Non-PKU mild hyperphenylalaninemia (MHP)--the dilemma.

Recent reviews have suggested that some patients with "non-PKU mild hyperphenylalaninemia" (MHP) might display neuropsychological executive function deficits and should be considered for treatment with tetrahydrobipterin (BH4) and/or phenylalanine (Phe) restricted diet. Patients with phenylketonuria (PKU)--Classical and Mild/Atypical variants--appear to need "mean lifetime phenylalanine (Phe) levels" of 120-360 µmol/L for optimal results. MHP patients, on the other hand, have natural Phe levels of 200-600 µmol/L. Until recently this was thought to be a benign condition. The available literature has been reviewed in detail and no good evidence, to date, has been uncovered to support treatment of MHP. It is suggested that more MHP subjects be tested to confirm this. A plea is made to formulate a consistent world-wide classification of the PKU phenotypes.

Phenylketonuria: questioning the gospel.

Phenylketonuria (PKU) was first described over 70 years ago, treatment was developed 50 years ago and universal newborn PKU screening was introduced 40 years ago. Phenylalanine-restricted dietary treatment has prevented mental retardation in thousands of individuals worldwide. We acknowledge, however, that there is still much to learn in the field. The incidence of mental retardation in untreated PKU is likely to be considerably less than the original estimates. Since dietary control is suboptimal in late childhood, adolescence and adulthood, alternative methods of treatment are being explored. These include large neutral amino acids, phenylalanine ammonia lyase, tetrahydrobiopterin and gene replacement. Evidence has surfaced that the semisynthetic, low-protein diet used to treat PKU may be deficient in certain important nutrients. Maternal PKU treatment may be successful even if initiated as late as 8-10 weeks into pregnancy. A plea is made for the immediate establishment of adult treatment centers for PKU (and other inherited metabolic diseases) for long-term treatment, follow-up and research.

Maternal Phenylketonuria Collaborative Study (MPKUCS)--the 'outliers'.

Analysis of outcome data from 305 of the 414 offspring from the Maternal Phenylketonuria Collaborative Study (MPKUCS), plus 70 control offspring, revealed significant deficits in the IQ (intelligence quotient), as measured by the Wechsler Intelligence Scale for Children--Revised (WISC-R), when maternal metabolic control during pregnancy was delayed and/or inadequate. There were, however, 23 'outliers' (7.5% of the 305) in which the offspring's intellectual IQ was worse (n =10) or better (n =13) than expected. The aim of this study was to determine whether collection parameters were incomplete or whether these subjects were true biological variants influenced by other undetected factors or, perhaps, by modifier genes. Among the 10 offspring whose intellectual functioning was worse than expected, additional complications were uncovered that could explain the poor outcome. Four of the 13 offspring with higher than expected IQ had mothers with mild variants of PKU in which the insult to the fetus would not be expected to be as profound. For the other nine offspring whose intellectual performance was better than expected, there was no explanation, based on the parameters studied. We hypothesize that modifier genes will, at times, protect the fetus despite high maternal concentrations of phenylalanine. Not all offspring from the same (untreated) PKU mother may be similarly affected. Finding the source of these modifiers might effect the treatment of MPKU.

Adult phenylketonuria.

Newborn screening for phenylketonuria began 35 to 40 years ago in most industrialized countries. Because of this initiative, which resulted in early institution of phenylalanine-restricted diets, there are now many young adults with this disease who have normal or near-normal intellectual function. In North America alone, 200 patients with phenylketonuria enter adulthood every year. Most expert panels recommend following a phenylalanine-restricted "diet for life." However, there are few adult physicians dedicated to continuing care of this group, with the possible exception of maternal phenylketonuria. Up to 10% of adults with classic phenylketonuria, and possibly 50% of those with milder variants, may not need treatment; after adolescence, intelligence does not appear to deteriorate, at least into early adulthood, even if diet therapy is discontinued or not in good control. However, neuropsychological and psychosocial problems develop frequently, needing focused and intensive support by health care providers. New investigative methods and treatment options are on the horizon. There is an urgent need for physicians who will orchestrate the care of adults with phenylketonuria.

Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study.

