Embryofetopathy caused by postnatally detected maternal phenylketonuria

A case of a now 10-month-old female infant is reported, who presented at birth with microcephalus, growth retardation, dystrophia, facial dysplasia and cardiac defect. Etiologically a classical phenylketonuria of the mother with very high levels of serum phenylalanine (51 and 41 mg/dl, respectively), which was not known until then, was diagnosed already after her confinement. The mother, aged 26, originates from Roumania. She had never been treated by any phenylalanine-limited diet. Psychological testing revealed a severely reduced intelligence (IQ = 63). The child, having normal levels of serum phenylalanine, presented with mild statomotor retardation at the age of ten months. Even in countries with a general neonatal screening program, a hitherto undiagnosed maternal phenylketonuria has to be considered within the differential diagnosis of a dystrophic microcephalic newborn, beside more common causes like the fetal alcohol syndrome.     

New England Maternal PKU Project: prospective study of untreated and treated pregnancies and their outcomes

Four women with classic phenylketonuria (blood phenylalanine greater than 1200 mumol/L) were given a phenylalanine-restricted diet; three also received L-tyrosine supplements. Biochemical measures of nutrition were normal except for iron deficiency anemia, and in one woman folate deficiency. One pregnancy in which treatment began before conception and another treated from 8 weeks gestation, both with blood phenylalanine levels maintained at 120 to 730 mumol/L, resulted in normal newborn infants whose postnatal growth and development have also been normal. A third pregnancy, treated from 6 gestational weeks, was marked by poor dietary compliance until the middle of the second trimester; fetal microcephaly was identified by ultrasonography at 28 weeks but not at 21 weeks. The child has microcephaly and motor delay. The fourth pregnancy, not treated until the third trimester, produced a child with microcephaly, mental retardation, hyperactivity, and neurologic deficits. It is likely that fetal damage from maternal phenylketonuria can be largely and perhaps entirely prevented by dietary therapy, but therapy must begin before conception for the best chance of a normal infant.     

Valine, isoleucine, and leucine. A new treatment for phenylketonuria

Early treatment of phenylketonuria by dietary phenylalanine restriction prevents brain damage. Behavioral and cognitive deficits occur when serum phenylalanine levels increase. Administration of valine, isoleucine, and leucine to patients with phenylketonuria may inhibit entry of phenylalanine into the brain and reduce its toxic effects on the central nervous system. Sixteen adolescents and young adults with phenylketonuria participated in double-blind trials in which a valine, isoleucine, and leucine mixture or a control mixture was given for four 3-month periods. Biochemical and neuropsychologic tests were carried out before and at the end of each period. Time to completion of a test that required substantial attention with mental processing (Attention Diagnostic Method) was faster during the valine, isoleucine, and leucine periods than during the control mixture periods. Improvement with valine, isoleucine, and leucine on a less demanding task (Continuous Performance Test) approached significance. These data lent support to the hypothesis that a regimen of valine, isoleucine, and leucine may help individuals unable to maintain low serum phenylalanine levels.     

Early breastfeeding is linked to higher intelligence quotient scores in dietary treated phenylketonuric children

Strict control of phenylalanine intake is the main dietary intervention for phenylketonuric children. Whether other dietary-related factors improve the clinical outcome for treated phenylketonuric children in neurodevelopmental terms, however, remains unexplored. We retrospectively compared the intelligence quotient (IQ) score of 26 school-age phenylketonuric children who were either breastfed or formula fed for 20-40 days prior to dietary intervention. Children who had been breastfed as infants scored significantly better (IQ advantage of 14.0 points, p = 0.01) than children who had been formula fed. A 12.9 point advantage persisted also after adjusting for social and maternal education status ( p = 0.02). In this sample of early treated term infants with phenylketonuria there was no association between 1Q scores and the age at treatment onset and plasma phenylalanine levels during treatment. We conclude that breastfeeding in the prediagnostic stage may help treated infants and children with phenylketonuria to improve neurodevelopmental performance.     

