Background: Although early diagnosis and treatment in phenylketonuria (PKU) leads to excellent outcomes, a population of adults born before the introduction of newborn screening exists. They can have severe intellectual disabilities and behavioural problems, and are often dependent on full-time carers. Anecdotal evidence suggests that a diet that lowers blood phenylalanine concentration can have significant benefits upon behaviour.
Methods: A prospective double-blind randomised placebo-controlled crossover trial of phenylalanine-restricted diet was performed in a group of 34 adults (aged 21–61 years, median 49) with late diagnosed PKU with severe challenging behaviour.
Results: Only 17 completed the 60 week study: seven withdrew before the end of the baseline period; five withdrew during the first diet period; five withdrew during the second diet period (after moving into placebo phase). The mean (SD) blood phenylalanine was 1570 (222) μmol/l during baseline, 553(158) μmol/l during the active phase and 1444 (255) μmol/l during the placebo phase. In the 22 participants exposed to both active and placebo phases, no differences were demonstrated in behaviour assessed by the Aberrant Behavior Checklist and Vineland Adaptive Behavior Scales, behaviour diaries or on video analysis of direct observations. However, 76% of carers’ comments were scored as positive during the active phase, compared with 54% during the placebo phase (χ2 = 38.06, p<0.001).
Conclusions: There are significant challenges in studying people with intellectual disabilities and considerable difficulties in instituting phenylalanine-restricted diet in this population. However, if attempted, there are potential benefits to quality of life for the individuals with PKU and their carers.
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An infant with phenylketonuria (PKU, OMIM 261600) born today can expect normal neuropsychometric outcome due to diagnosis on newborn screening followed by early institution of phenylalanine-restricted diet.1 However, this was not so for those born before the introduction of universal newborn screening in the 1960s.2 People late-diagnosed as having PKU usually have severe intellectual disabilities, challenging behaviour and a high frequency of epilepsy due to the cerebral effects of phenylalanine. Their care is expensive due to dependence on 24 h support and the need for psychotropic medication.3 Anecdotal evidence suggests that lowering blood phenylalanine concentrations with a phenylalanine-restricted diet can improve communication, relationships with carers and social skills, though not all show benefit.4–12 A survey of residential facilities in America found that 46% of 57 people with PKU had positive behaviour changes after diet intervention.13 All these studies can be criticised for using uncontrolled and unblinded methodology making it difficult to assess the impact of the diet itself.
Recently, we performed a nationwide survey to identify adults with PKU, born before newborn screening, with intellectual disabilities and challenging behaviour.14 Here we report the results of a randomised placebo-controlled double blind trial of phenylalanine-restricted diet in this late diagnosed group with challenging behaviour, the first such trial of diet in PKU.
Individuals with late diagnosed PKU were recruited following a UK-wide survey identifying 98 affected people.14 From this group and a further 35 individuals subsequently identified, 36 met the inclusion criteria: late diagnosed PKU confirmed by biochemical analysis; severe intellectual disabilities; challenging behaviour; and carers prepared to participate. Only one participant lived at home with his family during the trial; all the others lived in small staffed residential homes with other service users (in the UK, people with severe intellectual disabilities do not live in institutions but are cared for in small staffed homes in the community). One individual was excluded because her blood phenylalanine concentration was <1200 μmol/l (blood phenylalanine is >1200 μmol/l in classical PKU by definition),15 and another was excluded because staff at the care home did not manage the diet, collect blood samples or complete behavioural diaries. Of the remaining 34, 14 were male and 20 female. The median age was 49 years (range 21–61). The study was approved by an NHS Multi-site Research Ethics Committee and by each of the local research and development offices where participants resided.
The trial protocol is shown in fig 1. An 8-week baseline period was used to assess the practicalities of finger-prick blood tests to measure blood phenylalanine concentrations and to determine whether or not participants would drink the amino acid and micronutrient supplement used in the trial (XP/P Maxamum, SHS International, Liverpool, UK). At the first visit (start of the baseline period) definitions for the behavioural diaries were agreed with carers, and carers began completing daily record forms about the clients’ behaviour. All participants who successfully came through the baseline period were placed on a diet restricted in protein to 12 g/day for two periods of 24 weeks, separated by a 4-week washout phase during which normal, unrestricted diets were taken. The phenylalanine-restricted diet is complex, and during the baseline period, carers were trained by an experienced dietitian (LR) to enable the provision of an accurate and safe diet. Special low-protein products such as flour, pasta and rice were provided as needed. The rest of the amino acid requirements were provided in 150 g of a supplement that contained either no phenylalanine (XP Maxamum) in the active phase (24-weeks) or 3 g of phenylalanine (P Maxamum) in the placebo phase (24 weeks). The order of the phases was randomised, some receiving the active phase first and placebo second, and some vice versa. Carers and researchers were blind to which phase was active and which placebo throughout this double-blind crossover study.
