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 ...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)
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 ...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)
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 ...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
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 ...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
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. ...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
The diagnosis of APRT deficiency (also known as 2,8-dihydroxyadeninuria) [Edvardsson et al 2001, Bollee et al 2010, Nasr et al 2010] should be considered in:...
DiagnosisThe diagnosis of APRT deficiency (also known as 2,8-dihydroxyadeninuria) [Edvardsson et al 2001, Bollee et al 2010, Nasr et al 2010] should be considered in:Individuals with:Renal colic;Radiolucent kidney stones (based on imaging techniques capable of detecting radiolucent stones, e.g., ultrasound or computed tomography [CT]; they are not seen on a plain abdominal x-ray);Chronic kidney disease (CKD) of unknown cause;Crystalline nephropathy.Infants with a history of reddish-brown diaper stain, a frequent manifestation of DHA crystalluria in infants. The diagnosis, which is frequently made by the detection of the characteristic round, brown DHA crystals by urine microscopy, is confirmed by detection of absent APRT enzyme activity in red cell lysates or identification of functionally significant biallelic APRT mutations.TestingUrinalysisUrine microscopy. The pathognomonic round and brown DHA crystals can usually be detected by urine microscopy in individuals who are not oliguric (Figure 1A). Small and medium sized DHA crystals display a central Maltese cross pattern when viewed by polarized light microscopy (Figure 1B). Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced clearance of the DHA crystals by the kidney [Edvardsson et al 2001, Bollee et al 2010]. (2) High urine pH in individuals with radiolucent stones provides an additional clue to the diagnosis of APRT deficiency because uric acid stones develop in acidic urine (see Differential Diagnosis).Testing for DHA. DHA can be identified in urine samples by high-performance liquid chromatography (HPLC) with UV detection or HPLC coupled with mass spectrometry. FigureFigure 1. Urinary 2,8-dihydroxyadenine (DHA) crystals in an individual with adenine phosphoribosyltransferase deficiency. These crystals have a characteristic appearance and polarization pattern. A. Regular light microscopy shows the (more...)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 easily 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 uric acid.Note: Stone analysis with standard chemical and thermogravimetric methods does not distinguish DHA from other purines, such as uric acid, and is no longer recommended.APRT enzyme activity. APRT activity measured in red cell lysates ranges from 16 to 32 nmol/hr per mg hemoglobin in healthy controls.APRT enzyme activity measured in red cell lysates (or other cell extracts) is absent in almost all individuals with APRT deficiency; however, exceptions occur. For example, two enzyme isoforms resulting from the following APRT mutations have substantial activity in red cell lysates:p.Val150Phe [Deng et al 2001] (present in some individuals of northern European heritage) p.Met136Thr [Sahota et al 2001] (present in >70% of Japanese who are homozygous for this mutation)Thus, in individuals with these mutations, in vivo assays, such as uptake of adenine by intact erythrocytes or leukocytes, are required to verify APRT deficiency. Note: (1) If enzyme activity is within normal limits or in the heterozygote range in an individual who has recently received a red cell transfusion, enzyme activity measurement should be repeated after three months. (2) Heterozygotes for an APRT mutation cannot be reliably identified by enzyme assay in cell extracts as the enzyme activity range in these individuals overlaps with that of controls.Renal histopathologic examination. Renal histopathologic findings in persons with APRT deficiency and CKD or acute allograft dysfunction are characterized by diffuse DHA crystalline deposits and tubulointerstitial abnormalities, even in the absence of a history of kidney stones (see Figure 2) [Edvardsson et al 2001].FigureFigure 2. Kidney biopsy findings from a patient with adenine phosphoribosyltransferase deficiency and kidney failure due to 2,8- dihydroxyadenine crystalline nephropathy A. 2,8-Dihydroxyadenine (DHA) crystals are seen within tubular lumens (more...)Note: It is important not to confuse the histopathologic manifestations of crystalline nephropathy caused by APRT deficiency with those of other crystalline nephropathies, particularly those caused by oxalate and uric acid deposits [Nasr et al 2010].Molecular Genetic TestingGene. APRT is the only gene in which mutations are known to cause APRT deficiency. The diagnosis is confirmed in individuals with functionally significant biallelic mutations.Table 1. Summary of Molecular Genetic Testing Used in Adenine Phosphoribosyltransferase DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAPRTSequence analysisSequence variants 2, 3>95% 4ClinicalDeletion / duplication analysis 5Exonic and whole-gene deletionsSee footnote 6Research only 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. More than 40 mutations have been identified in the coding region of APRT in over 300 affected individuals from more than 25 countries, including at least 200 individuals from Japan (see Molecular Genetics).4. Mutations in APRT have not been identified in at least five individuals with APRT deficiency and it remains to be determined whether these mutations occur outside of the APRT coding region or are due to epigenetic changes.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Four described deletions include: a large homozygous contiguous gene deletion (~100 kb) [Wang et al 1999] (see Molecular Genetics); a 254-kb deletion in two families (one from Austria and the other from Italy) [Menardi et al 1997, Di Pietro et al 2007], and an uncharacterized large deletion in two individuals from Japan [Kamatani et al 1992].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Note that enzyme activity measurements in cell extracts alone may not be sufficient to determine the functional significance of novel mutations. (See Testing, APRT enzyme activity.)Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandAll individuals suspected of APRT deficiency should first be screened for DHA crystalluria (Figure 1). Although the typical urinary DHA crystals are diagnostic of APRT deficiency, APRT enzyme activity measurements or APRT molecular genetic testing are recommended to confirm the diagnosis. When the typical urinary DHA crystals are not seen or recognized (possibly due to advanced renal disease) or when findings consistent with crystalline nephropathy are present on kidney biopsy, measurement of APRT enzyme activity or APRT molecular genetic testing are recommended to confirm the diagnosis. When available, kidney stones should be analyzed. UV spectroscopy, infrared spectroscopy, or x-ray crystallography can be employed for detection of DHA in kidney stones. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview have been associated with mutations in APRT.
