Original Paper Ann Nutr Metab DOI: 10.1159/000510260
Received: April 2, 2020 Accepted: July 16, 2020 Published online: September 30, 2020
Everyday Life, Dietary Practices, and Health Conditions of Adult PKU Patients: A Multicenter, Cross-Sectional Study Annemarie Klimek a Christoph Baerwald b Martin Schwarz c Frank Rutsch d Klaus G. Parhofer e Ursula Plöckinger f Margret Heddrich-Ellerbrok g Stephan vom Dahl h Klaus Schöne i Markus Ott j Frauke Lang a Julia B. Hennermann a
aVilla
Metabolica, Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Mainz, Germany; bRheumatology Unit, Department of Internal Medicine, Neurology and Dermatology, University Medical Center Leipzig, Leipzig, Germany; cPractice Cooperation and Training Practice Kaarst, Kaarst, Germany; dDepartment of Pediatrics, University Medical Center Münster, Münster, Germany; eMedical Department IV - Grosshadern, University Munich, Munich, Germany; fInterdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité University Medicine Berlin, Berlin, Germany; gEndokrinologikum Hamburg, Hamburg, Germany; hDepartment for Gastroenterology, Hepatology and Infectious Diseases, University Medical Center Düsseldorf, Düsseldorf, Germany; iInstitute for Teachers’ Health, University Medical Center Mainz, Mainz, Germany; jNutricia GmbH, Metabolics Expert Centre DACH, Frankfurt, Germany
Abstract Background: Only few data on dietary management of adult phenylketonuria (PKU) patients are published. Objectives: This study aimed to assess living situation, dietary practices, and health conditions of early-treated adult PKU patients. Methods: A total of 183 early-treated PKU patients ≥18 years from 8 German metabolic centers received access to an online survey, containing 91 questions on sociodemographic data, dietary habits, and health conditions. Results: 144/183 patients (66% females) completed the questionnaire. Compared with German population, the proportion of singleperson households was higher (22 vs. 47%), the rate of child-
[email protected] www.karger.com/anm
© 2020 S. Karger AG, Basel
birth was lower (1.34 vs. 0.4%), but educational and professional status did not differ. 82% of the patients adhered to a low-protein diet, 45% consumed modified low-protein food almost daily, and 84% took amino acid mixtures regularly. 48% of the patients never interrupted diet, and 14% stopped diet permanently. 69% of the patients reported to feel better with diet, and 91% considered their quality of life at least as good. The prevalence of depressive symptoms was high (29%) and correlated significantly to phenylalanine blood concentrations (p = 0.046). However, depressive symptoms were only mild in the majority of patients. Conclusion: This group of early-treated adult German PKU patients is socially well integrated, reveals a surprisingly high adherence to diet and amino acid intake, and considers the restrictions of diet to their daily life as low. © 2020 S. Karger AG, Basel Data are part of the doctoral thesis of Annemarie Klimek.
Julia B. Hennermann Department of Pediatric and Adolescent Medicine, University Medical Center Mainz Langenbeckstr. 1 DE 55131 Mainz (Germany) julia.hennermann @ unimedizin-mainz.de
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Keywords Phenylketonuria · Diet · Amino acid mixture · Adulthood · Adherence
Phenylketonuria (PKU; OMIM 261600) is an autosomal-recessive inherited metabolic disorder caused by mutations of the gene encoding for phenylalanine hydroxylase (PAH; EC 1.14.16.1). A deficiency of PAH results in elevated concentrations of phenylalanine (Phe) in the blood, CSF, and brain. In general, untreated patients with PKU suffer from severe intellectual impairment, seizures, and psychiatric symptoms [1]. The incidence of PKU in Germany is estimated to be 1:5,500 with about 6,000 adult PKU patients living in Germany, Switzerland, and Austria [2]. Treatment of PKU aims at keeping Phe blood levels low to prevent mental retardation and neurological defects. Since the first therapy attempts in the early 1950s, a lifelong Phe-restricted diet combined with supplementation of Phe-free amino acid mixtures (AAM)/glycomacropeptide protein formulas (GMP) still is major treatment for patients with PKU. In 2008, chaperone therapy with sapropterin was approved for patients with a milder form of PKU allowing a relaxation of dietary therapy [3]. Just recently, enzyme substitution therapy was approved for PKU patients aged ≥16 years. However, this treatment is associated with severe side effects [3]. Currently, it is unclear whether strict Phe control is also important in adult life. Although recommended by a recent European consensus statement [4], many patients do not follow a strict diet after puberty [5]. Until now, only very few data are available on everyday life, dietary practices, compliance to treatment, and personal health conditions in adult PKU patients. Therefore, the objective of this study was a national multicenter evaluation of living situation, dietary practices, and health conditions in early-treated adult PKU patients.
