- Email: [email protected]
Neopterin and biopterin concentrations in cerebrospinal fluid in controls less than 1 year old
Brain & Development 21 (1999) 264–267
Original article
Neopterin and biopterin concentrations in cerebrospinal fluid in controls less than 1 year old Yoshitomo Sawada*, Haruo Shintaku, Gen Isshiki Department of Pediatrics, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka City 545-8585, Japan Received 6 October 1998; received in revised form 20 January 1999; accepted 2 February 1999
Abstract Neopterin and biopterin concentrations were measured in cerebrospinal fluid (CSF) and urine samples from controls less than 1 year old. This is the first time for CSF reference data for controls less than 1 year old to be reported. The ratio of neopterin to biopterin in CSF 0–30 days (n = 48) of age in control samples was 0.65 ± 0.31 (SD), which was far lower than that in urine over the same time period, 4.0 ± 1.9 (SD), (n = 51). This finding is very important when diagnosing 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency and peripheral form of PTPS deficiency in the neonatal period. Our CSF reference data for controls should be useful in the diagnosis of PTPS deficiency. 1999 Elsevier Science B.V. All rights reserved. Keywords: Neopterin; Biopterin; N/B ratio; Peripheral form; Cerebrospinal fluid; 6-Pyruvoyltetrahydropterin synthase deficiency; Tetrahydrobiopterin
1. Introduction Neopterin and biopterin concentrations in urine have been used to diagnose 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency, which is characterized by very high concentrations of neopterin and only traces of biopterin in urine (Fig. 1). Early diagnosis and administration of tetrahydrobiopterin (BH4) and neurotransmitter precursors are essential for normal development in patients with PTPS deficiency [1,2]. Since 1982, patients with peripheral form, a new type of PTPS deficiency, have been reported [3–6]. This peripheral form of PTPS deficiency has been reported to develop normally without neurotransmitter precursor replacement therapy; in these cases, PTPS activity has been considered to be normal in the brain but deficient in the liver. Patients with peripheral form have been reported to have normal biopterin and neurotransmitter metabolite concentrations in CSF despite evidence of PTPS deficiency in urine [3–6]. * Corresponding author. Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima-ku, Osaka 534-0021, Japan. Tel.:+81-6-69291221; fax: +81-6-6929-1091; e-mail: [email protected]
0387-7604/99/$ - see front matter PII: S03 87-7604(99)000 21-2
To differentiate peripheral form from PTPS deficiency, it is essential to assess pteridine concentrations in both CSF and urine. However, no accurate age-matched reference data for CSF pteridines has been reported to date, whereas there is much age-matched reference data for urinary pteridines [10,11]. This is because CSF specimens from healthy children cannot be collected due to ethical reasons. In order to address this problem, we constructed reference data for CSF neopterin and biopterin concentrations, choosing suitable CSF samples as reference data. We describe here a reassessment of the peripheral form of PTPS deficiency by comparing it with our CSF data.
2. Subjects and methods We measured concentrations of neopterin and biopterin in CSF and urine samples from subjects less than 1 year of age. CSF samples were obtained for assessment of central nervous system infection. A total of 69 CSF samples, which were within the normal range for CSF cell counts, protein and sugar concentrations, were chosen as control samples. About two-thirds of the patients from whom we obtained
1999 Elsevier Science B.V. All rights reserved.
265
Y. Sawada et al. / Brain & Development 21 (1999) 264–267 Table 2
Neopterin and biopterin concentrations in the urine of control samples
1–7 Days 8–14 Days 15–21 Days 22–30 Days 1–6 Months 7–11 Months
n
Neopterin (mmol/mol creatinine)
17 11 12 11 14 10
2212 1848 1742 1325 1467 1133
± ± ± ± ± ±
756 474 544 376 332 284
Biopterin (mmol/mol creatinine)
N/B
± ± ± ± ± ±
5.7 3.9 2.9 2.5 1.8 1.2
397 580 612 559 843 931
130 151 163 106 179 195
± ± ± ± ± ±
1.9 1.1 1.0 0.8 0.4 0.3
N/B, neopterin to biopterin ratio.
