Phe-restricted Diet Research Articles

Potential Role of Tetrahydrobiopterin in the Treatment of Maternal Phenylketonuria

To evaluate the clinical relevance of tetrahydrobiopterin (BH4) supplementation for pregnant women with phenylketonuria (PKU)/hyperphenylalaninemia (HPA) and the possibility of treating these patients with BH4 instead of a phenylalanine (Phe)-restricted diet. Genotyping was performed on 41 patients with PKU/HPA identified by newborn screening. Evaluating the genotype according to their BH4 responsiveness is published. Follow-up of 3 patients with mild PKU treated with BH4 is evaluated. Discussion of the transfer of these experiences to the possibility of treating mothers at risk for maternal PKU is presented. In 41 patients with PKU/HPA, we found 17 (41%) bearing at least 1 allele with a mutation described as being responsive to BH4. In 8 of the patients, BH4 loading had been performed in the newborn period, in 6 of whom the test showed a clear decrease of blood Phe 4 and 8 hours after loading. One of the nonresponders was reinvestigated at 3 years of age, showing a clear response (genotype Y414C/R408W): BH4 supplementation resulted in a much higher Phe tolerance (500 instead of 250 mg/day) with blood Phe levels <200 micromol/L. Two children (genotype E390G/IVS10-11g>a and L48S/L48S, respectively) were treated with BH4 only (15-20 mg/kg body weight/day), one from birth, the other from 2 years of age. Blood Phe decreased from >800 micromol/L to a mean of 321.4 and 331.7 micromol/L, respectively (range: 141-718 micromol/L) under a normal diet (total observation time: 4 years). Development was normal with no adverse reactions. BH4 supplementation seems to be a promising alternative treatment in some patients with mild PKU. Because blood Phe levels in maternal PKU should be maintained at 120 to 360 micromol/L, clinical relevance may be even greater than for treatment of children with PKU/HPA. BH4 supplementation may also be combined with a Phe-restricted diet, allowing higher Phe intake and protecting mothers from high Phe blood peaks. However, additional studies are necessary to prove the safety and economy of such an alternative treatment in patients with PKU/HPA, especially during pregnancy.

The Maternal Phenylketonuria International Study: 1984–2002

The purpose of this report is to review the obstetric medical, psychological, and nutritional aspects and outcome of the women and offspring enrolled in the Maternal Phenylketonuria Study, which was established to assess the efficacy of a phenylalanine (Phe)-restricted diet in preventing the morbidity associated with this disorder. A total of 382 women with hyperphenylalaninemia (HPA) were enrolled in the study and completed 572 pregnancies. Outcome measures were analyzed with chi2, Fisher exact text, analysis of variance, t test, Wilcoxon nonparametric test, and multiple logistic regression. Outcome measures were stratified according to maternal HPA classification and the time when dietary control was achieved. Optimal birth outcomes occurred when maternal blood Phe levels between 120 and 360 micromol/L were achieved by 8 to 10 weeks of gestation and maintained throughout pregnancy (trimester averages of 600 micromol/L). Mothers with mild HPA achieved similar birth outcomes as mothers who were in control preconceptually and those in control by 8 to 10 weeks of pregnancy. Before conception, counseling and early entrance into a prenatal care program is essential in achieving optimal fetal outcome in women with HPA. The achievement of pre- and periconceptional dietary control with a Phe-restricted diet significantly decreased morbidity in the offspring of women with HPA.

