Archives of Disease in Childhood 1996; 74: 412-417 Factors affecting the variation in plasma phenylalanine in patients with phenylketonuria on diet A MacDonald, G Rylance, S K Hall, D Asplin, I W Booth Abstract The optimal dietary management of children with phenylketonuria (PKU) has rarely been rigorously explored. The aim of this study was to assess longitudinally the effects of three factors thought to influence plasma phenylalanine concen- trations in PKU: total energy intake; pro- tein intake from natural foods allowed freely in addition to allocated phenyl- alanine exchanges; and the distribution of protein substitute throughout the day. Nineteen subjects, 15 girls and four boys aged 1-16 years, were enrolled. Food in- take was weighed, and twice daily plasma phenylalanine concentrations measured during either 3-day or 4-day periods, for a total of 21 days throughout six months. There was a negative correlation between the percentage of protein substitute eaten by the time of the evening meal and the fall in plasma phenylalanine concentra- tion during the day (r=-0941; p<00001). On average, 490/0 of pre-evening meal plasma phenylalanine concentrations were less than 100 pmol/ in children who had taken at least 65% of their protein substitute by the time of their evening meal. There was no correlation between excess natural protein intake from freely allowed foods and (a) pre-breakfast or pre-evening meal plasma phenylalanine concentrations or (b) the daily change between pre-breakfast and pre-evening meal concentrations. Nor was there any correlation between excess natural pro- tein intake on the previous day and plasma phenylalanine concentration on the foliowing morning. Energy intake was not correlated with plasma phenylalanine concentrations. It is therefore preferable to distribute the protein substitute evenly through the day in order to achieve stable phenylalanine concentrations, rather than to carry out further fine manipulation of the phenylalanine intake, which would make management of the diet even more difficult. (Arch Dis Child 1996; 74: 412-417) Keywords: phenylketonuria, diet, protein substitute. The early diagnosis and treatment of phenyl- ketonuria (PKU) has until recently been regarded as successful. A diet low in phenyl- alanine prevents mental retardation and its use is now well established. However, a working group of the Medical Research Council (MRC)1 reported that neurodevelopmental outcome in appropriately treated children with PKU may not be as reassuring as was pre- viously thought. Adverse problems in children treated within the first few weeks are often subtle and include a lower mean IQ of about 0-5 standard devia- tions below population norms,2 impaired attention span, and impaired perceptual-motor functioning, visuospatial planning, and organi- sational skills.3-5 Calculation tasks are per- formed more slowly and less well.6 Behavioural problems,7 hyperactivity, and delayed linguis- tic development8 have also been identified. In adults treated from birth, neurological signs such as brisk tendon jerks, ankle clonus, and intention tremor are seen.9 Furthermore, a significant proportion of adult patients have multiple areas of increased signal intensity in cerebral white matter on magnetic resonance imaging (MRI),10 and the severity of MRI changes has been associated with the degree of hyperphenylalaninaemia at the time of investi- gation and the number of years since dietary treatment was stopped. 