Introduction

Phenylketonuria (PKU) detection in the neonatal period and the medically prescribed dietary treatment have resulted in one of the great success stories of the last century for the effective prevention of neurological disability. Improvements in dietary management and formulas since the 1960s have been associated with steadily improving outcomes in intellectual functioning, as measured by standard I.Q. scores. Children with early and continuously treated PKU born from 1980s onwards can be expected to develop an I.Q. within the normal range (Burgard 2000).

Despite these improvements, children with early and continuously treated phenylketonuria (ECT-PKU) continue to be at increased risk for developing certain executive function (EF) deficits. EF directs purposeful, adaptive behaviors and the regulation of mood. EF specifically encompasses skills in integration of information across time and space, task switching, self monitoring, abstract and predictive reasoning, and working memory. The current population of children with ECT-PKU continues to show high levels of EF impairment, particularly in processing speed and working memory, resulting in a diagnosis of attention-deficit hyperactivity disorder (ADHD) diagnosis up to five times the norm (Antshel and Waisbren 2003; Arnold et al. 2004; Huijbregts et al. 2002a).

Most studies indicate that EF worsens with higher exposure to phenylalanine (phe) and that high levels of phe, earlier in childhood and across longer periods of time, correlate with steadily worsening EF (for a review and meta-analysis see Waisbren et al. 2007). Secondary problems arising from the biochemistry associated with PKU are thought to primarily affect the dopaminergic systems in the brain due to the disruption of the metabolism of phe to tyrosine (tyr), a precursor to dopamine (Diamond et al. 1997). Experimental data suggest that high phe in concert with low tyrosine (a high phe:tyr ratio) may better explain EF deficits in children with PKU than phe levels alone (Diamond et al. 1997; Luciana et al. 2001; Sharman et al. 2009, 2010). However, the potential role of the phe:tyr ratio in brain development has yet to be extensively researched because the focus of most studies involves phe-only measures, i.e. concurrently, historically, or both (e.g., Antshel and Waisbren 2003; Arnold et al. 2004; Huijbregts et al. 2002a, b).

Clinical applications of the dopamine hypothesis

The phe:tyr ratio in the non-PKU population is approximately 1:1 (Hilton et al. 1986) whereas phe:tyr ratios in the PKU population generally start at around 2.5:1 and can increase to well above 10:1 (Chace et al. 1998). Sharman et al. (2010) recently reported a clinical level of lifetime phe:tyr ratio that was associated with impaired EF. In this sample of children (n = 13; age range 10–17 years), a phe:tyr ratio above 6:1 was significantly and strongly associated with executive function impairment. Further, improved EF was observed in children with the lowest lifetime phe:tyr ratios.

Tyrosine and EF

A question remains as to why a high phe:tyr ratio is strongly related to EF impairments, given that low tyrosine on its own has not yet shown such an association. Mixed results have emerged from past ECT-PKU studies that included increased tyrosine supplementation as a variable (see Cochrane review: Poustie and Rutherford 1999).

It is also important to note that some researchers have questioned the validity of tyrosine treatment (van Spronsen et al. 2001). Nonetheless, there are emerging reports that treatment with tyrosine (over and above that contained in PKU formula) is specifically being used as an adjunct therapy to improve the EF of children with PKU who display deficits. For example, Posner et al. (2009) describe the successful use of supplemental tyrosine to ameliorate ADHD symptoms in a child with PKU.

Current clinical practice

Despite the emerging evidence regarding the potential role of tyrosine in the development of neuropsychological deficits in children with PKU, the extent to which the phe:tyr ratio and/or tyrosine levels are routinely monitored and/or treated in this population of children is largely unknown. Given this possible gap between current understanding and actual practice at the clinical level, the purpose of the following survey was to collect a brief snapshot of tyrosine monitoring and management in children receiving treatment for PKU in metabolic clinics.

Method

A short (20 question) web-based survey was developed to capture information about current clinical practice in the measurement and/or treatment of tyrosine levels in children with PKU, as well as any anecdotal information from clinics as to the perceived usefulness of tyrosine screening and treatment.

Procedure

The survey was emailed directly to all metabolic clinics across Australia and New Zealand where the research team is based. The same survey was also sent to the SSIEM National President/Secretary of each member nation requesting that the survey be forwarded to the clinics in their region that managed children with PKU.

Participants

In total, 20 clinics from 12 countries responded to the survey. Clinics were given the option to identify from which country they were responding. Those respondents who chose to identify their country of origin were located in Australia, Austria, Canada, Ireland, Italy, New Zealand, Spain, Sweden, Switzerland and the United States of America. Surveys were completed by the consultant metabolic physician (n = 17) or metabolic dietician (n = 3). The median number of children managed by each clinic was 60 (mean 105) with a range of 12–500.