Maternal Phenylketonuria: Experiences From the United Kingdom

Charles Dent was one of the first physicians to recognize the teratogenic effects of maternal phenylalanine (Phe) on the fetus in 1956. This article describes the clinical experiences of women with phenylketonuria (PKU) within the unit that was established by Dent in the United Kingdom. Between 1977 and 2002, 79 infants were born to women with PKU. Of the 79, 18 (23%) were conceived while the women were on a normal diet with high blood Phe levels. The mean birth weight was 2.89 kg, and head circumference was 32.8 cm. At 1 year, the mean developmental quotient was 105.5 and at 4 years was 82.3. Four of these infants had congenital heart disease (2 of whom died as a result). In the remaining 61 infants, Phe-restricted diet started before conception. None of them had congenital heart disease. The mean birth weight was 3.23 kg, and head circumference was 34.0 cm. At 1 year, mean developmental quotient was 108.0 and at 4 years was 90.9. They continue to be followed up with additional neuropsychometric assessments at 8 and 14 years of age. This cohort is a proportion of infants who were born to mothers with PKU in the United Kingdom. Between 1978 and 1997, 255 live births were reported. Of these, 56% were conceived on unrestricted diet with subsequently poor outcome. This relatively high rate of conception off PKU diet is likely to reflect the scarcity of medical services for adults with metabolic disorders. We conclude that many features of the maternal PKU syndrome can be prevented but still occur because of the lack of appropriate resources to care for at-risk women. The precise targets for blood Phe and other nutrients during pregnancy are not entirely clear, neither are the reasons that some offspring are spared the harmful effects of Phe. The impact of the postnatal environment in which these infants find themselves requires additional assessment, too.

Inhibition of Prepotent Responding and Attentional Flexibility in Treated Phenylketonuria

Inhibition of prepotent responding and attentional flexibility were assessed in 58 early and continuously treated phenylketonuria (PKU) patients and 69 controls, age 7 to 14 years. A computerized task was used requiring participants to process consecutive stimuli according to various attentional sets. Analysis of error rate suggested poorer inhibition of prepotent responding in PKU patients compared with controls. No influence of concurrent plasma phenylalanine (phe) was shown, neither in the younger (age < 11 years) nor in the older participants (age sup3; 11 years). Analysis of error rate provided strong evidence for poorer attentional flexibility in PKU patients compared with controls. The difference between attentional flexibility in controls and PKU patients could mainly be attributed to younger PKU patients, with concurrent phe levels higher than 360μmol/L.Younger PKU patients with phe levels below 360 μmol/L performed at the same level as age-matched controls. Performance of PKU patients was strongly associated with phe levels in age periods during the first 10 years of life, which are characterized by a strong development of executive functioning (ages 2-7 and age 9). High phe levels during these age periods could delay development of inhibitory control and attentional flexibility. With regard to treatment, analyses with lifetime and concurrent phe levels support strict dietary control throughout the first decade of life, after which the phe-restricted diet can be relaxed. However, based on the evidence that development of specific executive functions continues until approximately age 12, it is recommended to maintain phe levels below 360 μmol/L throughout early adolescence.

Phenylalanine Restricted Diet Treatment of the Aggressive Behaviours of a Person with Mental Retardation

Phenylketonuria is a genetic abnormality that triggers an incapacity to metabolise phenylalanine (Phe), an amino acid present in nutritional proteins. This incapacity leads to an accumulation of Phe and its by-products in the blood and tissues, which drastically compromises the neurological and intellectual development of a person (Pueschel, 1996). Following the establishment of national and state screening programmes (circa 1965), phenylketonuria has ceased to be a cause of mental retardation for the vast majority of persons affected by this incapacity. With the possibility of detection at birth and the immediate introduction of a Phe-restricted diet, development can progress at normal rates (Koch et al., 1996). However, individuals with phenylketonuria who were born before the development of these screening programmes and early interventions have, unfortunately, developed mental retardation. It is clear that the harmful effects of a high Phe blood level during the first years of life are largely irreversible, especially where intellectual development is concerned (Bruhl et al., 1965). However, certain toxic effects manifested in problem behaviours seem to be reversible, even in adults with phenylketonuria who have followed a regular diet throughout their entire lives.

A conference for the education of families who have a member with phenylketonuria.

