Neuropsychological outcome of subjects participating in the PKU Adult Collaborative Study: A preliminary review

Adult subjects with classical phenylketonuria (PKU) who were diagnosed and treated neonatally participated in this long-term follow-up study. Twenty-four subjects received neuropsychological (NP) assessment and a subset received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to identify: (1) pattern of cognitive dysfunction; (2) effect of high blood phenylalanine (Phe) level at time of cognitive testing; and (3) treatment variables that may be associated with cognitive difficulties in adulthood. All subjects had average IQ except one subject in the borderline range. Diet was initiated by the 15th day of life. All subjects except one were on diet until age 6 years (mean years of treatment = 15). Blood Phe levels at cognitive testing ranged from 157 to 1713 micromol/L (mean = 1038); 11 subjects had levels < 1000 micromol/L and 13 subjects had levels >1000 micromol/L. Results suggest that adults with early-treated PKU demonstrate specific cognitive deficits, a number of which are associated with the frontal and temporal area of the brain. Deficits were noted in several domains including executive functioning, attention, verbal memory, expressive naming and verbal fluency. Self-report measures of depression and anxiety were generally in the normal/mild range. The group with a Phe level > 1000 micromol/L scored lower than the group with Phe level < 1000 micromol/L on measures of focused attention, verbal fluency, reaction time, verbal recognition memory, visual memory and naming. Tests of cognitive functioning were often correlated with measures of treatment during childhood rather than with Phe level at the time of cognitive testing. Subjects with abnormal MRI scored significantly lower on two cognitive tests (Trails A and CVLT Recognition Memory). We found no significant correlation between current brain Phe level obtained through MRS (n = 10) and neuropsychological functioning. Future longitudinal investigation with a larger sample size will assist in clarifying the aetiology of neuropsychological deficits and association with treatment history.     

Executive function and memory in relation to olfactory deficits in alcohol-dependent patients

BACKGROUND: Prior research indicates that chronic alcoholism is accompanied by olfactory deficits. These have been suggested to reflect dysfunctions in olfactory brain regions. The present study investigated the role of neurocognitive functioning in tests (executive function and memory) sensitive to the functional integrity of brain areas that are crucial to olfactory processing in patients with alcohol dependence. METHODS: Performance on olfactory functions (detection threshold, quality discrimination, identification), executive function (Wisconsin Card Sorting Test), and memory (German version of the California Verbal Learning Test) was assessed in 32 alcohol-dependent patients and 30 healthy comparison subjects, comparable in age, gender, and smoking status. RESULTS: Compared with controls, alcohol-dependent patients were impaired in all 3 domains, olfactory functions, executive function, and memory. In patients, olfactory discrimination ability was positively correlated with executive function performance. Regression analyses conducted to clarify the relation between group (patients vs controls), executive function, memory, and olfactory functions indicated that group was the only significant predictor of olfactory detection threshold and identification, and both group and executive function were found to be the significant predictors of olfactory discrimination. CONCLUSIONS: Olfactory deficits in alcohol dependence appear to be associated with prefrontal cognitive dysfunction. Results indicate that olfactory quality discrimination deficits are related to executive function impairment. These findings add to the available research on frontal lobe dysfunction in alcoholism, suggesting that alcohol-related olfactory discrimination deficits may be associated with impairment in the functional integrity of the prefrontal lobe.     

Neuropsychological Deficits Are Correlated with Frontal Hypometabolism in Positron Emission Tomography Studies of Older Alcoholic Patients

In an extension of previous work, we studied the behavioral correlates of medial frontal lobe glucose hypometabolism in chronically alcohol-dependent patients. Thirty-one male patients who were detoxified, medically stable, and free of other central nervous system risk factors for neuropsychological impairment were examined with (1) anatomic imaging (CT or MR), (2) functional imaging with [¹⁸F] fluorodeoxyglucose (¹⁸F-FDG) and positron emission tomography (PET), and (3) a battery of neuropsychological tests, including two measures of abstraction known to be generally sensitive to frontal lobe disease or dysfunction [the Wisconsin Card Sorting Test (WCST) and the Halstead Category Test (HCT)]. ¹⁸F-FDG PET data from 18 age- and sex-matched normal control subjects were used for comparison. All patients met criteria for severe alcohol dependence and for at least a mild degree of alcoholic-induced cognitive impairment. Although the mean IQ level of the alcoholic patients was in the average range, the concepts attained and the error scores on the WCST and HCT were significantly impaired in comparison with established norms. Local cerebral metabolic rate for glucose (LCMRglc) was significantly decreased in a sagittal strip of the medial frontal cortex in the alcoholic patients as compared with the normal controls. Comparison of data from PET scans and anatomic images indicated that the reduced LCMRglc could not be attributed to reduced amounts of tissue alone. A statistically significant relationship was found between LCMRglc in the medial frontal region of the cerebral cortex and performance on the WCST, but not the HCT. These findings suggest that chronic alcohol intake results in impaired function of cerebral tissue in the medial frontal region. The impairment pertains both to tissue metabolic rates and the behavioral correlates of these rates.     

Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population

This study addressed two questions: is there an effect of dietary interventions that induce relatively small changes in phenylalanine (Phe) concentration on neuropsychological outcome of early- and continuously treated phenylketonuria (PKU) patients, and are there differences in effects for PKU children and adolescents? To answer the first question, the effect of a short-term dietary intervention (1-2 weeks) was compared for patients whose Phe concentrations increased vs those whose Phe concentrations decreased. Controls were tested twice to control for learning effects. To answer the second question, the effect of dietary interventions was examined in younger patients (aged 7-10 years) and older patients (aged 11-14 years). The effect of dietary interventions was determined with three neuropsychological tasks: one requiring sustained attention; a second demanding maintenance in working memory; and a third in which complex operations were performed in working memory. Relatively small fluctuations in Phe concentration were found to influence neuropsychological task performance of PKU patients. Patients whose Phe concentrations decreased at the second assessment showed generally more improvement than controls. Patients whose Phe concentrations had increased showed minimal improvement or deterioration of task performance. The strongest effects were observed when sustained attention and manipulation of working memory content were required. There were some indications of a greater sensitivity of younger patients to fluctuations in Phe concentration.     

Frontal lobe-dependent functions in treated phenylketonuria: Blood phenylalanine concentrations and long-term deficits in adolescents young adults

Summary Even early-treated phenylketonurics may suffer from phenylalanine-related deficits. Elevated phenylalanine concentrations can interfere with the development and function of the CNS. Outcome beyond childhood has not been extensively investigated. This long-term study was performed to determine whether adolescents and young adults with PKU show frontal lobe-dependent deficits when compared to diabetic patients. The comparative study covered 35 PKU patients, 13–21 years of age (mean 17.8 years), and 35 diabetic patients matched for sex, age and socioeconomic status. Patients were assessed for IQ (Culture Fair Intelligence Test), information processing (Trail Making Test), and selective and sustained attention (Stroop Task, Test d-2). Assessments were repeated within a 3-year follow-up. PKU patients showed no increase in blood phenylalanine concentrations at follow-up. They had significantly poorer test results than the diabetic patients at both assessment times. Within the tests, however, this was due to reduced performance speed but not to deficits in specific frontal lobe-dependent functions. Elevated phenylalanine concentrations seem to exert a global effect slowing performance speed. This effect is enduring in adolescence and early adulthood.     

Phenylalanine can be detected in brain tissue of healthy subjects by 1H magnetic resonance spectroscopy

Transport of phenylalanine (Phe) and the other large neutral amino acids across the blood-brain barrier plays a crucial role in the pathogenesis of phenylketonuria (PKU). Thus, investigation of Phe transport kinetics by means of proton magnetic resonance spectroscopy (1H MRS) became an important research area in the mid 1990s. As 1H MRS measurements of brain phenylalanine are restricted to tissue concentrations above 100-150 micromol/kg wet weight, this approach was possible only in PKU patients, and comparison with healthy controls was not achieved. Using standardized single-dose oral Phe loading in three healthy subjects, it was shown that Phe values increase steeply, peak at about 1 h post load, and decrease thereafter. In a single case study, repetitive Phe loading was then performed to achieve a plateau of high blood Phe concentrations for several hours. It was demonstrated that detection and monitoring of brain Phe concentrations is feasible by means of 1H MRS. This approach constitutes a prerequisite for describing carrier kinetics in health.     

Does maternal knowledge impact blood phenylalanine concentration in Turkish children with phenylketonuria?

