Neurocognitive functioning in adults with phenylketonuria: Report of a 10-year follow-up.

BACKGROUND: The long-term prognosis of early treated phenylketonuria (PKU) is still under discussion. Aim of this controlled long-term study was to assess the neurological and neuropsychological outcome in adult patients with early-treated PKU. METHODS: We investigated 35 patients with early-treated classical PKU aged 29 to 51 years (mean age 41 years) and 18 healthy controls matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), attention and information-processing abilities. Magnetic resonance imaging (MRI) of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a five-year and a ten-year follow-up. RESULTS: In the entire interval IQ, information processing and attention of patients and controls remained constant. At both follow-up assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (> 42 years) showed poorer information processing and attention at both assessment times compared to young adult patients (< 42 years) and controls. IQ, information processing and attention showed no correlation to imaging results. IQ, however, was significantly correlated to blood phenylalanine (Phe) levels in patients´ childhood and adolescence, and Phe levels had been higher in the adolescent years of older adult patients. CONCLUSIONS: Cognitive performance in adult patients with early-treated PKU does not seem to deteriorate in a ten-year interval. Neuropsychological assessment in adults with PKU revealed neurocognitive impairment particularly in older adult patients. This seems to refer to an early relaxation of diet that was recommended when the older patients were adolescents. Results indicate a benefit of dietary control during adolescence in PKU.

Recommendations for the nutrition management of phenylalanine hydroxylase deficiency.

The effectiveness of a phenylalanine-restricted diet to improve the outcome of individuals with phenylalanine hydroxylase deficiency (OMIM no. 261600) has been recognized since the first patients were treated 60 years ago. However, the treatment regime is complex, costly, and often difficult to maintain for the long term. Improvements and refinements in the diet for phenylalanine hydroxylase deficiency have been made over the years, and adjunctive therapies have proven to be successful for certain patients. Yet evidence-based guidelines for managing phenylalanine hydroxylase deficiency, optimizing outcomes, and addressing all available therapies are lacking. Thus, recommendations for nutrition management were developed using evidence from peer-reviewed publications, gray literature, and consensus surveys. The areas investigated included choice of appropriate medical foods, integration of adjunctive therapies, treatment during pregnancy, monitoring of nutritional and clinical markers, prevention of nutrient deficiencies, providing of access to care, and compliance strategies. This process has not only provided assessment and refinement of current nutrition management and monitoring recommendations but also charted a direction for future studies. This document serves as a companion to the concurrently published American College of Medical Genetics and Genomics guideline for the medical treatment of phenylalanine hydroxylase deficiency.

Undiagnosed phenylketonuria in parents of phenylketonuric patients, is it worthwhile to be checked?

In our phenylketonuria (PKU) cohort of 120 patients, we uncovered a couple of cases of undiagnosed mild phenylketonuria (mPKU)/hyperphenylalaninemia (mHPA) in maternal parents of the PKU cohort. This finding prompted us to evaluate the risk of either mild phenylketonuria or mild hyperphenylalaninemia in the parent population whose children were diagnosed with hyperphenylalaninemia (HPA). Taking into account the phenylalanine hydroxylase (PAH) mutation carrier frequency and the PAH mild mutation rate, we estimated that the prevalence of the parental mPKU/mHPA varied widely, from 1/74 in Turkey to 1/708 in Lithuania. The benefits of the parental detection procedure described here are the prevention of further maternal PKU syndrome, the follow-up of the newly detected patients and the accuracy of the genetic counseling provided to these families. This very simple procedure should be incorporated into neonatal PKU management of the hospitals in countries where a routine systematic neonatal screening is operational.

[Maternal phenylketonuria]. / Maternális phenylketonuria.

Elevated maternal phenylalanine levels during pregnancy are teratogenic, and may result in embryo-foetopathy, which could lead to stillbirth, significant psychomotor handicaps and birth defects. This foetal damage is known as maternal phenylketonuria. Women of childbearing age with all forms of phenylketonuria, including mild variants such as hyperphenylalaninaemia, should receive detailed counselling regarding their risks for adverse foetal effects, optimally before contemplating pregnancy. The most assured way to prevent maternal phenylketonuria is to maintain the maternal phenylalanine levels within the optimal range already before conception and throughout the whole pregnancy. Authors review the comprehensive programme for prevention of maternal phenylketonuria at the Metabolic Center of Budapest, they survey the practical approach of the continuous maternal metabolic control and delineate the outcome of pregnancies of mothers with phenylketonuria from the introduction of newborn screening until most recently.

Phenylketonuria.

Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase gene. Phenotypes can vary from a very mild increase in blood phenylalanine concentrations to a severe classic phenotype with pronounced hyperphenylalaninaemia, which, if untreated, results in profound and irreversible mental disability. Neonatal screening programmes identify individuals with phenylketonuria. The initiation of a phenylalanine-restricted diet very soon after birth prevents most of the neuropsychological complications. However, the diet is difficult to maintain and compliance is often poor, especially in adolescents, young adults, and pregnant women. Tetrahydrobiopterin stimulates phenylalanine hydroxylase activity in about 20% of patients, and in those patients serves as a useful adjunct to the phenylalanine-restricted diet because it increases phenylalanine tolerance and allows some dietary freedom. Possible future treatments include enzyme substitution with phenylalanine ammonia lyase, which degrades phenylalanine, and gene therapy to restore phenylalanine hydroxylase activity.

Bone Status in Patients with Phenylketonuria: A Systematic Review.

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. Although dietary and, in some cases, pharmacological treatment has been successful in preventing intellectual disability in PKU patients who are treated early, suboptimal outcomes have been reported, including bone mineral disease. In this systematic review, we summarize the available evidence on bone health in PKU patients, including data on bone mineral density (BMD) and bone turnover marker data. Data from cohort and cross-sectional studies of children and adults (up to 40 years of age) were obtained by searching the MEDLINE and SCOPUS databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For each selected study, quality assessment was performed applying the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS I) tool. We found that mean BMD was lower in PKU patients than in reference groups, but was within the normal range in most patients when expressed as Z-score values. Furthermore, data revealed a trend towards an imbalance between bone formation and bone resorption, favoring bone removal. Data on serum levels of minerals and hormones involved in bone metabolism were very heterogeneous, and the analyses were inconclusive. Clinical trials that include the analysis of fracture rates, especially in older patients, are needed to gather more evidence on the clinical implications of lower BMD in PKU patients.

[Diagnosis, treatment and long-term following up of 223 patients with hyperphenylalaninemia detected by neonatal screening programs].

OBJECTIVE: To investigate the incidence of hyperphenylalaninemia (HPA) caused by different etiologic factors in China and the relationship between the phenylalanine and mental development of patients with HPAs who were diagnosed by neonatal screening and early treated. METHODS: Two hundred and twenty-three patients with HPA detected by neonatal screening programs were refered to us at the age of (41 +/- 27) days after birth. The differential diagnosis was performed by BH(4) (20 mg/kg) loading test, urinary pterin analysis and dihydropteridine reductase (DHPR) activity determination respectively. The control of phenylalanine (Phe) metabolism, growth and mental development were evaluated in all treated patients. Related gene mutation analysis was performed in some patients RESULTS: One hundred and twenty-nine of 223 patients (57.8%) were diagnosed as phenylalanine hydroxylase deficiency (PAHD), 64 patients (28.7%) as BH(4) responsive PAHD, 30 patients (13.5%) as 6-pyruvoyl tetrahydropterin synthase deficiency (PTSD). One hundred and forty-nine patients were followed at age of 4 m - 2 y in our clinic. The 136 of 149 patients were treated according to different etiology at the age of 1.6 m (0.5 - 3.5 m) after birth. Thirteen patients were followed up without the need for treatment. All patients had normal growth development. One hundred and eight (79.4%) of 136 treated patients had normal mental development. The negative correlation (r = -0.439, P < 0.01) between IQ and average Phe levels were observed in 58 patients. Twenty-eight patients were able to go to primary school or even university. Nine kinds of PTS gene mutations were found in 9 cases with PTSD, among which 286G-->A and 259C-->T were most commonly seen, accounting for 45%. Seven kinds of PAH gene mutations were found in 13 cases with BH(4) responsive PAHD with the R241C (43.8%) mutation being the most frequent one. CONCLUSION: The differential diagnosis should be quickly made in all HPA patients detected by neonatal screening. Near 80% patients early treated had normal mental development. The good control of blood Phe level is a key factor for mental development.

Unplanned pregnancies in young women with diabetes. An analysis of psychosocial factors.