LTHOUGH RELATIVELY RARE, phenylkeonuria (PKU) has a profound effect on the families of those with this genetic disorder. The families have many educational and support needs that cannot be adequately met through individual patient/family teaching. The purpose of the South Texas Family PKU Conference was to establish a source of education and support for families who have a member with PKU. Diagnosed through newborn screening, this inborn error of metabolism results in a limited ability to convert phenylalanine (PHE) to tyrosine. When left untreated, the buildup of blood levels of PHE results in a number of problems, including neurological problems, developmental delays, and mental retardation. The only treatment for PKU is through a PHE-restricted diet, and the current recommendation is that persons with PKU continue the diet for life (Castiglioni & Rouse, 1995). The diet is protein restricted, and the logistics of maintaining the diet can be problematic, as well. Because essential amino acids are needed by all children, it is necessary to use special formulas for infants, and specialty foods such as low-PHE pasta and bread help older children maintain proper nutrition while adhering to dietary restrictions. One of the problems associated with this Iow-PHE diet is the high cost of these specialty foods and the often limited ability of families to receive reimburse-

Phenylalanine and Tyrosine Quantification by Stable Isotope Dilution Liquid Chromatography–Mass Spectrometry from Filter Paper Blood Spots

Phenylketonuria (PKU) is one of the more common inborn errors of metabolism, affecting 1 in 10 000–15 000 individuals (1). Newborn screening for PKU is performed in all 50 states and started with the development of the bacterial inhibition screening assay by Guthrie and Susi (2). Frequent monitoring of blood Phe concentrations is required to maintain the concentration as close as possible to the reference interval [60–120 μmol/L (1–2 mg/dL)] to prevent damage to the brain from increased Phe concentrations and to prevent a negative nitrogen balance from an overly Phe-restricted diet. Moreover, the high risk of birth defects for the fetus of a PKU mother requires extremely frequent monitoring of blood Phe concentrations and would greatly benefit from a rapid and accurate blood spot method. Phe determination from dried blood spots is feasible by various methods: bacterial (2), fluorometric (3), liquid chromatography (LC) (4), and tandem mass spectrometry (MS) (5). Of these methods, only tandem MS allows use of a stable isotope as internal standard. Although tandem MS is the most rapid method available, the extremely high equipment cost and the need for sample derivatization are disadvantages. We developed a rapid and precise blood-spot method for Phe and Tyr determination using stable isotope dilution reversed-phase LC-MS. The advantages of this method are the very short sample preparation without derivatization, a short chromatographic run, the use of selective detection to eliminate interference, and the use of ideal internal standardization (stable isotope). The method described herein is now used routinely in our PKU clinic. l-Phe ( M r 165.19) and l-Tyr ( M r 181.19) were purchased from Sigma Chemical Co. Stable isotopes [ring-d5]-l-phenylalanine ( M r 170.23) …

Economic impact of feeding a phenylalanine-restricted diet to adults with previously untreated phenylketonuria.

The aim of the present study was to estimate the direct healthcare cost of managing adults with previously untreated phenylketonuria (PKU) for one year before any dietary restrictions and for the first year after a phenylalanine- (PHE-) restricted diet was introduced. The resource use and corresponding costs were estimated from medical records and interviews with health care professionals experienced in caring for adults with previously untreated PKU. The mean annual cost of caring for a client being fed an unrestricted diet was estimated to be 83 996 pound silver. In the first year after introducing a PHE-restricted diet, the mean annual cost was reduced by 20 647 pound silver to 63 348 pound silver as a result of a reduction in nursing time, hospitalizations, outpatient clinic visits and medications. However, the economic benefit of the diet depended on whether the clients were previously high or low users of nursing care. Nursing time was the key cost-driver, accounting for 79% of the cost of managing high users and 31% of the management cost for low users. In contrast, the acquisition cost of a PHE-restricted diet accounted for up to 6% of the cost for managing high users and 15% of the management cost for low users. Sensitivity analyses showed that introducing a PHE-restricted diet reduces the annual cost of care, provided that annual nursing time was reduced by more than 8% or more than 5% of clients respond to the diet. The clients showed fewer negative behaviours when being fed a PHE-restricted diet, which may account for the observed reduction in nursing time needed to care for these clients. In conclusion, feeding a PHE-restricted diet to adults with previously untreated PKU leads to economic benefits to the UK's National Health Service and society in general.