The frequency and types of congenital heart disease in offspring from pregnancies in women with hyperphenylalaninemia were examined in the international prospective Maternal Phenylketonuria Collaborative Study. Relationships of congenital heart disease in offspring to the basal blood phenylalanine level in the mother, metabolic control through diet during pregnancy, and phenylalanine hydroxylase mutations in mother and offspring were determined. The 416 offspring from 412 maternal phenylketonuria pregnancies that produced live births and 100 offspring from the 99 control pregnancies were included in this examination. Thirty-four of the 235 offspring (14%; 95% CI, 10.2 to 19.6%) from pregnancies in phenylketonuric women with a basal phenylalanine level > or = 900 microM (15 mg/dL) [normal blood phenylalanine < 120 microM (2 mg/dL)] and not in metabolic control [phenylalanine level < or = 600 microM (10 mg/dL)] by the eighth gestational week had congenital heart disease compared with one control offspring (1%) with congenital heart disease. One offspring among the 50 (2%) from mothers with non-phenylketonuria mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented compared with expected percentages among those with congenital heart disease in the general population. A basal maternal phenylalanine level > 1800 microM (30 mg/dL) significantly increased the risk for bearing a child with congenital heart disease (p = 0.003). Phenylalanine hydroxylase mutations in the mothers and offspring did not have an independent relationship to congenital heart disease but were related through the basal maternal phenylalanine levels. The data in this study indicate that a basal maternal phenylalanine level of 900 microM may be a threshold for congenital heart disease, that women with the most severe degree of phenylketonuria are at highest risk for bearing such a child, and that prevention of the congenital heart disease requires initiation of the low phenylalanine diet before conception or early in pregnancy with metabolic control no later than the eighth gestational week.

The International Collaborative Study of Maternal Phenylketonuria: status report 1998.

UNLABELLED: The Maternal Phenylketonuria Study began in 1984 and during the intervening years, 572 pregnancies in hyperphenylalaninemic women and 99 controls and their outcomes have been evaluated. Among hyperphenylalaninemic women who delivered a live infant, only 15.9% were treated and in metabolic control preconceptually, however, another 18.4% were in control by 10 weeks. Compared to the results reported by Lenke and Levy in 1980, there is a marked improvement in outcome with treatment. Microcephaly was unusual in preconceptually treated pregnancies with well controlled phenylalanine restricted diets. Even in pregnancies that established control after conception but before the 8th week, congenital heart disease did not occur in the offspring, however, it did occur in 12% of pregnancies not achieving control until after 10 weeks of pregnancy. CONCLUSION: The recommended level of blood phenylalanine during pregnancy is 120-360 mumol/l. Best results were obtained by close cooperation between the attending obstetrician and a metabolic team experienced in the care of persons with phenylketonuria.

Maternal phenylketonuria: an international study.

Maternal phenylketonuria (PKU) syndrome results in multiple congenital anomalies in the offspring, usually consisting of microcephaly, intrauterine growth retardation, dysmorphology, and congenital heart disease. Pregnancies treated preconceptionally with a phenylalanine-restricted diet and control of maternal blood phenylalanine levels within the recommended range result in normal offspring. However, in this 15-year study, several significant factors resulted in microcephaly in 27% of the offspring, and 7% exhibited serious congenital heart disease. These results occurred chiefly in women with mean IQ scores of 83 associated with low socioeconomic status and decreased educational achievement. Another important factor associated with suboptimal control of blood phenylalanine levels during pregnancy was the fact that most pregnancies were not carefully planned and occurred in women off dietary treatment with phenylalanine-restricted products. These results indicate that greater effort must be developed to assist women with PKU in remaining on diet during their reproductive years. It appears that continued adherence to the diet, resulting in normal maternal intelligence, is an important contribution to improved fetal development.

"Hypotyrosinemia" in phenylketonuria.

It has been postulated that the significant incidence of learning disabilities in well-treated patients with phenylketonuria (PKU) may be due, in part, to reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membrane. Hypotyrosinemia has been reported in treated and untreated PKU but virtually no data are available. We decided to examine this in our patient population and to compare it with the published norms, patient data from our hospital clinical biochemical laboratory database, and a group of normal children and adolescents in a private pediatric practice. We found that the mean nonfasting plasma tyrosine in 99 classical PKU patients was 41.1 micromol/L, in 26 mild (atypical) PKU patients 53.3 micromol/L, and in 35 non-PKU mild hyperphenylalaninemia patients 66.6 micromol/L. This compared to nonfasting plasma tyrosine levels in 102 non-PKU subjects of 64.0 micromol/L in our hospital biochemistry database, 69.1 micromol/L in 58 volunteers in the private office practice, and 64-78.8 micromol/L in infants, children, and adolescents in the literature review. Our data support the previously undocumented statements in the literature that plasma tyrosine levels are low in PKU.