OBJECTIVE: To assess psychosocial factors related to preventing birth defects in children born to diabetic women. Diabetic women are at high risk for bearing children with congenital anomalies associated with teratogenic effects early in pregnancy. This study focuses on factors related to the family planning behavior of diabetic women. RESEARCH DESIGN AND METHODS: Sixty-six diabetic women were included in a 5-yr, prospective, longitudinal study along with 69 phenylketonuric women, who also face a high risk of bearing children with birth defects, and 68 healthy women. Annual interviews and questionnaires were administered. Women who did not want a pregnancy completed measures related to contraceptive behavior and quality of life. Areas assessed were knowledge, personality, attitudes, and social support. RESULTS: Diabetic women were more likely to be sexually active than women with phenylketonuria. Use and type of birth control were comparable among the groups except that diabetic women used condoms more often. For diabetic women, social support and positive attitudes towards birth control were associated with consistent birth control use. Of the diabetic women, 23 became pregnant, and only 6 (26%) were planned pregnancies. CONCLUSIONS: Birth control use by diabetic women needs to be addressed by health professionals. Attitudes about birth control of the women and those close to them appear to be important factors in consistent birth control use. Suggestions are made for addressing these factors.

[Screening for phenylketonuria in 726,998 neonates in Zhejiang Province].

OBJECTIVE: To analyze the results of screening for neonatal phenylketonuria (PKU) in Zhejiang Province. METHODS: The screening for neonatal PKU was conducted among 726,998 newborns in Zhejiang Province. Heel prick blood specimens were collected around 72 h after birth with 6 intakes of high protein milk and the specimens were dried on S and S903 filter papers. Phenylalanine (Phe) levels were determined quantitatively with Perkin Elmer Neonatal Fluorometric PKU kits. RESULTS: Among 726,998 newborns, elevated blood Phe levels were found in 152 infants. They were all recalled for serum amino acid analysis and 32 were confirmed to have PKU with 19 males and 13 females. The earliest time of confirmation was 16 d and latest was 105 d with the median of 32 d. CONCLUSION: The data shows that the detection rate of screening for neonatal phenylketonuria in Zhejiang Province was 1/22,718.

Phenylketonuria screening: effect of early newborn discharge.

OBJECTIVE: To determine the percentage of term newborns discharged by 24 hours of life and the actions taken by physicians and institutions to avoid false-negative phenylketonuria (PKU) screens in these infants. DESIGN: Descriptive cross-sectional survey. PARTICIPANTS: One hundred forty term nurseries and 157 pediatricians. SELECTION PROCEDURE: Stratified sampling techniques were used to sample nurseries from the 1992 American Hospital Association guide to provide equal representation of each region of the country. Pediatricians were systematically sampled from a national list of practicing pediatricians supplied by Ross Laboratories to provide equal sampling from each state. RESULTS: The response rates were 95% (n = 133) for term nurseries and 83% (n = 131) for pediatricians. Twenty-four percent of healthy newborns are discharged by 24 hours of life. Ninety-three percent of nurseries screen all infants for PKU before discharge. In states without laws mandating rescreening, only 48% of institutions that discharge the majority of their infants (> 50%) by 24 hours of life rescreen. Also, in states without rescreening laws, 64% of pediatricians rescreen. The timing of this repeat screen ranges from less than 72 hours of life to 4 weeks. Determining which infants to rescreen varies by practitioner; some rescreen all infants, whereas others rescreen those discharged early. Just more than half of all pediatricians, whether practicing in a state requiring repeat PKU screening, claim to be familiar with the American Academy of Pediatrics recommendations regarding repeated PKU screening of infants discharged by 24 hours of life. CONCLUSION: Twenty-four percent of term newborns in the United States are discharged by 24 hours of life. Most hospitals screen all infants for PKU before discharge regardless of age. The majority of states do not mandate rescreening; rescreening policies among pediatricians and institutions in those states vary widely. A significant number of infants do not receive repeated screening and are therefore at risk for delayed or missed diagnosis of PKU because of insensitive initial screens. Pediatrician awareness of the need to perform repeated PKU screens on infants discharged by 24 hours is poor.

Screening for biotinidase deficiency in newborns: worldwide experience.

Between January 24, 1984, and December 31, 1988, 29 screening programs for biotinidase deficiency in newborns were established in 12 countries, and 4,396,834 newborns were screened. The worldwide incidence is based on screening programs in Australia, Austria, Canada, Italy, Japan, Mexico, New Zealand, Scotland, Spain, Switzerland, The United States, and West Germany. Biotinidase deficiency was detected in 72 newborns; 32 had profound biotinidase deficiency (less than 10% of mean normal activity level) and 40 had partial deficiency (10% to 30% of mean normal activity level). The combined incidence of profound and partial deficiency was 1 case per 61,067 live births (1:49 500 to 1:79 544; 95% confidence interval), the estimated frequency of the recessive allele was 0.0040, and the frequency of heterozygosity was estimated to be 1:123. Profound deficiency occurred in 1 per 137,401 live births (1:109,300 to 1:211,200), and partial deficiency in 1 per 109,921 live births (1:86,600 to 1:159,700). Most available parents of children with profound and partial deficiency had biotinidase activity levels intermediate between zero and mean normal activity levels. Six children with profound deficiency were symptomatic at, or soon after, the time of diagnosis; no infant with partial deficiency has become symptomatic, but little is known about the natural history of infants with partial deficiency. Most children whose biotinidase deficiency was detected by newborn screening were white, one was black, and one Hispanic; biotinidase deficiency has not been detected in Oriental children. Although 8 pilot programs have terminated, 21 will continue either indefinitely or until predetermined targets are reached, and 3 new programs were scheduled to begin in January 1989.(ABSTRACT TRUNCATED AT 250 WORDS)