Results

Current Phe-screening protocols

As a reference point in terms of consistency of screening protocols for children with PKU internationally, clinics were first asked to indicate both their recommendations to patients regarding frequency of phe monitoring and the actual frequency of phe monitoring for each age range. Questions regarding phe and tyrosine monitoring were split into three age groups according to the Australian Society for Inborn Errors of Metabolism (ASIEM) guidelines (infants 0–12 months, children 1–12 years, adolescents 12–18 years; ASIEM 2005).

Agreement among clinics regarding recommended frequency of phe monitoring was high. During infancy, 80% of clinics both recommended and reported adherence to phe monitoring every 1–2 weeks, the remaining 20% of clinics recommended and received monthly phe monitoring. Phe monitoring during childhood was decreased to monthly by the majority (75%) of clinics. The beginning of attrition from recommended screening frequency in some patients/parents began during childhood, with 40% of patients providing blood samples less frequently than requested. By adolescence, 80% of clinics recommended monthly phe monitoring, the remainder quarterly; however, on average, only 30% of adolescents adhered to the recommended frequency of phe monitoring.

Forty-two percent of clinics indicated either their own country’s guidelines or international guidelines as their primary reference point regarding “safe” phe levels recommended to patients; 15% of clinics cited their “own guidelines” and/or “clinical experience” as their reference point. The remaining clinics listed the cut-offs they used but did not indicate where those figures came from (i.e. formal guidelines). One clinic acknowledged they were unsure of the reference and another noted that they disagreed with the National Institutes of Health (NIH 2000) consensus statement regarding appropriate phe levels.

Biochemical markers and cognitive outcomes

Clinicians were also asked to nominate which biochemical markers they believed best predicted cognitive outcomes in children with PKU. Clinicians were able to select more than one option (i.e. these results will not sum to 100). Fifty-five percent of clinics stated they believed that lifetime phe levels best predicted cognitive outcomes in children with PKU; 55% nominated phe levels prior to age 12 years; 5% stated phe:tyr ratio and 15% indicated that all biochemical markers (phe and tyr across childhood) are important to a similar degree.

Tyrosine monitoring/treatment

In comparison to phe-monitoring practices, frequency of tyrosine monitoring was highly variable, both within countries and internationally. Tyrosine monitoring at least monthly has clearly been on the rise during the last 5 years, with over 80% of clinics now routinely monitoring tyrosine levels in infancy. Figure 1 shows the comparison of tyrosine monitoring practices from over 5 years ago, compared to during the last 2 years.

Fig. 1
figure 1

Reported rate of tyrosine screening from over 5 years ago compared to during the last 2 years

Full size image

Twenty-five percent of clinics reported that they supplemented paediatric patients with tyrosine over and above that contained in PKU formula if their tyrosine levels dropped below “normal” levels. Clinics that recommended optimal tyrosine levels to patients stated they did so on the basis of the normal reference point from laboratory, published data and clinical concerns regarding neurotransmitter function.

Clinical situations/scenarios that were described as requiring supplemental tyrosine treatment included those with persistently low tyrosine levels and younger children with optimal phe levels. One clinic nominated 1 g tyrosine per day as a practical start, other clinics used the “smallest amount” or “whatever” was necessary to shift the tyrosine level back into normal range. The only contraindications to tyrosine supplementation noted were if the patient was allergic to tyrosine (sic) or if dietary control was already good.

Reported side effects/benefits of tyrosine supplementation

Those clinics who used supplemental tyrosine reported no noticeable adverse effects; likewise most reported no clinical improvement apart from one physician who noted that tyrosine supplementation appeared to improve mood if the patient had been exhibiting signs of depression in the first place. One clinic made the observation that in their experience, if PKU formula was adhered to and phe levels were within guidelines, tyrosine regulation was not observed to be necessary.

Neuropsychological data

Fifty percent of clinics reported routine assessments of cognitive function and/or psychological function during childhood. The other 50% reported no routine assessments. Assessments were mostly global measures of IQ and conducted prior to school entry.

Discussion

This practice survey provides a snapshot of current clinical practice, primarily to ascertain current protocols regarding tyrosine monitoring/treatment in children with ECT-PKU and any anecdotal information from clinics regarding their experience with the same. Whilst some caution in interpreting this data is warranted because results will not generalize to all clinics, the findings suggest that tyrosine screening and treatment practices are highly variable both internationally and within countries. This finding is consistent with recent practice surveys (van Spronsen et al. 2009). Approximately half the clinics surveyed did not routinely assess cognitive/neuropsychological function in their patients, and when they did, the test instruments chosen may not include those specific measures of EF known to be the primary deficit now observed in children early and continuously treated for PKU.

Whilst the ability of tyrosine supplementation to (1) restore poor tyrosine levels to normal or (2) improve (lower) the phe:tyr ratio has yet to be convincingly demonstrated, 25% of metabolic clinics from our practice survey were pursuing this as a treatment strategy for patients. As some clinics are already utilising this treatment strategy, further research is needed to determine if, and to what extent, manipulating tyrosine levels back to normal or to improve the phe:tyr ratio is advisable as an additional treatment strategy for patients with PKU.