Baby of a phenylketonuric mother: Inferences drawn from a single case

Reports on pregnancy in phenylketonuric women are rare, but fetal brain damage has been well documented and attributed to the mother''s biochemical disturbance. Reports on fetal health after the treatment of phenylketonuria (PKU) in pregnancy are even rarer. Since the treatment of PKU girls is often stopped or relaxed at various prepubertal ages, pregnancy may occur soon in apparently normal girls who have high phenylalanine levels and PKU. In view of the scarcity of information, implications are cautiously suggested from the experience gained of one case. More information is needed urgently, not about the effects of PKU alone, but also of hyperphenylalaninaemia. The present case suggests that it is possible for a fetus to escape malformation, brain damage, and growth failure if maternal dietary treatment is good from about the 20th week of gestation. It would be unwise, however, to accept this finding as holding true for all cases.     

Nutritional factors affecting serum phenylalanine concentration during pregnancy for identical twin mothers with phenylketonuria

The effect of energy, protein, fat, and phenylalanine on serum phenylalanine concentrations during pregnancy for a set of identical twins with phenylketonuria (PKU) was examined. Blood samples were collected one to two times per week. The subjects completed a 3-d food record prior to each blood collection. The effect of the factors on serum phenylalanine levels was evaluated statistically using time-series analysis. Dietary intakes of the nutrients evaluated were similar for the subjects. For one subject, there were highly significant effects of energy, protein, and fat on serum phenylalanine levels. In contrast, these nutrients had no significant effect on serum phenylalanine for the other subject. Dietary phenylalanine had no significant effect on serum phenylalanine for either twin. Conclusions: There was no effect of phenylalanine intake and no consistent effect of energy, protein, or fat on serum phenylalanine. Other dietary or environmental factors or a combination of factors may impact serum phenylalanine levels of pregnant women with PKU.     

American Academy of Pediatrics: Maternal phenylketonuria

Elevated maternal phenylalanine levels during pregnancy are teratogenic and may result in growth retardation, significant psychomotor handicaps, and birth defects in the offspring of unmonitored and untreated pregnancies. Women of childbearing age with all forms of phenylketonuria, including mild variants such as hyperphenylalaninemia, should receive counseling concerning their risks for adverse fetal effects optimally before conceiving. The best outcomes occur when strict control of maternal phenylalanine levels is achieved before conception and continued throughout the pregnancy.     

The international collaborative study of maternal phenylketonuria: status report 1994

Neonatal screening for phenylketonuria (PKU) has created a problem as females with PKU are reaching child-bearing age. Surveys have revealed that maternal phenylalanine blood concentrations greater than 1200 μmol/l are associated with fetal microcephaly, congenital heart defects and intrauterine growth retardation. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk of producing these fetal abnormalities. To examine this problem, the international maternal PKU collaborative study was developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings have indicated that phenylalanine restriction should begin before conception for females with PKU planning a pregnancy. Dietary control should maintain maternal blood phenylalanine levels between 120 and 360 μmol/l and should provide adequate energy, protein, vitamin and mineral intake. Pregnant hyperphenylalaninemic females who achieved metabolic control after conception or by the 10th week of pregnancy had a better offspring outcome than anticipated. The results of 402 pregnancies are reviewed.     

Variability of reproductive casualty in maternal phenylalaninemia

A biochemical survey of 4,000 parents of mentally retarded children did not identify any mothers with elevated phenylalanine blood levels. This' finding and an analysis of nearly 100 reported cases of maternal phenylalaninemia suggest a low risk of reproductive casualty in phenylalaninemic mothers who somehow escaped the usual effects of phenylketonuria. Recent observation on cases of maternal phenylalaninemia who were detected through unselected screening indicate that the reproductive risk associated with the condition may have been overestimated in the past. This risk is concentrated in mothers who had been affected themselves. Mental level appears to be a stronger predictor of reproductive outcome in phenylalaninemic women than the degree of phenylalaninemia. Selective prenatal intervention based on maternal mental level is not possible, however, where the natural history of the condition has been altered. This is the case in phenylketonuric girls who had been treated during childhood. These girls are now reaching child-bearing age in fast growing numbers, as a result of screening for phenylketonuria. Prenatal intervention is appropriate for all of them until predictors are established that can identify those at risk of reproductive casualty.     

