas the other was disease-free.

Population Genetics

Kamatani et al. (1992) stated that about 70 Japanese families with homozygous APRT deficiency have been reported, whereas the number of reported non-Japanese families is about 36. The estimated gene frequency among Japanese is about 1.2%. Kamatani et al. (1992) found that most APRT-deficient Japanese patients carry 1 of 3 mutant alleles. Among 141 defective APRT alleles from 72 different Japanese families, 96 (68%) carried the M136T mutation (102600.0003). Thirty (21%) and 10 (7%) alleles had the TGG-to-TGA nonsense mutation at codon 98 (102600.0005) and duplication of a 4-bp sequence in exon 3 (102600.0006), respectively.