1' Following a review of these studies, the MRC Working Group published a set of guidelines for optimum dietary management of PKU.12 These guidelines encompassed all aspects of management, but particular empha- sis was placed on maintaining lower plasma phenylalanine concentrations within narrower bands, and on frequent blood phenylalanine monitoring with standardised sample timing, the early morning being considered most appropriate. Current guidelines for plasma phenylalanine concentrations are as follows (in pumol/l): 0-4 years, 120-360; 5-10 years, 120-480; over 1 1 years, 120-700.12 Since its introduction in the 1950s, the British PKU diet has evolved by custom and practice, and comprises four parts: (1) forbid- den high protein foods such as meat, fish, eggs, and cheese; (2) allocation of dietary phenyl- alanine in a 50 mg phenylalanine exchange system (50 mg phenylalanine is equivalent to lg protein); (3) a phenylalanine-free protein substitute; and (4) low phenylalanine foods (for example, most fruits, many vegetables, and special low protein products), which are permitted in usual quantities, so called 'free' foods. This dietary approach has not been ade- quately validated and embodies a number of anomalies. The allowance of free natural foods which contain appreciable quantities of protein (and therefore phenylalanine) is the most The Children's Hospital, Ladywood Middleway, Ladywood, Birmingham B16 8ET A MacDonald G Rylance S K Hall D Asplin Institute of Child Health, Francis Road, Edgbaston, Birmingham B16 8ET Booth IW Correspondence to: Mrs A MacDonald, Head of Dietetic Services. Accepted 23 January 1996 412 on December 1, 2021 by guest. Protected by copyright. http://adc.bmj.com/ Arch Dis Child: first published as 10.1136/adc.74.5.412 on 1 May 1996. Downloaded from
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Archives of Disease in Childhood 1996; 74: 412-417
Factors affecting the variation in plasmaphenylalanine in patients with phenylketonuria ondiet
A MacDonald, G Rylance, S K Hall, D Asplin, I W Booth
AbstractThe optimal dietary management ofchildren with phenylketonuria (PKU) hasrarely been rigorously explored. The aimof this study was to assess longitudinallythe effects of three factors thought toinfluence plasma phenylalanine concen-trations in PKU: total energy intake; pro-tein intake from natural foods allowedfreely in addition to allocated phenyl-alanine exchanges; and the distribution ofprotein substitute throughout the day.Nineteen subjects, 15 girls and four boysaged 1-16 years, were enrolled. Food in-take was weighed, and twice daily plasmaphenylalanine concentrations measuredduring either 3-day or 4-day periods, for atotal of 21 days throughout six months.There was a negative correlation betweenthe percentage of protein substitute eatenby the time of the evening meal and thefall in plasma phenylalanine concentra-tion during the day (r=-0941; p<00001).On average, 490/0 of pre-evening mealplasma phenylalanine concentrationswere less than 100 pmol/ in children whohad taken at least 65% of their proteinsubstitute by the time of their eveningmeal. There was no correlation betweenexcess natural protein intake from freelyallowed foods and (a) pre-breakfast orpre-evening meal plasma phenylalanineconcentrations or (b) the daily changebetween pre-breakfast and pre-eveningmeal concentrations. Nor was there anycorrelation between excess natural pro-tein intake on the previous day andplasma phenylalanine concentration onthe foliowing morning. Energy intake wasnot correlated with plasma phenylalanineconcentrations. It is therefore preferableto distribute the protein substitute evenlythrough the day in order to achieve stablephenylalanine concentrations, rather thanto carry out further fine manipulation ofthe phenylalanine intake, which wouldmake management of the diet even moredifficult.(Arch Dis Child 1996; 74: 412-417)
Keywords: phenylketonuria, diet, protein substitute.
The early diagnosis and treatment of phenyl-ketonuria (PKU) has until recently beenregarded as successful. A diet low in phenyl-alanine prevents mental retardation and its useis now well established. However, a working
group of the Medical Research Council(MRC)1 reported that neurodevelopmentaloutcome in appropriately treated children withPKU may not be as reassuring as was pre-viously thought.
