***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Some people with phenylketonuria who were born before screening began were never treated and are still alive . Here we report that far fewer people with untreated phenylketonuria were detected than are thought to exist ( about 2000 ) . The majority of those traced had high support needs , challenging behaviour and other symptoms of phenylketonuria . No significant differences were found between those who had or had not tried the phenylalanine-restricted diet . A r and omised controlled trial is required to examine the effect of trying the low-phenylalanine diet for people with untreated phenylketonuria Concerns about the psychosocial risk of adults with early-treated phenylketonuria ( ETPKU ) are predicated on four sources of scientific data : ( 1 ) consistent documentation of increased behavioural risk in children with ETPKU ; ( 2 ) recent evidence of neurocognitive impairment in adults with ETPKU ; ( 3 ) reports of neuroimaging abnormalities in adults with ETPKU ; and ( 4 ) preliminary evidence of increased rates of psychiatric disturbance in this population . We studied the psychosocial adjustment of 25 patients , aged 18 years and older , with ETPKU . On most pscyhosocial outcome measures , patients were indistinguishable from 15 sibling controls . However , on a self-report inventory of psychiatric symptoms , 20 % of the patients demonstrated significant morbidity . Psychosocial outcome of these patients was unrelated to concurrent or historical biological dietary disease factors , unlike neurocognitive outcome . A strong relationship was demonstrated , however , between neurocognitive measures and psychosocial morbidity . These findings indicate that a significant minority of patients with ETPKU develop psychosocial difficulties with multiple clinical elevations on a psychiatric inventory . However , most adults with ETPKU cope with the challenges of young adulthood with the same degree of success as their unaffected siblings . Neuropsychological surveillance during childhood and adolescence is important in identifying patients at risk for both neurocognitive and psychosocial morbidity Recent studies indicate that individual blood – brain transport characteristics of phenylalanine may lead to different clinical outcomes in phenylketonuria ( PKU ) patients in spite of comparable dietary control . To check these preliminary data , we investigated four pairs of siblings with classical PKU ( and identical genotype ) using in vivo nuclear magnetic resonance spectroscopy in the course of an oral phenylalanine load ( 100 mg/kg body weight ) . Patients ' brain phenylalanine concentrations were different in spite of similar blood levels . Interindividual variations of the apparent transport Michaelis constant , Kt , app , ranged from 0.10 to 0.84 mmol/L. The ratio of the maximal transport velocity , Tmax , over the intracerebral consumption rate , Vmet , varied between 2.61 and 14.0 . Siblings with lower values for Kt , app , higher values for Tmax/Vmet , and higher concurrent brain phenylalanine levels showed a lower IQ and a higher degree of cerebral white matter abnormalities . The results indicate that blood – brain barrier transport characteristics and the result ant brain phenylalanine levels are causative factors for the individual clinical outcome in PKU Background The strict and dem and ing dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life ( HRQoL ) of patients and their families . Our aim was to describe the HRQoL of patients with PKU from a large international study , using generic HRQoL measures and an innovative PKU-specific HRQoL question naire ( PKU-QOL ) . Analyses were exploratory , performed post-hoc on data collected primarily to vali date the PKU-QOL . Methods A multicentre , prospect i ve , non-interventional , observational study conducted in France , Germany , Italy , The Netherl and s , Spain , Turkey and the UK . Patients diagnosed with PKU aged ≥9 years old and treated with a Phe-restricted diet and /or Phe-free amino acid protein supplements and /or pharmacological therapy were included in the study ; parents of at least one patient with PKU aged < 18 years were also included . HRQoL was assessed by generic measures ( Pediatric Quality -of-Life Inventory ; Medical Outcome Survey 36 item Short Form ; Child Health Question naire 28 item Parent Form ) and the newly developed PKU-QOL . Mean generic domain scores were interpreted using published reference values from the general population . PKU-QOL domain scores were described overall and in different subgroups of patients defined according to severity of PKU , overall assessment of patient ’s health status by the investigator and treatment with tetrahydrobiopterin ( BH4 ) . Results Data from 559 subjects were analysed : 306 patients ( 92 children , 110 adolescents , 104 adults ) and 253 parents . Mean domain scores of generic measures in the study were comparable to the general population . The highest PKU-QOL impact scores ( indicating greater impact ) were for emotional impact of PKU , anxiety about blood Phe levels , guilt regarding poor adherence to dietary restrictions or Phe-free amino acid supplement intake and anxiety regarding blood Phe levels during pregnancy . Patients with mild/moderate PKU and those receiving BH4 reported lower practical and emotional impacts of the diet and Phe-free amino acid supplement intake . Conclusion Patients with PKU showed good HRQoL in the study , both with the generic and PKU-specific measures . Negative impacts of PKU on a patient ’s life , including the emotional impact of PKU and its management , was delineated by the PKU-QOLs across all age groups 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 prospect i ve double-blind r and omised 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 Vinel and 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 study ing 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 The main debate in the treatment of Phenylketonuria ( PKU ) is whether adult patients need the strict phenylalanine (Phe)-restricted diet . Physicians and patients lack evidence -based guidelines to help them make well-informed choices . We have carried out the first r and omised double-blind placebo-controlled trial into the effects of short-term elevation of Phe levels on neuropsychological functions and mood of adults with PKU . Nine continuously treated adults with PKU underwent two 4-week supplementation periods : one