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Adult phenylketonuria outcome and management
Molecular Genetics and Metabolism 104 (2011) S26–S30
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Adult phenylketonuria outcome and management F. Trefz a,⁎, F. Maillot b, K. Motzfeldt c, M. Schwarz d a
Kreiskliniken Reutlingen GmbH, Reutlingen, Germany CHRU de Tours, Université François Rabelais, INSERM U921, Tours, France c Oslo University Hospital, Women and Children's Division, Department of Pediatrics and Newborn Screening, Oslo, Norway d Internal Medicine outpatient centre, Kaarst, Germany b
a r t i c l e
i n f o
Article history: Received 13 July 2011 Received in revised form 23 August 2011 Accepted 23 August 2011 Available online 26 August 2011 Keywords: Phenylketonuria Hyerphenylalaninemia Adult Sapropterin
a b s t r a c t The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase. Recent, partly double blind studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted. Late detected PKU patients (up to 4–6 years of age) benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may benefit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient. In early and well treated patients a number of studies have demonstrated that cognitive and neurosychologic tests are different from controls. In addition there is evidence that patients with higher blood phenylalanine (phe) levels demonstrate more often psychiatric symptoms like depression and anxiety. Medical problems are more often observed: there are certain risks as impaired growth, decreased bone mineral density and nutrional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe (mean blood phenylalanine N 600–900 μmol/L) on cognitive and neuropsychological functions and psychiatric symptoms. Further studies should consider the role of blood phe exposure for brain development in childhood and for brain function in all ages. Besides mean blood phe, fluctuation of blood phe over time is important. Fluctuation of blood phe is decreased by sapropterin treatment in responsive patients which would on the long term may have positive effects on cognitive outcome. Further studies also should include adult PKU patients. © 2011 Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . Untreated adult PKU patients . . . . . . . . . . . . . . . Treatment in late diagnosed but treated PKU patients . . . . Outcome in early treated but early discontinued patients . . Treatment results in early treated patients . . . . . . . . . 5.1. Cognitive and neuropsychological outcome . . . . . . 5.2. Psychiatric findings in early treated adult PKU patients 5.3. Nutritional deficiencies and growth . . . . . . . . . 5.4. Biochemical outcome parameters . . . . . . . . . . 5.5. CNS findings in early treated adult PKU patients . . . 5.5.1. MRI (magnetic resonance imaging) findings . . 5.5.2. CNS metabolic findings . . . . . . . . . . . 6. Future management in adult PKU . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbbreviations: phe, phenylalanine; PAH, phenylalanine hydroxylase; PKU, phenylketonuria; BH4, tetrahydrobioptern. ⁎ Corresponding author at: Kreiskliniken Reutlingen GmbH, Reutlingen, Germany. E-mail addresses: [email protected] (F. Trefz), [email protected] (F. Maillot), [email protected] (K. Motzfeldt), [email protected] (M. Schwarz). 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.08.025
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1. Introduction The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase (PAH). More than 600 mutations are described so far (http://www.pahdb.mcgill.ca/). The other problem consists in the fact that there are no prospective studies available and that in later life other modulators as lifestyle and aging become more important when evaluating brain development and brain function. Long term dietary treatment also shows development of other problems like osteopenia or metabolic imbalances. Having these problems in mind it is clear that up to now there are no evidence based treatment recommendations and only vague recommendations like “lifelong treatment” with very different suggestions for e.g. the blood phe targets as published in a European survey recently [1]. In this review we would like to describe outcome and management of adult PKU patients excluding maternal PKU but describing the different groups of adult PKU patients we see in our metabolic outpatient clinic. 1. PKU patients never treated, 2. PKU patients late treated (start 1– 6 years of age) 3. Patients early treated but early or with poor compliance and 4. Patients early treated with good compliance until adulthood. Data are based on literature review and personal clinical experiences.
2. Untreated adult PKU patients Patients with untreated PKU are severely retarded in most cases and in addition may show challenging behavioral problems (Table 1). Treatment studies in untreated PKU's are difficult to perform. Besides ethical issues to conduct such studies measurement of improvement is difficult. The results are controversial, the study population always small. In some studies severity of behavioral disturbances may be reduced after introduction of a phe restricted diet [2], Table 1. In a recent placebo controlled study in 17 patients [3] a significant difference between treatment and placebo group using standardized test procedures could not be demonstrated. However, the positive comments of carers in the treatment group were significant in respect to a positive change than in the placebo group. This indicates a positive effect in individual patients and the authors conclude that “this intervention should be offered to these individuals” [3]. According to our personal experiences a close monitoring, not only of the blood phe levels but also of the general health condition of these patients should be performed: excessive weight loss and development of dystrophy might be a severe side effect after introduction of a low phe diet. We also experienced that treatment of patients living still in the family is easier. Experiences of family members with the diet and a better environment may be reasons for this (Trefz, unpublished).