Biotin recycling impairment in phenylketonuric children with seborrheic dermatitis.

To investigate the effect of a therapeutic diet on serum biotin levels and to explain the seborrheic dermatitis in phenylketonuric (PKU) patients on a "loose" diet. Forty-seven patients were divided into two groups: group A (n=21) demonstrated good compliance to a special diet and group B (n=26) were on a "loose" diet. Most of the patients in group B (20/26), who suffered from mild seborrheic dermatitis, were requested to return to phenylalanine (Phe)-restricted diet for at least 15 days. Seventy-nine healthy children of comparable age were used as controls. Biotin serum levels and plasma biotinidase activity were measured in patients as well as controls. In addition, biotinidase activity was evaluated in vitro after incubation with various concentrations of Phe. Biotin levels in group A patients (636+/-118 ng/L) were statistically significantly elevated (P < 0.01) compared with those of group B patients before (412+/-184 ng/L) and after (501+/-160 ng/L) 15 days on a Phe-restricted diet, as well as with those of controls (337+/-290 ng/L). Furthermore, biotinidase activities were decreased in group B patients (4.2+/-1.68 nmol/min/L) compared with those of group A patients (6.4+/-0.7 nmol/min/L) and controls (6.10+/-0.8 nmol/min/L). Additionally, biotinidase activities in the patients of group B were restored to normal (5.78+/-0.81 nmol/min/L), with a simultaneous remission of their skin lesions, after 15 days on a Phe-restricted diet. Moreover, the in vitro findings showed a 51% inhibition of biotinidase activity when incubated with Phe (20 mg/dL). It is suggested that the high biotin levels in group A patients reflect the intake of water-soluble biotin of vegetable origin. In contrast, the low biotinidase activity in group B patients may be attributed to their high Phe plasma levels, which acts as an enzyme inhibitor, as shown by the in vivo and in vitro results. Consequently, the observed seborrheic dermatitis in PKU children (group B) is associated with an impairment of biotin recycling.

Kinetics of phenylalanine transport at the human blood–brain barrier investigated in vivo

In vivo proton magnetic resonance spectroscopy was used to investigate intracerebral phenylalanine (Phe) concentrations in nine patients with classical phenylketonuria (PKU). The study included serial examinations ( n=31; plasma Phe levels: 0.47–2.24 mmol/l) of patients either receiving a Phe-restricted diet (200 mg Phe per day; four patients) or a diet rich in Phe (1000 mg Phe per day; three patients). No spectrum showed metabolic abnormalities besides elevated Phe. Difference spectroscopy yielded intracerebral Phe concentrations between 0.20 and 0.76 mmol/l. Regional variations between parieto-occipital periventricular brain, frontal brain, and cerebellum were not statistically significant. Data could be fitted assuming saturable Phe transport into the brain, based on a symmetric Michaelis–Menten model (characterized by an apparent Michaelis transport constant, K t,app, and a maximum transport velocity, T max) and constant Phe consumption in the brain cells (described by a velocity V max). Non-linear least-squares fitting of the combined data from all patients yielded K t,app=0.16±0.11 mmol/l and ( T max / V max)=9.0±4.1. Carrier saturation and competitive inhibition of the influx of other large neutral amino acids can be expected at plasma Phe levels usually found in PKU patients.

Outcome implications of the International Maternal Phenylketonuria Collaborative Study (MPKUCS): 1994.

It is well established that women with phenylketonuria who remain untreated during pregnancy face serious problems in offspring outcome. Surveys have documented that maternal phenylalanine (Phe) blood concentrations above 1200 mumol/l are associated with microcephaly, congenital heart disease and intrauterine growth retardation among their offspring. To investigate the efficacy of the Phe restricted diet, the National Institute of Child Health and Human Development in Bethesda Maryland developed an international study to evaluate fetal outcome in pregnancies treated with the Phe restricted diet. The study involves over 100 metabolic clinics in the United States, Canada and Germany, and is now in its 10th year. The results included in this report are still preliminary in nature and the actual risk for such pregnancies remains to be determined.