Adverse problems in children treated withinthe first few weeks are often subtle and includea lower mean IQ of about 0-5 standard devia-tions below population norms,2 impairedattention span, and impaired perceptual-motorfunctioning, visuospatial planning, and organi-sational skills.3-5 Calculation tasks are per-formed more slowly and less well.6 Behaviouralproblems,7 hyperactivity, and delayed linguis-tic development8 have also been identified. Inadults treated from birth, neurological signssuch as brisk tendon jerks, ankle clonus, andintention tremor are seen.9 Furthermore, asignificant proportion of adult patients havemultiple areas of increased signal intensity incerebral white matter on magnetic resonanceimaging (MRI),10 and the severity of MRIchanges has been associated with the degree ofhyperphenylalaninaemia at the time of investi-gation and the number of years since dietarytreatment was stopped. 1'
Following a review of these studies, theMRC Working Group published a set ofguidelines for optimum dietary management ofPKU.12 These guidelines encompassed allaspects of management, but particular empha-sis was placed on maintaining lower plasmaphenylalanine concentrations within narrowerbands, and on frequent blood phenylalaninemonitoring with standardised sample timing,the early morning being considered mostappropriate. Current guidelines for plasmaphenylalanine concentrations are as follows (inpumol/l): 0-4 years, 120-360; 5-10 years,120-480; over 1 1 years, 120-700.12
Since its introduction in the 1950s, theBritish PKU diet has evolved by custom andpractice, and comprises four parts: (1) forbid-den high protein foods such as meat, fish, eggs,and cheese; (2) allocation of dietary phenyl-alanine in a 50 mg phenylalanine exchangesystem (50 mg phenylalanine is equivalent tolg protein); (3) a phenylalanine-free proteinsubstitute; and (4) low phenylalanine foods(for example, most fruits, many vegetables,and special low protein products), which arepermitted in usual quantities, so called 'free'foods.
This dietary approach has not been ade-quately validated and embodies a number ofanomalies. The allowance of free natural foodswhich contain appreciable quantities ofprotein(and therefore phenylalanine) is the most
The Children'sHospital, LadywoodMiddleway, Ladywood,Birmingham B16 8ETA MacDonaldG RylanceS K HallD Asplin
Institute of ChildHealth, Francis Road,Edgbaston,Birmingham B16 8ETBooth IW
Correspondence to:Mrs A MacDonald, Head ofDietetic Services.Accepted 23 January 1996
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Variation in plasma phenylalanine in patients with phenylketonuria
important of these. Free foods are definedas those which contain less than 0-3 g of pro-tein/100 g.12 Although the effect of additionaldietary phenylalanine from freely allowedfoods is unknown, the MRC working grouprecommended that the 'system of 50 mgphenylalanine food exchanges would need tobe refined and revised to encompass a muchwider range of the natural foods allowedfreely'.12 However, the extent of 'free' foodconsumption, and its impact on control ofplasma phenylalanine concentrations, hasnever been systematically studied, nor have theeffects of energy consumption or the timing ofthe ingestion of the protein substitute duringthe day.The aims of our study were to assess the
effects on control of variations in phenyla-lanine intake from free foods, as well as theeffect of total energy intake and the timing ofprotein substitute administration, factorswhich are also thought to have an influence oncontrol. In a longitudinal observational study,we therefore compared dietary intakes andplasma phenylalanine concentrations over a sixmonth period in a group of well controlledchildren with PKU.
MethodsSUBJECTSNineteen Caucasian children with classicalPKU were recruited. There were three inclu-sion criteria: maintenance of plasma phenyla-lanine concentrations within the rangesrecommended for age group by the MRCWorking Group'2 for 70% of the six monthsbefore entering the study; age 1 to 16 years;and parental ability to take skin punctureblood specimens at home by thumb prick.There were 15 girls and four boys, with amedian age of 6-6 years (range 1 to 16 years).The median number of 50 mg phenylalanineexchanges allocated was five per day (range 3to 17) or 5 g natural protein (table 1). The fol-lowing amounts of total protein/kg from pro-tein substitute and phenylalanine exchangeswere allocated: children 1 year of age, 3-0 g/kg;2-5 years, 2-5 g/kg; 6-10 years, 2-0 g/kg; over11 year of age, 1-5 g/kg. The brand of protein
Table I Age and phenylalanine tolerance ofpatients
Number per RecommendedSex day of 50 mg phenylalanine
Patient Age (male! phenylalanine concentrationsNo (years) female) exchanges (,umol4)
1 3 F 5 120-3602 3 F 3 120-3603 12 M 8 120-7004 16 F 14 120-7005 7 F 5-5 120-4806 3 F 5 120-3607 1 F 7 120-3608 4 F 4 120-3609 2 F 3-5 120-36010 4 F 3 120-36011 1 M 3 120-36012 14 F 12 120-70013 9 F 3 120-48014 9 F 12-5 120-48015 16 F 17 120-70016 6 M 4 120-48017 9 F 9 120-48018 3 M 3-5 120-36019 3 F 3 120-360
substitute used was chosen by the patient andwas administered either as a paste or drink.Twelve patients used XP Maxamaid (SHS),three patients used Aminogran Food Supple-ment (UCB), three used Phlexy 10 Drink Mix(SHS), and one used XP Maxamum (SHS).The study was approved by the committee
on medical ethics of South BirminghamHealth Authority. Informed consent wasobtained from all parents and from the patients(where maturity and understanding wereappropriate).
