Comparison of tandem mass spectrometry and amino acid analyzer for phenylalanine and tyrosine monitoring—Implications for clinical management of patients with hyperphenylalaninemia

Grošelj, Urh; Murko, Simona; Tanšek, Mojca Žerjav; Kovač, Jernej; Bakija, Alenka Trampuš; Lampret, Barbka Repič; Battelino, Tadej

doi:10.1016/j.clinbiochem.2014.09.014

Cited by 49 publications

(53 citation statements)

References 27 publications

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“…Phe concentrations from dried blood spots were lower than those from venous blood spots but this was consistent with differences reported in the literature [19–21]. In the Phe-restricted diet group, the adjusted mean blood Phe concentrations in the ITT population were stable over time, with a mean (±SD) increase of 23.1 (±21.9) μmol/L at week 26 (Fig.…”

Section: Resultssupporting

confidence: 90%

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Muntau

Burlina

Eyskens

et al. 2017

Orphanet J Rare Dis

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BackgroundSapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years.ResultsIn total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7–42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters.ConclusionsThe addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria.Trial registrationClinicalTrials.gov, NCT01376908. Registered June 17, 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0600-x) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 90%

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Muntau

Burlina

Eyskens

et al. 2017

Orphanet J Rare Dis

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“…The advantage is that the discussion on differences between measurement in blood spot versus plasma as shown in various articles is not of importance for this study. On the other hand, we do not know exactly how to translate our data and conclusions for measurements in plasma, knowing that the debate on the comparison between blood spot and plasma is ongoing (Gregory et al 2007;Kand'ár and Zakova 2009;De Silva et al 2010;Mo et al 2013;Groselj et al 2015).…”

Section: Methodological Issuesmentioning

confidence: 99%

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

et al. 2017

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Background: Treatment of hereditary tyrosinemia type 1 with nitisinone and phenylalanine and tyrosine restricted diet has largely improved outcome, but the best blood sampling time for assessment of metabolic control is not known. Aim: To study diurnal and day-to-day variation of phenylalanine and tyrosine concentrations in tyrosinemia type 1 patients. Methods: Eighteen tyrosinemia type 1 patients aged >1 year (median age 7.9 years; range 1.6-20.7) were studied. Capillary blood samples were collected 4 times a day (T1: pre-breakfast, T2: pre-midday meal, T3: before evening meal, and T4: bedtime) for 3 days. Linear mixed-effect models were used to investigate diurnal and day-to-day variation of both phenylalanine and tyrosine. Results: The coefficients of variation of phenylalanine and tyrosine concentrations were the lowest on T1 (13.8% and 14.1%, respectively). Tyrosine concentrations did not significantly differ between the different time points, but phenylalanine concentrations were significantly lower at T2 and T3 compared to T1 (50.1 mmol/L, 29.8 mmol/L, and 37.3 mmol/L, respectively). Conclusion: Our results indicated that for prevention of too low phenylalanine and too high tyrosine concentrations, measurement of phenylalanine and tyrosine pre-midday meal would be best, since phenylalanine concentrations are the lowest on that time point. Our results also indicated that whilst blood tyrosine concentrations were stable over 24 h, phenylalanine fluctuated. Day-to-day variation was most stable after an overnight fast for both phenylalanine and tyrosine. Therefore, in tyrosinemia type 1 patients the most reliable time point for measuring phenylalanine and tyrosine concentrations to enable interpretation of metabolic control is pre-breakfast.

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“…Furthermore, we would like to emphasize the importance of the Phe/Tyr ratio not only for TPN protocols during the neonatal period, but also for the long-term follow-up of HPA patients. Increased level of Phe/Tyr ratio is recently recognized as a sensitive indicator of the metabolic state in HPA patients, being strongly associated with cognitive deficits, often more than the increase of Phe level alone [16]. In addition, it is crucial the evaluation of the Phe/Tyr ratio when the follow-up is performed with a different method, such as an AA analyzer.…”

Section: Discussionmentioning

confidence: 99%

A Case of Suspected Hyperphenylalaninemia at Newborn Screening by Tandem Mass Spectrometry during Total Parenteral Nutrition

et al. 2020

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Phenylketonuria (PKU) is a rare autosomal recessive condition affecting about 1 in 10,000 people in the Europe, with a higher rate in some countries, like Ireland and Italy. In Italy, newborn screening (NBS) by MS/MS allows the diagnostic suspicion of PKU and its variants (Hyperphenylalaninemia (HPA), Tetrahydrobiopterin (BH4) synthesis deficiency, and Tetrahydrobiopterin (BH4) recycling deficiency) through the quantification of Phenylalanine (Phe) and the Phenylalanine/Tyrosine (Phe/Tyr) ratio in dried blood Spot (DBS) samples. Here, we report a case of an HPA whose suspicion was possible with expanded NBS, even if the normal-weight newborn was in total parenteral nutrition (TPN). It is known that TPN may present metabolic alterations, mainly for amino acids at NBS in MS/MS, frequently causing false positives. Actually, TPN is considered a special protocol in NBS, requiring several sample collections. In particular, a DBS sample is required before TPN, at basal time point (48 h after birth) and 72 h after the end of the procedure. In the case we report, even if the first DBS sample (before TPN) resulted negative, the repeated NBS tests revealed increased levels of Phe and dramatically high Phe/Tyr ratio. Thus, the newborn was recalled, and the NBS test was repeated several times before that HPA suspicion was confirmed by other specific biochemical tests. This case highlights the importance of Phe/Tyr ratio, only detectable by MS/MS analysis, in supporting the diagnostic suspicion during amino acids administration in the neonatal period.

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Comparison of tandem mass spectrometry and amino acid analyzer for phenylalanine and tyrosine monitoring—Implications for clinical management of patients with hyperphenylalaninemia

Cited by 49 publications

References 27 publications

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

A Case of Suspected Hyperphenylalaninemia at Newborn Screening by Tandem Mass Spectrometry during Total Parenteral Nutrition

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