Fig. 1. Tetrahydrobiopterin metabolism (GTP, guanosine triphosphate; PTPS, 6-pyruvoyltetrahydropterin synthase; q-BH2, quinonoid-dihydrobiopterin; DOPA, 3,4-dihydroxyphenylalanine; 5-OH-Trp, 5-hydroxytryptophan; 5-HIAA, 5-hydroxyindoleacetic acid).
CSF control samples had fever, but none of them showed neurological symptoms. A total of 75 urine samples were collected from healthy children in nurseries and daycare centers. Results from their urine analyses were normal. All samples were protected from light and frozen at −40°C shortly after collection. Samples were analyzed by the method described by Fukushima and Nixon [9] using HPLC with fluorimetric detection.
3. Results Tables 1 and 2 show the neopterin and biopterin concentrations and the ratios of neopterin to biopterin (N/B) in CSF and urine in the control samples less than 1 year of age. The CSF neopterin and biopterin concentration and N/B ratio measured in each CSF and urine control sample is plotted in Figs. 2 and 3, respectively. In CSF, biopterin concentrations were highest, 77.8 ± 12.5 (SD) nmol/l, at 1–7 days of age and decreased markedly thereafter. By contrast, neopterin concentrations did not change significantly. In urine, neopterin concentrations were highest, 2212 ± 756 (SD) mmol/mol creatinine and biopterin concentrations were lowest 397 ± 130 (SD) mmol/mol creatinine, at 1–7 days of age. The N/B ratios in the CSF samples were less than 1 and the Table 1 Neopterin and biopterin concentrations in the CSF control samples
1–7 Days 8–14 Days 15–21 Days 22–30 Days 1–6 Months 7–11 Months
n
Neopterin (nmol/l)
19 12 10 7 11 10
28.1 26.2 24.2 23.6 22.8 18.3
± ± ± ± ± ±
7.2 5.4 6.0 5.7 4.4 3.9
Biopterin (nmol/l) 77.8 53.8 38.5 35.7 26.4 20.2
± ± ± ± ± ±
12.5 11.0 14.4 7.9 10.1 5.8
N/B 0.36 0.52 0.67 0.70 0.95 0.97
N/B, neopterin to biopterin ratio; CSF, cerebrospinal fluid.
± ± ± ± ± ±
0.09 0.15 0.18 0.22 0.27 0.32
lowest ratio, 0.36 ± 0.09 (SD), occurred at 1–7 days of age (n = 19). On the other hand, N/B ratios in the urine were the highest, 5.7 ± 1.9 (SD), during the same time period (n = 17). N/B ratio in the CSF 1–30 days (n = 48) of age in control samples was 0.65 ± 0.31 (SD), which was far lower than that in urine over the same time period, 4.0 ± 1.9 (SD), (n = 51). The age-dependent changes in the N/B ratio of CSF samples were opposite of those in urine samples (Fig. 4).
4. Discussion According to our control results, the N/B ratio of CSF was the reverse of the N/B ratio in neonatal urine. This finding is very important because neonates are well-known to have the highest N/B ratios (often .5) in urine at all ages [10,11] and attending pediatricians might assume that neonatal CSF should also show the highest N/B ratios. It is unclear why the CSF bioterin concentration is the highest in the early neonatal period. One explanation is that it reflects increased synthesis of biogenic amines in the neonatal period [12,13], because BH4 is a common cofactor for tyrosine and tryptophan hydroxylases. In 1987, Scriver et al. reported a patient who was diagnosed to have a peripheral form of PTPS deficiency in the neonatal period but showed a progression of neurological symptoms several months later [7]. Dhondt et al. [8] also reported a girl treated with neurotransmitter precursors in addition to BH4, since it was feared that she would develop a clinical course similar to that of Scriver’s patient [7]. When the patient was 5 months old, neurotransmitter precursors were withdrawn to reevaluate BH4 metabolism. Within 24 h, the child became hypotonic and sleepy. In both Scriver’s and Dhondt’s patients [7,8], the CSF biopterin concentrations have been reported to be within the normal range during the neonatal period but below the normal range at five months of age. The difficulty in diagnosing the peripheral form of PTPS deficiency may be partly due to the assessment of pteridine concentrations in CSF. Table 3 presents a comparison between CSF data of reported patients with peripheral form and our CSF reference data. Although rigid comparison of reported data at
266
Y. Sawada et al. / Brain & Development 21 (1999) 264–267
Fig. 2. Neopterin and biopterin concentrations in cerebrospinal fluid in controls by age.
