Final Report Summary - TREPAPHEN (Early treated patients with PKU: Exploring the association between measures of metabolic control, cognitive performance and neurological health.)
OBJECTIVES. Phenylketonuria (PKU) is an inherited metabolic disease which, if left untreated, results in severe mental disabilities. The introduction of new-born screening programs and early treatment with a special Phenylalanine (Phe) free diet has prevented severe neurological damage and disabilities, but patients with PKU are not symptom-free. Maintaining a strict diet requires the use of unpalatable protein substitutes, it has side-effects and it may be psychologically and socially difficult. Thus, many adults with PKU are unable to achieve target metabolic control and choose to stop dietary management altogether. There is a lack of evidence to decide whether or not this is a safe choice. Indeed, we know that Phe levels have a strong impact on cognition during childhood, but the consequence of high Phe levels in adulthood are less clear. Now, the first cohort of early treated PKU patients has reached adulthood and this allows for the first time to relate adult levels of Phe and measures of neurological impairments to cognitive performance. TREPAPHEN overarching goal was to establish whether, still in adulthood, Phe levels relate to cognitive performance and measures of brain function. If cognitive performance is related to Phe levels even in adulthood, then, the advice to these patients should be to maintain a strict diet to achieve low Phe levels, otherwise dietary advice can be relaxed.
WORK PERFORMED
Research work. The research project has been developed at Aston University Birmingham in collaboration with the Birmingham University Hospital, and Birmingham Children’ Hospital. A sample of 42 early-treated patients with PKU and of 40 healthy controls have been recruited and have taken part into three testing sessions (3 hours for session) enabling to collect unprecedented number of measures. Specifically 38 neuropsychological tasks -- probing language in terms of spelling, reading, naming and pragmatic comprehension, visuo-spatial attention, visuo-motor coordination, navigational skills, memory and learning, emotion recognition, executive functions--, 3 mental and physical health questionnaires, and one dietary questionnaire were administered. Blood Phe levels were measured for each patient at the time of testing. In addition an extensive data-base of historical Phe values collected since birth was available for each patient. These results together with the results of neuropsychological testing, mental and physical health questionnaires, and dietary questionnaires have been organized in an integrated database.
International collaboration.
• A collaboration with the PKU group at the University of Rome, La Sapienza, has been set up to test Italian adult patients with comparable materials. This is important since there is a lack of studies comparing patients across countries where both dietary habits and the advice given to patients is different.
• A symposium on cognitive impairments in rare metabolic diseases has been organized as part of the 5th Conference of the European Societies of Neuropsychology (Tampere, Finland 2015).
• A special issue on cognitive impairments in rare metabolic diseases has been organized to appear on the journal Cognitive Neuropsychology.
Dissemination. Results acquired through TREPAPHEN have been disseminated through:
• Presentations to metabolic and neuropsychology teams (at University of Birmingham, University Hospital Birmingham, Birmingham Children’s Hospital; University College London Hospital);
• Presentations to patients and their families (at the PKU all-day clinics, University Hospital Birmingham, and at ‘PKU Latest Research Meeting’, Priory Rooms, Birmingham);
• Events for students and general public (e.g. Information Stand on the occasion of the Rare Disease Day, workshop at the Aston Research Centre for Healthy Ageing Open Day);
• Conference presentations: the Society for the Study of Inborn Errors of Metabolism (SSIEM, Innsbruck, Austria, 2014), British Neuropsychological Society (BNS, London, Autumn Meeting 2014), Dietary Management of Inherited Metabolic Disorders (DMIMD, London, 2015, invited talk) and 5th Conference of the European Societies of Neuropsychology (ESN, Tampere, Finland, 2015);
• A twitter page (twitter.com/trepaphen) a facebook page (facebook.com/TrepaphenMarieCurieAction) and a webpage (www.aston.ac.uk/lhs/staff/az-index/liana-palermo/trepaphen/).