Table 1 Symptoms and change of symptoms in 6 untreated PKU patients under dietary treatment. SIB: self injurious behavior. Adapted from Baumeister and Baumeister [3]. Patient/symptoms
% change
Treatment (months)
1/SIB 2/Assault/SIB face gouging
− 93% − 91% − 48% − 13% − 69% − 54% No change
36 26
3/SIB 4/Tantrums 5/Stereotypes 6/Hyperactivity
9 9 3 3
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In summary, a general recommendation for a phe restricted diet in severely retarded PKU patients cannot be given. Individual conditions should be considered and quality of life should not worsen especially in severely retarded patients with behavioral problems. On the other hand in some patients a blood phe level below 900 μmol/L may result in reduction of behavioral problems and increase of attention. 3. Treatment in late diagnosed but treated PKU patients Introduction of newborn screening and early dietary treatment resulted in the prevention of severe brain damage. However, due to screening failures and immigration of patients from countries where early detection and treatment of PKU is not yet established, there are a number of untreated PKU's in many European centers. In the last 20 years we saw in one center (Reutlingen, Germany) 10 patients missed by newborn screening due to various reasons (Table 2). After introduction of tandem mass spectrometry and a better computerized sample handling in the screening laboratories one can expect that missed cases will be minimized in the future. However, there are still a number of immigrants coming from countries where newborn screening is not yet established. From early prescreening experiences it is well known that after introduction of dietary treatment in later infancy and childhood partial reversibility of IQ loss may occur. Catch up of development retardation is especially seen in the first 4–6 years of life [4], but there is a large heterogeneity of treatment success as also shown recently in a review by Grosse [5]. As pointed out in this paper and based on personal experiences there is often an impressive improvement of development when introducing a phe restricted diet even in very late detected PKU patients. All of these patients benefit from a dietary treatment with phe levels b600 μmol/L beyond infancy and young adulthood. One may speculate that in these patients elevated blood phe levels cause brain dysfunction more likely than in early treated patients with an unaffected brain. 4. Outcome in early treated but early discontinued patients For many years dietary treatment of PKU was terminated at 10 years of age, in some countries even at 6 years of age. Investigations in patients with early diet termination revealed that there was a loss of intellectual function [6]. Koch and coworkers [7] could demonstrate that patients continuing the diet until adulthood had a better outcome than those who stopped the diet earlier. In addition in this collaborative study Koch et al. could demonstrate that treatment quality also had an influence on outcome: adults who had continued a dietary control with blood phe levels b15.6 mg/dL had a better IQ
Table 2 Neonatal screening failure in 10 patients with phenylketonuria (Trefz, unpublished); Phe = phenylalanine. Patient Age at diagnosis Phe-level at diagnosis (years) (mg/dL)
Reason for not screening, remarks
1 2 3
1.5 9 3.5
28 25 32
4 5 6 7
1.5 7 7 2.5
24 21 N 20 27
8 9 10
0.8 1 1.5
N 20 N 20 N 20
Born in Brazil Unclear Mixed blood on screening card Lab mistake Russian immigrant Russian immigrant Turkish guest worker family Lab mistake Lab mistake Lab mistake, infant with Down Syndome and PKU!
