Table 1.
Main characteristics of included studies.
| Reference | Country, Setting | Study Design | PKU Phenotype | Sample Size | Age | Gender (M:F) |
Ethnic Origin | |
|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Median (Range) | |||||||
| Acosta et al., 1998 [31] | USA, Multicentre | Prospective, longitudinal | cPKU | 35 | 13.7 (1.9) days | N/A | 20:15 | 33 Caucasian; 2 unknown |
| Aldámiz-Echevarría et al., 2014 [32] | Spain, 14 centres | Retrospective; longitudinal; multicenter | mildHPA mPKU moPKU cPKU All types |
226 43 78 158 505 a |
N/A | (1–18 years) | 236:269 | Caucasian |
| Aldámiz-Echevarría et al., 2013 [33] | Spain, 13 centres | Retrospective; longitudinal | mPKU moPKU cPKU All types |
24 99 15 138 b |
Pre-sapropterin Baseline: 2-y FU: 5.0 y (4.6) 5-y FU: 5.2 y (3.1) Diet Baseline: 2-y FU: 5.0 y 5-y FU: 5.0 y Diet Final: 2-y FU: 7.0 y 5-y FU: 10.2 (3.0) y |
N/A |
Pre-sapropterin Baseline: 2-y FU 18:18 5-y FU 6:4 Diet Group: 2-y FU 36:36 5-y FU 12:8 |
Caucasian |
| Aldámiz-Echevarría et al., 2015 [34] | Spain, 14 centres | Retrospective; longitudinal | mPKU moPKU cPKU All types |
15 42 9 66 c |
Pre-sapropterin Group: 16.9 (10.4) y Diet Group: 16.9 (10.3) y |
(0–4 y) |
Pre-sapropterin Group: 12:10 Diet Group: 24:20 |
Caucasian |
| Alm et al., 1986 [27] | Sweden, single centre | Prospective; longitudinal | All types | 23 d | N/A |
Final age: (8–19 y) |
12:11 | 22 Caucasian; 1 Syrian |
| Daly et al., 2017 [35] | UK, single centre | Prospective; longitudinal | All types | 22 e | N/A | 11 y (6–16 y) | 13:9 | 19 white European; 3 Pakistani |
| Daly et al., 2019 [36] | UK, 2 centres | Randomised; controlled; crossover | All types | 19 f | N/A | 10 y (6–16 y) | 7:11 | 17 white European; 2 Pakistani |
| Dobbelaere et al., 2003 [37] | France, single centre | Cross-sectional; longitudinal | All types | 20 | 4.5 (1.6) y | (8 mo–7 y) | 9:11 | N/A |
| Evans et al., 2017 [38] | Australia, single centre | Prospective; longitudinal | All types | 32 | 9.2 (4.7) y | (0.8–18 y) | 10:22 | N/A |
| Evans et al., 2018 [53] | UK, single centre | Retrospective; longitudinal | All types | 31 | N/A |
Baseline: 20 wk (13–37 wk) Total: (3–24 mo) |
16:15 | N/A |
| Evans et al., 2019 [39] | UK, 3 centres | Open label; longitudinal; prospective; case–control | All types | 20 | N/A |
Baseline: 4.3 mo (2.9–6.6 mo) Total: (3–24 mo) |
14:6 | Caucasian |
| Evers et al., 2018 [28] | The Netherlands 2 centres |
Retrospective; cohort | All types | 39 g |
Pre-sapropterin Group: 13.1 (9.2) y Diet Group: 13.0 (9.2) y |
Pre-sapropterin Group: (2.8–33.7 y) Diet Group: (1.4–33.4 y) |
Pre-sapropterin Group: 5:13 Diet Group: 7:14 |
N/A |
| Ferguson et al., 1996 [54] | UK, Multicentre | Randomised controlled trial | All types | 20 h | N/A | (9–15 y) | 13:7 | N/A |
| Giovaninni et al., 2014 [40] | Italy, 1 centre | Randomised-controlled | mildHPA mPKU cPKU All types |
60 40 15 115 |
mHPA: 9.3 (3.3) y cPKU + mPKU: 9.2 (3.4) y |
N/A | 50:65 | N/A |
| Gökmen-Özel et al., 2011 [41] | UK, 2 centres | Randomised-controlled; crossover |
All types | 14 | N/A | 6.3 (3.0–9.7) y | 12:2 | 13 Caucasian; 1 Asian |