The aim of this study was to compare the level of maternal knowledge and the blood phenylalanine (Phe) control in phenylketonuria (PKU; OMIM 261600). The study was conducted on 144 children (81 boys, 63 girls) with PKU, aged between 1 and 15 years, at Hacettepe University Ihsan Dogramaci Children's Hospital, Metabolism and Nutrition Unit. All subjects were treated with a low-Phe diet using a Phe-exchange system. A 20-question multiple-choice questionnaire was applied to the mothers to determine their knowledge about PKU and its dietary treatment. Questions in the test consisted of the knowledge about the disease (6 questions), general dietary knowledge (14 questions) and knowledge about specific exchange within the dietary questions (6 questions). The median blood Phe concentration for the previous 3-year period was used as an indicator of metabolic control. Eighty-seven children had a median blood Phe concentration above the MRC Working Party Guidelines. There was a negative correlation between maternal knowledge about exchange and median blood Phe concentration in the child (p<0.05). Maternal knowledge about a standard 15 mg Phe exchange system is correlated with dietary compliance as measured by blood Phe concentrations in our subjects. We would like to implement an easier method of measuring Phe exchanges to improve dietary knowledge in the mothers.     

Platelet serotonin concentrations in PKU patients under dietary control and tetrahydrobiopterin treatment

Summary Tetrahydrobiopterin (BH₄) supplementation has been applied in PKU treatment, resulting in successful control of blood phenylalanine (Phe) concentrations. We evaluated serotonin status in PKU patients under classical dietary treatment (n = 40) and in a group of 11 PKU patients under BH₄ treatment, both during a 6-month period. Platelet serotonin values were significantly lower in PKU patients under dietary treatment when compared with controls. A negative correlation was observed between plasma Phe and platelet serotonin concentrations (r = −0.367, p = 0.017) in PKU patients. Platelet serotonin concentration increased significantly after both 1 and 6 months of BH₄ therapy when compared with baseline conditions (Wilcoxon test: p = 0.013 and p = 0.021, respectively), while no differences were observed when comparing plasma Phe concentrations at the different points. Our results indicate that PKU patients under classical treatment have decreased platelet serotonin concentrations, probably owing to continued high Phe values, while BH₄ supplementation restored platelet serotonin values.     

Dietary treatment of phenylketonuria: the effect of phenylalanine on reaction time

There is no evidence that high phenylalanine (Phe) levels have irreversible effects on the adult brain. Many adults with phenylketonuria (PKU) no longer follow a protein-restricted diet. Neuropsychological studies have shown that reaction time in adults with PKU is slower than controls. There are no data to show that this is directly related to Phe levels. Another way to assess reaction time is to measure saccadic latency. We have used a portable, head-mounted saccadometer to measure latency in the outpatient setting. Patients with PKU were split into three groups: off-diet (Phe>1,200 μmol/l), on-diet (Phe <800 μmol/l) and maternal diet (Phe 100–400 μmol/l ). Reciprocal median latency (RML) was compared between groups. Latency was significantly slower in patients who were off-diet than in patients on-diet, on a maternal diet or in normal controls. Reaction times in both diet-treated groups were not significantly different from normal controls. In 16 women planning pregnancy we obtained values before and after they commenced the maternal diet. Stricter control of Phe levels resulted in a significant improvement in reaction times. We conclude that saccadometry is useful in monitoring PKU patients. Adult patients with PKU not on a protein-restricted diet have significantly slower reaction times than controls. In addition, off-diet patients have significantly slower reaction times than on-diet. Paired data show that effects of Phe levels on reaction time are reversible.     

Behaviour and school achievement in patients with early and continuously treated phenylketonuria

Thirty patients with early and continuously treated phenylketonuria (PKU) between 8 and 20 years of age were compared with 30 controls, matched individually for age, sex, and educational level of both parents, on behaviour rating scales for parents and teachers as well as a school achievement scale. PKU patients, as a group, demonstrated more problems in task-oriented behaviour and average academic performance than did matched controls. Interestingly, whereas male PKU patients were rated significantly lower on introversion by their teachers, female patients were rated significantly higher on introversion and lower on extraversion than matched controls. This sex difference was also reflected in the relationship between measures of dietary control and the behaviour clusters, suggesting that male and female patients respond differently to elevated Phe levels or the stress associated with PKU. The teacher rating on average academic performance of the PKU patients was associated with recent level of dietary control, which suggests that it might be improved by more strict adherence to the diet. In addition, academic performance correlated negatively with the behaviour cluster negative task orientation. Further studies are recommended to obtain a more complete evaluation of this relationship and to replicate the current findings on larger samples.     