Patients and Methods This multicenter cross-sectional prospective noninterventional study was conducted in 8 different adult PKU patients treating German metabolic centers (Mainz, Berlin, Düsseldorf, Hamburg, Leipzig, Kaarst, Münster, and Munich). Inclusion criteria were age ≥18 years, confirmed diagnosis of classical PKU or moderate PKU with indication for dietary therapy, and early diagnosis of PKU by newborn screening. Exclusion criteria were hyperphenylalaninemia with no need for treatment, late-diagnosed PKU, that is, diagnosis after newborn period, and mental retardation due to latediagnosed PKU. The survey contained 91 questions with various formats to answer (single choice, multiple choice, and free text), including a standardized disorder rating scale, the Giessen Subjective Com-
2
Ann Nutr Metab DOI: 10.1159/000510260
plaints List (Gießener Beschwerdebogen [GBB]) [6], and a standardized questionnaire on depression, the Patient Health Questionnaire-4 (PHQ-4) [7]. Questions concerned sociodemographic data, education, job, medical treatment, dietary habits, health conditions, quality of life, and interaction with other PKU patients. Main emphasis of the survey was the evaluation of dietary regimen with multiple questions on the type of diet, preferred/avoided food, AAM intake, and potential restrictions in daily life. Data on living situations and health conditions were compared with published data on age-matched German average population [8, 9]. The GBB contains questions on general health complaints for the domains exhaustion, stomach discomfort, pain, and heart problems and allows answering in 5 categories: “not at all”, “little”, “to some extent”, “moderate”, or “very burdensome”; the last 3 categories are rated as burdensome. The results of the GBB were compared with data of age-related German population [6]. The PHQ-4 is a standardized ultrabrief measure of depression and anxiety in adults. It consists of questions on overall feeling and wellbeing within the last 4 weeks that may be answered with “never”, “at some days”, “on more than half of the days”, or “every day”. Every answer was rated resulting in a final score that defines either no, mild, moderate, or severe depressive symptoms. The interview tool used for the survey was a platform named LimeSurvey, an international online application for surveys [10], hosted on a dedicated server of the University of Mainz. The surveys were performed anonymously. This format was chosen to obtain the most truthful answers. All patients were informed about the study by their treating metabolic center. After giving written informed consent, patients received an online link to start the survey. If requested by the patients, a printed version of the questionnaire was accessible. The study was approved by all responsible ethics committees. Statistics Statistical analyses were performed by IBM SPSS Statistics Version 20. Correlations between patients’ Phe blood concentrations, type of diet, and depression score were calculated with the Spearman test. Significance was defined as a p level of 1,200 Unknown 0
full time, 24% part-time, 2% were unemployed, 18% in training/university, and 9% in home-based work or “other.” Medical Treatment 89% of the patients indicated to have regular contact to a metabolic medical center: 16% >4 times/year, 24% 3–4 times/year, 24% twice a year, and 25% once a year. 95% of the patients indicated to control Phe blood concentrations at least once a year: 50% ≥5–6 times/year, 28% 3–4 times/year, and 17% 1–2 times/year. 5% reported to never control Phe concentrations. In total, 40% of the patients stated their recent Phe blood concentration to be 50% of adult PKU patients [13, 15–17]. Similarly, our study reveals a surprisingly high adherence to diet with regular AAM intake in >80% of the early-treated PKU patients. Almost 50% of the patients never had interrupted diet. This good result of dietary adherence might be due to changing recommendations for treatment for PKU, improving education of PKU patients and improving AAM formulation as well as establishing specialized adult centers for PKU patients that better meet the needs of adult patients. All this may have resulted in