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Diagnosis of Tetrahydrobiopterin Deficiency Using Filter Paper Blood Spots: Further Development of the Method and 5 Years Experience View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library J Inherit Metab Dis (2011) 34:819–826 DOI 10.1007/s10545-011-9300-1 ORIGINAL ARTICLE Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience Thomas Opladen & Bettina Abu Seda & Anahita Rassi & Beat Thöny & Georg F. Hoffmann & Nenad Blau Received: 3 December 2010 /Revised: 9 February 2011 /Accepted: 10 February 2011 /Published online: 17 March 2011 # SSIEM and Springer 2011 Abstract In every newborn with even mild hyperphenyla- teridine reductase) were identified. Reference values for laninemia (HPA) tetrahydrobiopterin (BH4) deficiencies neopterin and biopterin in DBS were calculated for each of need to be excluded as soon as possible. Differential the variants. 6-pyruvoyl-tetrahydropterin synthase and diagnosis is most commonly performed by analysis of GTP cyclohydrolase I deficiency can be diagnosed by urinary neopterin and biopterin. In 2005 a new method for neopterin and biopterin analysis alone, while for diagnosis the measurement of neopterin, biopterin and other pterins in of dihydropteridine reductase deficiency additional deter- dried blood spot (DBS) on filter paper was introduced. In mination of enzyme activity from the same DBS is order to evaluate the usefulness of this method as a standard essential. Regarding test sensitivity, the interpretation of tool for differential diagnosis of HPAs we analyzed neopterin and biopterin concentration per hemoglobin is neopterin, biopterin, pterin and dihydropteridine reduc- more valid than the interpretation of neopterin and tase activity in DBS from 362 patients with HPA over biopterin per liter. Percentage of biopterin, of the sum of the period of five years. Age-dependent reference values neopterin and biopterin should always be calculated. In were established for the HPA population. Sixty-four addition, determination of hemoglobin concentration is patients with BH4 deficiency (27 patients with 6- essential as a measure for efficient extraction of neopterin pyruvoyl-tetrahydropterin synthase deficiency, seven with and biopterin. Although the measurement of neopterin and GTP cyclohydrolase I deficiency, and 30 with dihydrop- biopterin in urine is more sensitive due to the higher concentrations present, our data prove the usefulness of Communicated by: K. Michael Gibson their measurement from DBS for the routine diagnosis of Competing interest: None declared BH4 deficiencies. : T. Opladen G. F. Hoffmann Abbreviations Division of Inborn Metabolic Diseases, BH Tetrahydrobiopterin University Children’s Hospital Heidelberg, 4 Heidelberg, Germany DBS Dried blood spot : : : DHPR Dihydropteridine reductase B. Abu Seda A. Rassi B. Thöny N. Blau (*) GTPCH GTP cyclohydrolase I Division of Clinical Chemistry and Biochemistry, HPA Hyperphenylalaninemia University Children’s Hospital Zürich, Zürich, Switzerland PCD Pterin-4a-carbinolamine dehydratase e-mail: [email protected] PKU Phenylketonuria PTPS 6-pyruvoyl-tetrahydropterin synthase B. Thöny : N. Blau Zürich Center for Integrative Human Physiology (ZIHP), Steinwiesstrasse 75, 8032 Zürich, Switzerland Introduction B. Thöny : N. Blau Research Center for Children (RCC), Tetrahydrobiopterin (BH4) is the essential cofactor not only Zürich, Switzerland of phenylalanine hydroxylase, but also of nitric oxide 820 J Inherit Metab Dis (2011) 34:819–826 synthase and of tyrosine and tryptophan hydroxylase, the Patients and methods two rate-limiting enzymes in the biosynthesis of catechol- amines and serotonin. Consequently, patients lacking BH4 Patients present with progressive neurological disorders due to neurotransmitter deficiency in addition to hyperphenylala- DBS from 362 patients with HPA (age 0.04 – 41.75 years, ninemia (HPA) (Blau et al. 2001). Most probably they are mean age 5.2 years) found in newborn screening or during also affected by a depletion of nitric oxide (NO) in the selective screening due to clinical symptoms were mea- central nervous system (CNS) (Zorzi et al. 2002). By this sured before introduction of diet. Parallel urine samples means, an early and specific differential diagnosis in every were obtained from 338 patients. All tests were performed newborn with even slightly elevated phenylalanine levels in within routine clinical and biochemical investigation and in newborn screening is essential to enable early substitutive accordance with local regulations. treatment. Screening for BH4 deficiencies must be done in all newborns with blood phenylalanine concentrations higher Sample preparation and HPLC of pterins than 120 μmol/l by analysis of neopterin and biopterin in urine and measurement of DHPR activity