Regression of neuropsychological deficits in early-treated phenylketonurics during adolescence

Even early-treated phenylketonuric patients suffer from phenylalanine-associated (mild) neuropsychological impairment. To date it is still unclear whether patients' deficits show a progression on ageing. This unsolved question seems to be an important aspect in the still ongoing debate about how long and how strictly the patients should be maintained on diet. Twenty early-treated (20±10, 9–30 days) adolescent phenylketonurics (10 boys, 10 girls) and 20 healthy controls, matched for age, sex and IQ, were inves-tigated twice at a mean ages of 11 and 14 years for their IQ (Culture Fair Intelligence Test–Scale 2; CFT-20), fine motor abilities (Motor PerformanceTask), sustained (Test d₂) and selective attention (Stroop-Task). At the first test, examinations revealed significant blood phenylalanine-correlated neuropsychological deficits in PKU patients. In spite of raised blood phenylalanine concentrations during the following 3 years and significantly elevated concurrent blood phenylalanine concentrations, the repeated measurements revealed a significant decrease of patients' deficits compared to controls. Clinical-neurological status of patients and controls was normal at both test times. The results indicate a decreased vulnerability of PKU-patients with respect to their neuropsychological functioning against elevated blood phenylalanine levels on ageing.     

Maternal PKU: Defining phenylalanine tolerance and its variation during pregnancy,according to genetic background

Background and aimsPhenylketonuria (PKU)-affected women may become pregnant, and dietary phenylalanine (Phe) intake must be adjusted according to Phe tolerance. We report our experience with maternal PKU in relation to genotype PKU heterogeneity.Methods and ResultsA total of 10 pregnancies in 7 PKU women (7 different genotypes) were followed up as part of personalized care. Phe tolerance during preconception and pregnancy was assessed by strict dietary control and weekly Phe measurement (blood spots) in relation to genotype.Most women had stopped PKU diet during childhood or adolescence and six pregnancies were unplanned; a phenylalanine-restricted diet was reinstituted soon after conception. Women were classified according to their Phe levels at birth screening and genotype. Phe tolerance increased systematically in the course of pregnancy in all cases, but the increase was different in subjects with classic PKU (cPKU) when compared with cases with mild hyperphenylalaninemia (mHPA), both on average (+297 mg/day in cPKU vs. 597 in mHPA; P = 0.017) and as percentage (+107% in cPKU vs. +17% in mHPA). Notably, Phe tolerance also varied in the same women in the course of different pregnancies, when body weight gain was also different. Two newborns from the same cPKU mother (unplanned pregnancies on free diet) were affected by congenital alterations.ConclusionsSeveral factors influence metabolic phenotype in maternal PKU, to an unpredictable extent even in the same woman. The number of maternal PKU cases is growing in dedicated Nutrition Units, and the burden associated with careful management of this condition for the health care system should be adequately considered.     

Behavioural factors related to metabolic control in patients with phenylketonuria

Summary Background. The objective of this study was to determine the importance of parental factors possibly related to dietary control in early and continuously treated patients with phenylketonuria (PKU). Methods. A questionnaire was disseminated among parents of 238 patients with PKU born after the nationwide introduction of newborn screening for PKU (1 September 1974) until 31 December 1995. The questionnaire was based on a behavioural model measuring people’s attitudes, subjective norms, and self-efficacy. Dietary control was defined on the basis of mean phenyl- alanine (Phe) concentration of the PKU patients measured between 1 January 1994 and 31 December 1996. Results. Response rate was 71%. Attitudes: children of parents who believed that their child adheres well to the diet, even if his or her Phe concentrations are sometimes too high, had lower Phe concentrations than children of parents who disagree with this statement (adjusted difference −103 μmol/L, p < 0.001). Subjective norm: Phe concentrations were higher when parents answered that their relatives did not approve when their child deviates from the diet (p = 0.004). Self-efficacy: children of parents who reported difficulties in having their child eat the synthetic protein substitute three times a day had higher Phe concentrations than those of parents who did not have such difficulties (adjusted difference 156 μmol/L, p = 0.007). Conclusion. More attention should be given to parents having their child eat the synthetic protein substitute at least three times a day and to teaching parents to keep strictly to the diet without being too rigid. These factors were strongly associated to dietary control and may be amenable to change.     

