Patient’s thoughts and expectations about centres of expertise for PKU

Phenylketonuria (PKU; McKusick #261600) is a rare autosomal recessive inborn error of phenylalanine (Phe) metabolism, caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH) [1]. As with many rare diseases, patients across countries and within the same countries, do not have equality of access to specialized diagnostics, treatment or care [2]. To improve access to care, in 2011, the European parliament supported cross-border healthcare by giving patients the right to receive medical treatment in another EU member state (Directive 2011/24/EU). To further improve access to care, European Reference Networks (ERNs) were created in 2017, through collaboration with the European Union, physicians and patients. An ERN is a virtual network consisting of centres of expertise (CE) distributed throughout Europe. CEs must meet specific criteria and conditions to become part of an ERN (2014/286/EU). The ERN specific for inherited metabolic disorders (MetabERN) aims to connect CEs across Europe to promote prevention, accelerate diagnosis and improve standards of care for patients living with these disorders.

In the Netherlands, the Dutch minister of Health, Welfare and Sport appointed 2 of 6 metabolic centres (University Medical Centre Groningen and Amsterdam University Medical Centre) as CE’s for PKU specifically because of their multidisciplinary care, leading PKU scientific research and specific quality criteria [3, 4]. In order to be considered as a CE, Hannerman-Weber et al. [5] emphasises centres must combine operational care with explorative activities. Indeed, both Dutch CEs for PKU are affiliated with the MetabERN.

Following the ERN structure, CEs in PKU should have assessed all patients with PKU in their designated area. This means that all patients should receive care from a CE, without the CE necessarily taking over routine care from the local metabolic treatment centres. In contrast, Germany and the United Kingdom (UK), do not appoint CEs in PKU. From 2013, Germany has developed a three-tiered structure for treating rare disorders including appointing all metabolic centres as CEs. However, not one centre is identified as providing additional expertise in a specific inborn error of metabolism [6]. In the UK, there are centres who provide speciality services to patients with inherited metabolic disorders, including PKU, but like Germany no one centre is identified as expert in PKU care. The thoughts and expectations of patients and caregivers about CEs have not been explored. With this study we aimed to evaluate patients and caregiver understanding, expectations and barriers about PKU care from a CE.

This is the first survey that evaluated the expectations of patients with PKU and caregivers about CEs. As numerous University centres have treated PKU for many years, we expected that the professionals and/or the patients would not see the advantages of travelling to a CE. Interestingly, only 3 of 83 respondents said they would not visit a CE (Fig. 1a). In addition, when participants ‘pictured’ their treatment in their own hospital as an appointed CE (n = 67), 61% (n = 41) expected more extensive examinations than they receive now.

Before discussing our findings in more detail, some limitations of this study need to be addressed. These small numbers of answers may not represent the aspirations and ideas of the total PKU society. Patients and caregivers who are less interested most likely did not complete the survey. The responder-rate was lower in the relatively larger countries UK and Germany. This probably reflects that this topic is of less interest and less understanding as no PKU centres have been officially appointed yet or the research team was not well known within the country.

In general, PKU is not the only rare disorder a metabolic team is responsible for. Considering there are over 500 rare inherited metabolic disorders described (https://​rarediseases.​info.​gov), it is impossible for a centre to be a leader in scientific research and be informed of all new treatment options and developments in all disorders. Therefore, university metabolic centres should choose disorders which they can provide a higher level of expertise. To continue building expertise, it is valuable that the CEs care for and evaluate a large patient cohort, to learn from and with these patients. Consequently, this new knowledge can be shared with the treatment centres, so that all are able to deliver a high patient care standard and simultaneously use their time to focus on the disorders for which their research and international experience fulfil the criteria of a CE. A study by Camfield et al. confirmed that centrally coordinated specialized care is beneficial for patients as this approach was associated with significant better control of blood Phe, more regular supervisory visits and less frequent discontinuation of diet compared with a decentralized care model [7]. Regarding research output and impact Hannemann-Weber et al. [5] found a positive association with the operational experience, expressed as number of patients treated, and supported the establishment of CEs. Including discussions about clinical studies as part of regular conversations during clinic visits is an important recruitment strategy for rare disease studies [8]. As CEs are leaders in knowledge about the latest developments and research, reviewing more patients with PKU can increase both research participation and output and then further expand knowledge. Together we need to build a structure of CEs within countries, to increase the quality of care.

The frequency patients and caregivers defined they would like to attend a CE along to their own metabolic centre differed. Only 17% of 83 respondents who ‘pictured’ to visit a CE expected to no longer visit their own hospital (Additional file 8: Table 7). In contrast 13 adults of the 37 patients with PKU answered they would like to visit a CE annually (Fig. 2a), which may be the same frequency as they visit their own general metabolic treatment centre. In practice there are barriers when patients visit a CE. In the survey participants identified distance from the CE. A practical solution could be that the CE undertakes ‘outreach’ clinics at different locations, or in the form of video/virtual consultations [9]. Even web-based neuropsychological test batteries are available [10‐12]. For discussing new developments and/or research recruitment, patient webinars could be organised.

Also, most CEs will not immediately have the capacity to see extra patients with PKU. The CE commencement of a new (drug) therapy, which requires expertise and additional monitoring could be the start of accepting additional patient referrals. Approximately 65% of all participants (n = 104) agreed that new treatments should first start in CEs. This is likely to result in increased efficiency as training and explanations will be given by a team who have already developed expertise. Furthermore, adult patients with PKU commonly have many outstanding questions regarding treatment, symptoms, and outcome, and would value from care in a CE. Also, patients and caregivers who choose to visit a CE should always be referred as a matter of right.

Another interesting point was that two thirds of the participants who ‘pictured’ their care was already established in a CE expected a more extensive review. In general, about half of all participants requested to see a psychology and neuropsychologist (Table 2). In most centres in the Netherlands, Germany and UK routine neuropsychological testing and psychological guidance is not part of their usual care package, even though it is a recommendation of the European PKU guidelines [13, 14]. This participant response shows there is patient demand for this service as previously reported [2, 15]. This is understandable as PKU is a brain disease and only blood phenylalanine is measured as a surrogate marker of outcome. It is established that only part of the neurocognitive outcome is explained by the phenylalanine concentrations [16, 17]. To help solve which mechanisms influence cerebral disturbances and cognitive reserve in adults and elderly patients with PKU, and identify which biomarkers optimally predict these mechanisms, CEs are crucial [18‐22]. But more importantly, participants requesting for neuropsychological testing underlines the patients need to explore brain function. If there is more data available about individual neurocognitive outcome, it will help direct the best treatment strategy.

In this study most participants expected that assigning CEs will change the structure and content of PKU care to some extent. Most patients would like to visit a CE or expect the content of their consultations to change when they are already treated in a CE. It is important that patient societies discuss this topic with their members as this is at least partially demand and supply driven. For health care centres it is worthwhile to think about the structure to keep building expertise in PKU care in order to strive for an optimal patient outcome.