CASE REPORT

Partial Adenine Phosphoribosyltransferase

Deficiency Detected by Ureterolithiasis
Kenjiroh Inagaki, Akihiro Muraoka, Itsuo Suehiro, Masatoshi Fujii,
Hirohisa Ueno, Tetsuya Hosooka, Kazuhisa Kida and Keiji Murakami

A 30-year-old womanwas admitted to our hospital because of recurrent ureterolithiasis. She

was suspected of having adenine phosphoribosyltransferase (APRT) deficiency based on the
presence of 2,8-dihydroxyadenine (DHA) crystals in her urinary sediment, infrared spectrophoto-
metric analysis of the excreted stone, and then the definitive diagnosis by gene analysis. A pedigree
study indicated only a slight possibility of this disease in the family. From these results, we consider
that urinary sediment and stone analysis should be used for screening while gene analysis should
be employedfor definitive diagnosis ofAPRTdeficiency, so that the complications of this condition
can be prevented.
(Internal Medicine 37: 69-72, 1998)
Key words: 2,8-dihydroxyadenine (DHA), urinary sediment, renal failure

Introduction matory reaction was found. No occult blood was present in the
urine. An abdominal echogram yielded no remarkable findings
Adenine phosphoribosyltransferase (APRT) deficiency is in either kidney. As the patient was pregnant at that time,
an emzymopathyof purine metabolism which is inherited as an roentogenographic examination was not performed.
autosomal recessive trait and causes recurrent urolithiasis, In spite of the lack of distinct evidence of ureterolithiasis,
urinary tract infection and renal failure. Wepresent a case of after ruling out gynecological diseases we suspected the patient
APRTdeficiency detected because of ureterolithiasis and de- to have left ureterolithiasis based on her physical examination
scribe the definitive diagnosis of the condition plus prevention and medical history. Soon after hydration therapy was per-
strategies against its complications. formed, the stone was excreted with disappearance of her
symptoms.
Case Report Analysis of the excreted stone by infrared spectrophotom-
etry revealed over 98% of it to be composed of 2,8-
A 30-year-old womanwas admitted to our hospital com- dihydroxyadenine (2,8-DHA). Examination of urinary sedi-
plaining of sudden left lumbar pain on July 8, 1995. At the age ment showedround crystals containing an axletree-like struc-
of 17, she was hospitalized because of the same symptom. At ture, compatible with 2,8-DHA crystals (Fig. 1). This led us to
that time, diagnosis of ureterolithiasis was madeand it healed suspect that the patient had APRTdeficiency.
by natural excretion. Her family history was not remarkable. To reach a definitive diagnosis, we performed a molecular
On admission, the patient's blood pressure was 145/82 analysis of the APRTgene using the polymerase chain reaction-
mmHg,her pulse rate was 84 beats/minute and regular, and her restriction fragment length polymorphism (PCR-RFLP) method
body temperature was 36.8°C. No abnormalities were detected (Fig. 2). Onthe electropherogram, control DNAswere run in
in a physical examination on admission except for tenderness at lanes 1-4 (Lane 1 : undigested DNA, Lane 2: control non J/non
the left costovertebral angle. J, Lane 3: control non J/J, Lane 4: control J/J) and the patient's
Table 1 shows the laboratory data on admission. There was DNAwas run in lane 5. All DNAsexcept that in lane 1 were
a microcytic, hypochromatic anemia. The white blood cell and digested by Nla III restriction enzyme before the run. The
platelet counts were within the normal range. Onbiochemical patient' s digested PCRproduct was compatible with control J/
examination, liver and renal function were normal. No inflam- J in lane 4 as shown by the appearance of two bands at 64 and
From the Department of Internal Medicine, Suma Red Cross Hospital, Kobe
Received for publication May 15, 1997; Accepted for publication September 26, 1997
Reprint requests should be addressed to Dr. Kenjiroh Inagaki, the Department of Internal Medicine, Suma Red Cross Hospital, 684- 1 , Myohoji-Suganoike, Suma,
Kobe654-01

