Preventing maternal phenylketonuria (PKU) syndrome: important factors to achieve good metabolic control throughout pregnancy.

BACKGROUND: Insufficient metabolic control during pregnancy of mothers with phenylketonuria (PKU) leads to maternal PKU syndrome, a severe embryo-/fetopathy. Since maintaining or reintroducing the strict phenylalanine (Phe) limited diet in adults with PKU is challenging, we evaluated the most important dietary and psychosocial factors to gain and sustain good metabolic control in phenylketonuric women throughout pregnancy by a questionnaire survey with 38 questions concerning therapy feasibility. Among them, the key questions covered 5 essential items of PKU care as follows: General information about maternal PKU, PKU training, diet implementation, individual metabolic care, personal support. In addition, all participating PKU mothers were asked to estimate the quality of their personal metabolic control of the concluded pregnancies. 54 PKU mothers with 81 pregnancies were approached at 12 metabolic centers in Germany and Austria were included. According to metabolic control, pregnancies of PKU women were divided in two groups: group "ideal" (not more than 5% of all blood Phe concentrations during pregnancy > 360 µmol/l; n = 23) and group "suboptimal" (all others; n = 51). RESULTS: The demand for support was equally distributed among groups, concerning both amount and content. Personal support by the direct social environment (partner, family and friends) ("suboptimal" 71% vs "ideal" 78%) as well as individual metabolic care by the specialized metabolic center (both groups around 60%) were rated as most important factors. The groups differed significantly with respect to the estimation of the quality of their metabolic situation (p < 0.001). Group "ideal" presented a 100% realistic self-assessment. In contrast, group "suboptimal" overestimated their metabolic control in 53% of the pregnancies. Offspring of group "suboptimal" showed clinical signs of maternal PKU-syndrome in 27%. CONCLUSION: The development of training programs by specialized metabolic centers for females with PKU in child bearing age is crucial, especially since those mothers at risk of giving birth to a child with maternal PKU syndrome are not aware of their suboptimal metabolic control. Such programs should provide specific awareness training for the own metabolic situation and should include partners and families.

Maternal PKU: Defining phenylalanine tolerance and its variation during pregnancy, according to genetic background.

BACKGROUND AND AIMS: Phenylketonuria (PKU)-affected women may become pregnant, and dietary phenylalanine (Phe) intake must be adjusted according to Phe tolerance. We report our experience with maternal PKU in relation to genotype PKU heterogeneity. METHODS AND RESULTS: A total of 10 pregnancies in 7 PKU women (7 different genotypes) were followed up as part of personalized care. Phe tolerance during preconception and pregnancy was assessed by strict dietary control and weekly Phe measurement (blood spots) in relation to genotype. Most women had stopped PKU diet during childhood or adolescence and six pregnancies were unplanned; a phenylalanine-restricted diet was reinstituted soon after conception. Women were classified according to their Phe levels at birth screening and genotype. Phe tolerance increased systematically in the course of pregnancy in all cases, but the increase was different in subjects with classic PKU (cPKU) when compared with cases with mild hyperphenylalaninemia (mHPA), both on average (+297 mg/day in cPKU vs. 597 in mHPA; P = 0.017) and as percentage (+107% in cPKU vs. +17% in mHPA). Notably, Phe tolerance also varied in the same women in the course of different pregnancies, when body weight gain was also different. Two newborns from the same cPKU mother (unplanned pregnancies on free diet) were affected by congenital alterations. CONCLUSIONS: Several factors influence metabolic phenotype in maternal PKU, to an unpredictable extent even in the same woman. The number of maternal PKU cases is growing in dedicated Nutrition Units, and the burden associated with careful management of this condition for the health care system should be adequately considered.

Maternal phenylketonuria in Turkey: outcomes of 71 pregnancies and issues in management.