| Green et al.; 2019 [42] | UK, Multicentre | Cross-sectional (pooled analysis of 2 multicenter intervention studies) |
All types | 16 | 29.5 (11.2) y | N/A | 7:9 | N/A |
| Hoeksma et al., 2005 [43] | The Netherlands, 8 centres |
Retrospective; longitudinal | All types | 174 i | N/A | (0–3 y) | N/A | Caucasian |
| Huemer et al., 2007 [44] | Austria, single centre | Prospective; longitudinal | All types | 34 |
Baseline: 8.7 (3.9) y |
(2 mo–15 y) | 22:12 | N/A |
| Kindt et al., 1983 [45] | Norway n/a |
Prospective; longitudinal | All types | 16 | N/A |
End of the study: (2–6 y) |
7:9 | N/A |
| MacDonald et al., 2006 [46] | UK, single centre | Randomised; prospective; crossover | All types | 25 | 6.0 (2.5) y | 6 (2–10) y | 11:14 | N/A |
| MacDonald et al.; 2003 [18] | UK, single centre | Randomised; crossover | All types | 16 j | 5.3 (3.1) y | 4.5 (2–11) y | 4:12 | 15 Caucasian; 1 mixed ethnicity |
| MacDonald et al., 1996 [57] | UK, single centre | Longitudinal observational study | All types | 19 | 6.6 (4.9) y | 4 (1–16) y | 15:4 | Caucasian |
| Pinto et al., 2019 [29] | Portugal, single centre |
Retrospective; longitudinal | mildHPA mPKU cPKU All types |
10 23 7 40 |
17 y | (12–29 y) | 24:16 | Caucasian |
| Ponzone et al., 2008 [47] | Italy, single centre |
Retrospective; longitudinal | mildHPA mPKU moPKU cPKU All types |
5 6 4 7 22 |
8.5 (4.3) y | 8 (1.7–14.7) y | 10:12 | N/A |
| Rocha et al., 2012 & 2013 [25,26] | Portugal, single centre |
Cross-sectional | mildHPA mPKU cPKU All types |
18 42 29 89 |
14.4 (6.6) y | (3–30 y) | 48:41 | Caucasian |
| Rohde et al., 2012 & 2014a [19,20] | Germany, single centre |
Randomised; cross-over | All types | 19 | 4.7 (2.1) y | (2–10) y | N/A | N/A |
| Rohde et al., 2015 [48] | Germany 10 centres |
Retrospective; cross-sectional |
All types | 149 | 7 (6.6) y | 7 (1–15) y | 77:72 | N/A |
| Rohde et al., 2014b [49] | Germany, Multicentre |
Cross-sectional | All types | 67 | N/A | (6–45) y | N/A | N/A |
| Schulpis et al., 2013 [50] | Greece, single centre |
Prospective; cohort | All types | 30 | 5.0 (3.2) y | N/A | 15:15 | N/A |
| Stockler-Ipsiroglu et al., 2015 [58] |
Canada, single centre | Retrospective chart review | mildHPA mPKU moPKU cPKU All types |
4 1 1 5 11 |
5.4 (4.8) y | 4.5 y (1 mo–15.5 y) |
7:4 | N/A |
| Sweeney et al., 2012 [30] | Australia, single centre |
Phase I: Randomised controlled Phase II: Prospective cohort |
moPKU cPKU All types |
2 17 19 |
10.5 (5.7) y | 9.5 y (1.5–20.5) y |
6:13 | N/A |
| Thiele et al., 2017 [51] | Germany, 2 centres | Retrospective; longitudinal | mildHPA cPKU All types |
41 183 224 |
N/A | (0–18 y) | 119:105 | Caucasian |
| Trefz et al., 2009 [52] | Germany, Poland, Spain, USA, 15 centres |
International; double-blind randomised; placebo controlled |
All types | 45 k |
Pre-sapropterin Baseline: 7.7 (2.8) y Placebo Baseline: 7.1 (2.0) y Total: 7.4 y |
(4–12 y) |
Pre-sapropterin Group:
20:13 Placebo: 6:6 |
N/A |
| van Spronsen et al., 2009 [55] | The Netherlands, 8 centres |
Retrospective; longitudinal | All types | 213 | N/A | (1 mo–10 y) | N/A | N/A |