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than those with higher levels. In addition adults with PKU being off diet had a higher rate of medical problems like eczema, phobias, depression and neurological symptoms. Treatment policy changed so that diet for life was suggested [8]. 5. Treatment results in early treated patients 5.1. Cognitive and neuropsychological outcome In the following cognitive and neuropsychologic outcomes of adult early treated PKU patients are discussed. A number of studies have demonstrated that cognitive outcome and neurosychologic tests are different from controls. In a meta analysis by Moyle et al. [9] including 5 studies there were reduced full scale IQ scores and reduced information processing speed and attention. In addition in 4 studies inhibitory abilities and motor control were reduced compared to controls. Except for working memory there was no difference to controls (3 studies). In a three year longitudinal study from a group in Münster, Germany, Feldman et al. [10] found a significant reduction of full scale IQ compared to a diabetic control group (104.9 vs 111.8, p b 0.05) but not at baseline. Information processing expressed as time to complete the test was also very different from the diabetic group (84.9 vs. 67.8 s, p b 0.01). There was evidence that these deficits in information processing were negatively correlated with elevated blood phe levels. For children and adolescents similar findings were reported by Albrecht et al. [11] from the group in Heidelberg, Germany, who found in a meta analysis of 20 studies published between 1987 and 2007 an inverse correlation between neuropsychological speed in children and adolescents and blood phe. However, in adult PKU's “as there is a lack of studies on adult PKU's” no such correlation could be found. The authors conclude from these results to keep blood phe in children up to 13 years at b360 μmol/L and in adolescents at b570 μmol/L. Other studies [12,13] were not conclusive to provide target blood phe levels for adults since the majority of patients investigated had highly increased blood phe levels (usually N1000 μmol/L). However, in the paper by Channon et al. [13] the diet continuation group scored somewhat better in cognitive function than the discontinuation group. Measuring reaction times in a Stroop task Sundermann et al. [14] could not show any significant difference in 17 adult PKU patients with an off diet blood phe level of 1140–1210 μmol/L and an additional phe load of 100 mg/kg bodyweight to healthy controls. Different results were found by ten Hoedt et al. [15] investigating nine early treated adult PKU patients in a double blind, placebo controlled study to determine whether mood and sustained reaction is influenced by high blood phe levels (1259 vs 709 μmol/L). The high blood phe group was characterized by impaired sustained attention, slower reaction times and slower recognition of complex patterns in a visuospatial pattern recognition task. In summary, there are some inconsistent results in early treated adult PKU patients, but most studies show a negative influence of blood phe levels N1000-1200 μmol/L on neuropsychological test batteries and cognitive outcomes. The effect of life long exposition to high blood phe levels appears to be an important issue in adult PKU's. Long term outcome of these patients is questionned with regard to the occurrence of neurodegenerative disorders (Parkinsonism, Alzheimer's disease or similar cognitive failure). To this purpose, a long term prospective study including adult PKU's diagnosed through neonatal screening will be launched in France in 2011–2012 (more than 200 patients will be enrolled). 5.2. Psychiatric findings in early treated adult PKU patients In the review by V.L. Brumm, et al. [12] a number of different psychiatric symptoms are described. Symptoms were primarily in the depressive category and more frequent in women.
It is difficult to give numbers of the frequency of these symptoms in early and well treated adult PKU patients in comparison to the general population. Most of the studies deal with a heterogeneous sample including patients who had been treated suboptimally. There is evidence that patients with higher blood phe levels demonstrate more often psychiatric symptoms like depression and anxiety. This had clearly been shown in a recent double blind study where moods of patients were tested under high and low phenylalanine [15]. Using a profile of “mood states” it could be shown, that under high blood phe there was an increase of these symptoms. In addition it could be demonstrated that “fluctuation in tempo during sustained attention” was higher under increased blood phe levels. Due to the design of the study these findings are very valuable giving additional arguments for a lifelong treatment also for this age group with a target level b700–900 μmol/L.
5.3. Nutritional deficiencies and growth Since the treatment partly consists of an artificial protein substitute there are concerns about the value of this protein for growth and protein status. Some studies have shown that growth is impaired in early treated PKU children and final height is decreased in comparison to age matched controls [16,17]. A positive correlation between growth and natural protein intake could be demonstrated in the study of Hoeksma et al. [18]. Influence of the diet on protein metabolism is also shown by decreased protein synthesis expressed by low serum prealbumin [19]. There is a decreased peak bone mass in young adults [20] and evidence that poor adherence to the diet may influence bone quality at least in children [21]. Others have shown in all age groups decreased bone mineral density. They also found that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and total n-3 fatty acids were significantly diminished in PKU patients compared with healthy controls. DHA, EPA, and total n-3 fatty acids were positively associated with bone mineral density [17]. Absolute and functional vitamin B12 deficiency was described in adult PKU patients opening another risk for brain dysfunction [22,23]. Our personal experiences support these findings. Many adult PKU's have some kind of a “vegan diet” but do not take the amino acid formula. Such eating behavior gives them a high risk to suffer from nutritional deficiencies without reaching target blood phe levels. In summary, long-term nutritional follow-up is recommended for adult PKU patients, whether they are compliant with the diet or not.