different laboratories is impossible, a rough comparison is possible, since the pteridine measuring methods used in different literatures was the Fukushima–Nixon method [4] or a slightly modified method [5] of Fukushima–Nixon. In the reported patients with peripheral form, CSF biopterin concentrations were almost within our control range but neopterin concentrations were much higher, thus resulting in higher N/B ratios. When our CSF control ranges are taken as reference values, CSF values of reported patients with peripheral form of PTPS deficiencies become abnormal. Regarding the N/B ratio as an index of PTPS activity, the higher CSF N/B ratio observed in some peripheral forms may imply a mild form of PTPS deficiency. This may account for the phenomenon reported in Scriver’s and Dhondt’s patient [7,8], although it is not clear why neurotransmitter metabolite concentrations were within the nor-
mal range at diagnosis of patients with the peripheral form. We support Niederwieser’s hypothesis [5] that patients with the peripheral form of PTPS deficiency retain sufficient residual activity to cover the modest BH4 requirements of tyrosine hydroxylase and tryptophan hydroxylase in the brain, but depending on phenylalanine intake or age, not enough to cover the much higher BH4 requirement of phenylalanine hydroxylase in the liver. This hypothesis is supported by the fact that some reported peripheral forms proved to be heterozygotes with PTPS deficiency [5]. In Niederwieser’s heterozygote case (patient F.S.), CSF neopterin, biopterin and the N/B ratio at the age of 11 weeks, were 25, 34 nmol/l and 0.7, respectively [5], which were within the normal range of our controls (1–6 months, 22.8 ± 4.4, 26.4 ± 10.1 nmol/l, 0.95 ± 0.27, respectively). When diagnosing PTPS deficiency, as well as peripheral
Fig. 3. Urinary neopterin and biopterin concentrations in controls by age.
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Y. Sawada et al. / Brain & Development 21 (1999) 264–267
Fig. 4. Ratio of neopterin to biopterin in cerebrospinal fluid and urine in controls by age. Table 3 Neopterin and biopterin concentrations in the CSF in patients with peripheral forms and control samples Reporter
Age
Neopterin (nmol/l)
Biopterin (nmol/l)
N/B
Hreidarsson et al., [3] Scriver et al., [7] Dhondt et al., [8] Hoganson et al., [4] Allanson et al., [6]
4 3 3 77 4
94.4 ± 10.5 115.9 183.4 68.1 86.8
59.9 ± 12.3 18.4 20.9 16.3 14.5
n.d. 6.3 8.8 4.2 6.0
Controls
1–7 Days (n = 19) 15–21 Days (n = 10) 1–6 Months (n = 11)
28.1 ± 7.2 24.2 ± 6.0 22.8 ± 4.4
77.8 ± 12.5 38.5 ± 14.4 26.4 ± 10.1
0.37 ± 0.11 0.67 ± 0.18 0.95 ± 0.27
Days Weeks Weeks Days Months
n.d., Not described; N/B, neopterin to biopterin ratio; CSF, cerebrospinal fluid.