evolving a new generation of early-treated adult PKU patients with better adherence to diet. However, there might be a bias in our study results as mainly patients adhering more strictly to diet may have participated in this study. The high rate of women in the study population may contribute to that, as, due to the need of strict diet during pregnancy, female PKU patients potentially better adhere to diet and more strictly keep contact to the metabolic centers. Nevertheless, these data underline the strong importance of an adequate follow-up and treatment of adult PKU patients. There seem to be barriers in the basic supply of modified low-protein food as only few patients are using them daily. In Germany, modified low-protein food is not covered by medical insurances. Costs for low-protein food are calculated to be 60–85% higher than for normal food [18]. This emphasizes that the special dietary needs of adult PKU patients should be investigated more in detail to develop even more suitable products beside the already existing variety of modified low protein and appropriate vegan food. Our study revealed a slightly lower prevalence of malign tumors in PKU patients. This finding seems to be a statistical phenomenon due to the small number of patients; however, in in vitro studies metabolites of Phe were shown to inhibit the proliferation of certain cancer cell lines [19]. In this study, the GBB was applied for the first time in PKU patients. The advantage of this well-established tool is the systematical assessment of a broad range of different health problems. The GBB revealed in PKU patients only an increase in need of sleep, fatigue, exhaustibility, weariness, and gastrointestinal discomfort. As reported
In addition, in more severe chronic diseases, for example, Gaucher disease, the interest in patients’ support groups is much higher [28]. Thus, our data underline that despite suffering from a chronic disease equal opportunities exist for patients with PKU, and a happy, normal life may be achieved by a very high percentage of affected patients. Although some of the results may have a bias due to selection of patients for this study, the power of this study is its multicenter design, including centers all over Germany (former eastern and former western part of Germany), and the high number of included patients. Conclusion
These data show that adult PKU patients are socially well integrated. Adherence to diet and intake of AAM in this group of adult PKU patients was shown to be astonishingly high, and restrictions in daily life due to diet have been considered as surprisingly low. The good adherence to diet is associated with a low rate of comorbidities.
secutively by the ethics committee in Berlin, Düsseldorf, Hamburg, Leipzig, Munich, and Westphalia-Lippe. Informed written consent including consent for publication was obtained from all patients before being included in the study.
Conflict of Interest Statement A.K., C.B., K.G.P., M.H.-E., and K.S. have no conflicts of interest. M.S. received travel support by Vitaflo and Dr. Schär Medical Nutrition. F.R. received consulting fees and grant support from BioMarin. U.P. received unrestricted grants from Milupa Nutricia Metabolics. S.V.D. receives lecture fees, is a member of advisory boards and did receive unrestricted research grants from Sanofi Genzyme, Shire, Falk, Roche, and Novartis. M.O. is a staff member of Nutricia GmbH, Nutricia Metabolics Expert Centre DACH. F.L. received travel support and/or speaker fees by Nutricia GmbH, Nutricia Metabolics Expert Centre DACH, Vitaflo, METAX GmbH, and BioMarin, Germany. J.B.H. received travel support from Nutricia GmbH, Nutricia Metabolics Expert Centre DACH.
Funding Sources This study was partially supported by Nutricia GmbH, Nutricia Metabolics Expert Centre DACH, Frankfurt.
Acknowledgements We thank Nutricia GmbH, Nutricia Metabolics Expert Centre DACH, Frankfurt, for financial support. In addition, we thank S. Singer, IMBEI University Medical Center Mainz, for counseling in establishing the questionnaire, and P. Mildenberger, IMBEI University Medical Center Mainz, for statistic counseling. Furthermore, we thank all patients for filling out the questionnaire.
