Bilder DA, Noel JK, Baker ER, et al.
Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults with Phenylketonuria.
Dev Neuropsychol. 2016;41(4):245-260. doi:10.1080/87565641.2016.1243109
There are two parts to this paper: firstly an in-depth look at 82 original studies and their findings and secondly a combining of the data which was gathered in some of these studies. Both the systematic review and the meta-analysis attempt to overcome the wide-ranging treatment histories in PKU adults who have been research subjects so far. This study’s conclusions are in line with previous findings about PKU in adulthood and symptoms connected with neuropsychiatric issues (mental health) and executive functions (a range of planning and thinking skills)
Neuropsychiatric or mental health symptoms associated with PKU are higher than general population estimates for inattention, hyperactivity, depression, and anxiety. High Phenylalanine levels are associated with an increased prevalence of neuropsychiatric symptoms and executive functioning deficits (poorer complex thinking skills). Low Phenylalanine levels are associated with improved neurological (brain and nervous system) performance. Findings support lifelong maintenance of low blood Phe - that is, the authors recommend diet for life.
Deborah A. Bilder, Joyce A. Kobori, Jessica L. Cohen-Pfeffer, Erin M. Johnson, Elaina R. Jurecki, Mitzie L. Grant;
Neuropsychiatric comorbidities in adults with phenylketonuria: A retrospective cohort study;
3714 individuals with PKU were identified within one of the American health insurance database, and these were compared with health insurance records from 7060 individuals with diabetes and records from 22,726 members of the general American population. The study is called a case- controlled study – the cases being people with PKU and the controls (or comparisons) being people with diabetes and also the people in the general population.
The group with PKU experienced significantly higher rates of several conditions – most notably intellectual disability, autism spectrum disorder, Tourette/tic disorders and eating disorders. Also rates of fatigue, epilepsy, sleep disturbance, personality disorders, phobias, psychosis and migraines were higher in people with PKU than the general population, but comparable to people with diabetes. An important finding is that there are lower rates of all of the above in younger adults with PKU compared to older adults with PKU.
Burton BK, Jones KB, Cederbaum S, et al.
Prevalence of comorbid conditions among adult patients diagnosed with phenylketonuria.
Mol Genet Metab. 2018;125(3):228-234. doi:10.1016/j.ymgme.2018.09.006
Burton et al carried out a retrospective case-controlled study in adults with PKU (aged 34.6±14.3 years) using the United States insurance claims database. The 15 Co-morbidities –that is, other illness being experienced alongside PKU, which the authors studied had been pre-selected. No information about treatment status of those with PKU was provided.
The prevalence of all 15 selected conditions was higher in the PKU population, compared to controls (the health insurance records of the group of individuals without PKU). Conditions relevant to ageing were renal insufficiency (with or without high blood pressure), obesity, osteoporosis, gastritis and oesophagitis.
It is difficult to draw any conclusions from this data because the treatment status of those with PKU isn’t known.
Chiara Cazzorla; Giacomo Biasucci, Vincenzo Leuzzi, Filippo Manti, Antonella Musumeci, Francesco Papadia, Vera Stoppioni, Albina Tummolo, Marcella Vendemiale Giulia Polo & Alberto Burlina;
Living with phenylketonuria in adulthood: The PKU ATTITUDE study;
Molecular Genetics and Metabolism Reports Volume 16, September 2018, Pages 39-45
111 Italian adults with PKU completed a structured questionnaire which aimed to collect information on the dietary habits of the participants as well as psychological factors about them, such as what factors influence their disease perception and sticking to diet.
About 40% of the respondents did not look at their PKU as a disease; 85% of respondents reported regular monitoring of bloodspots but the results were above the target of 600umol/l in nearly half of the respondents. Attending clinic and receiving blood results both helped people stay on the diet, however social pressure was reported as having a negative impact on taking amino acids.
Nutritional and Metabolic Characteristics of UK Adult Phenylketonuria Patients with Varying Dietary Adherence;
Nutrients 2019, 11(10), 2459; https://doi.org/10.3390/nu11102459
This paper shows a comparison of the nutritional intakes of 16 people over the age of 16, with PKU who are on diet compared to a group of 14 people off diet, using a 3-day food record, alongside amino acid blood samples. Those off diet were eating an average of 62g natural protein daily and those on diet were having an average of 18g protein daily.
The “off diet” group had intakes of the following nutrients significantly below the intake of the “on diet” group and also below the UK recommended intakes: iron, zinc, Vitamin D3, magnesium, calcium, selenium, iodine, vitamin C, vitamin A and copper. The average blood phenylalanine levels in the off-diet group was 861 umol/l compared to 464 umol/l in the “on diet” group.
The paper shows the nutritional and metabolic consequences of relaxing dietary adherence.