with Phe , mimicking normal dietary intake , and one with placebo in r and omly allocated order via a r and omisation coding list in a double-blind cross-over design . A set of neuropsychological tests ( Amsterdam Neuropsychological Tasks ) was administered at the end of each study period . In addition , patients and for each patient a friend or relative , completed weekly Profile of Mood States ( POMS ) question naires , evaluating the patients ’ mood . Phe levels were measured twice weekly . Mean plasma Phe levels were significantly higher during Phe supplementation compared with placebo ( p = 0.008 ) . Neuropsychological tests demonstrated an impairment in sustained attention during Phe supplementation ( p = 0.029 ) . Both patients and their friend or relative reported lower scores on the POMS question naires during Phe supplementation ( p = 0.017 and p = 0.040 , respectively ) . High plasma Phe levels have a direct negative effect on both sustained attention and on mood in adult patients with PKU .  A Phe-restricted “ diet for life ” might be an advisable option for many Background The aim of our study was to develop and vali date the first set of PKU-specific Health-related Quality of Life ( HRQoL ) question naires that : 1 ) were developed for patients with PKU and their parents , 2 ) cover the physical , emotional , and social impacts of PKU and its treatment on patients ’ lives , 3 ) are age specific ( Child PKU-QOL , Adolescent PKU-QOL , Adult PKU-QOL ) , 4 ) enable the evaluation of the HRQoL of children by their parents ( Parent PKU-QOL ) , and 5 ) have been cross-culturally adapted for use in seven countries ( i.e. France , Germany , Italy , The Netherl and s , Spain , Turkey and the UK ) . Methods The PKU-QOL question naires were developed according to reference methods including patients ’ , parents ’ and healthcare professionals ’ interviews ; testing in a pilot study ( qualitative step in six countries ) , and linguistic validation of the finalised pilot versions in Turkish . For finalisation and psychometric validation , the pilot versions were included in a multicentre , prospect i ve , non-interventional , observational study conducted in 34 sites in France , Germany , Italy , The Netherl and s , Spain , Turkey and the UK . Iterative multi-trait analyses were conducted . Psychometric properties were assessed ( concurrent and clinical validity , internal consistency reliability and test-retest reliability ) . Results Data from 559 subjects ( 306 patients , 253 parents ) were analysed . After finalisation , the PKU-QOL question naires included 40 items ( Child PKU-QOL ) , 58 items ( Adolescent PKU-QOL ) , 65 items ( Adult PKU-QOL ) and 54 items ( Parent PKU-QOL ) , distributed in four modules : PKU symptoms , PKU in general , administration of Phe-free protein supplements and dietary protein restriction . The measurement properties of the Adolescent , Adult and Parent PKU-QOL question naires were overall fairly satisfactory , but weaker for the Child question naire . Conclusions The four PKU-QOL question naires developed for different ages ( Child PKU-QOL , Adolescent PKU-QOL , Adult PKU-QOL ) , and for parents of children with PKU ( Parent PKU-QOL ) are valid and reliable instruments for assessing the multifaceted impact of PKU on patients of different age groups ( children , adolescents and adults ) and their parents , and are available for use in seven countries . They are very promising tools to explore how patients ’ perceptions evolve with age , to increase knowledge of the impact of PKU on patients and parents in different countries , and to help monitor the effect of therapeutic strategies During 1967–1983 , the Maternal and Child Health Division of the Public Health Services funded a collaborative study of 211 newborn infants identified on newborn screening as having phenylketonuria ( PKU ) . Subsequently , financial support was provided by the National Institute of Child Health and Human Development ( NICHD ) . The infants were treated with a phenylalanine (Phe)-restricted diet to age 6 years and then r and omized either to continue the diet or to discontinue dietary treatment altogether . One hundred and twenty-five of the 211 children were then followed until 10 years of age . In 1998 , NICHD scheduled a Consensus Development Conference on Phenylketonuria and initiated a study to follow up the participants from the original Collaborative Study to evaluate their present medical , nutritional , psychological , and socioeconomic status . Fourteen of the original clinics ( 1967–1983 ) participated in the Follow-up Study effort . Each clinic director was provided with a list of PKU subjects who had completed the original study ( 1967–1983 ) , and was asked to evaluate as many as possible using a uniform protocol and data collection forms . In a subset of cases , magnetic resonance imaging and spectroscopy ( MRI/MRS ) were performed to study brain Phe concentrations . The medical evaluations revealed that the subjects who maintained a phenylalanine-restricted diet reported fewer problems than the diet discontinuers , who had an increased rate of eczema , asthma , mental disorders , headache , hyperactivity and hypoactivity . Psychological data showed that lower intellectual and achievement test scores were associated with dietary discontinuation and with higher childhood and adult blood Phe concentrations . Abnormal MRI results were associated with higher brain Phe concentrations . Early dietary discontinuation for subjects with PKU is associated with poorer outcomes not only in intellectual ability , but also in achievement test scores and increased rates of medical and behavioural problems OBJECTIVE To determine psychiatric disorders in patients with phenylketonuria ( PKU ) and to test whether biochemical control , intellectual functioning , white matter abnormalities visible on magnetic resonance imaging ( MRI ) , and /or style of parenting influence psychop 
    Output:
    
The overall quality of life ( QoL ) of ETPKU adults was good or comparable to control population s , and there was no evidence for a significant incidence of psychiatric disease or social difficulties .
Neuroimaging revealed that brain abnormalities are present in ETPKU adults , but their clinical significance remains unclear .
Generally , intelligence quotient ( IQ ) appears normal but specific deficits in neuropsychological and social functioning were reported in early-treated adults compared with healthy individuals .