Untreated phenylketonuria (PKU) in pregnancy causes a severe embryopathy called maternal PKU syndrome. Here, we aimed to assess management issues and pregnancy outcomes in the first published series of PKU pregnancies from the developing world. Data were collected retrospectively in a single center from 71 pregnancies and 45 live births of 32 women with PKU, 11 of whom were diagnosed in adulthood after having an affected child. Microcephaly, intellectual disability, and dysmorphic facies were more prevalent in offspring of untreated than treated pregnancies with classical PKU (100% vs. 0%, 91% vs. 0%, and 73% vs. 23% with p < 0.001, p < 0.001, and p = 0.037, respectively). In treated pregnancies, phenylalanine levels were higher during weeks 6-14 than other periods of gestation (4.38 vs. 3.93, 2.00 and 2.28 mg/dl; p < 0.05). Poor compliance correlated with higher phenylalanine levels (ρ = - 0.64, p = 0.019) and fluctuations (ρ = - 0.66, p = 0.014).Conclusion: More frequent phenylalanine measurements during late first trimester are crucial to improve outcomes in treated pregnancies. In order to prevent untreated pregnancies via detecting undiagnosed adults, countries where significantly many women of childbearing age were not screened as newborns may consider pre-pregnancy PKU screening. Microcephaly in the newborn should prompt screening for PKU in the mother. What Is Known •Untreated phenylketonuria during pregnancy causes maternal phenylketonuria syndrome in the newborn. •Effective treatment throughout pregnancy can prevent adverse fetal outcomes. What Is New: •Metabolic control is related to frequency of follow-up and worsens during late first trimester. Closer follow-up during this period may improve metabolic control. •In order to prevent untreated pregnancies, pre-pregnancy phenylketonuria screening may be considered if many women of childbearing age were not screened as newborns.

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.

Tetralogy of Fallot variant with pulmonary atresia (pseudotruncus arteriosus) in a case of maternal PKU syndrome.

The authors report on a child with a rare variant of the Tetralogy of Fallot with pulmonary atresia also known as Pseudotruncus arteriosus, who was born by a mother affected by classic phenylketonuria (PKU), diet free of phenylalanine until the age of seven years. According to the authors, this is the first example of such rare variant in an offspring of maternal PKU syndrome.

A case of maternal phenylketonuria syndrome presenting with unilateral renal agenesis.

Maternal phenylketonuria (mPKU) during pregnancy leads to the risk of spontaneous abortion or a teratogenic syndrome depending on the level of maternal phenylalaninemia. Mental retardation, microcephaly, congenital cardiopathy and intrauterine growth retardation are frequently seen in patients who intake an unrestricted diet before conception. The clinical picture shows variation in classic PKU. Severe neurological symptoms are not seen in all untreated cases of PKU syndromes. For this reason, mPKU can be seen in undiagnosed mothers. We hereby present a case who underwent investigations due to the presence of microcephaly and congenital cardiopathy. The diagnosis of PKU syndrome of the mother was determined following assessment of the baby. Furthermore, the unilateral renal agenesis that was detected in our case is the first case reported in the literature in which mPKU accompanies renal agenesis.

Enhancing the quality and efficiency of newborn screening programs through the use of health information technology.

A variety of efforts are underway at national, state, regional, and local levels to enhance the performance of programs for early detection of inherited diseases and conditions of newborn infants. Newborn screening programs serve a vital purpose in identifying nonsymptomatic clinical conditions and enabling early intervention strategies that lessen morbidity and mortality. Currently, the programs of most intense focus are early hearing detection and intervention, using physiological techniques for audiology screening and use of newborn dried blood spots for detection of metabolites or proteins representing inherited disorders. One of the primary challenges to effective newborn screening programs to date has been the inability to provide information in a timely and easily accessible way to a variety of users. Other challenging communication issues being faced include the complexity introduced by the diversity of conditions for which testing is conducted and laboratory methods being used by each state's screening programs, lack of an electronic information infrastructure to facilitate information exchange, and variation in policies that enable access to information while protecting patient privacy and confidentiality. In this study, we address steps being taken to understand these challenges, outline progress made to date to overcome them, and provide examples of how electronic health information exchange will enhance the utility of newborn screening. It is likely that future advances in science and technology will bring many more opportunities to prevent and preempt disabilities among children through early detection programs. To take their advantage, effective communication strategies are needed among the public health, primary care practice, referral/specialty service, and consumer advocacy communities to provide continuity of information required for medical decision-making throughout prenatal, newborn, and early childhood periods of patient care.

[The maternal phenylketonuria syndrom--still current problem]. / Zespól fenyloketonurii matczynej--problem nadal aktualny.