Pre-attentive processing in children with early and continuously-treated PKU. Effects of concurrent Phe level and lifetime dietary control

Sixty-four children, aged 7 to 14 years, with early-treated PKU, were compared with control children on visual evoked potential (VEP) amplitudes and latencies and auditory mismatch negativity (MMN) amplitudes. It was further investigated whether indices of dietary control would be associated with these evoked potentials parameters. There were no significant differences between controls and children with PKU in VEP- and MMN-indices. However, higher lifetime Phe levels were, in varying degree and stronger than concurrent Phe level, related to increased N75 amplitudes, suggesting abnormalities in attention, and longer P110 latencies, indicating a reduction in speed of neural processing, possibly due to deficits in myelination or reduced dopamine levels in brain and retina. Similarly, higher lifetime Phe levels and Index of Dietary Control (IDC) were associated with decreased MMN amplitudes, suggesting a reduced ability to respond to stimulus change and poorer triggering of the frontally mediated attention switch. In summary, the present study in children with PKU investigated bottom-up information processing, i.e., triggered by external events, a fundamental prerequisite for the individual’s responsiveness to the outside world. Results provide evidence that quality of dietary control may affect the optimal development of these pre-attentive processes, and suggest the existence of windows of vulnerability to Phe exposure.     

Estimating the probability of IQ impairment from blood phenylalanine for phenylketonuria patients: a hierarchical meta-analysis

Though the control of blood phenylalanine (Phe) levels is essential for minimizing impairment in individuals with phenylketonuria (PKU), the empirical basis for the selection of specific blood Phe levels as targets has not been evaluated. We evaluated the current evidence that particular Phe levels are optimal for minimizing or avoiding cognitive impairment in individuals with PKU. This work uses meta-estimates of blood Phe-IQ correlation to predict the probability of low IQ for a range of Phe levels. We believe this metric is easily interpretable by clinicians, and hence useful in making recommendations for Phe intake. The median baseline association of Phe with IQ was estimated to be negative, both in the context of historical (median?=??0.026, 95 % BCI?=?[?0.040, ?0.013]) and concurrent (?0.007, [?0.014, 0.000]) measurement of Phe relative to IQ. The estimated additive fixed effect of critical period Phe measurement was also nominally negative for historical measurement (?0.010, [?0.022, 0.003]) and positive for concurrent measurement (0.007, [?0.018, 0.035]). Probabilities corresponding to historical measures of blood Phe demonstrated an increasing chance of low IQ with increasing Phe, with a stronger association seen between blood Phe measured during the critical period than later. In contrast, concurrently-measured Phe was more weakly correlated with the probability of low IQ, though the correlation is still positive, irrespective of whether Phe was measured during the critical or non-critical period. This meta-analysis illustrates the utility of a Bayesian hierarchical approach for not only combining information from a set of candidate studies, but also for combining different types of data to estimate parameters of interest.     

The role of cognitive event-related potentials in executive dysfunction

Frontal lobes are great and are a late-developing region of the neocortex that play a critical role in human behavior and executive function. The aim of this study was to clarify the role of event-related potentials (ERPs) in executive dysfunction and its relationship between generator mechanism and cognitive significance. We recruited 20 patients with frontal lobe lesion (FLL) and 27 age-matched controls. All patients submitted to comprehensive Frontal Test Battery and auditory ERPs measurement. In comparison with controls, the patients with FLL had significantly decreased executive function and manifested the delay of P300 latency, which reflected a delay of mental processing speed in these patients. Our findings suggest that patients with FLL may have prolonged P300 latency, which has a good correlation with executive dysfunction, poor performance, and longer P300 latencies. P300 ERPs are considered to be a useful method to identify the alteration of frontal-parietal connection.     