Michel Hochuli, Sandra Bollhalder, Carina Thierer, Julie Refardt, Philipp Gerber, Matthias R. Baumgartner;
Effects of Inadequate Amino Acid Mixture Intake on Nutrient Supply of Adult Patients with Phenylketonuria;
Ann Nutr Metab 2017;71:129–135 DOI: 10.1159/000479746
20 patients with PKU from the adult metabolic clinic in Zurich and Basel in Switzerland were given a 4-day food diary to complete, at some point in the 4 weeks after the clinic appointment at the start of the study. The patients’ weights and heights were measured at clinic, with nutritional biochemistry tests done on their venous blood at that appointment too – as per the standard clinical routine in this outpatient clinic.
The 20 patients were categorized into 2 groups – 15 in Group A who were taking their prescribed amino acids daily, and 5 patients in Group B who were not taking regular amino acids at the prescribed amount.
The study found that group B were taking a larger amount of natural protein than group A but were still having less than the recommended intake of protein, and this was also true of trace elements selenium, and Vitamin B12 and folate. Group B had a higher fat intake than group A – mainly from saturated fats.
The authors conclude that care needs to be taken to ensure adequate nutrition for all adults with PKU.
Hofman DL, Champ CL, Lawton CL, Henderson M, Dye L.
A systematic review of cognitive functioning in early treated adults with phenylketonuria.
Orphanet J Rare Dis. 2018;13(1):150. doi:10.1186/s13023-018-0893-4
The author has systematically reviewed 22 publications from 16 separate studies which all focus on the thinking abilities of adults with PKU who have been diagnosed and treated for PKU following newborn screening (called Early Treated Adults with PKU or ETAPKU).
The author concludes that the findings in the 16 studies are not consistent ie not making the same conclusions about different measures of intellectual ability in PKU in adulthood.
The treatment history of the people studied, the “ETAPKU” is highly variable, since the “diet for life” or “treatment for life” recommendations have only recently been widely adopted, many people in the studies may have had time off treatment, and the amount of time off treatment could be variable.
This means that the groups of patients reported in each of the 16 different studies are quite different (heterogeneous) in the treatment they received and the metabolic control they had – this makes the studies difficult to compare, match or draw conclusions from when the studies are considered together such as in this review. Other reasons for inconsistent findings in the research reviewed, are the differences in tools used to assess cognitive (thinking) function by the different researchers. Some papers used many tools which would have greater sensitivity, and some studies just measured a few mental functions using only a few assessments or tools.
Jahja R, et al;
Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study;
J Inherit Metab Dis (2016) 39:355–362
This is a comparison, or case-control observational study on some neuropsychological aspects of PKU or phenylketonuria.
95 people with PKU ages ranging from 10 to 31 (average age 21) were tested and compared to 95 people of similar age and background. (The authors also looked at PKU control and linked it to the performance of those with PKU).
Social cognition involves all mental processes that underlie social interactions and involves the ability to recognize, to interpret and to respond appropriately to signs and signals shown by others. Basic social-cognitive skills include face recognition, emotion recognition and Theory of Mind (ToM), i.e. the ability to attribute and understand thoughts, feelings and intentions to/of other people.
The tests included computerized and paper-and-pencil tasks measuring social-cognitive abilities and parent- and self-reported social skills. PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social cognitive functioning was negatively related to recent Phe levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years old.
The author highlights that problems she studied seem to be more evident among adolescents and adults with PKU.
Rianne Jahja (2017) et al;
Long-Term Follow-Up of Cognition and Mental Health in Adult Phenylketonuria: A PKU-COBESO Study;
Behav Genet; DOI 10.1007/s10519-017-9863-1
This is an observational study of 21 people with PKU at two timepoints.
The study shows results of in-depth neuropsychological (brain function) testing linked to phenylalanine levels over time. The first time of testing was 10 and a half years old on average, and the second time when subjects were an average age of 26 years old. The subjects’ blood phenylalanine was collected for their life from diagnosis up to 12 years old and also from 13 years onwards.
Study subjects with a greater increase in phenylalanine levels after the age of 12 performed more poorly on executive function tasks at the 2nd time of testing (age 26). Executive functions help individuals “get things done”, they are are the mental processes that enable people to plan, focus attention, remember instructions, and juggle multiple tasks successfully.
Group-based analyses showed that patients with phenylalanine below 360 μmol/L in childhood and phenylalanine above 360 μmol/L from age 13 onwards (n=11) had better cognitive (thinking) flexibility and executive motor control (control of movements) than those who had phenylalanine above 360 μmol/L throughout life (n=7), supporting the recommended upper treatment target of 360 μmol/L during childhood for better outcome in adulthood.
Ulrike Mütze, Alena Gerlinde Thiele, Christoph Baerwald, Uta Ceglarek, Wieland Kiess and Skadi Beblo;
Ten years of specialized adult care for phenylketonuria – a single-centre experience;
Orphanet Journal of Rare Diseases (2016) 11:27
This paper describes responses to a patient survey by 96 adults (ages 18-62) attending one specialist adult metabolic centre in Eastern Germany (University of Leipzig). During the 3 years before the survey, 81% of the patients who had transitioned to the adult service had been in contact with the centre, (ie 81% of the adult caseload were under active follow up at the centre).