Maternal hyperphenylalaninaemia as a cause of microcephaly and mental retardation

We attempted to evaluate the role of maternal hyperphenylalaninaemia (HPA) as an isolated cause of mental retardation and microcephaly in children. This transversal study observed the plasma phenylalanine from mothers of 161 children with mental retardation and/or microcephaly of unknown origin. In this sample, we found two women with previously undiagnosed HPA, a frequency (2/161) higher than expected for our general population (1:12 500) ( p < 0.001). We concluded that the plasma phenylalanine levels should be determined during preconceptional evaluation of every woman of reproductive age that already has had a child affected either by mental retardation or microcephaly of unknown cause. It is particularly significant where women currently having their pregnancies have not been screened for phenylketonuria as newborns, as happens in most developing countries.     

Behavioral and biochemical correlates of diet change in phenylketonuria.

The investigation was designed to explore the use of tests tapping reversible aspects of behavior and performance and to find out whether these data can be correlated with concurrent metabolic changes in different dietary phases. The four subjects had classic phenylketonuria, diagnosed on the basis of a high level of serum phenylalanine on a regular diet, and severe mental retardation. Three types of diet were used: the general institutional diet, a low phenylalanine diet, and a low phenylalanine diet with added L-phenylalanine. A position discrimination and reversal task was used. Blood samples were taken every week on the day before psychological testing, and one 24-hr urine sample was collected during each dietary phase. In subjects I and II performance deteriorated upon elevation of the serum phenylalanine level, but these changes were transient only, thus showing an adaptation to the effects of the high serum phenylalanine level. Subject III showed increased response latencies (slower test responses) during high phenylalanine diet phases and faster responses while on a low phenylalanine diet. The correlation between response time and phenylalanine level is highly significant (r = 0.86, P less than 0.001). On the low phenylalanine diet subject IV's responses were fast and her performance was very stable, which contrasted with erratic performance during the high phenylalanine phases. Calculations show a significant association with phenylalanine level, both for response time (r = 0.47, P less than 0.05) and for variability in response time within each session (r = 0.46, P less than 0.05). Biochemical variability was observed in metabolic responses to phenylalanine loading, especially in the excretion of tryptophan metabolites.     

Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia

ABSTRACT There is international consensus that patients with phenylalanine (Phe) levels <360 microM on a free diet do not need Phe-lowering dietary treatment whereas patients with levels >600 microM do. Clinical outcome of patients showing Phe levels between 360 and 600 microM in serum on a free nutrition has so far only been assessed in a small number of cases. Therefore, different recommendations exist for patients with mild hyperphenylalaninemia. We investigated in a nationwide study 31 adolescent and adult patients who persistently displayed serum Phe levels between 360 and 600 microM on a normal nutrition with a corresponding genotype. Because of limited accuracy of measurements, Phe levels should be looked on as an approximation, but not as an absolute limit in every instance. In addition to serum Phe levels, the assessment program consisted of comprehensive psychological testing, magnetic resonance imaging of the head, (1)H magnetic resonance spectroscopy, and genotyping. We found a normal intellectual (intelligence quotient, 103 +/- 15; range, 79-138) and educational (school performance and job career) outcome in these subjects as compared with healthy control subjects (intelligence quotient, 104 +/- 11; range, 80-135). Magnetic resonance imaging revealed no changes of cerebral white matter in any patient, and (1)H magnetic resonance spectroscopy revealed brain Phe levels below the limit of detection (<200 microM). In the absence of any demonstrable effect, dietary treatment is unlikely to be of value in patients with mild hyperphenylalaninemia and serum Phe levels <600 microM on a free nutrition, and should no longer be recommended. Because of a possible late-onset phenylketonuria, Phe levels of untreated patients should be monitored carefully at least during the first year of life. Nevertheless, problems of maternal phenylketonuria should still be taken into account.     

Problems stemming from pregnancy in a woman with phenylketonuria

A normal infant was born to a 25 year-old mother with phenylketonuria who had never been treated. The mother had been fed a phenylalanine restricted diet for 3 months before the beginning of the pregnancy. Dietary control was maintained throughout the whole gestation. The problems of dietary control in a mentally retarded woman are analysed.     

母源性苯丙酮尿症的临床特征与干预

母源性苯丙酮尿症是由于苯丙酮尿症孕妇在孕前及孕中苯丙氨酸水平持续升高导致的综合征,其表现为小头及面部畸形、先天性心脏病、智力低下和行为及情感异常.合理控制苯丙酮尿症孕妇血苯丙氨酸水平并保持在120～360μmol/L,能够降低和避免胎儿畸形不良结局的发生.母源性苯丙酮尿症应倡导三级干预.     