Care of the adult with phenylketonuria.

Forty-three adults with classical phenylketonuria were identified by neonatal screening and treated with a phenylalanine (Phe) restricted diet. Nineteen have remained on dietary treatment with varying levels of blood Phe control and 24 have discontinued the diet at an average age of 7.8 years. Follow up at an average age of 22 years revealed that the cohort remaining on dietary treatment have achieved substantially better social and academic achievement than the 24 who discontinued dietary treatment. Another group of 19 adults who were not diagnosed until an average age of 2.5 years have also been evaluated after an average of 22 years on a Phe restricted diet. This report is based upon Wechsler Adult Intelligence Revised Test scores, attendance at college, employment and marital status.

Biotinidase activity in patients with phenylketonuria

In patients with biotinidase deficiency, an autosomal recessive condition (McKusick 253260) (Wolf et al 1985), skin rashes, alopecia, seizures, hypotonia, developmental regression and ataxia occur usually after the age of 3 months. Additionally, seborrhoeic or atopic dermatitis (eczema) are common symptoms in untreated phenylketonuria patients (PKU) (McKusick 261600), and Burton et al (1975) have found that there is an abnormality in their sebaceous gland function. We therefore measured biotinidase activity in plasma of PKU children under dietary treatment . . . . . . Fifty-three patients with classic phenylketonuria were classified into two groups according to their annual mean plasma phenylalanine concentration (Phe mean). Group A (n--27), mean age 4.8 +3.5 years, had good compliance with the special diet; their Phe mean was 192+ll .5/nnol/L. Group B (n=26), mean age 7.9+3.7 years, did not adhere very well to this diet; their Phe mean was 597+ 187/maol/L. Group C (n=21), mean age 6.7+2.3 years, was the control group with Phe mean 109_+24/zmol/L. All PKU patients had been put on the special Phe-restricted diet during their neonatal period. Nine (38%) of the patients in group B suffered from seborrhoeic dermatitis or eczema. Blood (5ml) was withdrawn from each individual for biotinidase assay and liver function tests. Phe was measured with a quantitative enzymatic assay on dried blood samples on filter paper (2992 Schleicher-Schull) with Porton Cambridge reagents. Biotinidase activity was assayed with a fluorimetric method (Ebrahim and Dekisnamur 1986). At the time of blood collection for biotinidase assay, the mean phenylalanine concentration was 133+24/nnol/L in group A, which was statistically significantly different from that of group B at 473+127/zmol/L. Biotinidase activity in group A (5 .58+l .77nmol /min per L) was not significantly different from the controls (5.98+2.08nmol/min per L). However, the mean biotinidase activity in group B (4.21 + 1.68nmol/min per L) was significantly decreased (p--0.006) compared to that of group A as well as to that of controls (p<0.001). Biotinidase activity in group A did not correlate with mean phenylalanine concentration (r=0.08) nor that at the time of investigation (r=0.23). In contrast, in group B biotinidase activity correlated negatively with Phe mean ( r=-0 .59) and Phe concentration at the time of investigation (r---0.60). Vegetables and fruits, which are the main part of the PKU diet (group A), contain watersoluble forms of biotin. The PKU children in group B, who do not adhere well to the special diet, consume more animal products, in which biotin is in firmly bound complexes insoluble in water. However, biotin deficiency does not alter biotinidase activity in vitro: the activities in the sera of several patients who became biotin-deficient were normal (Wolf

In-vivo NMR spectroscopy in patients with phenylketonuria: changes of cerebral phenylalanine levels under dietary treatment.