in dried blood spots The term ‘pterins’ is used for different metabolites; e.g., (DBS). Hereby the four forms of BH4 deficiencies associated neopterin, biopterin, and pterin. Pterin itself is a main with HPA, i.e., autosomal recessive GTP cyclohydrolase degradation product resulting from a side-chain cleavage of (GTPCH), 6-pyruvoyl-tetrahydrobiopterin synthase (PTPS), BH4 (Niederwieser et al. 1986) and most probably also of pterin-4a-carbinolamine dehydratase (PCD) and dihydropter- dihydroneopterin. idine reductase (DHPR) deficiencies can be diagnosed and Sample preparation was performed as described before differentiated by specific pterins pattern. The systematic (Zurflüh et al. 2005). Briefly, four DBS (6 mm diameter screening BH4 deficiencies over the last 30 years and the each) were cut out of the filter paper. Neopterin and early initiation of treatment have improved the natural course biopterin were extracted with 0.25 ml of 20 mmol/L HCl of the diseases. for 30 sec in an ultrasonic bath (Sonorex RK31, Bandelin), Recently, Zurflüh et al. published a newly developed and for 10 min at room temperature. Extracts were method for the measurement of the different pterins centrifuged at 1’800xg for 5 min. Hemoglobin (Hb) content (neopterin, biopterin and pterin) in DBS (Zurflüh et al. was determined in the clear supernatant (HemoCue Pho- 2005). The main advantage of using DBS instead of tometer, Ängelholm, Sweden). The remaining supernatant urine is the easier sample collection and handling, and was ultra-filtrated on Ultrafree (NMWL 10000; Millipore) the less expensive shipping of samples at room at 5000g for 5 min and analyzed by HPLC and fluores- temperature instead of on dried ice. In brief, in this cence detection without prior oxidation according to (Blau method neopterin and biopterin are eluted from DBS on and Thöny 2008).SeparationwasachievedonaC8 filter paper, deproteinized, and measured by reverse-phase Spherisorb, 5 μm pre-column 40×4.6 mm) and an ODS-1 HPLC with fluorometric detection. Neopterin and biopterin Spherisorb, 5 μm analytical column (250×4.6 mm) (both concentrations are calculated according to the amount of from Stagroma, Rheinach, Switzerland). A 1.5 mmol/L hemoglobin (Hb) in the sample. Pterins pattern in blood potassium hydrogen phosphate buffer, pH 4.6, with 8% (v/v) spots was compared with that in urine by linear regression methanol was used as a mobile phase. Neopterin and analysis and a positive correlation for both biopterin + biopterin were detected by native fluorescence (λex pterin (pterin is a degradation product of biopterin) and 350 nm; λem 450 nm). Recovery of neopterin and biopterin neopterin has been demonstrated. The authors suggested from DBS determined by spiking samples with that one single DBS card allows the analysis of neopterin corresponding standard of neopterin (20 nmol/L), biopterin and biopterin, DHPR activity and amino acids, an optimal (20 nmol/L), and pterin (5 nmol/L) yielded 63-69%. alternative for the differential diagnosis of the BH4 Neopterin and biopterin concentration was expressed as deficiencies. nmol/L and as nmol per gram of hemoglobin (nmol/g Hb) In this study, we evaluated data from a 5-year test period content. Percentage of biopterin (%biopterin) was calculated in our laboratory, in order to validate the usefulness of this according to the formula: %biopterin=100 * biopterin/ method for the routine differential diagnosis of BH4 (neopterin + biopterin). deficiencies. For this purpose neopterin and biopterin in DBS from 362 patients with HPA were analyzed. Neopterin Stability to light exposure and biopterin stability, test sensitivity, and age-dependent reference values for both control persons and patients with DBS from one healthy adult person were kept either at BH4-deficiency were established. daylight or in dark at room temperature for up to 14 days. J Inherit Metab Dis (2011) 34:819–826 821 Neopterin and biopterin were analyzed immediately after the deficiency was excluded, show a broad variation. Mean blood draw (T0) and after one, five, seven and 14 days. and 5th – 95th percentile were comparable with results from the pilot study (Zurflüh et al. 2005), but since Statistical analyses normal values for neopterin and biopterin in urine are age- dependant (Blau et al. 2005), age dependency was also Descriptive statistics and calculation of sensitivity were investigated in this group. In parallel to the age groups for done with SPSS 17.0 or MS Excel 2003. pterin excretion in urine, we distinguished two age groups (<10 years and >10 years). Since pterin is a degradation product of BH4, a sum of biopterin and pterin were Results initially used for the differential diagnosis (Zurflüh et al. 2005). Neopterin and biopterin concentrations in DBS
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