form, one should be careful to take into account the timedependent change in N/B ratios for CSF. As Niederwieser [5] and Dhondt [8] recommended, it is wise to treat newborns as BH4 deficient and give neurotransmitter precursors, even if CSF data suggest a peripheral form. A re-investigation, by age, of the neopterin and biopterin concentrations in CSF samples from patients with peripheral form of PTPS deficiency is also recommended. References
[6]
[7]
[8] [9] [10]
[1] Shintaku H. Early diagnosis of 6-pyruvoyltetrahydropterin synthase deficiency. Pteridines 1994;5:18–27. [2] Blau N, Barnes I, Dhondt JL. International database of tetrahydrobiopterin deficiencies. J Inher Metab Dis 1996;19:8–14. [3] Hreidarsson S, Valle D, Holtzman N, et al. A peripheral defect in biopterin synthesis: a new mutant? Pediatr Res 1982;16:192A. [4] Hoganson G, Berlow S, Kaufman S, Milstien S, Schuett V, Matalon R, et al. Biopterin synthesis defects: problems in diagnosis. Pediatrics 1984;74:1004–1011. [5] Niederwieser A, Shintaku H, Leimbacher W, Curtius HC, Hyanek J, Zelman J, et al. ‘Peripheral’ tetrahydrobiopterin deficiency with hyperphenylalninaemia due to incomplete 6-pyruvoyl tetrahydro-
[11]
[12]
[13]
pterin synthase deficiency or heterozygosity. Eur J Pediatr 1987;146:228–232. Allanson J, McInnes R, Bradley L, Tarby T, Naylor E, Nardella M. Combined transient and peripheral defects in tetrahydrobiopterin synthesis. J Pediatr 1991;118:261–263. Scriver CR, Clow CL, Kaplan P, Niederwieser A. Hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase. Unusual gene dosage effect in heterozygotes. Hum Genet 1987;77:168–171. Dhondt JL, Farriaux JP. Atypical cases of phenylketonuria. Eur J Pediatr 1987;146 (Suppl. 1 ):A38–A43. Fukushima T, Nixon JC. Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem 1980;102:176–188. Dhondt JL, Ardouin P, Hayte JM, Farriaux JP. Developmental aspects of pteridine metabolism and relationships with phenylalanine metabolism. Clin Chim Acta 1981;116:143–152. Shintaku H, Isshiki G, Hase Y, Tsuruhara T, Oura T. Normal pterin values in urine and serum in neonates and its age-related change throughout life. J Inherit Metab Dis 1982;5:241–242. Langlais PJ, Walsh FX, Bird ED, Levy HL. Cerebrospinal fluid neurotransmitter metabolites in neurologically normal infants and children. Pediatrics 1985;75:580–586. Hyland K, Surtees RA, Heales SJ, Bowron A, Howells DW, Smith I. Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 1993;34:10–14.
Original article
Neopterin and biopterin concentrations in cerebrospinal fluid in controls less than 1 year old Yoshitomo Sawada*, Haruo Shintaku, Gen Isshiki Department of Pediatrics, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka City 545-8585, Japan Received 6 October 1998; received in revised form 20 January 1999; accepted 2 February 1999
Abstract Neopterin and biopterin concentrations were measured in cerebrospinal fluid (CSF) and urine samples from controls less than 1 year old. This is the first time for CSF reference data for controls less than 1 year old to be reported. The ratio of neopterin to biopterin in CSF 0–30 days (n = 48) of age in control samples was 0.65 ± 0.31 (SD), which was far lower than that in urine over the same time period, 4.0 ± 1.9 (SD), (n = 51). This finding is very important when diagnosing 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency and peripheral form of PTPS deficiency in the neonatal period. Our CSF reference data for controls should be useful in the diagnosis of PTPS deficiency. 1999 Elsevier Science B.V. All rights reserved. Keywords: Neopterin; Biopterin; N/B ratio; Peripheral form; Cerebrospinal fluid; 6-Pyruvoyltetrahydropterin synthase deficiency; Tetrahydrobiopterin
1. Introduction Neopterin and biopterin concentrations in urine have been used to diagnose 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency, which is characterized by very high concentrations of neopterin and only traces of biopterin in urine (Fig. 1). Early diagnosis and administration of tetrahydrobiopterin (BH4) and neurotransmitter precursors are essential for normal development in patients with PTPS deficiency [1,2]. Since 1982, patients with peripheral form, a new type of PTPS deficiency, have been reported [3–6]. This peripheral form of PTPS deficiency has been reported to develop normally without neurotransmitter precursor replacement therapy; in these cases, PTPS activity has been considered to be normal in the brain but deficient in the liver. Patients with peripheral form have been reported to have normal biopterin and neurotransmitter metabolite concentrations in CSF despite evidence of PTPS deficiency in urine [3–6]. * Corresponding author. Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima-ku, Osaka 534-0021, Japan. Tel.:+81-6-69291221; fax: +81-6-6929-1091; e-mail: [email protected]
0387-7604/99/$ - see front matter PII: S03 87-7604(99)000 21-2
To differentiate peripheral form from PTPS deficiency, it is essential to assess pteridine concentrations in both CSF and urine. However, no accurate age-matched reference data for CSF pteridines has been reported to date, whereas there is much age-matched reference data for urinary pteridines [10,11]. This is because CSF specimens from healthy children cannot be collected due to ethical reasons. In order to address this problem, we constructed reference data for CSF neopterin and biopterin concentrations, choosing suitable CSF samples as reference data. We describe here a reassessment of the peripheral form of PTPS deficiency by comparing it with our CSF data.