ASSESSMENT OF PHENYLALANINE AND ENERGYINTAKEParents performed 21 day serial weighed foodintakes over 6 months at home. In months 1, 3,and 5, parents or patients weighed andrecorded their food intake from Monday toWednesday inclusive. In months 2, 4, and 6,weighed food intakes were performed fromThursday to Sunday inclusive. Parentsrecorded only food actually eaten, and anywaste food was reweighed and deducted fromthe total weight. They also described cookingtechniques, precise food brand, kept nutri-tional labels of manufactured foods eaten, andidentified individual ingredients of any home-made dishes prepared. Parents were instructedto use Salter electronic scales. Immediatelyafter each study period, parents were visited athome by one ofus (AM) to check food records.Each meal and snack consumed by the childwas reviewed with the parents to checkaccuracy. In addition, the weighing techniqueof each of the mothers was assessed and con-firmed as adequate by one of us (AM) byweighing 10 different food items at the start ofthe study. Timing and quantity of protein sub-stitute consumed were also recorded prospec-tively.
Nutritional analysis of food intake was cal-culated using the Microdiet computer programbased on McCance and Widdowson's The compo-sition of foods,14 with supplementary analysisdata provided by the Royal Society ofChemistry.15-'8 Additional information onprotein substitutes and low protein specialproducts was provided by manufacturers andadded to the database. Energy intake wascalculated as a percentage of the estimatedaverage requirement for energy (EAR).19The excess natural dietary protein intake
was calculated in addition to the prescribedallocation of 50 mg phenylalanine or 1 0 gprotein exchanges, assuming that 1 g protein isequivalent to 50 mg of phenylalanine.13
ASSESSMENT OF PLASMA PHENYLALANINECONCENTRATIONSTwice daily serial skin puncture blood speci-mens for phenylalanine were taken in the homeon the same days as the weighed food intake.Blood specimens were taken at the same timeeach day, standardised for each patient, butalways pre-breakfast and pre-evening meal.The blood specimens were collected byparents and immediately posted to the hospital
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laboratory. Blood collection technique hadbeen taught and competence assessed by aspecialist nurse. Blood specimens wereanalysed for phenylalanine by high pressureliquid chromatography (HPLC).20 All patientswere free from intercurrent infections on thedays of the study.
If a patient became ill immediately before orduring the study days, the plasma phenyla-lanine measurements and weighed food intakewere deferred until the patient had recovered.
STATISTICAL ANALYSESStatistical analysis was by Pearson productmoment correlation coefficient (r) comparingintake of dietary protein from 'freely' allowedfoods, timing of protein substitute, and energyintake on plasma phenylalanine concentra-tions. Paired t tests were used to comparepre-breakfast and pre-evening plasma phenyla-lanine concentrations.
ResultsVARIATION BETWEEN PLASMA PHENYALANINECONCENTRATIONS IN EARLY MORNING ANDLATE AFITERNOON BLOOD SPECIMENSFor some patients, there was considerable vari-ability between day to day early morning andlate afternoon plasma phenylalanine concen-trations: plasma phenylalanine, mean am 282(SD 162) p,mol/l; mean pm 243 (184) ,umol/l.There was a significant difference betweenmean early morning and late afternoon plasmaphenylalanine concentrations (p=0-012) and awidespread variation in the change betweenearly morning and late afternoon concentra-tions: mean plasma phenylalanine change -40(62) ,umol/l (table 2).