5.4. Biochemical outcome parameters There are different biochemical outcome parameters used to measure quality of dietary treatment. Mean blood phe concentrations per half year, year or lifetime are mostly taken as treatment measure. In a meta analysis by Waisbren et al. [24] there was a 1.3 to 4.1-point reduction in IQ for every 100 μmol/L increase in blood phe in children 0 to 12 years. Similar results were reported from another group [25]. Besides mean blood phe fluctuation of blood phe is an important parameter for outcome [26,27]. In the paper by Burgard et al. [26] it could be shown that the IQ at 9 years of age is more (negatively) correlated to the lifelong fluctuation of blood phe than to the mean blood phe concentration. Similar results have recently been found by Anastasoai etal. who conclude “that stability of blood phe levels may be more important to cognitive functioning than overall exposure to phe in early and continuously treated PKU”[27]. The blood phe/tyrosine ratio may also be used as index of dietary control. In a study by Luciana et al. [28] there are advantages to maintaining dietary control for both phe and tyrosine concentrations in adulthood for various neuropsychological parameters.
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5.5. CNS findings in early treated adult PKU patients 5.5.1. MRI (magnetic resonance imaging) findings MRI investigations of the brain in PKU patients have gained new interest after better techniques like diffusion weighted, imaging diffusion tensor imaging and “functional” MRI have been applied. By these methods it was possible to better attribute the findings to certain anatomical locations and to quantify them to some extent [29–31]. There was a clear correlation between quality of treatment as e.g. duration of therapy and mean blood phe levels with these changes. However, there is no additional value for treatment monitoring. 5.5.2. CNS metabolic findings In adult PKU patients brain metabolism has also been investigated using modern imaging techniques like PET with labeled L-dopamine (FDOPA). [32]. It could be shown that influx and distribution of FDOPA is severely impaired and rate of decarboxylation of FDOPA is markedly reduced. However, even with this metabolic similarity to Parkinson disease no special symptoms were observed. The explanation remains speculative to explain this. Another finding found recently concerns cerebral protein synthesis [33]. In adult PKU patients measuring cerebral tyrosine incorporation rate it could be shown that protein synthesis is reduced with phe levels above 600 to 800 μmol/L. The authors discuss that this impact on cerebral protein metabolism would be another argument for lifelong treatment. 6. Future management in adult PKU Recent (partly double blind) studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted [34,35]. Therefore other treatment options like pharmacologic treatment with sapropterin have to be considered [36,37]. However, so far there are no long term controlled studies to prove that such a treatment is more successful than the diet. Further studies should consider the impact of blood phe exposure on brain development in childhood and brain function at all ages. Mean blood phe concentrations per half year, year or lifetime are mostly taken as treatment measure. Besides mean blood phe, fluctuation of blood phe over time is important. Burton et al. [38] has shown that fluctuation of blood phe is decreased by Sapropterin treatment which in the long term may have positive effects on cognitive outcome. As discussed, at this time it is difficult to give general treatment recommendations in adult PKU patients. However, there is no doubt that late detected PKU patients benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may profit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient. Long term results in early treated patients are suboptimal. In addition there are certain risks as impaired growth, decreased bone mineral density and nutritional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe levels than 600–900 μmol/L on cognitive and neuropsychological function and psychiatric symptoms. Sapropterin treatment for responsive patients should lead to better phe control, less phe fluctuation and should provide a diet with higher amount of natural protein for these patients. Further studies must prove if adults with PKU may also profit from a better treatment. References [1] F. Feillet, F. van Spronsen, A. MacDonald, F.K. Trefz, M. Demirkol, M. Giovannini, A. Bélanger-Quintana, N. Blau, Challenges and pitfalls in the management of phenylketonuria, Pediatrics 126 (2010) 333–341.