Every week, on a specific day of the week and time of the day agreed with each care home, finger-prick blood samples were collected onto filter paper cards and sent by post for measurement of whole blood phenylalanine concentration via tandem mass spectrometry. These results were faxed to an experienced dietitian (ML), who made dietary adjustments to keep blood phenylalanine concentrations 300–700 μmol/l in the active phase. Bogus adjustments were made to individuals in the placebo phase to keep carers and observers blinded.
At the start of the baseline period, carers were visited by a research psychologist (AA) and instructed how to record participants’ behaviour using a diary. The behaviour diary required them to report frequency and intensity of three negative behaviours and three positive behaviours three times each day. Negative behaviours chosen by the carers included everyday occurrences for their participants, differing from one individual to another, that met the Emerson definition of challenging behaviour16 (ie, behaviours putting participants’ own physical safety at risk; or putting others’ physical safety at risk; or limiting their use of community facilities). The three positive behaviours were common to all participants, but were anchored for each individual, and were behaviours previous studies identified as improving following PKU diet.
A number of assessments were carried out by the research psychologist at each visit (fig 1). Assessments included the completion of two standardised behaviour questionnaires: the Aberrant Behavior Checklist17 and Vineland Adaptive Behavior Scale.18 Also, videoing of participants in three standard situations—eating, performing puzzle tasks and sitting alone—allowed direct observations of the percentage duration of behaviours in each situation. Finally, at each visit, carers were asked whether they had noticed any changes in participants’ behaviour (“carers’ comments”).
If carers decided to stop the trial for any reason, a final set of assessments was performed. The daily behavioural diaries, the questionnaires, videos and the carers’ comments were all scored prior to unblinding.
Data were first checked for normality, and parametric statistics were only used where appropriate.
For week-by-week analyses, behavioural data from the behaviour diaries were averaged across shifts and across days, within weeks, within phases, for the purpose of correlation with the weekly blood data.
For phase-by-phase analyses, blood data were averaged across each phase for each individual (“mean phase phenylalanine”). Behavioural diary data were treated in a similar way, resulting in “mean phase behaviour.” ANOVAs were completed to examine changes in blood phenylalanine, behavioural diary data, standardised measures of skills and challenging behaviours and direct observational data across phases. χ2 or Fisher exact tests were used where ordinal data were generated.
A description of the trial is shown in fig 2. Of the seven withdrawing during the baseline period, three disliked the amino acid supplement, and it was impossible to obtain finger-prick blood samples from the other four: biochemical monitoring is an essential part of PKU management. Of the 27 entering the trial following baseline, five withdrew during the first 24-week diet period (four because they disliked the amino acid supplement), five withdrew during the second 24-week diet period, and just 17 (50%) completed the whole trial.
The mean (SD) blood phenylalanine concentration was 1570 (222) μmol/l during the baseline (n = 29), 553 (158) μmol/l during the active period (n = 24), 1500 (248) μmol/l in the washout period (n = 22) and 1444 (255) μmol/l in the placebo phase (n = 23). Nineteen per cent of samples were >700 μmol/l during the active phase.
Challenging behaviours varied considerably between individuals and included aggression, agitation, self-harm and shouting/screaming. Although some individuals demonstrated behaviour changes during the different study phases, this was not true for everyone. Overall, there were no statistically significant differences between frequencies of challenging behaviour (as recorded in the behaviour diaries) during the active PKU diet phase compared with the placebo diet phase, either when data from the 17 participants who completed the trial were analysed, or when data from the five who dropped out in the diet 2 phase were included. Similarly, there were no significant changes in positive behaviours. Scores on the Aberrant Behavior Checklist and the Vineland Adaptive Behavior Scales at the end of the two diet phases were not significantly different, and nor were analyses of the videos. No significant correlations were found between mean blood phenylalanine and negative or positive behaviours (averaged across weeks); nor were there any correlations between negative behaviours and positive behaviours (averaged across weeks).