| Wendel et al., 1990 [56] | Germany, single centre | Retrospective; longitudinal | All types | 139 | N/A | (1–6 y) | 66:73 | N/A |
Abbreviations: mildHPA, mild hyperphenylalaninaemia; mPKU, mild phenylketonuria; moPKU, moderate phenylketonuria; cPKU, classical phenylketonuria; mo; months; y, years; FU, follow-up; sapropterin, tetrahydrobiopterin; M:F, male:female; N/A, not available. a From a total of 505 patients (236 M, 269 F), only 98 (53 M, 45 F) were included in the nutritional analysis. b There were two cohorts in this study: (1) sapropterin-treated group followed for 2 years and 5 years, and (2) a diet-only treated group followed for 2 years and 5 years. Only data at baseline (pre-sapropterin treatment) were included in the analysis in the sapropterin-treated group. Phenotype distribution of patients who were followed for 2 years and 5 years in the sapropterin group were as follows: 7 mPKU, 24 moPKU, 5 cPKU (N = 36); and 1 mPKU, and 9 moPKU (N = 10), respectively. Phenotype distribution of diet-only treated patients who were followed for 2 years and 5 years was as follows: 14 mPKU, 48 moPKU, and 10 cPKU (N = 72); 2 mPKU and 18 moPKU (N = 20), respectively. c There were two cohorts in this study: (1) sapropterin-treated group, and (2) diet-only-treated group. Only data at baseline (pre-sapropterin treatment) were included in the analysis in the sapropterin-treated group. Phenotype distribution of patients in the sapropterin- and diet-only-treated groups were as follows: 5 mPKU, 14 moPKU, and 3 cPKU (N = 22); and 10 mPKU, 28 moPKU, and 6 cPKU (N = 44), respectively. d From a total of 23 patients (12 M, 11 F), only 18 were included in the nutritional analysis. e There were two cohorts in this study: (1) patients (N = 13) using glycomacropeptide (CGMP) as a low-Phe protein substitute, and (2) patients (N = 9) using Phe-free amino acid mixtures (AA). After withdrawal of 1 patient from CGMP group, the study was completed with a total of 21 patients. f At baseline, 19 patients were enrolled. After the withdrawal of 1 patient (12 y old), the study was completed with a total of 18 patients. g There were two cohorts in this study: (1) a sapropterin-treated group (N = 21), and (2) diet-only-treated group (N = 19). Only data at baseline (pre-sapropterin treatment) were included in the analysis in the sapropterin-treated group. h At baseline, 20 patients were allocated, but 6/20 patients were excluded due to high blood Phe levels (serum Phe > 700 mmol/L), and 2/20 patients self-withdrew from study. The study was completed with 12 patients. i Due to insufficient dietary data, there were 41, 39, and 57 dropouts in the data on total protein, protein substitute, and natural protein intake, respectively, leaving 133, 135, and 117 subjects to be analysed. j After the withdrawal of a 2 y old girl, the study was completed with N = 15 patients. Prescribed dietary intake data at baseline was shown for N = 16. k Thirty-three patients received sapropterin treatment, and twelve patients received a placebo. Baseline dietary intake data was obtained for only 39 patients (N = 30 sapropterin-treated and N = 9 placebo).