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[34] J.H. Walter, F.J. White, Blood phenylalanine control in adolescents with phenylketonuria, Int. J. Adolesc. Med. Health 16 (2004) 41–45. [35] N. Blau, F.J. van Spronsen, H.L. Levy, Phenylketonuria, Lancet 376 (2010) 1417–1427. [36] H.L. Levy, A. Milanowski, A. Chakrapani, M. Cleary, P. Lee, F.K. Trefz, B. Chester, C.B. Whitley, F. Feillet, A.S. Feigenbaum, J.D. Bebchuk, H. Christ-Schmidt, A. Dorenbaum, for the Sapropterin Research Group*, Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlledstudy, Lancet 370 (2007) 504–510. [37] F.K. Trefz, B.K. Burton, N. Longo, M.M. Casanova, D.J. Gruskin, A. Dorenbaum, E.D. Kakkis, E.A. Crombez, D.K. Grange, P. Harmatz, M.H. Lipson, A. Milanowski, L.M. Randolph, J. Vockley, C.B. Whitley, J.A. Wolff, J. Bebchuk, H. Christ-Schmidt, J.B. Hennermann, Sapropterin Study Group, Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study, J. Pediatr. 154 (2009) 700–707. [38] B.K. Burton, H. Bausell, R. Katz, H. Laduca, C. Sullivan, Sapropterin therapy increases stability of blood phenylalanine levels in patients with BH4-responsive phenylketonuria (PKU), Mol. Genet. Metab. 101 (2010) 110–114.
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Adult phenylketonuria outcome and management F. Trefz a,⁎, F. Maillot b, K. Motzfeldt c, M. Schwarz d a
Kreiskliniken Reutlingen GmbH, Reutlingen, Germany CHRU de Tours, Université François Rabelais, INSERM U921, Tours, France c Oslo University Hospital, Women and Children's Division, Department of Pediatrics and Newborn Screening, Oslo, Norway d Internal Medicine outpatient centre, Kaarst, Germany b
a r t i c l e
i n f o
Article history: Received 13 July 2011 Received in revised form 23 August 2011 Accepted 23 August 2011 Available online 26 August 2011 Keywords: Phenylketonuria Hyerphenylalaninemia Adult Sapropterin
a b s t r a c t The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase. Recent, partly double blind studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted. Late detected PKU patients (up to 4–6 years of age) benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may benefit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient. In early and well treated patients a number of studies have demonstrated that cognitive and neurosychologic tests are different from controls. In addition there is evidence that patients with higher blood phenylalanine (phe) levels demonstrate more often psychiatric symptoms like depression and anxiety. Medical problems are more often observed: there are certain risks as impaired growth, decreased bone mineral density and nutrional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe (mean blood phenylalanine N 600–900 μmol/L) on cognitive and neuropsychological functions and psychiatric symptoms. Further studies should consider the role of blood phe exposure for brain development in childhood and for brain function in all ages. Besides mean blood phe, fluctuation of blood phe over time is important. Fluctuation of blood phe is decreased by sapropterin treatment in responsive patients which would on the long term may have positive effects on cognitive outcome. Further studies also should include adult PKU patients. © 2011 Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . Untreated adult PKU patients . . . . . . . . . . . . . . . Treatment in late diagnosed but treated PKU patients . . . . Outcome in early treated but early discontinued patients . . Treatment results in early treated patients . . . . . . . . . 5.1. Cognitive and neuropsychological outcome . . . . . . 5.2. Psychiatric findings in early treated adult PKU patients 5.3. Nutritional deficiencies and growth . . . . . . . . . 5.4. Biochemical outcome parameters . . . . . . . . . . 5.5. CNS findings in early treated adult PKU patients . . . 5.5.1. MRI (magnetic resonance imaging) findings . . 5.5.2. CNS metabolic findings . . . . . . . . . . . 6. Future management in adult PKU . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbbreviations: phe, phenylalanine; PAH, phenylalanine hydroxylase; PKU, phenylketonuria; BH4, tetrahydrobioptern. ⁎ Corresponding author at: Kreiskliniken Reutlingen GmbH, Reutlingen, Germany. E-mail addresses: [email protected] (F. Trefz), [email protected] (F. Maillot), [email protected] (K. Motzfeldt), [email protected] (M. Schwarz). 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.08.025
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1. Introduction The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase (PAH). More than 600 mutations are described so far (http://www.pahdb.mcgill.ca/). The other problem consists in the fact that there are no prospective studies available and that in later life other modulators as lifestyle and aging become more important when evaluating brain development and brain function. Long term dietary treatment also shows development of other problems like osteopenia or metabolic imbalances. Having these problems in mind it is clear that up to now there are no evidence based treatment recommendations and only vague recommendations like “lifelong treatment” with very different suggestions for e.g. the blood phe targets as published in a European survey recently [1]. In this review we would like to describe outcome and management of adult PKU patients excluding maternal PKU but describing the different groups of adult PKU patients we see in our metabolic outpatient clinic. 1. PKU patients never treated, 2. PKU patients late treated (start 1– 6 years of age) 3. Patients early treated but early or with poor compliance and 4. Patients early treated with good compliance until adulthood. Data are based on literature review and personal clinical experiences.