RESULTS
Cognitive outcomes. Performance in the PKU group varied across individuals. Some participants (22% of sample) performed very well across the board, while others showed impairments (38%). Variability was also present across cognitive domains. As a group, PKU participants showed a reduced speed of processing, but good accuracy across timed and untimed tasks and good performance in memory and learning tasks. The speed deficit appeared to be linked to a slower visuo-spatial analysis of the stimuli. Performance in the visuo-spatial was consistent with a reduction in speed of processing because the difference in reaction times (RTs) between PKU and control participants increased systematically with the difficulty of the condition. Instead, in language tasks, differences remained stable across conditions which suggest no additional differences in processing linguistic stimuli. Performance in executive functions was also variable. It was impaired with tasks probing planning and monitoring-- e.g. rule extraction, verbal fluency, working memory, and sustained attention-- but normal with tasks probing inhibitory control --e.g. we found normal effects of inhibition with the stroop tasks, normal effects of semantic inhibition in picture naming; normal switching with the trail making task. This is in contrast with studies on children with PKU and suggests that inhibitory control although may show a developmental delay in PKU may in the end to be acquired to a normal level. Finally, our adults with PKU did not show any increase in mental health problems (e.g. depression) or a worse health related quality of life than controls.
Association with metabolic control. Cognitive outcomes were related to blood Phe both in terms of average levels and fluctuations throughout the life span. These associations, however, were task and time dependent. Functions which showed no group impairment --i.e. memory and learning-- were still associated with Phe, because individuals who relinquished metabolic control in adulthood performed worse. Moreover, associations differed throughout the lifespan: visuo-spatial processing was mainly associated with childhood Phe levels. Instead, visuo-motor coordination, sustained attention, and memory and learning were particularly associated with adult Phe levels. Health related quality of life in terms of physical health was also strongly associated with Phe levels. In stark contrast, we found null or negative correlations between mental health measures and dietary control.
CONCLUSIONS AND IMPACT
TREPAPHEN has provided patients with PKU and the medical community with a number of important findings.
• By providing an unprecedented complete picture of cognitive functioning in adults with PKU, it has shown that there is no a general cognitive disability in this group, but, instead, a pattern of strengths (e.g. accuracy in language) and weaknesses (slower speed of processing and planning and monitoring difficulties). This pattern is important to monitor for disease progression and a possible acceleration of ageing in this population.
• It has shown that performance in a number of cognitive domains (visuo-motor coordination, sustained attention, learning) is modulated by adult Phe levels at the net of influences at previous times (adolescence). This is an indication of the importance to keep a strict diet even in adulthood.
• We have found no indication of mental health difficulties in our group. If anything we found some suggestion of possible emotional costs of keeping diet. If confirmed, this should also be considered in the advice and support given to patients.
TREPAPHEN results are important to manage PKU not only in the UK, but also in Europe at large (and internationally, in countries wherever the incidence is high). They will contribute to set up common health policies and put Europe at the forefront of developing best practices which will enhance the well-being of these patients and reduce medical and societal costs.
WORK PERFORMED
Research work. The research project has been developed at Aston University Birmingham in collaboration with the Birmingham University Hospital, and Birmingham Children’ Hospital. A sample of 42 early-treated patients with PKU and of 40 healthy controls have been recruited and have taken part into three testing sessions (3 hours for session) enabling to collect unprecedented number of measures. Specifically 38 neuropsychological tasks -- probing language in terms of spelling, reading, naming and pragmatic comprehension, visuo-spatial attention, visuo-motor coordination, navigational skills, memory and learning, emotion recognition, executive functions--, 3 mental and physical health questionnaires, and one dietary questionnaire were administered. Blood Phe levels were measured for each patient at the time of testing. In addition an extensive data-base of historical Phe values collected since birth was available for each patient. These results together with the results of neuropsychological testing, mental and physical health questionnaires, and dietary questionnaires have been organized in an integrated database.
International collaboration.
• A collaboration with the PKU group at the University of Rome, La Sapienza, has been set up to test Italian adult patients with comparable materials. This is important since there is a lack of studies comparing patients across countries where both dietary habits and the advice given to patients is different.
• A symposium on cognitive impairments in rare metabolic diseases has been organized as part of the 5th Conference of the European Societies of Neuropsychology (Tampere, Finland 2015).
• A special issue on cognitive impairments in rare metabolic diseases has been organized to appear on the journal Cognitive Neuropsychology.