EFFECT OF DIETARY PHENYLALANINE INTAKEFROM FREELY ALLOWED FOODS ON PLASMAPHENYILAANINE CONCENTRATIONSAssuming that 1 0 g of protein is equivalent to50 mg of phenylalanine, patients consumed amean (SD; range) of49% (37, 12 to 162) extranatural protein from free foods in addition totheir daily allocation of natural protein fromphenylalanine exchanges. There was a verylarge day to day variation for some patients(fig 1) with a mean (SD; range) coefficient ofvariation of 60% (32; 1 1 to 150) for the entiregroup of patients.
For almost all patients there was no signifi-cant within subject correlation between excessnatural protein intake or total protein intakeand (1) pre-breakfast or pre-evening mealplasma phenylalanine concentrations; (2) dailychange between pre-breakfast and pre-eveningmeal plasma phenylalanine concentrations.Similarly there was no significant correlationbetween excess natural protein intake on theprevious day and plasma phenylalanine cor-relation on the following morning (tables 3and 4).
Number of 50 mg phenylalanine exchanges per subjectFigure 1 Excess protein intake in addition to phenylalanine exchanges (points denote daily per cent natural protein intakecompared with allocated phenylalanine exchanges).
-50 0
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Variation in plasma phenylalanine in patients with phenylketonuria
Table 3 Effect ofexcess percentage protein intake on plasma phenylalanine concentration
CorrelationCorrelation Correlation coefficientforcoefficientfor coefficientfor excess percentageexcess percentage excess percentage protein intakeprotein intake protein intake v am-pmv am plasma vpm plasma change in plasma
Patient phenylalanine p phenylalanine p phenylalanine pNo concentrations Value concentrations Value concentrations Value
EFFECT OF ENERGY INTAKE ON PLASMAPHENYLALANINE CONCENTRATIONSPatients had a mean (SD, range) energy intakeof 105% (17%; 77% to 178%) of the estimatedaverage requirement.17 For the majority ofpatients there was no significant correlationbetween energy intake and (1) pre-breakfast orpre-evening meal plasma phenylalanine con-centrations; (2) the difference between pre-breakfast and pre-evening meal plasmaphenylalanine concentrations. Nor was theprevious day's energy intake significantlyrelated to the following morning's plasmaphenylalanine concentration (table 5).
EFFECT OF TIMING OF PROTEIN SUBSTITUTE ONPLASMA PHENYLALANINE CONCENTRATIONSAlthough patients were advised to consume theprotein substitute in equal amounts three timesdaily, at set times with meals, actual practicesvaried considerably. For at least 80% of thestudy, only 37% of the patients took the proteinsubstitute three times daily at mealtimes, 42%took it twice daily at breakfast and with the
Table 4 Effect of excess percentage protein intake and energy intake on plasmaphenylalanine concentration
Correlationcoefficient forexcess percentage Correlation Correlationprotein intake coefficient of coefficient ofvfollowing energy intake energy intakeam plasma v am plasma v pm plasma
Patient phenylalanine p phenylalanine p phenylalanine pNo concentrations Value concentrations Value concentrations Value
taken by evening mealFigure 2 Effect of timing ofprotein substitute on changein plasma phenylalanine concentrations during the day.
evening meal, and 21% took all the protein sub-stitute in the morning or in the evening. Twentysix percent of these patients varied the timingfor a small number of the study days.The timing of protein substitute ingestion
had a major impact on changes in plasmaphenylalanine concentration. There was astrong negative correlation between theamount of protein substitute taken by the timeof the evening meal and the change in plasmaphenylalanine concentrations during the day(r=0-941, p<0-0001) (fig 2). The more pro-tein substitute taken early in the day, thegreater the fall in plasma phenylalanine con-centrations during the course of that day. As itis usually recommended that patients withPKU take the protein substitute three timesdaily with meals, it can be expected thatpatients should have taken at least 65% of it bythe evening meal. Overall, of children who hadtaken more than 65% of their protein substi-tute by the time of their evening meal, 49°/O ofpre-evening meal plasma phenylalanine con-centrations were less than 100 ,umol/l.Conversely, the less the protein substitutetaken before the evening meal, the higher theincrease in plasma phenylalanine concentra-tions during the day.There was a positive correlation between the
quantity of protein substitute taken by the timeof the evening meal and the overnight changein plasma phenylalanine concentration whichsubsequently took place between the pre-evening meal and the following pre-breakfastsamples (r=0-8724, p<0-0001; fig 3).