Predictors of intelligence quotient and intelligence quotient change in persons treated for phenylketonuria early in life

Ninety-one individuals with phenylketonuria who were treated early in life were followed for as many as 22 years. Regression analyses were used to determine the best predictors of IQ and IQ change. Among treatment-related variables, good dietary control of the blood phenylalanine level stood out as the best predictor of IQ. Diet discontinuation and the natural (off diet) blood phenylalanine level best predicted IQ loss, suggesting that diet continuation may be important for children with natural blood phenylalanine levels greater than 18 mg/dL.     

Decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents

Four adolescent or young adult patients with phenylketonuria were examined before and after discontinuation of dietary treatment. Plasma and CSF phenylalanine concentrations increased about two-fold in three patients. In these patients the CSF concentration of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) decreased markedly; 5-HIAA to extremely low values. The reaction time variability increased in these patients. In the fourth case plasma phenylalanine levels, CSF HVA and 5-HIAA levels, and reaction time variability were essentially unchanged. The relationship between reaction time variability and the CSF 5-HIAA level for all four patients could be presented as a linear function. However, a causal relationship is still unproven. These preliminary findings demonstrate that there may be hazards in the discontinuation of dietary treatment, even in adolescents or young adults, for neurotransmitter metabolism and mental function.Abbreviations PKU phenylketonuria - RT reaction time - HVA homovanillic acid - 5-HIAA 5-hydroxyindoleacetic acid     

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.     

Maternal TSH-receptor antibodies and TSH antibodies in screening for congenital hypothyroidism

Serum samples from 30 mothers who had given birth to at least one child with a positive neonatal thyrotropin (TSH) screening test were analysed for TSH-receptor antibodies. One mother with hypothyroidism after thyroiditis who had two sons who had had transient congenital hypothyroidism, showed significantly elevated concentrations of TSH receptor blocking IgG antibodies in her serum. The three daughters of another mother had neonatal hyperthyrotropinaemia but normal thyroid hormone levels. This woman had elevated serum levels of TSH but was clinically and biochemically euthyroid. The apparent hyperthyrotropinaemia in this family was due to an artifact in the TSH radioimmunoassay caused by maternal anti-TSH IgG antibodies. It is obvious that placental transfer of maternal IgG antibodies to the thyroid TSH receptor is one cause of transient congenital hypothyroidism. Likewise, maternal IgG directed against TSH interferes with radioimmunoassays of TSH and the results may be falsely interpreted as hyperthyrotropinaemia. It is concluded that in neonatal hyperthyrotropinaemia analysis of the mother's serum is indicated, and that maternal TSH receptor blocking antibodies must be considered as a cause of congenital hypothyroidism, especially if the mother has a history of thyroid dysfunction.     

An exceptional Albanian family with seven children presenting with dysmorphic features and mental retardation: maternal phenylketonuria

Background  

Phenylketonuria is an inborn error of amino acid metabolism which can cause severe damage to the patient or, in the case of maternal phenylketonuria, to the foetus. The maternal phenylketonuria syndrome is caused by high blood phenylalanine concentrations during pregnancy and presents with serious foetal anomalies, especially congenital heart disease, microcephaly and mental retardation.     

Intellectual development in 12-year-old children treated for phenylketonuria

Intelligence and achievement test scores were evaluated for 95 12-year-old children with phenylketonuria who had begun dietary therapy during the neonatal period. Dietary control of blood phenylalanine below 900 mumol/L was maintained beyond age 10 years in 23 children; 72 others had blood phenylalanine persistently above that level at ages ranging from 18 months to 10 years. Test scores at age 12 years were negatively correlated with the age at initiation of diet and with blood phenylalanine levels from ages 4 to 10 years, and positively correlated with parent IQ scores and the age at loss of dietary control. Children who maintained phenylalanine levels below 900 mumol/L beyond age 10 years showed no deficits in test scores, except for arithmetic, the scores of which declined between ages 6 and 12 years in 90% of the children in this study. These data strongly support a recommendation that dietary restriction of phenylalanine should be maintained through adolescence.