Theory and practice of psychopharmacogenetics.

This article attempts to elucidate the theory and practice of psychopharmacogenetics. Eight working models were identified and characterized with a distinct view of risk factors in the host, the pathophysiology of disease, and the strategies for optimum therapy. The biochemical culprits related to adverse drug reaction in each case can be used to identify a risk and thus contribute to prevention research. Since the phenomenology of these uncommon conditions covers a broad spectrum of neuropsychiatric manifestations, the insights they generated might presage a better understanding of the natural history of a wider range of mental disorders associated with genetic vulnerability. The emerging information suggests that psychopharmacogenetics could be defined from clinical perspectives as multidimensional analysis of genes, drugs, and behaviour for the treatment and prevention of psychiatric disorders.

Is universal neonatal hemoglobinopathy screening cost-effective?

OBJECTIVE: To determine whether and where universal neonatal screening for hemoglobinopathies, chiefly sickle-cell disease, could be performed at socially acceptable costs. METHODS: We made projections of the cost-effectiveness of nonuniversal and universal sickle-cell disease screening throughout the United States. We then compared the cost-effectiveness of universal sickle-cell disease screening with that of universal phenylketonuria screening. Finally, we asked if "high-cost" states, that is, those in which the cost of finding a case of sickle-cell disease exceeded one half the cost of finding a case of phenylketonuria, could enhance their cost-effectiveness by joining demographically complementary states in screening cooperatives. RESULTS: If all states conducted independent screening and if the value of finding a case of sickle-cell disease were no more than one half that of finding a case of phenylketonuria, seven of the 19 states that do not currently conduct universal screening for hemoglobinopathies would begin to do so, but six of the 34 that currently do so would stop. Of the six that would stop, three have already formed a screening cooperative, reducing their projected average costs for finding either sickle-cell disease or phenylketonuria or both; the other three could similarly improve cost-effectiveness through cooperative arrangements. Nineteen states realize economies of scale in six cooperative groups; more could do so. CONCLUSION: Universal neonatal hemoglobinopathy screening can be made available at socially acceptable costs to the citizens of demographically various states.

A cost-benefit analysis of the Quebec Network of Genetic Medicine.

Certain serious diseases, including several major genetic disorders, cannot be treated effectively unless they are detected before symptoms appear. In such cases, only systematic population screening can ensure that the necessary preventive treatment can be administered to affected individuals. The question of whether to establish such screening programs, which may be relatively costly, is a pressing problem for many public administrations. This study of the costs and benefits of the Quebec Network of Genetic Medicine has as its main objective the development of an analytical framework which can be generally applied to such problems. In this article, we attempt to evaluate the profitability of the Network to society. For the evaluation of the less tangible costs and benefits, we adopted the minimum profitability principle, which essentially involves establishing a lower bound on the value of the profitability of the Network. The net benefits assessed by this study, although certainly underestimated, are still very significant. Since the Network is administered by a team of researchers, the study also throws some light on the links existing between research and development activities on the one hand and public services on the other, and hence on the general question of the socioeconomic profitability of biomedical research.

KIE: The Quebec Network of Genetic Medicine was established in 1969 by a group of researchers concerned with the systematic early detection of congenital disorders in neonates. The authors performed a cost-benefit analysis of the profitability of the Network during the period 1969-1980. They quantified the costs and benefits of detecting phenylketonuria and hypothyroidism and found significant savings to society. In the cases of Tay Sachs disease and tyrosinemia, for which there are no curative treatments, a quantitative analysis was not performed but costs were calculated and potential benefits considered. Overall, the Network was found to be both socially advantageous and financially profitable, at least partly because it has been managed by active researchers.

Audit of neonatal screening programme for phenylketonuria and congenital hypothyroidism.