Kidney stones are by far the most common clinical manifestation of APRT deficiency in both children and adults [Edvardsson et al 2001, Harambat et al 2012]; chronic kidney disease (CKD) is the second most common manifestation in adults [Edvardsson et al 2001, Harambat et al 2012]. Acute kidney injury due to bilateral DHA calculi and urinary tract obstruction is a well-recognized presentation in children [Debray et al 1976, Greenwood et al 1982, Chiba et al 1988, Edvardsson et al 2001]....
Natural HistoryKidney stones are by far the most common clinical manifestation of APRT deficiency in both children and adults [Edvardsson et al 2001, Harambat et al 2012]; chronic kidney disease (CKD) is the second most common manifestation in adults [Edvardsson et al 2001, Harambat et al 2012]. Acute kidney injury due to bilateral DHA calculi and urinary tract obstruction is a well-recognized presentation in children [Debray et al 1976, Greenwood et al 1982, Chiba et al 1988, Edvardsson et al 2001].APRT deficiency may present at any age; there is no typical age of onset. In a recently reported French series [Bollee et al 2010], only 37% of individuals with APRT deficiency were diagnosed before age 16 years. Fifteen of 32 (47%) Icelandic individuals with data in the APRT Deficiency Registry of the Rare Kidney Stone Consortium presented or were diagnosed before age 18 years [unpublished observation].Many children, however, remain asymptomatic and in at least half of instances the diagnosis of APRT deficiency is not made until adulthood. Of note, abdominal ultrasound and CT examinations performed for other reasons may identify kidney stones in individuals with APRT deficiency who may be asymptomatic. In a significant number of asymptomatic individuals, APRT deficiency has been diagnosed by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals [Edvardsson et al 2001, Harambat et al 2012].The majority of symptomatic individuals with APRT deficiency experience recurrent DHA kidney stones, abdominal pain, and/ or urinary tract infections for years. They also frequently develop CKD secondary to DHA crystalline nephropathy in which the crystals are typically located in tubular lumina, inside renal epithelial cells, and in the interstitium. Studies have shown that 15% of individuals had progressed to end-stage renal disease (ESRD) at the time of diagnosis of APRT deficiency [Edvardsson et al 2001, Bollee et al 2010, Harambat et al 2012]. In some of these individuals the diagnosis was not made until after kidney transplantation [Benedetto et al 2001, Cassidy et al 2004, Nasr et al 2010]. When recognized early, the deleterious consequences of APRT deficiency and 2,8-dihydroxyadeninuria may be prevented with effective pharmacologic therapy (see Management).APRT deficiency is not known to affect organs other than the kidney; however, the authors and other investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort [Neetens et al 1986; Author, personal observation).
No genotype-phenotype correlations have been established; clinical features are known to vary greatly between individuals with the same mutation [Edvardsson et al 2001, Bollee et al 2010]....
Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been established; clinical features are known to vary greatly between individuals with the same mutation [Edvardsson et al 2001, Bollee et al 2010].
Differential diagnosis of APRT deficiency includes other known causes of radiolucent kidney stones such as xanthinuria and uric acid nephrolithiasis....