2. Subjects and methods We measured concentrations of neopterin and biopterin in CSF and urine samples from subjects less than 1 year of age. CSF samples were obtained for assessment of central nervous system infection. A total of 69 CSF samples, which were within the normal range for CSF cell counts, protein and sugar concentrations, were chosen as control samples. About two-thirds of the patients from whom we obtained
1999 Elsevier Science B.V. All rights reserved.
265
Y. Sawada et al. / Brain & Development 21 (1999) 264–267 Table 2
Neopterin and biopterin concentrations in the urine of control samples
1–7 Days 8–14 Days 15–21 Days 22–30 Days 1–6 Months 7–11 Months
n
Neopterin (mmol/mol creatinine)
17 11 12 11 14 10
2212 1848 1742 1325 1467 1133
± ± ± ± ± ±
756 474 544 376 332 284
Biopterin (mmol/mol creatinine)
N/B
± ± ± ± ± ±
5.7 3.9 2.9 2.5 1.8 1.2
397 580 612 559 843 931
130 151 163 106 179 195
± ± ± ± ± ±
1.9 1.1 1.0 0.8 0.4 0.3
N/B, neopterin to biopterin ratio.
Fig. 1. Tetrahydrobiopterin metabolism (GTP, guanosine triphosphate; PTPS, 6-pyruvoyltetrahydropterin synthase; q-BH2, quinonoid-dihydrobiopterin; DOPA, 3,4-dihydroxyphenylalanine; 5-OH-Trp, 5-hydroxytryptophan; 5-HIAA, 5-hydroxyindoleacetic acid).
CSF control samples had fever, but none of them showed neurological symptoms. A total of 75 urine samples were collected from healthy children in nurseries and daycare centers. Results from their urine analyses were normal. All samples were protected from light and frozen at −40°C shortly after collection. Samples were analyzed by the method described by Fukushima and Nixon [9] using HPLC with fluorimetric detection.
3. Results Tables 1 and 2 show the neopterin and biopterin concentrations and the ratios of neopterin to biopterin (N/B) in CSF and urine in the control samples less than 1 year of age. The CSF neopterin and biopterin concentration and N/B ratio measured in each CSF and urine control sample is plotted in Figs. 2 and 3, respectively. In CSF, biopterin concentrations were highest, 77.8 ± 12.5 (SD) nmol/l, at 1–7 days of age and decreased markedly thereafter. By contrast, neopterin concentrations did not change significantly. In urine, neopterin concentrations were highest, 2212 ± 756 (SD) mmol/mol creatinine and biopterin concentrations were lowest 397 ± 130 (SD) mmol/mol creatinine, at 1–7 days of age. The N/B ratios in the CSF samples were less than 1 and the Table 1 Neopterin and biopterin concentrations in the CSF control samples
1–7 Days 8–14 Days 15–21 Days 22–30 Days 1–6 Months 7–11 Months
n
Neopterin (nmol/l)
19 12 10 7 11 10
28.1 26.2 24.2 23.6 22.8 18.3
± ± ± ± ± ±
7.2 5.4 6.0 5.7 4.4 3.9
Biopterin (nmol/l) 77.8 53.8 38.5 35.7 26.4 20.2
± ± ± ± ± ±
12.5 11.0 14.4 7.9 10.1 5.8
N/B 0.36 0.52 0.67 0.70 0.95 0.97
N/B, neopterin to biopterin ratio; CSF, cerebrospinal fluid.