Statement of Ethics All procedures followed were in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2013. This study was approved by the ethics committee in Rhineland-Palatinate (Reference No. 837.037.15 [9805]) and con-
Author Contributions A. Klimek was involved in conception and design of the study, analysis and interpretation of the data, and drafting the article. C. Baerwald, M. Schwarz, F. Rutsch, K.G. Parhofer, U. Plöckinger, M. Heddrich-Ellerbrok, S. vom Dahl, and M. Ott were involved in conception of the study, evaluation of data, and revising the manuscript critically for important intellectual content. K. Schöne was involved in establishing the online survey, analyses of data, and revising the manuscript critically. F. Lang was involved in conception and design of the study, interpretation of the data, and revising the article critically for important intellectual content. J.B. Hennermann was involved in conception and design of the study, analysis and interpretation of the data, drafting the article, and revising it critically for important intellectual content. All authors read and approved the final version of the manuscript.
References
PKU Diet in Adults
3 Lichter-Konecki U, Vockley J. Phenylketonuria: current treatments and future developments. Drugs. 2019;79(5):495–500. 4 van Spronsen FJ, van Wegberg AM, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. 2017; 5(9):743–56.
Ann Nutr Metab DOI: 10.1159/000510260
5 Walter JH, White FJ, Hall SK, MacDonald A, Rylance G, Boneh A, et al. How practical are recommendations for dietary control in phenylketonuria? Lancet. 2001;360(9326):55–7. 6 Brähler E, Hinz A, Scheer JW. GBB-24. Der gießener beschwerdebogen. [Gießen body complaint list]. Manual. 3rd revised and standardized version. Bern: Verlag Hans Huber; 2008.
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1 Waisbren S, White DA. Screening for cognitive and social-emotional problems in individuals with PKU: tools for use in the metabolic clinic. Mol Genet Metab. 2010;99(Suppl 1):S96–9. 2 Burgard P, Wendel U. Hyperphenylalaninämie/phenylketonurie. In: vom Dahl S, Lammert F, Ullrich K, Wendel U, editors. Angeborene Stoffwechselkrankheiten bei Erwachsenen. Berlin, Heidelberg: Springer; 2014. p. 265–74.
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15 Bik-Multanowski M, Didycz B, Mozrzymas R, Nowacka M, Kaluzny L, Cichy W, et al. Quality of life in noncompliant adults with phenylketonuria after resumption of the diet. J Inherit Metab Dis. 2008;31(Suppl 2):S415–8. 16 Cazzorla C, Bensi G, Biasucci G, Leuzzi V, Manti F, Musumeci A, et al. Living with phenylketonuria in adulthood: the PKU ATTITUDE study. Mol Genet Metab Rep. 2018;16: 39–45. 17 Das AM, Goedecke K, Meyer U, Kanzelmeyer N, Koch S, Illsinger S, et al. Dietary habits and metabolic control in adolescents and young adults with phenylketonuria: self-imposed protein restriction may be harmful. JIMD Rep. 2014;13:149–58. 18 Peul S. Financial burden due a diet caused with inborn metabolic disorder. Monatsschrift Kinderheilkd. 2008;156:841. 19 Han S, Wada RK, Sidell N. Differentiation of human neuroblastoma by phenylacetate is mediated by peroxisome proliferator-activated receptor gamma. Cancer Res. 2001;61(10): 3998–4002. 20 Koch R, Burton B, Hoganson G, Peterson R, Rhead W, Rouse B, et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis. 2002;25(5):333–46. 21 Robertson LV, McStravick N, Ripley S, Weetch E, Donald S, Adam S, et al. Body mass index in adult patients with diet-treated phenylketonuria. J Hum Nutr Diet. 2012;26(Suppl 1):1–6. 22 Bilder DA, Noel JK, Baker ER, Irish W, Chen Y, Merilainen MJ, et al. Systematic review and meta-analysis of neuropsychiatric symptoms and executive functioning in adults with phenylketonuria. Dev Neuropsychol. 2016;41(4): 245–60.