Differential DiagnosisDifferential diagnosis of APRT deficiency includes other known causes of radiolucent kidney stones such as xanthinuria and uric acid nephrolithiasis.The diagnosis of APRT deficiency should be considered in all individuals with chronic kidney disease (CKD) or kidney failure, particularly in those with renal histopathologic features of crystalline nephropathy, even in the absence of a history of nephrolithiasis. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with APRT deficiency, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with APRT deficiency, the following evaluations are recommended:Assessment of kidney involvement: Measure serum creatinine concentration.Screen for proteinuria.Assess kidney stone burden with ultrasound or CT examination.Perform kidney biopsy in individuals with reduced renal function and/or proteinuria.Ophthalmology consultation if eye symptoms are presentConsideration of medical genetics consultationTreatment of ManifestationsNo treatment guidelines have been published.Treatment with the XDH inhibitor allopurinol is effective and generally well-tolerated in individuals with APRT deficiency. Allopurinol 5-10 mg/kg/day (maximum daily dose 800 mg), either once daily or in two divided doses, minimizes DHA crystalluria, stone formation, crystal deposition in the kidney, and the development of kidney failure [Edvardsson et al 2001, Bollee et al 2010]. Treatment with allopurinol can even dissolve DHA kidney stones and improve kidney function in individuals with advanced renal failure [Edvardsson et al 2001, Bollee et al 2010]. Allopurinol treatment is monitored by clinical evaluation and urine microscopy with the absence of urinary DHA crystals indicative of adequate therapy.The recently introduced XDH inhibitor febuxostat may be an alternative treatment option for affected individuals allergic to or intolerant of allopurinol [Becker et al 2005]. No data have been published on the use of febuxostat in individuals with APRT deficiency. However, using a daily febuxostat dose of 80 mg the authors observed a significant reduction in DHA crystalluria in one adult with APRT deficiency who is allergic to allopurinol [unpublished observation].Low purine diet and ample fluid intake provide adjunctive benefits to pharmacologic therapy.Surgical management of DHA kidney stones is the same as for the management of other types of stones, including extracorporeal shock-wave lithotripsy.Treatment of ESRDDialysis. Of note, it is not known if individuals with APRT deficiency on dialysis benefit from allopurinol therapy.Kidney transplantation. All individuals with APRT deficiency undergoing renal transplantation require treatment with allopurinol.Treatment of eye manifestations. No recommendations are available.Prevention of Primary ManifestationsAdequate treatment of APRT deficiency with allopurinol prevents kidney stone formation and the development of CKD in most, if not all individuals with the disorder [Edvardsson et al 2001, Bollee et al 2010, Harambat et al 2012]. Therefore, all affected individuals should receive lifelong treatment with allopurinol. Note: Febuxostat should be tried in individuals allergic to or intolerant of allopurinol.SurveillanceNo surveillance guidelines have been developed. However, all individuals with APRT deficiency should see their physician every six to 12 months to:Monitor kidney function;Assess the urinary excretion of DHA crystals (disappearance of the crystals is considered an adequate treatment response);Facilitate medication compliance. Agents/Circumstances to AvoidAzathioprine should be avoided by individuals taking XDH inhibitors.Evaluation of Relatives at RiskOnce the disease-causing mutations in a family have been identified, it is recommended that sibs of an affected individual undergo molecular genetic testing to allow early diagnosis and treatment in order to improve long-term outcome. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic mutations.Note: Approximately 15% of individuals with APRT deficiency may be asymptomatic [Edvardsson et al 2001, Bollee et al 2010]; they are usually identified during family screening. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementThe safety of allopurinol in human pregnancy has not been systematically studied. Animal studies using high doses have revealed evidence of adverse fetal effects in mice but not in rats or rabbits; it is not clear if these effects are a result of direct fetal toxicity or maternal toxicity. Thus, allopurinol should only be prescribed during pregnancy when the benefit of treatment is believed to outweigh the risk. Treatment with allopurinol during pregnancy should be considered in women with APRT deficiency who have CKD with reduced GFR or who have undergone kidney transplantation.Some post-transplantation immunosuppressive therapies can also have adverse effects on the developing fetus.A thorough discussion of the risks and benefits of maternal medication use during pregnancy should ideally take place with an appropriate health care provider prior to conception.Therapies Under InvestigationSearch Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Adenine Phosphoribosyltransferase Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDAPRT16q24.3Adenine phosphoribosyltransferaseAPRT homepage - Mendelian genesAPRTData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Adenine Phosphoribosyltransferase Deficiency (View All in OMIM) View in own window 102600ADENINE PHOSPHORIBOSYLTRANSFERASE; APRTNormal allelic variants. Fourteen