0 04- CE ._Ce.Xamcr0 C0)0
c 0.0 00 0(MM(0-0M00C o
200 r0
150 [-
100 h
50
0 H
-50 _-
-100
-1500 10 20 30 40
0
0
0
r= -0.8724
II50 60 70 80 90 100
Mean percent protein substitutetaken by evening meal
Figure 3 Effect of timing ofprotein substitute onsubsequent overnight change in plasma phenylalanineconcentrations.
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DiscussionThis study shows large diurnal fluctuations inplasma phenylalanine concentrations in agroup of patients who were carefully selectedon the basis that they maintained routinelytaken plasma phenylalanine concentrationswithin ranges recommended by the MRCworking group. Furthermore, it shows thatblood samples before breakfast did not alwaysreflect the highest plasma phenylalanine con-centration of the day, although it is recom-mended in the MRC report that bloodspecimens should be taken in the early morn-ing when plasma concentrations were con-
sidered to be at a peak. Plasma phenylalanineconcentrations were strongly influenced by thetiming of the protein substitute, but not bytotal energy or excess natural protein intakefrom 'freely' allowed foods. Patients who hadtaken 65% or more of their protein substituteby the time of their evening meal showed a fallin plasma phenylalanine concentration duringthat day. In contrast, patients who delayedmost or all of their protein substitute until aftertheir evening meal showed a rise in plasmaphenylalanine concentration during the day.Patients who took their protein substitute intwo doses evenly distributed between morningand evening showed little variation in theirplasma phenylalanine concentrations. For thestudy group overall, there was significantlygreater variability in evening plasma phenyla-lanine concentrations than for morning con-centrations.Knowledge of the extent of diurnal variation
in plasma phenylalanine concentrations is par-ticularly important when one considers thenarrow concentration ranges within which it isrecommended that they are maintained. It isalso crucial when defining the ideal time atwhich blood specimens are taken. It is surpris-ing that there are so few data on this subject. In1969, Guttler et al described two children withPKU aged 3 years in whom serum phenyla-lanine concentrations were found to be higherin the morning than in the evening, at variancewith the pattern seen in normal children.21
Farquhar et al showed a similar pattern in a 22year old pregnant patient with classical PKU.22In contrast, van Spronsen et al concluded thatthe daily fluctuations in plasma phenylalanineconcentrations were small, although measure-ments were made in only seven patients atregular intervals before and after lunch.23Because the administration of amino acids inthe form of a protein substitute appears todepress the catabolism of protein, therebyinhibiting the net release of amino acids -including phenylalanine - into the plasmapool, it is likely that equal distribution of a pro-tein substitute throughout the day will lead togreater stability in plasma phenylalanine con-centrations. In a study on 10 normal men,administration of a single dose of L-aminoacids resulted in an initial rise in plasmaphenylalanine. However, after 90 minutesthere was a rapid decline in phenylalanine24and by 240 minutes the concentrations hadfallen below the baseline figure, suggesting thatexcessive administration of non-phenylalanineamino acids in PKU at one time ofthe day mayexaggerate this process.
