Ten years of specialized adult care for phenylketonuria – a single-centre experience

The need for consistent life-long care for chronically ill patients with special health care issues is increasingly recognized and requires further attention and development [1]. Especially the transition of adolescents from paediatric to adult health care is highly vulnerable [2–4]. They face new responsibilities for their own health care, calling for personal initiative and independence with respect to their disease management. In this situation, they are at risk to drop out of medical care [5, 6]. This is especially true for patients with inherited metabolic diseases, such as phenylketonuria (PKU; OMIM 261600) [7–9]. So far, the majority of adults with PKU are still treated in paediatric centres [8]; specialized adult centres are rare [8, 9]. Current guidelines recommend life-long treatment and medical attention to obtain the best possible neurologic outcome and to avoid comorbidities [10–12]. In addition, with an increasing number of PKU patients reaching reproductive age, the prevention of maternal PKU syndrome, a severe embryopathy affecting the unborn child of insufficiently controlled PKU mothers, is of increasing importance [13].

To overcome these challenges, an adult outpatient clinic and a coordinated transition process for patients with inherited errors of metabolism was established in 2005 in a cooperation of the paediatric outpatient clinic and the department of internal medicine at the University Hospital of Leipzig, Germany [9]. Since then, all patients 18 years and older with inherited metabolic diseases were transferred from paediatric to adult care. The adult metabolic care includes regular clinic visits and laboratory controls as well as dietary counselling and educational training.

The aim of this study was to evaluate the appropriateness of specialized adult metabolic care 10 years after its establishment. For this purpose, we retrospectively analysed medical records with respect to metabolic control, frequency of clinic visits, and adherence to treatment. Also, data on pregnancies and pregnancy outcome as well as sociodemographic data and educational status were recorded. In addition, a cross-sectional survey was performed regarding current therapy, life satisfaction and satisfaction with the transition process and adult care.

Transition from paediatric to adult health care is a particularly vulnerable period for patients with inherited metabolic diseases [20]. Data revealed so far show the need for a special education in inherited metabolic diseases for adult health care providers, new guidelines for adult patients, and an improvement of the structures for transition [7–9, 11, 21]. Most PKU adults are cared for in paediatric centres [8] and there are only few specialized adult outpatient clinics. Therefore, only limited data about PKU adult care are available. In 2005, a transition program and outpatient clinic for adults with inherited metabolic diseases was established in Leipzig [9]. Now, a retrospective data analysis and cross-sectional survey evaluating the first 10 years of specialized adult PKU care was performed.

Analysing clinical practice in a specialized adult outpatient clinic for inherited metabolic diseases over a 10-year period, 81 % of the transferred PKU patients still kept contact to the adult care centre in the last 3 years. Metabolic control was stable over the evaluation period and dried blood Phe concentrations mostly remained within the therapeutic range [17]. Overall sociodemographic, economic and life satisfaction data were comparable to the reference population and 83 % of the PKU adults were satisfied with the transition process and adult care.

Frequency of contact to the metabolic centre varied widely. Some patients did not attend the clinic for some time only to come back for regular care after a while. Looking at 3-year periods, about 80 % of all transferred patients had at least one contact. Due to vocational training or professional and personal reasons, some patients moved to other metabolic centres. Less than 12 % appear to be lost to the specialized care. These data indicate that a successful, continuous follow-up of adult PKU patients is achievable. With a median age of 32 years, our cohort extends previously reported experience from an international survey of adults with PKU, reporting outcomes at a median age below 29 years [8].

During the 10-year follow-up, all supervised PKU patients showed good metabolic control with individual mean Phe concentrations within the therapeutic range according to the current guidelines for the German speaking countries [17]. No significant difference in metabolic control during adulthood could be detected with respect to age at diagnosis or therapeutic strategy during childhood/adolescence. However, as expected, the analysis of the survey yielded significantly higher Phe concentrations in patients off diet compared to those on diet. Patients with optimal metabolic control were also those who attended the clinic more often (data not shown). This indicates that realisation of recommended therapeutic targets, which were shown to improve outcome [22, 23], requires constant patient education. In light of the recently updated US guidelines and the expected European guidelines, which both advocate even stricter metabolic targets, this issue becomes even more important [23]. This stricter recommendation might improve patients’ outcome, but will also carry an even greater burden for the patients to successfully adhere to treatment. Former studies showed therapy adherence declined especially during adolescence and adulthood [9, 24]. In the present survey, half of the adult patients interrupted therapy at least once over an extended period (>4 years). Reasons were former guidelines in the eastern part of Germany, no longer in place [14], but also the typical difficulties in treatment of adolescents and young adults with chronic diseases. Nevertheless, the majority of these patients restarted therapy after picking up regular consultations in the specialised metabolic centre.