2. Untreated adult PKU patients Patients with untreated PKU are severely retarded in most cases and in addition may show challenging behavioral problems (Table 1). Treatment studies in untreated PKU's are difficult to perform. Besides ethical issues to conduct such studies measurement of improvement is difficult. The results are controversial, the study population always small. In some studies severity of behavioral disturbances may be reduced after introduction of a phe restricted diet [2], Table 1. In a recent placebo controlled study in 17 patients [3] a significant difference between treatment and placebo group using standardized test procedures could not be demonstrated. However, the positive comments of carers in the treatment group were significant in respect to a positive change than in the placebo group. This indicates a positive effect in individual patients and the authors conclude that “this intervention should be offered to these individuals” [3]. According to our personal experiences a close monitoring, not only of the blood phe levels but also of the general health condition of these patients should be performed: excessive weight loss and development of dystrophy might be a severe side effect after introduction of a low phe diet. We also experienced that treatment of patients living still in the family is easier. Experiences of family members with the diet and a better environment may be reasons for this (Trefz, unpublished).
Table 1 Symptoms and change of symptoms in 6 untreated PKU patients under dietary treatment. SIB: self injurious behavior. Adapted from Baumeister and Baumeister [3]. Patient/symptoms
% change
Treatment (months)
1/SIB 2/Assault/SIB face gouging
− 93% − 91% − 48% − 13% − 69% − 54% No change
36 26
3/SIB 4/Tantrums 5/Stereotypes 6/Hyperactivity
9 9 3 3
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In summary, a general recommendation for a phe restricted diet in severely retarded PKU patients cannot be given. Individual conditions should be considered and quality of life should not worsen especially in severely retarded patients with behavioral problems. On the other hand in some patients a blood phe level below 900 μmol/L may result in reduction of behavioral problems and increase of attention. 3. Treatment in late diagnosed but treated PKU patients Introduction of newborn screening and early dietary treatment resulted in the prevention of severe brain damage. However, due to screening failures and immigration of patients from countries where early detection and treatment of PKU is not yet established, there are a number of untreated PKU's in many European centers. In the last 20 years we saw in one center (Reutlingen, Germany) 10 patients missed by newborn screening due to various reasons (Table 2). After introduction of tandem mass spectrometry and a better computerized sample handling in the screening laboratories one can expect that missed cases will be minimized in the future. However, there are still a number of immigrants coming from countries where newborn screening is not yet established. From early prescreening experiences it is well known that after introduction of dietary treatment in later infancy and childhood partial reversibility of IQ loss may occur. Catch up of development retardation is especially seen in the first 4–6 years of life [4], but there is a large heterogeneity of treatment success as also shown recently in a review by Grosse [5]. As pointed out in this paper and based on personal experiences there is often an impressive improvement of development when introducing a phe restricted diet even in very late detected PKU patients. All of these patients benefit from a dietary treatment with phe levels b600 μmol/L beyond infancy and young adulthood. One may speculate that in these patients elevated blood phe levels cause brain dysfunction more likely than in early treated patients with an unaffected brain. 4. Outcome in early treated but early discontinued patients For many years dietary treatment of PKU was terminated at 10 years of age, in some countries even at 6 years of age. Investigations in patients with early diet termination revealed that there was a loss of intellectual function [6]. Koch and coworkers [7] could demonstrate that patients continuing the diet until adulthood had a better outcome than those who stopped the diet earlier. In addition in this collaborative study Koch et al. could demonstrate that treatment quality also had an influence on outcome: adults who had continued a dietary control with blood phe levels b15.6 mg/dL had a better IQ
Table 2 Neonatal screening failure in 10 patients with phenylketonuria (Trefz, unpublished); Phe = phenylalanine. Patient Age at diagnosis Phe-level at diagnosis (years) (mg/dL)
Reason for not screening, remarks
1 2 3
1.5 9 3.5
28 25 32
4 5 6 7
1.5 7 7 2.5
24 21 N 20 27
8 9 10
0.8 1 1.5
N 20 N 20 N 20
Born in Brazil Unclear Mixed blood on screening card Lab mistake Russian immigrant Russian immigrant Turkish guest worker family Lab mistake Lab mistake Lab mistake, infant with Down Syndome and PKU!