Internal Medicine Vol. 37, No. 1 (January 1998) 69

 Inagaki et al

Table 1. Laboratory Findings

Complete blood count Alanine aminotransferase 1 3 IU//
Red blood cells 45 1 x lO4/mm3 Aspartate aminotransferase 12 IU//
Hemoglobin 9.6 g/dl Glucose 82 mg/dl
Hematocrit 3 1.4% Blood urea nitrogen 10.4 mg/dl
MCV 69.6 fl Creatinine 0.8 mg/dl
MCH 21.3 Pg Uric acid 2.0 mg/dl
MCHC 30.6 g/dl Na 135 mEq/dl
White blood cells 5,600/mm3 K 3.82 mEq/dl
Eosinophils 4% Cl 106 mg/dl
Segmented neutrophils 52% Ca 8.3 mg/dl
Lympocyte 33% P 3.9 mg/dl
Monocyte 1 1 %
Platelets 24.7x 1 04/mm3 Serology
C-reactive protein 0.2 mg/dl
Blood chemistry
Total protein 6.4 mg/dl Erythrocyte sedimentation rate 19 mm/h
Albumin 3.7 mg/dl
Cholinesterase 0.67 ApH Urinalysis
Alkaline phosphatase 79 IU// Occult blood (-)
Leucine aminopeptidase 34 IU// Protein (-)
Lactic acid dehydrogenase 3 1 1 IU// Sugar (-)
MCV:mean corpuscular volume, MCH:mean corpuscular hemoglobin, MCHC:mean corpus-
cular hemoglobin concentration.

1 2 3 4 5

299 bp (undigested)
235 bp (J)
140 bp (non J)
95 bp (non J)
64 bp

Figure 2. Molecular analysis of APRTgene. 1.

undigested DNA(PCR product). 2. control non J/non
J. 3. control non J/J. 4. control J/J. 5. patient's DNA
(Lanes 2-5: Nla III digested). The electropherogram
shows that the patient's DNA(Lane 5) is compatible
with control J/J (Lane 4).
Figure 1. Examination of urinary sediment, containing
axletree-like structure inside, compatible with 2,8-DHAcrystals
(x400).
Ureterolithiasis similar to that of the patient was not found in
any other family member. All her relatives had normal renal
function, but exhibited an APRTaseactivity below the lower
235 base pair (bp). Onthe basis of these data and her clinical limit of the normal range (5.8-7.4 nmol/h/mg protein, that is
features, the patient was diagnosed as having partial APRT 25-32%). The activity of this enzyme was markedly reduced
deficiency which arose by the homozygote for the APRT*J only in the patient but was not completely absent (3.0 nmol/h/
allele.
The results of her pedigree study are shown in Fig. 3.
mg protein, that is 13%), 2,8-DHA crystals were not observed
in urinary sediments except in the patient. Fromthese results,
70
Internal Medicine Vol. 37, No. 1 (January 1998)
 Partial APRTDeficiency

APRT* 1/*J APRT* 1/*J

I 64y.o. jT 59y.o.

Cr l.l Cr0.9
APRTase 5.8 APRTase 7.4
DHAcrystal (-) DHAcrystal (-)

^- APRT*1/*1 I APRT*J/*J APRT*1/*1

or * l/*J Patient
32 y.o. 30 y.o. hH
Cr0.7
APRTase3.0
DHAcrystal (+)

1 APRT*1/*J ~1 APRT*1/*J

5 y.o. 1 y.o.
Cr0.6
APRTase7.4
DHAcrystal (-)

Standard
Cr : 0.7-1.4 mg/dl (serum)
APRTase : 14-26 nmol/h/mg protein (erythrocyte)
DHAcrystal : (-) (urinary sediment)

Figure 3. Pedigree study of the patient. Serum creatinine (Cr) levels were within the normal range, but erythrocyte
APRTaseactivities were below the lower level, and particularly reduced in the patient. 2,8-DHAcrystals were observed
only in her urinary sediment. From these results, genotypes of her relatives were suspected; only the patient's genotype
was defined by gene analysis.

the family were suspected as having heterozygous genotypes ciency, recurrent clinical symptoms such as those of the present
such as APRT* 1/APRT*J or APRT* 1/APRT* 1, which rarely patient are often recognized, and examination of urinary sedi-
lead to complications. Concerning the patient, alimentary therapy ment or analysis of any excreted stones is necessary to confirm
with a low purine element diet alone was insufficient to prevent the diagnosis. At present, infrared spectrophotometry is the
the occurrence of 2,8-DHAcrystals in her urinary sediment and only technique available for the latter purpose. In patients with
additional pharmacotherapy with allopurinol was necessary. these symptoms,therefore, careful observation of the urinary
sediment is very important in order to detect round crystals
Discussion containing axletree-like structure (4).
The APRTgene is located on chromosome 16, and there are
APRTdeficiency is an enzymopathy of purine metabolism two alleles which cause APRTdeficiency, APRT*Q0and
which is inherited as an autosomal recessive trait. As a result of APRT*J. The presence of the APRT*Q0allele which arises by
this enzymedeficiency, adenine is not transformed to adenosine mutation of TGG(triptophane) to TGA(stop codon) at codon
monophosphate together with 5-phosphoribosyl- l -pyrophos- 98 or others, leads to complete deficiency. While the APRT*J
phate (PRPP), but to 8-hydroxyadenine, which is further me- allele results from a missense mutation of ATG(methionine) to
tabolized to 2,8-DHA by xanthine oxidase (1). Because 2,8- ACG(threonine) at codon 1 36 (Fig. 4) and leads to the synthesis
DHAis extremely insoluble, it forms crystals during excretion of an abnormal enzyme with reduced affinity for PRPP. Com-
in urine (2). APRTdeficiency can thus cause urolithiasis, and binations of these alleles cause differences in phenotypes, such
urinary tract infection from an early stage (3), and, in severe as complete or partial deficiency. Erythrocyte APRTaseactiv-
cases, renal failure due to it's renal toxicity. In APRTdefi- ity is not entirely absent, although it is very low even in