Especially the supervision of PKU females in childbearing age represents a great challenge [13]. For this group of patients, strict metabolic control with Phe concentrations between 120 and 360 μmol/l is indispensable before and during pregnancy in order to prevent maternal PKU syndrome [25]. The majority of the evaluated pregnancies in this cohort were planned, well supervised and, therefore, under good metabolic control, in accordance to the current recommendation [25]. One-third of the pregnancies, however, were unplanned and, therefore, occurred under unfavourable metabolic conditions: in unplanned pregnancies significantly higher Phe concentrations were recorded compared to planned pregnancies. This again underscores the importance of specialized adult care in PKU adults. All three children with maternal PKU syndrome were born after unplanned pregnancy with insufficient metabolic control [26]. Unfortunately, the mothers refused to follow any of the recommendations, despite every effort by the metabolic team. Importantly, these documented cases of maternal PKU syndrome might not be representative of the entire scope of maternal PKU syndrome even in our cohort. Since clinically normal infants from PKU mothers are not routinely followed up so far, the incidence of mild forms may be underestimated [27].

Successful transition requires an experienced multidisciplinary team of paediatric and adult health care providers. The majority of the included patients were satisfied with their transition process and care during the last 10 years and cope well with their therapy. For most, adherence to therapy is easier as adults than during childhood. However, especially female patients expressed the wish for an even more intensive care, referring to dietary counselling, real-time information about Phe values and a closer contact for following therapy adaptions (data not shown).

Most of the survey participants still followed a Phe restricted diet and took AAM, albeit not as strictly as during childhood. Moreover, the majority reported good metabolic control to be personally important and were satisfied with their current metabolic control.

Regarding life satisfaction, all patients showed a good general life satisfaction with a mean score above the score of a German reference sample [16]. This is in accordance with former findings in patients with PKU [9, 28]. One might question the relevance of these data as the investigated group is rather small. However, in order to exclude potential confounding factors, strict inclusion criteria were implemented. Life satisfaction of patients on diet was higher with a score difference of 20 points compared to patients off diet. Interestingly, patients on diet scored higher than the general population mean, while those off diet scored lower than the general population mean by the same degree. Due to high variance of scores in patients and the general population, these differences missed significance. This important aspect of therapy continuation is in accordance with a former study reporting that patients’ quality of life improved after reintroduction of a Phe-restricted diet [29]. The resumption of the Phe-restricted diet, however, often represents a great challenge for the patients as they show low therapy adherence or terminate the diet again after a short while [29]. Again, this supports the recommendations for continuous therapy and adult specialised care.

Social outcome acts as an important indicator for the effective life-long treatment of inherited metabolic diseases. In a previous study, we reported some minor differences regarding school graduation compared to the reference population [9]. This is in accordance with similar studies by other groups [30–33]. Despite important improvements in therapeutic management over the past decades, differences of sociodemographic development remain between PKU patients and the control population. This depends not only on time of diagnosis, but also on continuity of consistent treatment throughout childhood, adolescence and the transition period. As expected, patients diagnosed late did not visit regular school, and consequently did not reach a general educational degree. Early diagnosed patients who interrupted their treatment during childhood and adolescence for several years performed markedly poorer with respect to school graduation and educational attainment. In contrast, early diagnosed and continuously treated patients showed no differences in socioeconomic data compared to the healthy population. In some fields they even perform better, as shown by the very low rate of these young PKU adults leaving school without graduation.

The distribution of net income was comparable between early diagnosed PKU patients and the control cohort independent from therapy interruption. It improved since 2008, correcting for inflation and the general economic situation in the state of Saxony [9, 18, 19]. Fortunately, and in contrast to former studies reporting rare parenthood in adult PKU patients [9, 30], the percentage of adults with PKU having children was comparable to the reference population. PKU seems no longer to discourage patients from establishing a family.

The cohort size of the survey was limited by strict inclusion criteria. The lower percentage of patients on diet than in our prior study (73 % vs. 92 %) [9] is influenced by exclusion of women with planned or current pregnancies. As always, a selection bias by inclusion of motivated patients must be considered, especially for the survey data.

The obvious limitation of a single-centre study can currently not be overcome since adult PKU centres are only being established, so that comparable longitudinal data are not available from other sites. Analysis of larger study groups, once available, may add important and interesting aspects.

Continuous care for adult PKU patients in a specialized outpatient clinic is successful, leading to good to satisfactory metabolic control and social outcomes. Uninterrupted consistent metabolic treatment throughout childhood and adolescence positively influences educational, professional and economic success in later life. Despite enormous efforts, prevention of maternal PKU syndrome remains a challenge. Further effort in specialized paediatric and adult metabolic care is needed to prevent loss of follow-up and to support the recommended life-long treatment and/or care.