Pregnancy in phenylketonuria: dietary treatment aimed at normalising maternal plasma phenylalanine concentration.

The transport characteristics of the placenta, which favour higher phenylalanine concentrations in the fetus than in the mother, and regression data of head circumference at birth against phenylalanine concentration at conception in maternal phenylketonuria (PKU), suggest that treatment of maternal PKU should ideally aim to maintain plasma phenylalanine concentration within the normal range throughout pregnancy. A patient with classical PKU was treated from before conception by aiming to maintain plasma phenylalanine concentration within the range 50-150 mumol/l and tyrosine within the range 60-90 mumol/l. The diet was supplemented with phenylalanine-free amino acids (100-180 g/day) and tyrosine (0-5 g/day). Plasma amino acid concentrations were monitored weekly by amino acid analyser. Dietary phenylalanine intake ranged from 6 mg/kg/day at conception to 30 mg/kg/day at delivery. Normal weight gain and fetal growth were maintained throughout the pregnancy. A normal baby was born at term with a head circumference of 35.5 cm; at 1 year of age no abnormality is detectable. These results show that with careful monitoring and compliance it is possible, and may be advisable, to maintain plasma phenylalanine concentration within the normal range in the management of PKU pregnancy.     

Case studies of the effect of tyrosine administration in children with phenylketonuria on cognitive processes]

Eight patients with phenylketonuria and low protein nutrition were treated in a double blind crossover study for the time of 3 month with 150 mg tyrosine per kg body weight and day and placebo thereafter or vice versa. The concentration of phenylalanine in serum was not influenced by the administration of tyrosine whereas tyrosine in serum markedly increased. Psychological tests were 7 times repeated in monthly intervals. From the study it is to suggest that there is an improvement of the test results caused by an effect of training due to the repeated tests and an additional improvement caused by tyrosine.     

Increased Vigilance and Dopamine Synthesis by Large Doses of Tyrosine or Phenylalanine Restriction in Phenylketonuria

ABSTRACT. In a group of 9 patients with classical phenylketonuria (PKU) aged 15–24 years we examined the effect of phenylalanine restricted diet on vigilance, as judged by the continuous visual reaction times, and neurotransmitter synthesis, as judged by cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) levels. HVA and 5-HIAA levels decreased significantly with increase in plasma phenylalanine concentration on free diet ( p <0.01 and p <0.0005 respectively). Vigilance improved on phenylalanine restricted diet in 6 of the 7 patients with abnormally long reaction times on free diet. Addition of tyrosine (160 mg/kg/24 h) to the free diet resulted in an increased HVA/5-HIAA ratio in CSF in the six patients examined. In 14 patients on free diet supplemented with tyrosine, an improvement in vigilance (reaction times at the 90 percentile) was seen in all 12 patients with values longer than the normal mean (264 msec) ( p <0.001). Tyrosine treatment may be a therapeutical alternative when phenylalanine restriction is impractical.     

Increased vigilance and dopamine synthesis by large doses of tyrosine or phenylalanine restriction in phenylketonuria

In a group of 9 patients with classical phenylketonuria (PKU) aged 15-24 years we examined the effect of phenylalanine restricted diet on vigilance, as judged by the continuous visual reaction times, and neurotransmitter synthesis, as judged by cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) levels. HVA and 5-HIAA levels decreased significantly with increase in plasma phenylalanine concentration on free diet (p less than 0.01 and p less than 0.0005 respectively). Vigilance improved on phenylalanine restricted diet in 6 of the 7 patients with abnormally long reaction times on free diet. Addition of tyrosine (160 mg/kg/24 h) to the free diet resulted in an increased CSF in the six patients examined. In 14 patients on free diet supplemented with tyrosine, an improvement in vigilance (reaction times at the 90 percentile) was seen in all 12 patients with values longer than the normal mean (264 msec) (p less than 0.001). Tyrosine treatment may be a therapeutical alternative when phenylalanine restriction is impractical.     

Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis.