The performance of the neonatal screening programme was audited against clinical standards in the Bath clinical area from 1 April 1994 to 31 March 1996. The standards and policy were agreed by local service provider representatives of the screening and were audited, using laboratory and child health computer systems and medical records. Two annual reports were produced with recommendations for improvement communicated to representatives of the service. Thus the first audit loop has been completed. The audit shows that the coverage of the service is excellent, with all eligible babies being offered screening; those with congenital hypothyroidism or phenylketonuria receive appropriate treatment by the 28 day standard. The process works extremely well, although areas for improvement have been identified, to increase the efficiency of the service. It is concluded that an effective and efficient audit cycle can be established, to monitor and improve the performance of the neonatal screening service.

Health economic analysis of the Swedish neonatal metabolic screening programme. A method of optimizing routines.

A benefit-cost analysis was carried out to optimize the routines for neonatal metabolic screening. The basis of the study was provided by results of the Swedish neonatal screening programme from 1965 to 1979. During this period over one million infants were screened by the Guthrie test for phenylketonuria and galactosaemia, and for limited periods also for tyrosinaemia, homocystinuria and histidinaemia. The benefit-cost ratio was calculated for combinations of different screening tests, recall routines, and varying degrees of coverage. The largest benefit-cost ratio was obtained with combined screening for phenylketonuria and galactosaemia, using a borderline blood phenylalanine level of 0.50 mmol/L in the Guthrie test for phenylketonuria. However, the inaccuracy of this test necessitated the use of a lower blood phenylalanine level of 0.25 mmol/L and the acceptance of a lower benefit-cost ratio. An increase in the present 98% coverage of newborns by the screening programme was found to be an effective means of improving the benefit-cost ratio in the present programme.

Prepregnancy testing for single-gene disorders by polar body analysis.

Preventive measures for single-gene disorders are currently based on carrier screening in pregnancy and prenatal diagnosis. Although this has been extremely effective for preventing new cases of common inherited conditions, the major limitation is still termination of 25% of wanted pregnancies following detection of affected fetuses. To overcome this important problem, we developed a method for prepregnancy genetic testing that involves DNA analysis of the first and second polar bodies, which are extruded during maturation and fertilization of oocytes. We offered this option to 28 couples at risk for having children with single-gene disorders. Fifty clinical cycles were performed from these patients for the following conditions: 20 for cystic fibrosis, 18 for thalassemia, 6 for sickle cell disease, 2 each for Gaucher disease and LCHAD (long-chain 3-hydroxyacyl-COA dehydrogenase deficiency), and 1 each for hemophilia B and phenylketonuria. Oocytes obtained from these patients using in vitro fertilization procedures (IVF) were tested by a sequential multiplex nested PCR analysis of the first and second polar body to detect the gene involved simultaneously with linked polymorphic markers. A total of 191 of 399 oocytes with predicted genotype were mutation free and preselected for fertilization and transfer. In all but three cycles, one to three unaffected embryos with predicted unaffected genotypes were transferred, resulting in 20 pregnancies, from which 19 healthy children have been born. The follow-up analysis of embryos resulting from oocytes with predicted affected genotype, confirmed the diagnosis in 97% of cases, demonstrating the reliability of prepregnancy diagnosis of single-gene defects by polar body analysis.

The development of a patient knowledge test on maternal phenylketonuria.

A short multiple-choice knowledge test on maternal phenylketonuria was developed and validated. It was administered to 49 young female patients participating in a longitudinal study. The test was analyzed for its psychometric qualities and was found to be reliable: Cronbach alpha 0.62. Its validity was indicated by a moderate correlation with IQ scores (r = 0.40) and by its significantly differentiating between subjects who participated in patient education group meetings and those who did not. Items varied in difficulty, indicating which areas of knowledge need special educational efforts. The test was recommended for use to assess patients' knowledge, to identify misconceptions that appear to be remedied by patient education, to stimulate group discussions and to help evaluate educational programs.

Screening for phenylketonuria in New York City. Threshold values reconsidered.

In New York City from 1966 to 1970, almost all 736,469 newborns were screened for phenylketonuria (PKU). Among 1,094 infants with presumptive positive test results, 763 were followed up and 46 of them were judged to require preventive treatment. The considerable annual variation observed in the frequency of values of 4 to 6 mg/100 ml bood phenylalanine suggested low reliability at this level. Screening test results of 4 mg/100 ml, with no cases detected among them, represented 53% of all false positive results; newborns with 6 mg/100 ml results yielded 1 infant in need of treatment and accounted for 40% of the false positive results. The large volume of presumptive positive results generated by these levels presumably contributed to incomplete followup. If the threshold value for followup were raised, the effectiveness and the efficiency of the screening program could be improved. The experiences of other large PKU programs in the United States support these observations.