23 Gentile JK, Ten Hoedt AE, Bosch AM. Psychosocial aspects of PKU: hidden disabilities: a review. Mol Genet Metab. 2010;99(Suppl 1): S64–7. 24 Bretschneider J, Kuhnert R, Hapke U. Depressive symptomatik bei erwachsenen in deutschland. J Health Monit. 2017;2:81–8. 25 Burlina AP, Lachmann RH, Manara R, Cazzorla C, Celato A, van Spronsen FJ, et al. The neurological and psychological phenotype of adult patients with early-treated phenylketonuria: a systematic review. J Inherit Metab Dis. 2019;42(2):209–19. 26 Weikert B, Buttery AK, Heidemann C, Rieckmann N, Paprott R, Maske UE, et al. Glycaemic status and depressive symptoms among adults in Germany: results from the German Health Interview and Examination Survey for Adults (DEGS1). Diabet Med. 2018; 35(11): 1552–61. 27 Bradley C, Eschwège E, de Pablos-Velasco P, Parhofer KG, Simon D, Vandenberghe H, et al. Predictors of quality of life and other patient-reported outcomes in the PANORAMA multinational study of people with type 2 diabetes. Diabetes Care. 2018;41(2):267–76. 28 Žnidar I, Collin-Histed T, Niemeyer P, Parkkinen J, Lauridsen AG, Zariņa S, et al. The European Gaucher Alliance: a survey of member patient organisations’ activities, healthcare environments and concerns. Orphanet J Rare Dis. 2014;9:134.
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7 Löwe B, Wahl I, Rose M, Spitzer C, Glaesmer H, Wingenfeld K, et al. A 4-item measure of depression and anxiety: validation and standardization of the Patient Health Questionnaire-4 (PHQ-4) in the general population. J Affect Disord. 2010;122(1–2):86–95. 8 Available from: https: //www.destatis.de/EN/ Homepage.html. 9 Available from: https: //www.rki.de/DE/ Home/homepage_node.html. 10 Available from: https: //www.limesurvey.org/ de/. 11 Simon E, Schwarz M, Roos J, Dragano N, Geraedts M, Siegrist J, et al. Evaluation of quality of life and description of the sociodemographic state in adolescent and young adult patients with phenylketonuria (PKU). Health Qual Life Outcomes. 2008;6:25. 12 Mütze U, Thiele AG, Baerwald C, Ceglarek U, Kiess W, Beblo S. Ten years of specialized adult care for phenylketonuria: a single-centre experience. Orphanet J Rare Dis. 2016;11: 27. 13 Trefz FK, van Spronsen FJ, MacDonald A, Feillet F, Muntau AC, Belanger-Quintana A, et al. Management of adult patients with phenylketonuria: survey results from 24 countries. Eur J Pediatr. 2015;174(1):119–27. 14 Burgard P, Bremer HJ, Bührdel P, Clemens PC, Mönch E, Przyrembel H, et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr. 1999;158(1):46–54.