A patient with atypical phenylketonuria (defective BH2 synthesis), detected at age 6 months because of severe muscle hypotonia and serum phenylalanine of 20 mg/100 ml, had normal activities of phenylalanine-4-hydroxylase and DHPR in liver biopsy, but only 2% activity in the phenylalanine-4-hyroxylase in vivo test using deuterated phenylalanine. After IV administration of 2.5 mg/kg chemically pure tetrahydrobiopterin bishydrochloride (BH4 . 2HCl), serum phenylalanine decreased from 20.4 to 2.1 mg/100 ml within 3 hours. Administration of 25 mg BH4 . HCl and 100 mg ascorbic acid through a gastric tube decrease; serum phenylalanine from 13.7 to less than 1.6 mg/100 ml within 3 hours and it remained less than 2 mg/100 ml for 2 days.     

Detection of phenylketonuria in the very early newborn blood specimen

Early hospital discharge of newborns is leading to collection of the newborn screening blood specimen during the first day of life in increasing numbers of newborns. There is concern that neonates with phenylketonuria who are tested this early may be missed. To examine this question, the authors screened specimens collected during the first 24 hours of life from 23 neonates at risk for hyperphenylalaninemia. The blood phenylalanine level in each of the 6 neonates with phenylketonuria and a seventh with mild hyperphenylalaninemia was greater than 2 mg/dL as early as 4 hours of age and 6 mg/dL or greater by 24 hours of age. A newborn screening phenylalanine cutoff level of 2 mg/dL would have identified all of these neonates within the first 24 hours of life, but a cutoff level of 4 mg/dL would have missed 2 of the 6 with phenylketonuria before 24 hours of life. Newborn screening programs should adopt a blood phenylalanine level of 2 mg/dL as the cutoff for suspicion of phenylketonuria and request for a second specimen. Breast-fed affected neonates had higher early blood phenylalanine elevations than formula-fed neonates, perhaps reflecting the higher protein (phenylalanine) content of colostrum.     

Tetrahydrobiopterin loading test in hyperphenylalaninemia.

Some cases of primary hyperphenylalaninemia are not caused by the lack of phenylalanine hydroxylase, but by the lack of its cofactor tetrahydrobiopterin. These patients are not clinically responsive to a phenylalanine-restricted diet, but need specific substitution therapy. Thus, it became necessary to examine all newborns screened as positive with the Guthrie test for tetrahydrobiopterin deficiency. Methods based on urinary pterin or on specific enzyme activity measurements are limited in their availability, and the simplest method, based on the lowering of serum phenylalanine after loading with cofactor, was discouraged by the finding that some dihydropteridine reductase-deficient patients were unresponsive. The preliminary observation that this limitation could be overcome by increasing the dose of the administered cofactor prompted us to reevaluate the potential of the tetrahydrobiopterin loading test in hyperphenylalaninemia. Fifteen patients, eight with ultimate diagnosis of phenylketonuria, three with 6-pyruvoyl tetrahydropterin synthase-, and four with dihydropteridine reductase-deficiency, have been examined by administering synthetic tetrahydrobiopterin both orally, at doses of 7.5 and 20 mg/kg, and i.v., at a dose of 2 mg/kg. All the tetrahydrobiopterin-deficient patients, unlike those with phenylketonuria, responded to the oral dose of 20 mg/kg cofactor by lowering their serum phenylalanine concentration markedly below baseline to an extent easily detectable by Guthrie cards. This method allows for a simple screening method when enzyme or pterin studies are not available.     

四氢生物蝶呤负荷试验诊断四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症的临床研究

目的探讨四氢生物蝶呤(BH4)反应性苯丙氨酸羟化酶(PAH)缺乏症的临床诊断方法,进一步了解其临床特征,为该型患儿应用BH4药物治疗提供科学依据。方法73例高苯丙氨酸血症(HPA)患儿,男47例,女26例,平均年龄1.93个月。所有患儿都进行口服BH4负荷试验,同时进行尿蝶呤谱分析、红细胞二氢蝶啶还原酶测定。对其中血苯丙氨酸(Phe)浓度<600μmol/L者给予口服Phe BH4联合负荷试验,对部分BH4反应性PAH缺乏症患儿,在普食条件下给予BH4片剂(10～20mg/kg)替代治疗6～7天,观察其疗效。结果(1)在BH4负荷试验中,不同类型HPA患儿的血Phe浓度表现出特征性的曲线改变,22例诊断为经典型苯丙酮尿症(PKU),39例中度PKU,12例四氢生物蝶呤缺乏症;(2)在中度PKU患儿中发现22例(56.4%)对BH4有反应;(3)6例BH4反应性PAH缺乏症患儿以BH410mg/kg治疗6～7天,其中4例血Phe浓度能控制到正常或接近正常治疗水平,另2例BH4需增加到20mg/kg使Phe浓度显著下降。结论在BH4负荷试验中,部分因苯丙氨酸羟化酶缺乏引起的中轻度PKU患儿对BH4有反应性,给予这些患儿BH4治疗可部分或全部替代低苯丙氨酸饮食治疗,拓宽了PKU的治疗方法,有助于提高患儿的生活质量。     