It is of some concern that almost half of allevening plasma phenylalanine concentrationswere less than 100 ,umol/l in children who hadtaken 65% or more of their protein substituteby the time of their evening meal, despitehaving morning blood phenylalanine concen-trations within the MRC recommended range.As dietitians usually recommend that proteinsubstitute is taken three times daily with meals,many children who maintain morning bloodphenylalanine concentrations of between 120and 360 ,mo1/l may have low concentrationsin the evening. The length of time during theday within which these patients maintain aplasma phenylalanine of less than 100 pumo/l isunknown, as is the significance of persistentlylow evening concentrations. However, it maybe that such low concentrations adverselyaffect IQ and growth.25 In data from theNational Phenylketonuria Register, Smith et alshowed that IQ fell by four points for each fivemonths during which phenylalanine concen-trations were below 120 ,umol/1.7 However, theanalysis of outcome of these results may relatelargely to morning rather than evening concen-trations and plasma phenylalanine wasanalysed primarily from bacterial inhibitionassays or paper chromatography, which are notparticularly accurate at low concentrations.Some studies from the early 1970s reportedpoor growth linked to overzealous restrictionof dietary phenylalanine and low plasmaphenylalanine concentrations in the first fewmonths of life.25 26 Even then, it was suggestedthat low plasma phenylalanine and malnutri-tion in the infant with PKU may have anadverse effect on mental development.26The lack of an effect of excess natural
protein on plasma phenylalanine concentra-tions is surprising. In addition to daily allo-cated natural protein in the form of 50 mgphenylalanine exchanges, natural protein wasincreased by a further 50% by free foods, andmost patients had a wide day to day variationin excess natural protein intake, although
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Variation in plasma phenylalanine in patients with phenylketonuria 417
official exchange foods were carefullymeasured in the diet. Free vegetables wereresponsible for the majority of excess naturalprotein intake, and these included cauliflower,tinned tomatoes, and fried mushrooms andonions. However, despite these dietary anom-alies, our data provide no evidence to supportthe suggestion that better phenylalanine con-trol will be achieved by making the dietarysystem more rigorous, and even more onerous,by incorporating some of these free foods intothe phenylalanine exchange system.
Energy supplements are widely advocated inPKU, but there are no published data to sup-port their efficacy. In our study, energy intakefluctuated significantly within and betweenpatients and did not appear to influenceplasma phenylalanine control. Four patientsconsumed only a mean of 80% or less than theestimated average requirement for energy butstill achieved acceptable morning plasmaphenylalanine concentrations. Giittler et a!21showed that the administration of a protein-free snack in a child with PKU had no impacton plasma phenylalanine concentrations. Thisis supported by a further case study in an adultwith PKU, in which a high carbohydrate snackwas given late in the evening and did not pre-vent the nocturnal rise in phenylalanine con-centrations.22Our study showed that there is considerable
diurnal variation in plasma phenylalanine con-centrations, related specifically to the timing ofL-amino acid (protein substitute) intake.Although intuitively plausible, neither excessnatural protein from freely allowed foods norenergy intake appears to influence plasmaphenylalanine concentrations significantly inwell controlled patients. Future emphasisshould be placed on even distribution of dailyprotein substitute rather than further finemanipulation of phenylalanine intake whenattempting to achieve stable phenylalanineconcentrations throughout the day, althoughthe exact distribution of protein substituteremains to be determined.The authors wish to thank Mrs Deborah Wills for her technicalskills in performing the HPLC phenylalanine analyses. In addi-tion, they wish to thank the West Midlands Support Group forPhenylketonuria for financial support for this study.
1 Report of Medical Research Council Working Party onPhenylketonuria. Phenylketonuria due to phenylalaninehydroxylase deficiency: an unfolding story. BMJ 1993;306: 115-9.
2 Smith I, Beasley M, Ades AE. Intelligence and quality ofdietary treatment in phenylketonuria. Arch Dis Child1990; 65: 472-8.
3 Welsh MC, Pennington BF, Ozonoff S, Rouse B, McCabeERB. Neuropsychology of early treated phenylketonuria:
specific executive function deficits. Child Dev 1990; 61:1697-713.
4 Lou HC, Guttler G, Lykkelund C, Bruhn P, NiederweiserA. Decreased vigilance and neurotransmitter synthesisafter discontinuation of dietary treatment of phenyl-ketonuria in adolescents. EurJ Pediatr 1985; 144: 17-20.