Received: April 2, 2020 Accepted: July 16, 2020 Published online: September 30, 2020
Everyday Life, Dietary Practices, and Health Conditions of Adult PKU Patients: A Multicenter, Cross-Sectional Study Annemarie Klimek a Christoph Baerwald b Martin Schwarz c Frank Rutsch d Klaus G. Parhofer e Ursula Plöckinger f Margret Heddrich-Ellerbrok g Stephan vom Dahl h Klaus Schöne i Markus Ott j Frauke Lang a Julia B. Hennermann a
aVilla
Metabolica, Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Mainz, Germany; bRheumatology Unit, Department of Internal Medicine, Neurology and Dermatology, University Medical Center Leipzig, Leipzig, Germany; cPractice Cooperation and Training Practice Kaarst, Kaarst, Germany; dDepartment of Pediatrics, University Medical Center Münster, Münster, Germany; eMedical Department IV - Grosshadern, University Munich, Munich, Germany; fInterdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité University Medicine Berlin, Berlin, Germany; gEndokrinologikum Hamburg, Hamburg, Germany; hDepartment for Gastroenterology, Hepatology and Infectious Diseases, University Medical Center Düsseldorf, Düsseldorf, Germany; iInstitute for Teachers’ Health, University Medical Center Mainz, Mainz, Germany; jNutricia GmbH, Metabolics Expert Centre DACH, Frankfurt, Germany
Abstract Background: Only few data on dietary management of adult phenylketonuria (PKU) patients are published. Objectives: This study aimed to assess living situation, dietary practices, and health conditions of early-treated adult PKU patients. Methods: A total of 183 early-treated PKU patients ≥18 years from 8 German metabolic centers received access to an online survey, containing 91 questions on sociodemographic data, dietary habits, and health conditions. Results: 144/183 patients (66% females) completed the questionnaire. Compared with German population, the proportion of singleperson households was higher (22 vs. 47%), the rate of child-
[email protected] www.karger.com/anm
© 2020 S. Karger AG, Basel
birth was lower (1.34 vs. 0.4%), but educational and professional status did not differ. 82% of the patients adhered to a low-protein diet, 45% consumed modified low-protein food almost daily, and 84% took amino acid mixtures regularly. 48% of the patients never interrupted diet, and 14% stopped diet permanently. 69% of the patients reported to feel better with diet, and 91% considered their quality of life at least as good. The prevalence of depressive symptoms was high (29%) and correlated significantly to phenylalanine blood concentrations (p = 0.046). However, depressive symptoms were only mild in the majority of patients. Conclusion: This group of early-treated adult German PKU patients is socially well integrated, reveals a surprisingly high adherence to diet and amino acid intake, and considers the restrictions of diet to their daily life as low. © 2020 S. Karger AG, Basel Data are part of the doctoral thesis of Annemarie Klimek.
Julia B. Hennermann Department of Pediatric and Adolescent Medicine, University Medical Center Mainz Langenbeckstr. 1 DE 55131 Mainz (Germany) julia.hennermann @ unimedizin-mainz.de
Downloaded by: HSC Library-Serials Dept., SUNY 129.49.5.35 - 10/3/2020 7:01:35 PM
Keywords Phenylketonuria · Diet · Amino acid mixture · Adulthood · Adherence
Phenylketonuria (PKU; OMIM 261600) is an autosomal-recessive inherited metabolic disorder caused by mutations of the gene encoding for phenylalanine hydroxylase (PAH; EC 1.14.16.1). A deficiency of PAH results in elevated concentrations of phenylalanine (Phe) in the blood, CSF, and brain. In general, untreated patients with PKU suffer from severe intellectual impairment, seizures, and psychiatric symptoms [1]. The incidence of PKU in Germany is estimated to be 1:5,500 with about 6,000 adult PKU patients living in Germany, Switzerland, and Austria [2]. Treatment of PKU aims at keeping Phe blood levels low to prevent mental retardation and neurological defects. Since the first therapy attempts in the early 1950s, a lifelong Phe-restricted diet combined with supplementation of Phe-free amino acid mixtures (AAM)/glycomacropeptide protein formulas (GMP) still is major treatment for patients with PKU. In 2008, chaperone therapy with sapropterin was approved for patients with a milder form of PKU allowing a relaxation of dietary therapy [3]. Just recently, enzyme substitution therapy was approved for PKU patients aged ≥16 years. However, this treatment is associated with severe side effects [3]. Currently, it is unclear whether strict Phe control is also important in adult life. Although recommended by a recent European consensus statement [4], many patients do not follow a strict diet after puberty [5]. Until now, only very few data are available on everyday life, dietary practices, compliance to treatment, and personal health conditions in adult PKU patients. Therefore, the objective of this study was a national multicenter evaluation of living situation, dietary practices, and health conditions in early-treated adult PKU patients.