± ± ± ± ± ±
0.09 0.15 0.18 0.22 0.27 0.32
lowest ratio, 0.36 ± 0.09 (SD), occurred at 1–7 days of age (n = 19). On the other hand, N/B ratios in the urine were the highest, 5.7 ± 1.9 (SD), during the same time period (n = 17). N/B ratio in the CSF 1–30 days (n = 48) of age in control samples was 0.65 ± 0.31 (SD), which was far lower than that in urine over the same time period, 4.0 ± 1.9 (SD), (n = 51). The age-dependent changes in the N/B ratio of CSF samples were opposite of those in urine samples (Fig. 4).
4. Discussion According to our control results, the N/B ratio of CSF was the reverse of the N/B ratio in neonatal urine. This finding is very important because neonates are well-known to have the highest N/B ratios (often .5) in urine at all ages [10,11] and attending pediatricians might assume that neonatal CSF should also show the highest N/B ratios. It is unclear why the CSF bioterin concentration is the highest in the early neonatal period. One explanation is that it reflects increased synthesis of biogenic amines in the neonatal period [12,13], because BH4 is a common cofactor for tyrosine and tryptophan hydroxylases. In 1987, Scriver et al. reported a patient who was diagnosed to have a peripheral form of PTPS deficiency in the neonatal period but showed a progression of neurological symptoms several months later [7]. Dhondt et al. [8] also reported a girl treated with neurotransmitter precursors in addition to BH4, since it was feared that she would develop a clinical course similar to that of Scriver’s patient [7]. When the patient was 5 months old, neurotransmitter precursors were withdrawn to reevaluate BH4 metabolism. Within 24 h, the child became hypotonic and sleepy. In both Scriver’s and Dhondt’s patients [7,8], the CSF biopterin concentrations have been reported to be within the normal range during the neonatal period but below the normal range at five months of age. The difficulty in diagnosing the peripheral form of PTPS deficiency may be partly due to the assessment of pteridine concentrations in CSF. Table 3 presents a comparison between CSF data of reported patients with peripheral form and our CSF reference data. Although rigid comparison of reported data at
266
Y. Sawada et al. / Brain & Development 21 (1999) 264–267
Fig. 2. Neopterin and biopterin concentrations in cerebrospinal fluid in controls by age.
different laboratories is impossible, a rough comparison is possible, since the pteridine measuring methods used in different literatures was the Fukushima–Nixon method [4] or a slightly modified method [5] of Fukushima–Nixon. In the reported patients with peripheral form, CSF biopterin concentrations were almost within our control range but neopterin concentrations were much higher, thus resulting in higher N/B ratios. When our CSF control ranges are taken as reference values, CSF values of reported patients with peripheral form of PTPS deficiencies become abnormal. Regarding the N/B ratio as an index of PTPS activity, the higher CSF N/B ratio observed in some peripheral forms may imply a mild form of PTPS deficiency. This may account for the phenomenon reported in Scriver’s and Dhondt’s patient [7,8], although it is not clear why neurotransmitter metabolite concentrations were within the nor-
mal range at diagnosis of patients with the peripheral form. We support Niederwieser’s hypothesis [5] that patients with the peripheral form of PTPS deficiency retain sufficient residual activity to cover the modest BH4 requirements of tyrosine hydroxylase and tryptophan hydroxylase in the brain, but depending on phenylalanine intake or age, not enough to cover the much higher BH4 requirement of phenylalanine hydroxylase in the liver. This hypothesis is supported by the fact that some reported peripheral forms proved to be heterozygotes with PTPS deficiency [5]. In Niederwieser’s heterozygote case (patient F.S.), CSF neopterin, biopterin and the N/B ratio at the age of 11 weeks, were 25, 34 nmol/l and 0.7, respectively [5], which were within the normal range of our controls (1–6 months, 22.8 ± 4.4, 26.4 ± 10.1 nmol/l, 0.95 ± 0.27, respectively). When diagnosing PTPS deficiency, as well as peripheral
Fig. 3. Urinary neopterin and biopterin concentrations in controls by age.