Investigation of oxidative stress parameters in treated phenylketonuric patients

Phenylketonuria (PKU) is the most frequent disturbance of amino acid metabolism being caused by severe deficiency of phenylalanine hydroxylase activity. Untreated PKU patients present severe mental retardation whose pathophysiology is not completely estabilished. Despite the low-Phe diet, a considerable number of phenylketonuric patients present a mild to moderate psychomotor delay and decreased cognitive functions. In the present study we evaluated various parameters of oxidative stress namely thiobarbituric acid-reactive species (TBA-RS), total antioxidant reactivity (TAR) and activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in two groups of treated PKU patients, one with well controlled and the other with high Phe blood levels in order to investigate whether blood Phe concentrations could be correlated with the extend of oxidative stress. We initially verified a marked increase of TBA-RS, and a decrease of TAR in plasma, as well as a reduction of erythrocyte GSH-Px activity which were similar in both groups of PKU patients, when compared to controls of similar ages. In contrast, CAT and SOD activities were not altered in PKU patients. These results show that oxidative stress occurs in PKU patients and that this pathogenic process is probably not directly correlated to Phe blood levels.     

Tackling frontal lobe–related functions in PKU through functional brain imaging: a Stroop task in adult patients

Background  

Profound mental retardation in phenylketonuria (PKU) can be prevented by a low phenylalanine (Phe) diet. However, even patients treated early have inconsistently shown deficits in several frontal lobe–related neuropsychological tasks such as the widely accepted Stroop task. The goal of this study was to investigate whether adult patients exhibit altered brain activation in Stroop-related locations in comparison to healthy controls and if an acute increase in blood Phe levels in patients has an effect on activation patterns.     

Haemostatic variables in phenylketonuric children under dietary treatment

Summary Classical phenylketonuria (PKU) (McKusick 261600) is an inborn error of metabolism treated by a controlled low-phenylalanine (Phe) diet started as soon as possible in the first days of life. Such a diet can be achieved with vegetable protein and can be considered non-atherogenic because of the reduction of animal products. Thirty patients with PKU were classified into two groups according to their annual mean Phe levels. Their daily protein intake was largely replaced by PKU2 Milupa which contains a mixture of amino acids. The product has no phenylalanine or fat of any kind. Thirty-eight (38) individuals of comparable age were used as controls. Group A (n=15) had good compliance with the special diet (Phe mean 192±115 µmol/L); group B (n=15) did not strictly adhere to the diet (Phe mean 595±263 µmol/L). Certain haemostatic components (factors I, VII, VIII, and X, antithrombin III, protein C, and plasminogen) and lipid variables (cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein) as well as Phe levels were estimated. All the haemostatic factors studied were found within the normal range with the exception of a significant reduction in protein C in both groups of PKU patients. Furthermore, a statistically significant reduction in factor VII and X concentrations was observed in patients on strict diet. Cholesterol and low-density lipoprotein concentrations were significantly lower in PKU children compared to normal controls. It is suggested that even though the special diet of PKU children, especially in group A, is rich in vegetables, the reduced fat intake might have impaired the absorption of vitamin K and its delivery to the site of synthesis of vitamin K-dependent haemostatic factors.     

Elevated plasma phenylalanine concentrations may adversely affect bone status of phenylketonuric mice

Children with phenylketonuric (PKU) are at risk for fractures. This study used a PKU murine model (PAH ^enu-2 ) to evaluate effects of moderate dietary protein restriction and elevated plasma phenylalanine concentration impact upon bone status. Fifty-four male weanling PKU and control mice were assigned to either an elemental phenylalanine (Phe)-restricted diet (treated) or Phe-unrestricted diet (untreated) with low or normal protein levels for 56 days. Untreated mice and control mice received equal amounts of dietary Phe; treated mice consumed prescribed dietary Phe to maintain plasma Phe concentrations between 120 and 480µmol/L. Plasma Phe, osteocalcin, and urine deoxypyridinoline (DPD)/creatinine were analysed at baseline and at days 28 and 56. Femur strength, bone mineral density (BMD) and bone mineral content (BMC) were analysed at day 56. Moderate protein restriction did not significantly affect bone status. Mean plasma Phe concentrations were significantly greater in untreated vs treated and control mice (p<0.0001). Total body weight was significantly less in untreated vs control mice (p<0.01). Mean femur weight was reduced in untreated mice vs both treated and control mice (p<0.03). Untreated mice had smaller mean femur length than control mice (p<0.002). Femur strength was greater in treated mice compared to control mice (p<0.01) but not compared to untreated mice. No significant difference among groups was found in BMD and BMC. At day 56 there was a statistical trend (p<0.056) towards higher urine DPD/creatinine excretion in untreated mice than in treated mice. Plasma Phe concentration was positively correlated with urine DPD/creatinine. These data suggested that hyperphenylalaninaemia may adversely affect bone status in PKU mice.