Patients and Methods This multicenter cross-sectional prospective noninterventional study was conducted in 8 different adult PKU patients treating German metabolic centers (Mainz, Berlin, Düsseldorf, Hamburg, Leipzig, Kaarst, Münster, and Munich). Inclusion criteria were age ≥18 years, confirmed diagnosis of classical PKU or moderate PKU with indication for dietary therapy, and early diagnosis of PKU by newborn screening. Exclusion criteria were hyperphenylalaninemia with no need for treatment, late-diagnosed PKU, that is, diagnosis after newborn period, and mental retardation due to latediagnosed PKU. The survey contained 91 questions with various formats to answer (single choice, multiple choice, and free text), including a standardized disorder rating scale, the Giessen Subjective Com-
2
Ann Nutr Metab DOI: 10.1159/000510260
plaints List (Gießener Beschwerdebogen [GBB]) [6], and a standardized questionnaire on depression, the Patient Health Questionnaire-4 (PHQ-4) [7]. Questions concerned sociodemographic data, education, job, medical treatment, dietary habits, health conditions, quality of life, and interaction with other PKU patients. Main emphasis of the survey was the evaluation of dietary regimen with multiple questions on the type of diet, preferred/avoided food, AAM intake, and potential restrictions in daily life. Data on living situations and health conditions were compared with published data on age-matched German average population [8, 9]. The GBB contains questions on general health complaints for the domains exhaustion, stomach discomfort, pain, and heart problems and allows answering in 5 categories: “not at all”, “little”, “to some extent”, “moderate”, or “very burdensome”; the last 3 categories are rated as burdensome. The results of the GBB were compared with data of age-related German population [6]. The PHQ-4 is a standardized ultrabrief measure of depression and anxiety in adults. It consists of questions on overall feeling and wellbeing within the last 4 weeks that may be answered with “never”, “at some days”, “on more than half of the days”, or “every day”. Every answer was rated resulting in a final score that defines either no, mild, moderate, or severe depressive symptoms. The interview tool used for the survey was a platform named LimeSurvey, an international online application for surveys [10], hosted on a dedicated server of the University of Mainz. The surveys were performed anonymously. This format was chosen to obtain the most truthful answers. All patients were informed about the study by their treating metabolic center. After giving written informed consent, patients received an online link to start the survey. If requested by the patients, a printed version of the questionnaire was accessible. The study was approved by all responsible ethics committees. Statistics Statistical analyses were performed by IBM SPSS Statistics Version 20. Correlations between patients’ Phe blood concentrations, type of diet, and depression score were calculated with the Spearman test. Significance was defined as a p level of 1,200 Unknown 0
full time, 24% part-time, 2% were unemployed, 18% in training/university, and 9% in home-based work or “other.” Medical Treatment 89% of the patients indicated to have regular contact to a metabolic medical center: 16% >4 times/year, 24% 3–4 times/year, 24% twice a year, and 25% once a year. 95% of the patients indicated to control Phe blood concentrations at least once a year: 50% ≥5–6 times/year, 28% 3–4 times/year, and 17% 1–2 times/year. 5% reported to never control Phe concentrations. In total, 40% of the patients stated their recent Phe blood concentration to be 50% of adult PKU patients [13, 15–17]. Similarly, our study reveals a surprisingly high adherence to diet with regular AAM intake in >80% of the early-treated PKU patients. Almost 50% of the patients never had interrupted diet. This good result of dietary adherence might be due to changing recommendations for treatment for PKU, improving education of PKU patients and improving AAM formulation as well as establishing specialized adult centers for PKU patients that better meet the needs of adult patients. All this may have resulted in evolving a new generation of early-treated adult PKU patients with better adherence to diet. However, there might be a bias in our study results as mainly patients adhering more strictly to diet may have participated in this study. The high rate of women in the study population may contribute to that, as, due to the need of strict diet during pregnancy, female PKU patients potentially better adhere to diet and more strictly keep contact to the metabolic centers. Nevertheless, these data underline the strong importance of an adequate follow-up and treatment of adult PKU patients. There seem to be barriers