267
Y. Sawada et al. / Brain & Development 21 (1999) 264–267
Fig. 4. Ratio of neopterin to biopterin in cerebrospinal fluid and urine in controls by age. Table 3 Neopterin and biopterin concentrations in the CSF in patients with peripheral forms and control samples Reporter
Age
Neopterin (nmol/l)
Biopterin (nmol/l)
N/B
Hreidarsson et al., [3] Scriver et al., [7] Dhondt et al., [8] Hoganson et al., [4] Allanson et al., [6]
4 3 3 77 4
94.4 ± 10.5 115.9 183.4 68.1 86.8
59.9 ± 12.3 18.4 20.9 16.3 14.5
n.d. 6.3 8.8 4.2 6.0
Controls
1–7 Days (n = 19) 15–21 Days (n = 10) 1–6 Months (n = 11)
28.1 ± 7.2 24.2 ± 6.0 22.8 ± 4.4
77.8 ± 12.5 38.5 ± 14.4 26.4 ± 10.1
0.37 ± 0.11 0.67 ± 0.18 0.95 ± 0.27
Days Weeks Weeks Days Months
n.d., Not described; N/B, neopterin to biopterin ratio; CSF, cerebrospinal fluid.
form, one should be careful to take into account the timedependent change in N/B ratios for CSF. As Niederwieser [5] and Dhondt [8] recommended, it is wise to treat newborns as BH4 deficient and give neurotransmitter precursors, even if CSF data suggest a peripheral form. A re-investigation, by age, of the neopterin and biopterin concentrations in CSF samples from patients with peripheral form of PTPS deficiency is also recommended. References
[6]
[7]
[8] [9] [10]
[1] Shintaku H. Early diagnosis of 6-pyruvoyltetrahydropterin synthase deficiency. Pteridines 1994;5:18–27. [2] Blau N, Barnes I, Dhondt JL. International database of tetrahydrobiopterin deficiencies. J Inher Metab Dis 1996;19:8–14. [3] Hreidarsson S, Valle D, Holtzman N, et al. A peripheral defect in biopterin synthesis: a new mutant? Pediatr Res 1982;16:192A. [4] Hoganson G, Berlow S, Kaufman S, Milstien S, Schuett V, Matalon R, et al. Biopterin synthesis defects: problems in diagnosis. Pediatrics 1984;74:1004–1011. [5] Niederwieser A, Shintaku H, Leimbacher W, Curtius HC, Hyanek J, Zelman J, et al. ‘Peripheral’ tetrahydrobiopterin deficiency with hyperphenylalninaemia due to incomplete 6-pyruvoyl tetrahydro-
[11]
[12]
[13]
pterin synthase deficiency or heterozygosity. Eur J Pediatr 1987;146:228–232. Allanson J, McInnes R, Bradley L, Tarby T, Naylor E, Nardella M. Combined transient and peripheral defects in tetrahydrobiopterin synthesis. J Pediatr 1991;118:261–263. Scriver CR, Clow CL, Kaplan P, Niederwieser A. Hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase. Unusual gene dosage effect in heterozygotes. Hum Genet 1987;77:168–171. Dhondt JL, Farriaux JP. Atypical cases of phenylketonuria. Eur J Pediatr 1987;146 (Suppl. 1 ):A38–A43. Fukushima T, Nixon JC. Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem 1980;102:176–188. Dhondt JL, Ardouin P, Hayte JM, Farriaux JP. Developmental aspects of pteridine metabolism and relationships with phenylalanine metabolism. Clin Chim Acta 1981;116:143–152. Shintaku H, Isshiki G, Hase Y, Tsuruhara T, Oura T. Normal pterin values in urine and serum in neonates and its age-related change throughout life. J Inherit Metab Dis 1982;5:241–242. Langlais PJ, Walsh FX, Bird ED, Levy HL. Cerebrospinal fluid neurotransmitter metabolites in neurologically normal infants and children. Pediatrics 1985;75:580–586. Hyland K, Surtees RA, Heales SJ, Bowron A, Howells DW, Smith I. Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 1993;34:10–14.