Looking at carers’ comments, these were divided up into single phrases as some carers made quite lengthy comments. Then, each phrase was scored as positive, negative or neutral by raters blinded to the study phase (fig 3). At the end of the active phase, 76% of phrases carers gave in their comments were positive, 23% were negative, and 1% was neutral. During the washout period, 23% of phrases were positive, 67% were negative, and 10% were neutral. Finally, at the end of the placebo phase, 53% of phrases were positive, 41% were negative, and 6% were neutral. There were significantly more positive phrases made by carers while participants were in the active compared with the washout or placebo phases (χ2 = 38.06, p<0.001).
Interestingly, 7/14 (50%) randomised to active phase first dropped out after switching to the placebo phase, while 10/10 (100%) randomised to placebo phase first, continued to the trial end (Fisher exact two-tailed test, p<0.018). At the trial end, carers for 15 decided to continue with the phenylalanine-restricted diet and phenylalanine-free supplements.
No randomised controlled trial of phenylalanine-restricted diet therapy has ever been carried out before. Nevertheless, the management of PKU through diet treatment has been hailed as one of the success stories of 20th-century medicine, converting a condition causing severe intellectual disabilities to one with near normal outcome. We report the first ever randomised placebo-controlled trial of phenylalanine-restricted diet in PKU, examining its impact in individuals with severe intellectual disabilities and challenging behaviour born prior to newborn screening. We found carers, blinded to diet therapy, made significantly more positive comments about the participants during the phase in the trial when blood phenylalanine concentrations were lowered compared with when they remained high and 15 chose to keep their clients on a phenylalanine-restricted diet after the trial.
PKU is an autosomal recessive genetic deficiency of hepatic phenylalanine hydroxylase. Since 1969, infants diagnosed as having PKU have been successfully treated using phenylalanine-restricted diet, and currently, most guidelines, including those for the UK, recommend diet should continue lifelong.19
But what should the recommendations be for those adults with PKU born prior to newborn screening? Many such individuals have severe intellectual disabilities associated with very challenging behaviour and need care in appropriate residential homes. The economic cost of their care is high due to their 24 h care and medication requirements.3 A number of reports of attempts to assess the impact of phenylalanine-restricted diet on behaviour in this group exist,4–12 but they can all be criticised for lack of comparison with placebo intervention or control group. These reports suggested that behaviour and quality of life could be improved; further reinforced by the findings of a nationwide US survey13 in which 88 individuals with PKU cared for in residential homes because of severe intellectual disabilities had been administered a restricted PKU diet. Forty-six per cent of them were felt to show positive changes in behaviour generally within 3–8 weeks of commencing diet, but again the study was without controls.
Intellectual disabilities research
Very few controlled trials of therapeutic interventions have been performed in adults with intellectual disabilities.20 Disentangling the various organic and psychosocial causes of challenging behaviour is difficult in those with intellectual disabilities whose needs cannot be easily assessed due to inherent communication issues. The evidence base on likely successful interventions is understandably limited, and attempts at identifying single solutions may be set up to fail. Ethical issues around consent, population heterogeneity and difficulties in choosing appropriate end-points are possible reasons for this. However, the intervention used in our trial does have the advantage of being scientifically linked to the cause of the intellectual disabilities in PKU. Our trial commenced before the introduction of new European Union regulations which meant approval was required from many Ethical Committees and Research and Development Offices. Once this was achieved, consent for enrolment was required from the family, the care home manager and/or an appropriate guardian. Some areas required “best interests” meetings before consent was agreed. As a result, it took longer than anticipated to recruit the planned 36 participants, but this was achieved. Using a crossover design helped to maximise the study power and is commonly employed in trials of rare disorders or when there is significant individual variation within a population.
It was disappointing that only 17 (50%) completed the trial. Although this limits the power of the study, it reflects important issues in the management of adults with PKU, especially those with intellectual disabilities. Reduced frequency of blood test collection and non-compliance with relatively unpalatable synthetic amino acid supplements are well described in the screened PKU population, increasing markedly with age.21 22 In our study, four participants (12%) were withdrawn because carers were unable to collect capillary blood samples. A further eight participants (24%) withdrew because they were unable to take sufficient amino acid supplement, during either the baseline or the first diet phase. These are the practicalities of introducing this form of therapy and should be seen as treatment failures.
Twenty-two participants were exposed to both active and placebo phases. The interventions chosen had the intended effect: the active phenylalanine-restricted diet lowered blood phenylalanine concentrations to 553 μmol/l on average (the UK recommendations for diet are to keep phenylalanine concentrations <700 μmol/l)19 and the placebo diet maintained phenylalanine concentrations near untreated levels at 1444 μmol/l. Despite this, we were unable to demonstrate statistically significant changes in the end points measured using quantitative measures, and there were no changes in seizure frequency or severity of eczema during the trial periods.