in the basic supply of modified low-protein food as only few patients are using them daily. In Germany, modified low-protein food is not covered by medical insurances. Costs for low-protein food are calculated to be 60–85% higher than for normal food [18]. This emphasizes that the special dietary needs of adult PKU patients should be investigated more in detail to develop even more suitable products beside the already existing variety of modified low protein and appropriate vegan food. Our study revealed a slightly lower prevalence of malign tumors in PKU patients. This finding seems to be a statistical phenomenon due to the small number of patients; however, in in vitro studies metabolites of Phe were shown to inhibit the proliferation of certain cancer cell lines [19]. In this study, the GBB was applied for the first time in PKU patients. The advantage of this well-established tool is the systematical assessment of a broad range of different health problems. The GBB revealed in PKU patients only an increase in need of sleep, fatigue, exhaustibility, weariness, and gastrointestinal discomfort. As reported
In addition, in more severe chronic diseases, for example, Gaucher disease, the interest in patients’ support groups is much higher [28]. Thus, our data underline that despite suffering from a chronic disease equal opportunities exist for patients with PKU, and a happy, normal life may be achieved by a very high percentage of affected patients. Although some of the results may have a bias due to selection of patients for this study, the power of this study is its multicenter design, including centers all over Germany (former eastern and former western part of Germany), and the high number of included patients. Conclusion
These data show that adult PKU patients are socially well integrated. Adherence to diet and intake of AAM in this group of adult PKU patients was shown to be astonishingly high, and restrictions in daily life due to diet have been considered as surprisingly low. The good adherence to diet is associated with a low rate of comorbidities.
secutively by the ethics committee in Berlin, Düsseldorf, Hamburg, Leipzig, Munich, and Westphalia-Lippe. Informed written consent including consent for publication was obtained from all patients before being included in the study.
Conflict of Interest Statement A.K., C.B., K.G.P., M.H.-E., and K.S. have no conflicts of interest. M.S. received travel support by Vitaflo and Dr. Schär Medical Nutrition. F.R. received consulting fees and grant support from BioMarin. U.P. received unrestricted grants from Milupa Nutricia Metabolics. S.V.D. receives lecture fees, is a member of advisory boards and did receive unrestricted research grants from Sanofi Genzyme, Shire, Falk, Roche, and Novartis. M.O. is a staff member of Nutricia GmbH, Nutricia Metabolics Expert Centre DACH. F.L. received travel support and/or speaker fees by Nutricia GmbH, Nutricia Metabolics Expert Centre DACH, Vitaflo, METAX GmbH, and BioMarin, Germany. J.B.H. received travel support from Nutricia GmbH, Nutricia Metabolics Expert Centre DACH.
Funding Sources This study was partially supported by Nutricia GmbH, Nutricia Metabolics Expert Centre DACH, Frankfurt.
Acknowledgements We thank Nutricia GmbH, Nutricia Metabolics Expert Centre DACH, Frankfurt, for financial support. In addition, we thank S. Singer, IMBEI University Medical Center Mainz, for counseling in establishing the questionnaire, and P. Mildenberger, IMBEI University Medical Center Mainz, for statistic counseling. Furthermore, we thank all patients for filling out the questionnaire.
Statement of Ethics All procedures followed were in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2013. This study was approved by the ethics committee in Rhineland-Palatinate (Reference No. 837.037.15 [9805]) and con-
Author Contributions A. Klimek was involved in conception and design of the study, analysis and interpretation of the data, and drafting the article. C. Baerwald, M. Schwarz, F. Rutsch, K.G. Parhofer, U. Plöckinger, M. Heddrich-Ellerbrok, S. vom Dahl, and M. Ott were involved in conception of the study, evaluation of data, and revising the manuscript critically for important intellectual content. K. Schöne was involved in establishing the online survey, analyses of data, and revising the manuscript critically. F. Lang was involved in conception and design of the study, interpretation of the data, and revising the article critically for important intellectual content. J.B. Hennermann was involved in conception and design of the study, analysis and interpretation of the data, drafting the article, and revising it critically for important intellectual content. All authors read and approved the final version of the manuscript.
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