Outcome at age 4 years in offspring of women with maternal phenylketonuria: the Maternal PKU Collaborative Study.

CONTEXT: Untreated maternal phenylketonuria (PKU) increases risk for developmental problems in offspring. The extent to which this risk is reduced by maternal dietary therapy at various stages of pregnancy is not known. OBJECTIVE: To determine whether dietary treatment during pregnancy of women with PKU affects developmental outcomes of offspring. DESIGN: The Maternal PKU Collaborative Study, an ongoing, longitudinal prospective study begun in 1984. SETTING: A total of 78 metabolic clinics and obstetrical offices in the United States, Canada, and Germany. PARTICIPANTS: A total of 253 children of women with PKU (n = 149), with untreated mild hyperphenylalaninemia (n = 33), or without known metabolic problems (comparison group; n = 71) were followed up to age 4 years. INTERVENTION: Women with PKU were offered a low-phenylalanine diet prior to or during pregnancy with the aim of maintaining metabolic control (plasma phenylalanine < or =10 mg/dL [< or =605 micromol/L]). Women with mild hyperphenylalaninemia, who had plasma phenylalanine levels of no more than 10 mg/dL (605 micromol/L) on a normal diet, were not treated. MAIN OUTCOME MEASURES: Children's scores on cognitive and behavioral assessments (McCarthy Scales of Children's Abilities, Test of Language Development, Achenbach Child Behavior Checklist, Vineland Adaptive Behavior Scales, and Home Observation for Measurement of the Environment), compared by maternal metabolic status at 0 to 10 weeks', 10 to 20 weeks', and after 20 weeks' gestation. RESULTS: Scores on the McCarthy General Cognitive Index decreased as weeks to metabolic control increased (r = -0.58; P<.001). Offspring of women who had metabolic control prior to pregnancy had a mean (SD) score of 99 (13). Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks' gestation had a General Cognitive Index score 2 SDs below the norm. Overall, 30% of children born to mothers with PKU had social and behavioral problems. CONCLUSIONS: Our data suggest that delayed development in offspring of women with PKU is associated with lack of maternal metabolic control prior to or early in pregnancy. Treatment at any time during pregnancy may reduce the severity of delay.

The international study of pregnancy outcome in women with maternal phenylketonuria: report of a 12-year study.

OBJECTIVE: The purpose of this report was to update the results of the Maternal Phenylketonuria Collaborative Study, which was established to assess the efficacy of a phenylalanine-restricted diet in preventing morbidity among the offspring of women with hyperphenylalaninemia. STUDY DESIGN: During a 12-year period 576 women with hyperphenylalaninemia were enrolled in this study. Outcome measures were stratified according to classification of maternal hyperphenylalaninemia and the time at which dietary control of phenylalanine level was achieved. RESULTS: Optimal physical and cognitive fetal outcomes occurred when maternal blood phenylalanine level <600 micromol/L was achieved by 8 to 10 weeks' gestation and maintained throughout pregnancy (trimester average,

Maternal phenylketonuria syndrome: congenital heart defects, microcephaly, and developmental outcomes.

OBJECTIVE: A cohort of women with phenylketonuria (PKU) were selected to explore the impact of phenylalanine (Phe) levels and other factors on congenital heart defects (CHDs), microcephaly, and development of their offspring. STUDY DESIGN: Three hundred fifty-four women with PKU were followed up weekly with diet records, blood Phe levels, and sonograms obtained at 18 to 20 and 32 weeks' gestation. At birth, 413 offspring were examined and followed up at 6 months and annually by means of Bayley Mental Developmental Index and Psychomotor Developmental Index tests at 1 and 2 years. The women had Wechsler Adult Intelligence Scales and DNA testing. RESULTS: Thirty-one offspring had CHDs; of these, 17 also had microcephaly. Mean Phe levels at 4 to 8 weeks' gestation predicted CHDs (P <.0001). An infant with a CHD had a 3-fold risk of having microcephaly when the mother had higher Phe levels (P =.02). The Bayley Mental Developmental Index and Psychomotor Developmental Index scores correlated with both CHDs (P =.037 and.0015, respectively) and microcephaly (P =.0001 for both). No direct relationship to the PKU mutation was found. CONCLUSION: None of the women whose offspring had CHDs had blood Phe levels in control during the first 8 weeks of gestation. Women with PKU need to be well controlled on a low-phenylalanine diet before conception and throughout pregnancy.