Localized proton magnetic resonance spectroscopy at short echo times was used to measure phenylalanine (Phe) in parieto-occipital periventricular brain. Six treated adult patients with phenylketonuria were investigated repeatedly following reinstitution of a Phe-restricted diet. Difference spectroscopy clearly enabled the identification of elevated cerebral Phe levels by subtracting spectra obtained from healthy volunteers. Estimates of absolute brain concentrations always yielded values well below the serum levels with ratios [Phe]brain/[Phe]serum ranging from 0.27 to 0.63. A plot of [Phe]brain versus [Phe]serum could be fitted to a straight line (R = 0.90) if [Phe]serum was below 1.3 mM. Measurements at higher serum levels could only be performed in one patient and yielded brain Phe concentrations of 0.63 +/- 0.10 mM suggesting a saturation of the carrier systems. The feasibility to quantify Phe transport across the blood-brain barrier in humans non-invasively employing in-vivo proton spectroscopy can effectively improve the prognostic significance of serum data.

Effect of high-protein meal plus aspartame ingestion on plasma phenylalanine concentrations in obligate heterozygotes for phenylketonuria

The effect of a protein-rich meal alone or in combination with 85 μmol/kg body weight aspartame (APM) on plasma phenylalanine and large neutral amino acids (LNAA) was evaluated in obligate heterozygotes for phenylketonuria (PKU) and normal subjects (controls). Thirteen PKU heterozygotes (seven women, six men) and 13 controls (five women, eight men) ingested a 12-noon meal providing approximately 303 μmol/kg Phe. In addition, 10 PKU heterozygotes (five women, five men) and 10 controls (five women, five men) ingested the same meal with 85 μmol/kg APM (providing 75 μmol/kg Phe). Plasma amino acids were analyzed at baseline (−4 and 0 hours) and at 1, 3, and 20 hours after the meal or meal plus APM. Compared with the meal alone, ingestion of the meal plus APM significantly increased plasma Phe concentrations in both controls and PKU heterozygotes. Mean plasma Phe values were higher for controls at 1 hour (95 ± 7 μmol/L) and for PKU heterozygotes at 3 hours (153 ± 21 μmol/L). After the addition of APM to the meal, the highest mean plasma Phe concentration was only slightly greater than the usual postprandial range for both controls and PKU heterozygotes. Ingestion of the meal did not increase the plasma Phe/LNAA ratio in either controls or PKU heterozygotes. Compared with baseline, the plasma Phe/LNAA ratio increased significantly 1 hour after combined ingestion of the meal plus APM in both groups ( P = .020 and P = .008, respectively); however, the ratios were well below the range of Phe/LNAA values in individuals with mild hyperphenylalaninemia, who are clinically normal and do not require a Phe-restricted diet. In conclusion, AMP in doses up to 10 times current consumption (90th percentile) resulted in plasma Phe concentrations well below values associated with known adverse effects.

Differential diagnosis of hyperphenylalaninaemia by a combined phenylalanine-tetrahydrobiopterin loading test.

We describe a new fully reliable method for the differential diagnosis of tetrahydrobiopterin-dependent hyperphenylalaninaemia (HPA). The method comprises the combined phenylalanine (Phe) plus tetrahydrobiopterin (BH4) oral loading test and enables the selective screening of BH4 deficiency when pterin analysis is not available or when a clear diagnosis has not been previously made. It should be performed together with the measurement of dihydropteridine reductase (DHPR) activity in blood. The new combined loading test was performed in nine patients with primary HPA, three with classical phenylketonuria (PKU), three with DHPR deficiency, and three with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency. Three hours after oral Phe loading (100 mg/kg body weight), synthetic BH4 was administered orally at doses of either 7.5 or 20 mg/kg body weight. Amino acid (Phe and tyrosine) and pterin (neopterin and biopterin) metabolism and kinetics were analysed. By exploiting the decrease in serum Phe 4 and 8 h after administration, a clear response was obtained with the higher BH4 dose (20 mg/kg body weight), allowing detection of all cases of BH4 deficiency, as well as differentiation of BH4 synthesis from regeneration defects. Since DHPR deficient patients who were previously shown to be non-responsive to the simple BH4 loading test gave a positive response, the combined Phe plus BH4 loading test can be used as a more reliable tool for the differential diagnosis of HPA in these patients. Moreover, it takes advantage of being performed while patients are on a Phe-restricted diet.