Hyperphenylalaninemia due to impaired dihydrobiopterin biosynthesis

A fourteen month-old boy with atypical phenylketonuria was treated with 5-hydroxytryptophan, L-dopa and peripheral aromatic amino acid decarboxylase inhibitor (Ro 4-4602:benserazide). Despite the good control of plasma phenylalanine on a low phenylalanine diet, he had shown no improvement in his development but progressive neurological symptoms, such asiirritability, convulsions and decrease voluntary movement. After beginning neurotransmitter therapy, his irritability disappeared promptly and the other symptoms diminished. He gradually reached his developmental milestones. At two and a half years of age, he had recovered sufficiently to be able to walk freely on treatment with 13 mg/kg/day of 5-hydroxytryptophan, 11 mg/kg/day of L-dopa and 2.7 mg/kg/day of benserazide in combination with slight restriction of phenylalanine intake (100 mg/kg/day).Levels of serotonin and 5-hydroxyindoleacetic acid were low in the patient's CSF. His urinary biopterin (Crithidia factor) excretion was low. An increase in serum biopterin following L-phenylalanine loading was not found. Dihydropteridine reductase activity in his skin fibroblasts was normal. He excreated large amounts of erythro- and threo-neopterins (but only a trace of biopterin) in his urine. After loading with phenylalanine the urinary excretion of neopterins was even more enhanced, but biopterin remained at low levels. These findings indicated that the patient has a dihydrobiopterin synthetase deficiency.     

Dietary management of oculocutaneous tyrosinemia in an 11-year-old child

An 11-year-old girl with keratitis and plantar keratosis had tyrosinemia. The concentration of tyrosine in the plasma was 16.5 mg/dL. Dietary intake of phenylalanine and tyrosine was systematically varied, and the plasma concentrations of tyrosine and nitrogen balance were studied. It was necessary to achieve a total intake of phenylalanine and tyrosine less than 100 mg/kg/day to obtain plasma concentrations of tyrosine of less than 10 mg/dL. After dietary therapy was started, the keratitis resolved promptly, and the patient remained asymptomatic during a period of 16 months in which the mean plasma concentration of tyrosine was 11.1 mg/dL. The dietary management of a child at this age presents a different problem from that of a young infant. It can be successfully pursued at home, as well as in the carefully regulated environment of a clinical research center.     

Metabolism of intravenous phenylalanine by babies born before 33 weeks of gestation

Random urine samples collected weekly from 22 infants of 25-32 weeks of gestation were analyzed by capillary gas chromatography-mass spectrometry to define the normal organic acid profile. Increased excretion of phenolic acid derivatives of phenylalanine and tyrosine was found in 21 samples from 13 babies during established parenteral nutrition. Compared with 53 samples collected during milk feeding, phenyllactic acid, 4-hydroxy-3-methoxyphenyllactic acid, and N-acetyltyrosine were excreted significantly more often and 4-hydroxyphenyllactic and 4-hydroxyphenylpyruvic acids at significantly higher concentrations. The mean daily intake of phenylalanine (197 mg/kg) was significantly higher and that of tyrosine (22 mg/kg) significantly lower during parenteral nutrition. Three cyclohexanediol isomers were identified which might have derived from phenylalanine or one of its metabolites.     

Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids

Tyrosine supplementation has not consistently been found to improve neuropsychologic function in phenylketonuria (PKU), possibly because of failure to achieve adequate levels of tyrosine in the brain. OBJECTIVES: To evaluate blood levels achieved after tyrosine supplementation in treated PKU and calculate brain influxes of tyrosine and other large neutral amino acids before and with tyrosine supplementation. STUDY DESIGN: Ten subjects with PKU receiving a phenylalanine-restricted diet were studied over 48 hours; each received tyrosine supplementation (300 mg/kg) on day 2. Plasma phenylalanine and tyrosine were measured every 2 hours, and all free amino acids were measured every 6 hours. Brain influxes of tyrosine and other large neutral amino acids were calculated. RESULTS: Plasma tyrosine levels were low normal at baseline. With supplementation there was a substantial but unsustained rise in plasma tyrosine. Calculated brain influx of tyrosine was 27% +/- 19% of normal before supplementation, increasing to 90% +/- 58% of normal with supplementation. Nevertheless, calculated influx remained less than 70% of normal at 50% of the time points. The calculated brain influxes of all other large neutral amino acids except tryptophan were 20% to 40% of normal before and with tyrosine supplementation. CONCLUSIONS: Tyrosine supplementation in the diet for PKU produces marked but nonsustained increases in plasma tyrosine levels, with calculated brain influx that often remains suboptimal. This could explain the lack of consistent neuropsychologic benefit with tyrosine supplementation.     

The neurochemistry of phenylketonuria

The mechanisms by which deficiency of hepatic phenylalanine hydroxylase causes central nervous system disease are reviewed. The neurological disease appears to be secondary to increased concentrations of phenylalanine and a decrease in the concentrations of other large neutral amino acids, especially methionine and tyrosine, within the central nervous system. This causes a deficiency of the neurotransmitter dopamine, reduced protein synthesis and demyelination. Similar mechanisms appear to be operating when blood phenylalanine concentrations are in the range expected for early continuously treated phenylketonuria. Conclusion The severe brain disease found in phenylketonuria is caused by a raised blood phenylalanine content which increases the brain free phenylalanine and decreases the concentration of other large neutral amino acids. Brain protein synthesis is decreased, myelin turnover is increased and there are abnormalities in amine neurotransmitter systems.     

Evidence that phenylalanine may not provide the full needs for aromatic amino acids in children

Phenylalanine is nutritionally classified as an indispensable amino acid and can be converted to tyrosine by phenylalanine hydroxylation. The initial goal of the present study was to determine the aromatic amino acid (phenylalanine plus tyrosine) requirements in healthy children fed a diet without tyrosine by using the indicator amino acid oxidation (IAAO) method using lysine as the indicator amino acid. Healthy school-age children (n = 5) were fed in random order a diet with eight graded intakes of phenylalanine without tyrosine. The requirement was determined by the rate of recovery of CO2 from L-[1-C]lysine oxidation (FCO2). Phenylalanine (total aromatic amino acid) requirement, in the absence of tyrosine, for children was determined to be 28 mg/kg/d, which was only 64% of the adult requirement, which is biologically absurd. A possible reason for the lower estimate of phenylalanine requirement could be lower phenylalanine hydroxylation rate in children, which is supported by the finding of lower urinary tyrosine/phenylalanine ratios in children compared with adults. In conclusion, this study indicates that phenylalanine may not provide the total needs for aromatic amino acids in children fed an amino acid-based diet without tyrosine.     

Outcome of pregnancy in a phenylketonuric mother after low phenylalanine diet introduced from the ninth week of pregnancy

A mother with classical phenylketonuria was treated from the ninth week of pregnancy with a tyrosine augmented, low phenylalanine diet. Assessment of the infant up to the age of twelve months suggests normal development, although further follow up is planned.     

Three-year audit of the hyperphenylalaninaemia/phenylketonuria spectrum in Victoria

AIMS: To determine the prevalence, the types and severity of hyperphenylalaninaemia (including phenylketonuria (PKU)) in Victoria and to report on a new treatment modality of PKU. METHODS: We reviewed the medical records of all patients diagnosed with high blood phenylalanine levels by newborn screening between November 2001 and October 2004. RESULTS: We identified 17 newborn babies with high levels of blood phenylalanine (total samples: 190,835). Dihydrobiopterin reductase deficiency was excluded in all babies. Five babies had persistent phenylalanine levels of 200-300, and do not receive any dietary or pharmaceutical therapy. One baby was diagnosed as having pyruvoyl tetrahydro-pterin synthase deficiency. Following reports of tetrahydrobiopterin (BH(4))-responsive PKU, we have performed a BH(4) load (20 mg/kg, 6R-5,6,7,8-tetrahydro-L-biopetrin dehydrochloride; Schricks Laboratories, Jona, Switzerland) in 10 newborn babies with PKU (one baby with a phenylalanine level of 2600 micromol/L was started on diet without prior load). Three babies had a significant response to BH(4) (>35% decrease in phenylalanine level). Protein restriction (1.2 g/kg/day) and introduction of phenylalanine-free formula, in addition to BH(4) treatment, were necessary in one patient. The other patients maintain good metabolic control with BH(4) treatment only (at approximately 11 mg/kg/day) and an intake of 2-3 g protein per day. Of the nine babies who are on a full PKU diet, three have high phenylalanine tolerance (consistently >40 mg/kg/day). CONCLUSION: There is a spectrum of severity of hyperphenylalaninaemia in the population. The detection of BH(4)-responsive PKU patients offers them a less restrictive dietary regimen and an improved quality of life, and may enable near normal life-style in adolescence.     

Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria

OBJECTIVE—To test the efficacy of tyrosine supplementation, as an adjunct to dietary treatment, on neuropsychological test performance in individuals with phenylketonuria.
DESIGN—A randomised controlled trial of tyrosine supplementation using a double blind crossover procedure with three four week phases.
SETTING—The Hospital for Sick Children, Toronto.
PARTICIPANTS—21 individuals with phenylketonuria (ages 6 to 28 years, mean 11.3).
INTERVENTION—Participants were given 100 mg/kg body weight/d of L-tyrosine or L-alanine (placebo).
RESULTS—At baseline, performance on several of the neuropsychological test measures was correlated with tyrosine levels. Dietary supplements of tyrosine increased plasma tyrosine concentrations; however, no change in test performance was found across the tyrosine and placebo phases of the study.
CONCLUSIONS—Tyrosine supplementation of this type does not appear to alter neuropsychological performance in individuals with phenylketonuria.

     

Dopamine precursors and brain function in phenylalanine hydroxylase deficiency

Phenylalanine and tyrosine constitute the two initial steps in the biosynthesis of dopamine, which, in its turn, is the metabolic precursor of noradrenaline and adrenaline. The extracellular phenylalanine concentration influences brain function in phenylalanine deficiency (PHD) by decreased dopamine synthesis. It has been shown to induce EEG slowing, and prolonged the performance time on neuropsychological tests. The tyrosine concentration in the CNS is reduced in PHD, possibly implying insufficient substrate (= tyrosine) for catecholamine synthesis due to competition inhibition, for instance across the blood brain barrier. In experimental studies it has been shown that the synthesis and release of dopamine can be influenced by an increase in the availability of tyrosine. In PHD an extra dietary intake of three doses of tyrosine (160mg/kg/24h) induced a shortsning of reaction time and decreased variability, and in a double-blind crossover study a similar dose has been reported to induce an improvement on psychological tests. In a study with lower doses of tyrosine (110mg/kg/24h) no effect was found on reaction time tests. These findings need to be substantiated, and more detailed information should be obtained.     

ON INDICATIONS FOR TREATMENT OF THE HYPERPHENYLALANINEMIC NEONATE

Abstract. Of 488 006 neonates tested by Guthrie screening 58 showed values above 2.5 mg/100 ml. Thirty-two showed values between 2.5 nig/100 ml and 15 mg/100 ml. Eighteen of these infants appeared to have phenylketonuria (PKU) and fourteen to have persistent hyperphenylalaninemia (HPA). Neither the initial Guthrie test-value nor the confirmatory test were able to differentiate between these two conditions. Consequently a phenylalanine restricted diet is started in any child with serumphenylalanine values exceeding 10 mg/100 ml (605 μmol/1). The data show that the course of the dietary tolerance of phenylalanine and a 24-hour phenylalanine load test will differentiate infants with PKU from those with HPA.     

Phenylketonuria masked by low protein feeds.

Two patients with phenylketonuria (PKU) requiring treatment were fed on low protein milks. Both had blood phenylalanine levels below 1200 micronmol/l (20mg/100 ml) until given a phenylalanine challenge. Phenylalanine content of mature breast milk may provide intakes similar to those used in treating PKU. Diagnosis of PKU is unlikely to be missed if screening is carried out on the sixth or seventh day of life because of higher phenylalanine in breast milk during the first week. Interpretation of screening tests requires knowledge of the infants'' feeds and a blood phenylalanine above 360 micronmol/l (6 mg/100 ml) in the absence of tyrosinaemia requires careful investigation.