normal allelic variants have been identified in the sequences flanking APRT [Sahota et al 2001]. Six of these normal variants were located in a 1.2-kb fragment upstream of the initiation codon and eight were located in a 1.8-kb fragment downstream of the termination codon. The majority were identified in both white and Japanese individuals. In addition, four normal variants in introns have been reported in individuals from Japan. All affected individuals of Japanese ancestry with the c.329G>A (p.Trp98X) mutation examined to date have a silent base substitution at codon 99 (GCC to GCT, Ala). Pathologic allelic variants. More than 40 mutations have been identified in the coding region of APRT in over 300 affected individuals from more than 25 countries, including at least 200 individuals from Japan. Approximately 10% of mutant alleles in affected white individuals and 5% in affected Japanese remain to be identified [Sahota et al 2001, Bollee et al 2010]. Mutations include missense, frameshift, and nonsense mutations and small deletions/insertions ranging in size from one to eight base pairs.The most common mutations in affected white individuals are:T insertion at the intron 4 splice donor site (IVS4+2insT) which leads to deletion of exon 4 from mRNA because of aberrant splicing. This mutation has been found in individuals from many European countries as well as in an affected individual from the US.A-to-T transversion in exon 3 (c.194A>T, p.Asp65Val), described in affected individuals from Iceland, Britain, and Spain.The three most common mutations in affected Japanese individuals, in order of decreasing frequency, are:T-to-C missense mutation in exon 5 (c.442T>C)G-to-A nonsense mutation in exon 3(c.329G>A)A four-base pair (CCGA) duplication in exon 3 that leads to a frameshift after codon 186.Large deletions and contiguous gene rearrangementsA contiguous gene deletion of APRT and GALNS can result in APRT deficiency and Morquio syndrome. One affected individual from the Czech Republic who was homozygous for a contiguous gene deletion involving APRT and GALNS has been reported [Wang et al 1999]. The size of the deletion was approximately 100 kb and it spanned the region distal to GALNS exon 2 and proximal to APRT exon 3.A Japanese individual with hemizygosity for APRT and GALNS has been reported [Fukuda et al 1996]. A point mutation in the other GALNS allele accounted for the loss of GALNS activity. A second mutant APRT allele was not identified and the individual was not reported to be symptomatic for APRT deficiency.A 254-kb deletion was reported in two families (one from Austria and the other from Italy [Menardi et al 1997, Di Pietro et al 2007].Table 2. Selected APRT Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid Change (Alias 1)Reference SequencesNormal(1453C>T)p.Ala99AlaNG_008013.1 NM_000485.2 NP_000476.1Pathologic(IVS4+2insT)(Ala108GluX3)c. 229A>T (1350A>T)p.Asp65Valc.442T>C (2066T>C)p.Met136Thrc. 329G>A (1450G>A)p.Trp98X(1415_1418 insCCGA) 2(Arg87Pfs*23)c.483G>T (2107G>T)p.Val150PheSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Kamatani et al [1992]Normal gene product. APRT is a cytoplasmic enzyme that catalyzes the Mg++-dependent synthesis of 5´-adenosine monophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate (PRPP) [Sahota et al 2001]. The enzyme is a homodimer with each subunit consisting of 179 amino acid residues, yielding a molecular weight of 19,481 Daltons [Sahota et al 2001].The crystal structure of recombinant human APRT in complex with adenosine monophsophate (AMP) has been determined [Silva et al 2004]. The protein, which comprises nine β-strands and six α-helices, forms three domains:A core that includes the PRPP-binding motifA flexible loop besides the core region which may be involved in the catalytic functionA variable region primarily involved in base recognitionFrom studies based on the crystallized enzyme in relation to clinically relevant mutations, the investigators predicted that water is an important element for PRPP binding [Silva et al 2004].Abnormal gene product. APRT activity in red cell lysates from individuals with APRT deficiency is typically less than 1% of control values [Sahota et al 2001]. The two reported exceptions are:The vast majority of affected individuals from Japan who are homozygotes or compound heterozygotes for the p.Met136Thr mutation, which decreases the affinity for the co-substrate PRPP compared with the wild-type enzyme, while the affinity for adenine is unchanged [Sahota et al 2001]. The wild-type enzyme and the variant with the p.Met136Thr mutation have the same isoelectric point, but both forms can be detected by electrophoresis or by the increased Km for PRPP for the mutant enzyme.An individual of northern European heritage who had considerable residual enzyme activity in cell extracts but was a compound heterozygote for the IVS4+2insT and p.Val150Phe mutations [Deng et al 2001]. Enzyme kinetic studies in this individual have not been reported.APRT heterozygotes. Since APRT is a dimer of identical subunits, individuals who are heterozygous for a null mutation would be expected to have about 25% of normal enzyme activity in cell extracts. In the very few immunochemical studies that have been reported, immunoreactive protein in cell extracts from homozygous APRT-deficient individuals ranged from undetectable to normal, suggesting that, in the first instance, the protein was either not synthesized or was rapidly degraded, and in the second instance, the protein was synthesized but was non-functional.