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than those with higher levels. In addition adults with PKU being off diet had a higher rate of medical problems like eczema, phobias, depression and neurological symptoms. Treatment policy changed so that diet for life was suggested [8]. 5. Treatment results in early treated patients 5.1. Cognitive and neuropsychological outcome In the following cognitive and neuropsychologic outcomes of adult early treated PKU patients are discussed. A number of studies have demonstrated that cognitive outcome and neurosychologic tests are different from controls. In a meta analysis by Moyle et al. [9] including 5 studies there were reduced full scale IQ scores and reduced information processing speed and attention. In addition in 4 studies inhibitory abilities and motor control were reduced compared to controls. Except for working memory there was no difference to controls (3 studies). In a three year longitudinal study from a group in Münster, Germany, Feldman et al. [10] found a significant reduction of full scale IQ compared to a diabetic control group (104.9 vs 111.8, p b 0.05) but not at baseline. Information processing expressed as time to complete the test was also very different from the diabetic group (84.9 vs. 67.8 s, p b 0.01). There was evidence that these deficits in information processing were negatively correlated with elevated blood phe levels. For children and adolescents similar findings were reported by Albrecht et al. [11] from the group in Heidelberg, Germany, who found in a meta analysis of 20 studies published between 1987 and 2007 an inverse correlation between neuropsychological speed in children and adolescents and blood phe. However, in adult PKU's “as there is a lack of studies on adult PKU's” no such correlation could be found. The authors conclude from these results to keep blood phe in children up to 13 years at b360 μmol/L and in adolescents at b570 μmol/L. Other studies [12,13] were not conclusive to provide target blood phe levels for adults since the majority of patients investigated had highly increased blood phe levels (usually N1000 μmol/L). However, in the paper by Channon et al. [13] the diet continuation group scored somewhat better in cognitive function than the discontinuation group. Measuring reaction times in a Stroop task Sundermann et al. [14] could not show any significant difference in 17 adult PKU patients with an off diet blood phe level of 1140–1210 μmol/L and an additional phe load of 100 mg/kg bodyweight to healthy controls. Different results were found by ten Hoedt et al. [15] investigating nine early treated adult PKU patients in a double blind, placebo controlled study to determine whether mood and sustained reaction is influenced by high blood phe levels (1259 vs 709 μmol/L). The high blood phe group was characterized by impaired sustained attention, slower reaction times and slower recognition of complex patterns in a visuospatial pattern recognition task. In summary, there are some inconsistent results in early treated adult PKU patients, but most studies show a negative influence of blood phe levels N1000-1200 μmol/L on neuropsychological test batteries and cognitive outcomes. The effect of life long exposition to high blood phe levels appears to be an important issue in adult PKU's. Long term outcome of these patients is questionned with regard to the occurrence of neurodegenerative disorders (Parkinsonism, Alzheimer's disease or similar cognitive failure). To this purpose, a long term prospective study including adult PKU's diagnosed through neonatal screening will be launched in France in 2011–2012 (more than 200 patients will be enrolled). 5.2. Psychiatric findings in early treated adult PKU patients In the review by V.L. Brumm, et al. [12] a number of different psychiatric symptoms are described. Symptoms were primarily in the depressive category and more frequent in women.
It is difficult to give numbers of the frequency of these symptoms in early and well treated adult PKU patients in comparison to the general population. Most of the studies deal with a heterogeneous sample including patients who had been treated suboptimally. There is evidence that patients with higher blood phe levels demonstrate more often psychiatric symptoms like depression and anxiety. This had clearly been shown in a recent double blind study where moods of patients were tested under high and low phenylalanine [15]. Using a profile of “mood states” it could be shown, that under high blood phe there was an increase of these symptoms. In addition it could be demonstrated that “fluctuation in tempo during sustained attention” was higher under increased blood phe levels. Due to the design of the study these findings are very valuable giving additional arguments for a lifelong treatment also for this age group with a target level b700–900 μmol/L.