Catalytic activity of tetrahydrobiopterin in dihydropteridine reductase deficiency and indications for treatment.

It is now widely accepted that tetrahydrobiopterin (BH4), the natural cofactor of aromatic amino acid hydroxylases, in the absence of its regenerating enzyme dihydropteridine reductase (DHPR), will function only stoichiometrically in the phenylalanine (Phe) hydroxylating system. This has limited the use of pterin cofactor in diagnosis and treatment of patients suffering from inherited DHPR deficiency, one of the most common forms of hyperphenylalaninemia caused by BH4 deficiency. This is despite the observation of a dramatic fall in serum Phe concentration after BH4 loading in such patients. In this study, quantitation of this phenomenon was obtained by comparing the kinetics of serum Phe after either a simple Phe or a combined Phe plus BH4 oral loading in patients with Phe hydroxylase or with DHPR deficiency. Only in the latter was the total body clearance of Phe enhanced up to 5 times by the cofactor administration, resulting in the molar equivalent of Phe hydroxylated/mol of BH4 ranging from at least 6 to 10, against the postulated 1. As a consequence, BH4 administration should be attempted therapeutically in DHPR-deficient patients, thus avoiding a lifelong Phe-restricted diet. Preliminary experience with such treatment is given with two cases.

Controlled diet in phenylketonuria may cause serum carnitine deficiency

Serum carnitine levels may be reduced in patients with phenylketonuria (PKU) owing to low carnitine intake, deficient carnitine synthesis and acylcarnitine production from phenylalanine metabolites. In order to investigate the possible carnitine deficiency we determined serum carnitine in its different forms and the precursors and cofactors involved in its synthesis in a group of patients with PKU or hyperphenylalaninaemia. Free, total and acylcarnitine values were significatively reduced only in PKU patients with Phe-restricted diet which had not been supplemented with carnitine. Acylcarnitine/free carnitine ratio and all the other parameters studied were normal in all patients. We conclude that the low serum carnitine levels in PKU patients with a strict diet are a consequence of the low carnitine intake.

School achievement in treated PKU children.

Phenylketonuric children who were treated early and maintained a pherestricted diet through age 10 were compared with those who discontinued the diet after age 6 on a standardized test of intelligence, school achievement, language and perceptual skills. Mean IQ, reading and spelling test scores improved between ages 6 and 10 for the on-diet children in comparison to those who were off-diet. However, mean scores on arithmetic, language and perceptual skills declined at a uniform rate for both groups. Children with PKU scored significantly lower than did their non-PKU siblings on tests of visual perception and visual-motor skills. Because the school years, particularly, the early teens, pose increased stress in affected PKU individuals, it is recommended that dietary restriction at least through the high school years is prudent for their optimal physical, mental, emotional and educational growth.

PHENYLALANINE PRODUCES CHANGES IN PLASMA L-DOPA, EEG MEAN POWER FREQUENCY AND PERFORMANCE IN TREATED PHENYLKETONURIC PATIENTS

We previously reported in 10 patients with phenylketonuria (PKU) that performance and biogenic amine excretion fell when blood phenylalanine (phe) was elevated (Ped. Res. 17:213A, 1983). Here we extend this study to include four additional children with PKU age 7-10 years and evaluate electrical changes by EEG using mean power frequencies (MPF) determined by Fourier transformation. We altered the diet during three, nine-day periods using a triple-blind, double cross-over research protocol. All patients achieved a plasma phe concentration of greater than 1.2 μM during the loading phase. Plasma L-DOPA was measured and EEGs were performed on the 7,8, and 9th days of each study period. On the 9th day of each period, tests of neuropsychological performance, attention and vigilance were administered. During phe loading the plasma L-DOPA fell, tests of performance deteriorated and attention was not sustained. When blood phe was elevated the MPF of EEGs decreased reflecting a shift to slow wave forms. During periods of phe restricted diet these parameters reverted to baseline. We conclude that the EEG-MPF and certain tests of performance are impaired by high plasma phe concentration, that these effects are mediated through decreased L-DOPA, and that they are transient.