The heterogeneity of the group in terms of the abilities of the participants, coupled with the small numbers completing the trial, would have required large changes in behaviour to occur, and perhaps the Aberrant Behavior Checklist and Vineland questionnaires were insufficiently sensitive to detect subtle alterations. Considerable day-to-day fluctuations in behaviour occurred in these individuals, and analysis of the videos, made under controlled environmental conditions, was again unable to detect differences due to the PKU diet. These data differ in this respect from that in another double-blind study that examined the behavioural effects of phenylalanine-free amino acid tablet supplementation in adults with untreated PKU, where some changes in behaviour were detected (though the standardised Vineland scale was not used, and the allocation to groups was not randomised).23
However, in our trial it was striking that carers made significantly more positive comments about participants’ behaviour during active phase compared with placebo phase, despite being blinded to the treatment. This suggests phenylalanine lowering may have beneficial effects on quality of life of the participants, and consequently of the carers, that the standardised measurement tools were unable to detect. The fact that 50% of those exposed to active diet initially withdrew when moving into the placebo phase is also of interest. This is in contrast to all those participants randomised to the placebo phase initially who continued to the trial end. The withdrawals were mostly due to deterioration in behaviour, presumably associated with phenylalanine concentrations increasing towards untreated levels. Finally, the carers of 15 of these 22 participants decided to keep their clients on phenylalanine-restricted diet at the trial end, before the results had been analysed. The effort required to prepare and deliver a phenylalanine-restricted diet is considerable and requires sustained motivation. So, even though their ratings of the specific behaviours targeted in the diaries failed to show measurable changes, the carers’ blinded observations of their clients during the different phases of the trial were sufficient to convince them of the benefits of continuing this therapeutic approach.
Although the trial design was double-blinded, it may be argued carers were not truly blinded due to potential changes in body odour and darkening hair colour when blood phenylalanine falls. This is something that was not mentioned to them as a possibility and indeed was not reported during the trial, so it seems unlikely to be an important factor. Of course, those entering the trial may have been partly selected by the carers’ motivation, presumably hoping for positive results. However, they were sufficiently blinded throughout to make this an unlikely source of bias.
Our main concern about the study was the small number of untreated adults with PKU who entered and completed the trial, making it more likely that important effects were missed. Unfortunately, this is typical in studies of rare disorders, and indeed the changes observed suggest they were biologically and socially significant. We would have liked the treatment phases to have lasted longer, but clinical opinion at the time this study started suggested that 6 months was sufficient to pick up changes and was ethically justifiable. Further research is needed to resolve these questions. A replication of this study design, carried out in a country where adults with PKU live in large institutions, might allow recruitment of larger numbers of participants, longer treatment phases and good control of the PKU diet. In the UK, people with severe intellectual disabilities now almost all live in small staffed homes in the community, something that we welcome, as it has a very positive effect on their quality of life, even though it makes randomised controlled trials like this one extremely difficult to conduct.
The results of this double-blind placebo-controlled randomised trial of phenylalanine-restricted diet in a group of adults with late diagnosed PKU and severe intellectual disabilities and challenging behaviour suggest that this intervention should be offered to these individuals. Carers should be counselled about the difficulties of providing the diet, as some people will find the supplements unpalatable, and with others it will be impossible to collect capillary blood samples to monitor phenylalanine. Nevertheless, with a reduction in blood phenylalanine concentration to below 600 μmol/l throughout a 6-month period, some people will benefit, as perceived by their carers. There are also potential cost savings to social and health services as a consequence. Longer follow-up periods may allow even greater benefits to be observed, but motivated carers supported by appropriately trained dietitians are required for any chance of success.
We are extremely grateful to all the carers and participants without whom this study would not have been possible. We thank RN Dalton, for measuring blood phenylalanine concentrations, and P Portnoi and H Shaw of SHS International, for their invaluable contributions throughout the study. We also wish to thank the National Society for Phenylketonuria for their support.
See Editorial Commentary, p 585
Funding: The study was funded by generous grants from the Wellcome Trust and SHS International.
Competing interests: None.
Ethics approval: Ethics approval was provided by an NHS Multi-site Research Ethics Committee and by each of the local research and development offices where participants resided.
Patient consent: Obtained.
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