5 Pennington BF, van B Doornick WJ, McCabe LL,McCabe ER. Neurological deficits in early-treatedphenylketonurics. Am J Ment Deficiency 1985; 89:467-74.
6 de Sonnerville LMJ, Schmidt E, Michel U, Batzler U.Preliminary neuropsychological test results. Eur J Pediatr1990; 149 (suppl 1): S39-44.
7 Smith I, Beasley ME, WolffOH, Ades AE. Behavior distur-bance in 8 year old children with early treated phenyl-ketonuria. J Pediatr 1988; 112: 403-8.
8 Melnick CR, Michals KK, Matalon R. Linguistic develop-ment of children with phenylketonuria and normal intelli-gence.JPediatr 1981; 98: 269-72.
9 Thompson AJ, Smith I, Brenton D, et al. Neurologicaldeterioration in young adults with phenylketonuria.Lancet 1990; 336: 602-5.
10 Bick U, Fahrendorf G, Ludolph AC, Vassallo P, Weglage J,Ullrich K. Disturbed myelination in patients with treatedhyperphenylalaninemia: evaluation with magnetic reso-nance imaging. EurJPediatr 1991; 150: 185-9.
11 Thompson AJ, Tillotson S, Smith I, Kendall B, Moore SG,Brenton DP. Brain MRI changes in phenylketonuria.Brain 1993; 116: 811-21.
12 Report of Medical Research Council Working Party onPhenylketonuria. Recommendations on the dietary man-agement of phenylketonuria. Arch Dis Child 1993; 68:426-7.
13 MacDonald A. Diet and phenylketonuria: time for change?J Hum Nutr Diet 1994; 7: 105-14.
14 Holland B, Welch AA, Unwin ID, Buss DH, Paul AA,Southgate DAT. McCance and Widdowson's 'The composi-tion of foods', 5th ed. Cambridge: Royal Society ofChemistry and Ministry of Agriculture, Fisheries andFood, 1991.
15 Holland B, Unwin ID, Buss DH. Fruit and nuts.Cambridge: Royal Society of Chemistry and Ministry ofAgriculture, Fisheries and Food, 1991.
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17 Holland B, Unwin ID, Buss DH. Milk products and eggs.Cambridge: Royal Society of Chemistry and Ministry ofAgriculture, Fisheries and Food, 1989.
18 Holland B, Unwin ID, Buss DH. Cereals and cereal products.Cambridge: Royal Society of Chemistry and Ministry ofAgriculture, Fisheries and Food, 1988.
19 Department of Health. Dietary reference values for food,energy and nutrients for the United Kingdom. Report onHealth and Social Subjects No 41. London: HMSO,1991.
20 Atherton ND, Green A. HPLC measurement of phenyla-lanine in plasma. Clin Chem 1988; 34: 2241-4.
21 Guttler F, Oleson ES, Wamberg E. Inverse diurnal varia-tions of serum phenylalanine and tyrosine in phenylke-tonuric children on low-phenylalanine diet. In: Allan JD,Holt KS, Ireland JT, Politt KJ, eds. Enzymopenicanaemias, lysosomes and other papers. Proceedings of theSixth Symposium of the Society for the Study of InbornErrors of Metabolism. Edinburgh: Livingstone, 1969:149-58.
22 Farquhar DL, Steven F, Westwood A. Preliminary reporton inverse diurnal variation of phenylalanine: implicationsin maternal phenylketonuria. Hum Nutr Appl Nutr 1985;39A: 224-6.
23 van Spronsen Hj, van Rijn M, van Dijk T, et aL Plasmaphenylalanine and tyrosine responses to different nutri-tional conditions (fasting/postprandial) in patients withphenylketonuria: effect of sample timing. Pediatrics 1993;92: 570-3.
24 Gropper SS, Gropper DM, Acosta PB. Plasma aminoacid responses to ingestion of L-amino acids andwhole protein. Y Pediatr Gastroenterol Nutr 1993; 16:143-50.
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