Dissemination. Results acquired through TREPAPHEN have been disseminated through:
• Presentations to metabolic and neuropsychology teams (at University of Birmingham, University Hospital Birmingham, Birmingham Children’s Hospital; University College London Hospital);
• Presentations to patients and their families (at the PKU all-day clinics, University Hospital Birmingham, and at ‘PKU Latest Research Meeting’, Priory Rooms, Birmingham);
• Events for students and general public (e.g. Information Stand on the occasion of the Rare Disease Day, workshop at the Aston Research Centre for Healthy Ageing Open Day);
• Conference presentations: the Society for the Study of Inborn Errors of Metabolism (SSIEM, Innsbruck, Austria, 2014), British Neuropsychological Society (BNS, London, Autumn Meeting 2014), Dietary Management of Inherited Metabolic Disorders (DMIMD, London, 2015, invited talk) and 5th Conference of the European Societies of Neuropsychology (ESN, Tampere, Finland, 2015);
• A twitter page (twitter.com/trepaphen) a facebook page (facebook.com/TrepaphenMarieCurieAction) and a webpage (www.aston.ac.uk/lhs/staff/az-index/liana-palermo/trepaphen/).
RESULTS
Cognitive outcomes. Performance in the PKU group varied across individuals. Some participants (22% of sample) performed very well across the board, while others showed impairments (38%). Variability was also present across cognitive domains. As a group, PKU participants showed a reduced speed of processing, but good accuracy across timed and untimed tasks and good performance in memory and learning tasks. The speed deficit appeared to be linked to a slower visuo-spatial analysis of the stimuli. Performance in the visuo-spatial was consistent with a reduction in speed of processing because the difference in reaction times (RTs) between PKU and control participants increased systematically with the difficulty of the condition. Instead, in language tasks, differences remained stable across conditions which suggest no additional differences in processing linguistic stimuli. Performance in executive functions was also variable. It was impaired with tasks probing planning and monitoring-- e.g. rule extraction, verbal fluency, working memory, and sustained attention-- but normal with tasks probing inhibitory control --e.g. we found normal effects of inhibition with the stroop tasks, normal effects of semantic inhibition in picture naming; normal switching with the trail making task. This is in contrast with studies on children with PKU and suggests that inhibitory control although may show a developmental delay in PKU may in the end to be acquired to a normal level. Finally, our adults with PKU did not show any increase in mental health problems (e.g. depression) or a worse health related quality of life than controls.
Association with metabolic control. Cognitive outcomes were related to blood Phe both in terms of average levels and fluctuations throughout the life span. These associations, however, were task and time dependent. Functions which showed no group impairment --i.e. memory and learning-- were still associated with Phe, because individuals who relinquished metabolic control in adulthood performed worse. Moreover, associations differed throughout the lifespan: visuo-spatial processing was mainly associated with childhood Phe levels. Instead, visuo-motor coordination, sustained attention, and memory and learning were particularly associated with adult Phe levels. Health related quality of life in terms of physical health was also strongly associated with Phe levels. In stark contrast, we found null or negative correlations between mental health measures and dietary control.
CONCLUSIONS AND IMPACT
TREPAPHEN has provided patients with PKU and the medical community with a number of important findings.
• By providing an unprecedented complete picture of cognitive functioning in adults with PKU, it has shown that there is no a general cognitive disability in this group, but, instead, a pattern of strengths (e.g. accuracy in language) and weaknesses (slower speed of processing and planning and monitoring difficulties). This pattern is important to monitor for disease progression and a possible acceleration of ageing in this population.
• It has shown that performance in a number of cognitive domains (visuo-motor coordination, sustained attention, learning) is modulated by adult Phe levels at the net of influences at previous times (adolescence). This is an indication of the importance to keep a strict diet even in adulthood.
• We have found no indication of mental health difficulties in our group. If anything we found some suggestion of possible emotional costs of keeping diet. If confirmed, this should also be considered in the advice and support given to patients.
TREPAPHEN results are important to manage PKU not only in the UK, but also in Europe at large (and internationally, in countries wherever the incidence is high). They will contribute to set up common health policies and put Europe at the forefront of developing best practices which will enhance the well-being of these patients and reduce medical and societal costs.