The efficacy of stethoscope placement when not in use: traditional versus "cool".

OBJECTIVE: To determine whether the "cool" or circumcervical placement of the stethoscope when not in use is as efficacious as the traditional placement in terms of transfer time to the functional position. METHODS: Measurement of time taken by 100 health care professionals in each group to transfer stethoscope to functional position. RESULTS AND INTERPRETATION: The cool group was much slower than the traditional group, despite their younger years. This wasted time could translate into a substantial financial burden on Canada's health care system.

Neuropsychological function in mild hyperphenylalaninemia.

Whether specific cognitive deficits related to frontal-lobe dysfunction that have been reported in individuals with phenylketonuria (PKU) are also characteristic of mild hyperphenylalaninemia (MHP) was investigated. Tests of executive function and control tasks not assessing executive function were administered to a group of individuals with MHP and a group without MHP, similar in age, gender, and IQ. Tests of academic skills and behavior-rating questionnaires were also administered to the group with MHP. No group differences were found for any measure, suggesting that the mild elevations of phenylalanine in individuals with MHP are not sufficient to produce behavioral and cognitive impairments characteristic of PKU.

Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.

OBJECTIVE: To examine the relationship of phenylalanine hydroxylase (PAH) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria (PKU). METHODOLOGY: PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study (MPKUCS). A total of 84 different mutations were detected, and complete genotype was obtained in 199 individuals. Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to one of four classes of severity (severe PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). Then, 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications. The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity. These patients are considered functionally hemizygous. RESULTS: The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level. Cognitive performance (IQ) was also significantly related to genotype. The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96, respectively, whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84, respectively. Of the patients with PKU, 92% had been treated during childhood. Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations. Females with moderate or mild PKU who were treated early and treated for >6 years showed IQ scores 10 points above average for their group. CONCLUSIONS: The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances. Both factors depend on the intellectual resources of the mother with PKU. The significant relationship among genotype, biochemical phenotype, and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy.

Undiagnosed maternal phenylketonuria: the need for prenatal selective screening or case finding.

OBJECTIVES: The aims of this article are to report on a review of cases of maternal phenylketonuria in the International Maternal Phenylketonuria Collaborative Study that were initially diagnosed during or after a pregnancy, to alert health care practitioners to the possible existence of women with undiagnosed phenylketonuria whose fetuses are at risk, and to emphasize that not all adults with untreated phenylketonuria are mentally retarded. STUDY DESIGN: The study was conducted through retrospective database review. RESULTS: Of 414 women with live-born infants, 17 fulfilled our criteria. Six had phenylketonuria diagnosed after they had produced >/=1 affected offspring, 2 had phenylketonuria diagnosed as a result of transient postnatal hyperphenylalaninemia in an offspring, and 9 had phenylketonuria diagnosed by prenatal screening. Undiagnosed maternal phenylketonuria in North America and Europe is currently estimated at 1 case/100,000 births; this rate could be higher elsewhere. CONCLUSIONS: Physicians and midwives should consider a protocol of selective prenatal screening or case finding to detect undiagnosed phenylketonuria among their patients.

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.

Neonatal neurological assessment of offspring in maternal phenylketonuria.

This study assesses the impact of prenatal and postnatal factors in maternal phenylketonuria (PKU). The Dubowitz Neurological Assessment of the Preterm and Full-term Newborn Infant was administered within the first 8 days of life to 56 offspring of women with PKU and 45 controls. Follow-up testing of the maternal PKU offspring at age 1 year consisted of the Bayley Scales of Infant Development and the Receptive-Expressive Emergent Language Scale (REEL). In addition, the Home Observation for Measurement of the Environment (HOME Scale) was given. Birth weight was lower (z = 2.0, p = 0.045), birth length was lower (z = 2.1, p = 0.03) and birth head circumference was smaller (z = 3.5, p = 0.0005) in the maternal PKU offspring than in the control infants. Examiners rated 29% of the maternal PKU offspring and 9% of the control infants abnormal (Fisher's exact test, p = 0.01). At 1 year of age, 19% of the maternal PKU offspring attained a Bayley Developmental Quotient (DQ) and a score on the Bayley Motor Scale below 85; 19% had receptive language delay; and 26% had expressive language delay. The gestational age at which the mother attained metabolic control was an important factor associated with birth measurements, the Dubowitz Rating and subsequent developmental scores. The Dubowitz Neurological Assessment score did not predict developmental outcome (chi-square = 1.3, p = 0.53), while the HOME score correlated with the DQ (r = 0.36, p = 0.02). In logistic regression analyses, the home environment was a greater determinant of risk for a low DQ than whether or not the mother attained metabolic control prior to pregnancy (OR = 0.85, p = 0.02). These results suggest that treatment strategies addressing both prenatal and postnatal factors will most effectively reduce risks in maternal PKU.

Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae.

Maternal phenylketonuria (PKU) in untreated women has resulted in offspring with microcephaly, mental retardation, congenital heart disease (CHD), and intrauterine growth retardation. The Maternal Phenylketonuria Collaborative Study (MPKUCS) was designed to determine the effect of dietary control of blood phenylalanine (Phe) during pregnancy in preventing damage to the fetus associated with untreated Maternal PKU. A cohort of offspring from MPKUS pregnancies was ascertained and examined to evaluate malformations, including CHD, craniofacial abnormalities, microcephaly, intrauterine and postnatal growth retardation, other major and minor defects, and early abnormal neurological signs. For analysis, the women were grouped according to their mean Phe levels in mumol/liter, < or = 360, 361-600, 601-900, or > 900, during critical gestational weeks of 0-8 (N = 203) and 8-12 (N = 190), and average for Phe exposure throughout pregnancy (N = 183). Frequencies of congenital abnormalities increased with increasing maternal Phe levels. Significant relationships included average Phe 0-8 weeks and CHD (P = 0.001); average Phe 8-12 weeks and brain, fetal, and postnatal growth retardation (P < 0.0005 for all), wide nasal bridge (P < 0.0005), and anteverted nares (P = 0.001); and average Phe exposure during the entire pregnancy and neurological signs (P < 0.0005). Although 14% of infants had CHD, none of the CHD occurred at 120-360 mumol/liter and only one (3%) at 361-600 mumol/liter. At levels of 120-360 mumol/liter, there were three infants (6%) with microcephaly, two (4%) with postnatal growth, and none with intrauterine growth retardation, in contrast to 85%, 51%, and 26%, respectively, with Phe above 900 mumol/liter. These data support the concept that women with PKU should begin a low-phenylalanine diet to achieve Phe levels of < 360 mumol/liter prior to conception and should maintain this throughout pregnancy.

Newborn phenylketonuria (PKU) Guthrie (BIA) screening and early hospital discharge.

Recent policies of early discharge of postpartum mothers and their infants has raised concerns of possible decreased sensitivity in Guthrie bacterial inhibition assay (BIA) phenylketonuria (PKU) screening resulting in missed cases. In order to assess the potential impact of early discharge from hospital on neonatal screening for PKU and its variants, we performed 18 standard BIA screening tests on 11 newborn infants with the disease. Blood spot samples were collected from 1 to 24 h after birth and were analyzed at the Ontario Ministry of Health newborn screening laboratory according to the routine screening protocol. Except for one 4-hour postnatal sample from an infant with 'non-PKU mild hyperphenylalaninemia' (MHP) all blood samples showed phenylalanine levels > or = 240 mumol/l, irrespective of the age of the baby. During our 29 year experience with neonatal PKU screening (3.9 million infants tested), employing a cutoff blood phenylalanine of 240 mumol/l in blood spots obtained at > or = 24 h of age, only two biological false negative (one confirmed) tests were discovered in infants subsequently shown to have classical PKU: another three false negative tests were discovered in sibs of infants with MHP. The sensitivity of the screening test was 99.2% for infants with classical and mild PKU. Ascertainment of patients with MHP is unknown and is very likely incomplete. Over a 3-year period (1992-4) the specificity of the test was 99.9% for those screened after 24 h. The positive predictive value was 12.8%. Although early discharge may have an impact on other screened diseases, we conclude, from our studies, that early discharge may not affect the detection of infants with classical and mild (atypical) PKU, but would probably increase the number of infants with MHP missed using the BIA and a cutoff level of 240 mumol/l. Because of our experience and that of others, we recommend that neonates be at least 12 h of age before initial BIA PKU screening be carried out. To confirm this recommendation further prospective studies should be initiated.