The average blood phenylalanine was 673umol/l. 83% of the adults were satisfied with their transition process and their current adult care. 25 pregnancies had been completed and of these there were 3 newborns who had maternal PKU syndrome, having been born due to an unplanned pregnancy.
Palermo L, Geberhiwot T, MacDonald A, Limback E, Hall SK, Romani C.
Cognitive outcomes in early-treated adults with phenylketonuria (PKU): A comprehensive picture across domains. Neuropsychology.
This is a detailed observational study of 37 adults with PKU in Birmingham in the UK, who undertook extremely in-depth neuropsychological assessments – the tests included 28 tasks and 44 different measures. The measures that were looked at include measures of:
- short term memory or working memory,
- speed of processing
- sustained attention,
- visuo-spatial attention,
- visuomotor co-ordination
The same tests were applied to 30 people matched for gender and age, but without PKU. The overall results for the PKU group were lower than for those without PKU – however, 38% of those with PKU had a completely standard performance and though 24% were clearly impaired.
The researchers report that their results show “extreme variability” amongst the participants with PKU and across the different cognitive (thinking) functions. Overall the PKU groups showed good performance in learning tasks but had reduced speed of processing and complex executive function deficits. Executive functions help individuals “get things done”, they are are the mental processes that enable people to plan, focus attention, remember instructions, and juggle multiple tasks successfully.
Finally: the researchers call for more research to build an understanding of why these differences in brain function happen in PKU.
Romani C, Palermo L, MacDonald A, Limback E1, Hall SK, Geberhiwot T; (2017)
The impact of phenylalanine levels on cognitive outcomes in adults with phenylketonuria: Effects across tasks and developmental stages. Neuropsychology.
The researchers looked at the impact of metabolic control at different ages on cognitive (thinking) performance in 37 early treated adults with PKU – that is, adults who had been diagnosed through newborn screening and had received dietary treatment very promptly after diagnosis. The different individuals will have all had slightly different levels of metabolic control (ie control of their blood phenylalanine) and their control over their childhood and their adulthood were looked at separately and then compared to how well each of them performed in the thinking tasks and tests used by these researchers.
For some tasks, the current and adult blood Phenylalanine were stronger predictors of performance than childhood or adolescent Phe, showing the importance of a strict diet even in adulthood.
How close the link was between thinking performance and Phenylalanine levels varied depending on time and cognitive domain (type of thinking).
For some functions (sustained attention, visuomotor or hand-to eye coordination), Phenylalanine at the time of testing was the best predictor – this means that to perform well in these areas it is important to keep blood phenylalanine controlled throughout life, or certainly at the time when good performance is needed or wished for. For other functions (visual attention, executive functions) there was a diminishing or stable relationship across time – these types of thinking were more influenced by metabolic control (phenylalanine levels) in childhood.
Cristina Romani, Filippo Manti, Francesca Nardecchia, Federica Valentini, Nicoletta Fallarino, Claudia Carducci, Sabrina De Leo, Anita MacDonald, Liana Palermo and Vincenzo Leuzzi;
Adult cognitive outcomes in phenylketonuria: explaining causes of variability beyond average Phe levels;
Orphanet Journal of Rare Diseases (2019) 14:273
The aim of this study was to explore in-depth the metabolic control of adults with PKU (in UK and in Italy) comparing metabolic control and neuropsychological performance (brain processes and brain control on thinking and doing tasks).
The in-depth metabolic exploration involved examining variations in blood phenylalanine levels – not just looking at average Phe over time but blood phe peaks in both childhood and adults. The people with PKU taking part performed a set of “cognitive tasks” (jobs to test thinking abilities) as well as having their IQ (intelligence quotient) tested.
Combining adult average blood phenylalanine and the childhood variation in phenylalanine, these two predicted about 40% of the cognitive task scores between individuals with PKU.
Trefz KF, Muntau AC, Kalstein KM, et al.
Clinical burden of illness in patients with phenylketonuria (PKU) and associated comorbidities - a retrospective study of German health insurance claims data.
This recent study of German Insurance claims included 377 adults with PKU (age range 18-96 years) and 3770 matched controls – people of similar age groupings without PKU.
43% of those with PKU were early treated, though not all remained on diet, and few were receiving BH4 and so the other 57% were late diagnosed and late treated. Conditions with a statistically higher prevalence rate (over 1.5) in adults with PKU were depression, ischaemic heart disease, asthma, Chronic obstructive pulmonary disease, dizziness/ giddiness, diabetes mellitus, gastroenteritis/ colitis, stress and adjustment disorders and acquired limb deformities. Chronic Kidney Disease had a prevalence rate above 1.5 in late diagnosed adults with PKU. The Charlson co-morbidity index – which predicts 10-year mortality of patients who may have a range of conditions - was higher in the adults with PKU in this study.
The way in which these other illnesses have arisen in people with PKU, is not described.