5.3. Nutritional deficiencies and growth Since the treatment partly consists of an artificial protein substitute there are concerns about the value of this protein for growth and protein status. Some studies have shown that growth is impaired in early treated PKU children and final height is decreased in comparison to age matched controls [16,17]. A positive correlation between growth and natural protein intake could be demonstrated in the study of Hoeksma et al. [18]. Influence of the diet on protein metabolism is also shown by decreased protein synthesis expressed by low serum prealbumin [19]. There is a decreased peak bone mass in young adults [20] and evidence that poor adherence to the diet may influence bone quality at least in children [21]. Others have shown in all age groups decreased bone mineral density. They also found that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and total n-3 fatty acids were significantly diminished in PKU patients compared with healthy controls. DHA, EPA, and total n-3 fatty acids were positively associated with bone mineral density [17]. Absolute and functional vitamin B12 deficiency was described in adult PKU patients opening another risk for brain dysfunction [22,23]. Our personal experiences support these findings. Many adult PKU's have some kind of a “vegan diet” but do not take the amino acid formula. Such eating behavior gives them a high risk to suffer from nutritional deficiencies without reaching target blood phe levels. In summary, long-term nutritional follow-up is recommended for adult PKU patients, whether they are compliant with the diet or not.
5.4. Biochemical outcome parameters There are different biochemical outcome parameters used to measure quality of dietary treatment. Mean blood phe concentrations per half year, year or lifetime are mostly taken as treatment measure. In a meta analysis by Waisbren et al. [24] there was a 1.3 to 4.1-point reduction in IQ for every 100 μmol/L increase in blood phe in children 0 to 12 years. Similar results were reported from another group [25]. Besides mean blood phe fluctuation of blood phe is an important parameter for outcome [26,27]. In the paper by Burgard et al. [26] it could be shown that the IQ at 9 years of age is more (negatively) correlated to the lifelong fluctuation of blood phe than to the mean blood phe concentration. Similar results have recently been found by Anastasoai etal. who conclude “that stability of blood phe levels may be more important to cognitive functioning than overall exposure to phe in early and continuously treated PKU”[27]. The blood phe/tyrosine ratio may also be used as index of dietary control. In a study by Luciana et al. [28] there are advantages to maintaining dietary control for both phe and tyrosine concentrations in adulthood for various neuropsychological parameters.
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5.5. CNS findings in early treated adult PKU patients 5.5.1. MRI (magnetic resonance imaging) findings MRI investigations of the brain in PKU patients have gained new interest after better techniques like diffusion weighted, imaging diffusion tensor imaging and “functional” MRI have been applied. By these methods it was possible to better attribute the findings to certain anatomical locations and to quantify them to some extent [29–31]. There was a clear correlation between quality of treatment as e.g. duration of therapy and mean blood phe levels with these changes. However, there is no additional value for treatment monitoring. 5.5.2. CNS metabolic findings In adult PKU patients brain metabolism has also been investigated using modern imaging techniques like PET with labeled L-dopamine (FDOPA). [32]. It could be shown that influx and distribution of FDOPA is severely impaired and rate of decarboxylation of FDOPA is markedly reduced. However, even with this metabolic similarity to Parkinson disease no special symptoms were observed. The explanation remains speculative to explain this. Another finding found recently concerns cerebral protein synthesis [33]. In adult PKU patients measuring cerebral tyrosine incorporation rate it could be shown that protein synthesis is reduced with phe levels above 600 to 800 μmol/L. The authors discuss that this impact on cerebral protein metabolism would be another argument for lifelong treatment. 6. Future management in adult PKU Recent (partly double blind) studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted [34,35]. Therefore other treatment options like pharmacologic treatment with sapropterin have to be considered [36,37]. However, so far there are no long term controlled studies to prove that such a treatment is more successful than the diet. Further studies should consider the impact of blood phe exposure on brain development in childhood and brain function at all ages. Mean blood phe concentrations per half year, year or lifetime are mostly taken as treatment measure. Besides mean blood phe, fluctuation of blood phe over time is important. Burton et al. [38] has shown that fluctuation of blood phe is decreased by Sapropterin treatment which in the long term may have positive effects on cognitive outcome. As discussed, at this time it is difficult to give general treatment recommendations in adult PKU patients. However, there is no doubt that late detected PKU patients benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may profit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient. Long term results in early treated patients are suboptimal. In addition there are certain risks as impaired growth, decreased bone mineral density and nutritional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe levels than 600–900 μmol/L on cognitive and neuropsychological function and psychiatric symptoms. Sapropterin treatment for responsive patients should lead to better phe control, less phe fluctuation and should provide a diet with higher amount of natural protein for these patients. Further studies must prove if adults with PKU may also profit from a better treatment. References [1] F. Feillet, F. van Spronsen, A. MacDonald, F.K. Trefz, M. Demirkol, M. Giovannini, A. Bélanger-Quintana, N. Blau, Challenges and pitfalls in the management of phenylketonuria, Pediatrics 126 (2010) 333–341.
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