Internal Medicine Vol. 37, No. 1 (January 1998) 71

 Inagaki et al

APRT gene
base number
1 2496 2653 2794 301 6

I -^d 1 h 1

GGATG 2500

Figure 4. Location of primers in gene analysis are indicated by single underline, and finally 299bp is amplified by PCRmethod.
Point mutation at base number 2653 (T to C) causes APRT*Jallele (double underline), so that the PCRproduct can not be digested
by Nla III restriction enzyme on this point, which leads to appearance of only two bands (64 and 235bp) in the electropherogram,
(references 10, ll; and personal communication with SRL Company, Limited, July 18, 1997).

asymptomatic carriers, heterozygous for APRT*Jallele unless can be a marker of therapy control.
complete deficiency resulting from the APRT*Q0/APRT*Q0
combination is present (5). Consequently, measurement of References
APRTaseactivity is not available for diagnosis. In the pedigree 1) Hesse A, Miersch WD, Classen A, Thon A, Doppler W. 2,8-
study in this case, the genotypes of the patient's family mem- dihydroxyadeninuria: Laboratory diagnosis and therapy control. Urol Int
bers were suspected to be APRT*1/APRT*J or APRT*1/ 43: 174, 1988.
APRT*1 from their lack of clinical symptoms and laboratory 2) Cartier P, Hamet M, Vincens A, Perignon JL. Complete adenine
findings. Thus, APRT deficiency involving the APRT*J allele, phosphoribosyltransferase deficiency in two siblings: report of a new
which is only a partial deficiency, can be definitely diagnosed 3)case. Adv Exp Med Biol 122A: 343, 1980.
Masuda K, Takei S, Miyata K, et al. A case ofpediatric complete adenine
only by gene analysis, although this examination is very costly. phosphoribosyltransferase deficiency. Shoni Naika 26(5): 747, 1994.
As for treatment, alimentary therapy with a low purine 4) Konishi K, Takeshita K, Yasui H. A case of adenine
element diet and pharmacotherapy with allopurinol, a xanthine phosphoribosyltransferase deficiency discovered by urine examination.
oxidase inhibitor have been suggested to be effective. As the Nippon Jinzo Gakkaishi 36: 1 191, 1994 (Abstract in English).
present patient was pregnant at the time of diagnosis, she was 5)deficiency
Suyama K, Okamoto S, Nagata M, Nukui F, Fujimoto Y. Complete
of adenine phosphoribosyltransferase: a case report. Nishi-
treated by diet alone. However, 2,8-DHA crystals were still Nihon Hinyokika 53: 386, 1991 (Abstract in English).
observed in her urine, indicating lack of efficacy. Oral allopu- 6) Van Acker KJ, Simmonds HA, Potter C, Cameron JS. Complete defi-
rinol therapy after delivery was expected to reduce the occur- ciencyJMed297: of adenine127, phosphoribosyltransferase,
1977.
report of a family. NEngl
rence of these crystals (6, 7).
There are relatively few reports regarding APRTdeficiency 7)phosphoribosyltransferase
Van Acker KJ, Simmonds HA. Long-term evolution of type 1 adenine
deficiency. Adv Exp Med Biol 309B: 91,
although it is not very rare. This disease is suspected to be 1991.

frequent in Japanese, 1-1.25% have APRT*J allele, and 0.003- 8) Kamatani N. Adenine phosphoribosyltransferase deficiency. Nippon
0.004% are homozygous (8). This is probably because most Rinsho 51: Suppl: 1087, 1993.
patients with this condition are overlooked and are diagnosed as 9) KodaH, KondohH, OkadaS,etal. Acaseofrenalfailuredueto 2,8-DHA
having ureterolithiasis because they have no peculiar clinical urolithiasis with partial APRTdefect. Naika (Internal Medicine) 70(6):
1165, 1992.
symptoms or laboratory findings (9), though APRTdeficiency 10) Hidaka Y. APRT deficiency. Nippon Rinsho 47 Suppl: 372, 1989.
can cause renal failure in severe cases. In patients with recurrent ll) Hidaka Y, Tarle SA, O'Toole TE, Kelley WN, Palella TD. Nucleotide
ureterolithiasis, careful observation of the urinary sediment is sequence of the human APRT gene. Nucleic Acids Res 15: 9086, 1987.
simple and a useful screening method for APRTdeficiency and

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