UNLABELLED: Phenylketonuria (OMIM 261600) is a congenital genetically conditioned error of metabolism phenylalanine to tyrosine. Being untreated or insufficiently treated phenylketonuria (PKU) sometimes leads to irreversible damage of mielin. Similarly, high phenylalanine concentration in the blood of pregnant woman with PKU exert the teratogenic effect on growing and developing foetus (in the majority of cases being the carrier of PKU), which leads to appearance of maternal phenylketonuria syndrom (MPKU syndrom). The features of MPKU syndrome consist: low weight at birth, the congenital heart defects, digestive tract defects, osseous arrangements, microcephaly, handicap of intellectual development. Spontaneous miscarriages at pregnant women with PKU are more often. THE AIM OF WORK: the evaluation of influence hyperphenylalaninemia of pregnant woman with PKU on her foetus, depending on the metabolic control in the pre- and postconception period. MATERIAL AND METHOD: under the care of Outpatient Metabolic Clinic of University Children's Hospital in Cracow remain 430 patients aged from 0 to 56 years with hyperphenylalaninemia. In the register of Outpatient Metabolic Clinic there are the data about 50 pregnancies of 21 women with hyperphylalaninemia (from mild hyperphenylalaninemia to classic PKU). Only 10 pregnancies were planned - the low-phenylalanine diet was obligatory introduced 3 months before conception and was applied throughout the whole period of pregnancy in order to maintain the levels of phenylalanine in the range of 2 to 6 mg/dl. One pregnancy finished with spontaneous miscarriage, the other 9- the birth of healthy offspring. By contrast, out of 40 unplanned pregnancies 8 ended in spontaneous miscarriage, and of the remaining 32 unplanned pregnancies 33 children were born: 24 (75%) newborns with the maternal PKU features, 1 child died during thel-st year of life, 3 have the lack of any data, and only 5 (15.6%) children were born clinically healthy (1 twin birth). Among the children with maternal PKU syndrome: microcephaly was diagnosed in 17 cases, congenital heart defect and microcephaly in 6 children, and microcephaly and the anal atresia in 1 child. Among the children, born from unplanned pregnancies, there are two (twins), whose mother from the 6 week of gestation had returned to applying diet (average phe levels 6.37 mg/dl); two children of mothers who were conducting the therapeutic implemented since 18-th and 32-th weeks of gestation (average phe 7.5 mg/dl) (there is the lack of detailed data about these children, because the women are never reported to our Outpatient Clinic), and one child, whose mother raised and began the therapy from 12-th week of gestation (average phe levels 10.37 mg/dl), who presents the features of ADHD syndrome. CONCLUSIONS: 1. All pregnancies of women with hyperphenylalaninemia should be planned to avoid the complications in the form of maternal PKU syndrom. 2. It is essential to educate the women with PKU and their families about the problems concerning maternal PKU. 3. It is also necessary to inform pediatricians, family physicians and gynaecologists-obstetricians about the features of maternal PKU syndrom.

[Did the change of technique of screening investigations influence on improvement of test credibility in recognizing and differentiating diagnostics of hiperphenylalaninemias?]. / Czy zmiana techniki badan przesiewowych wplynela na poprawe wiarygodnosci testu w rozpoznawaniu i diagnostyce róznicowej hiperfenyloalaninemii?

UNLABELLED: The phenylketonuria (PKU)/hyperphenylalaninemia (HPA) it is the most frequent inborn genetically conditioned error of metabolism of amino acids. It's occurrence in Polish population was estimated on the level 1:7.000 - 8.500. A. Folling was the first who described the phenylketonuria in 1934. It's diagnosed by neonatal screening, which was initiated in 1963 by prof. R. Guthrie. MATERIAL: since 1985 till 2007 1,172,310 newborns investigated by the neonatal screening proceeding by the Laboratory of Screening and Inborn Errors of Metabolism in Cracow. METHOD: in the years 1985-1998 the phenylalanine concentration in drop of blood on the blotting-paper was measured with half-quantitative Guthrie method. However after 1999 the colorimetric quantitative method measurement of phenylalanine concentration in capilar blood was introduced. It 2004 the cut-off value of phenylalanine in drop of blood on filter paper in neonatal screening investigation has was established below 3 mg/dl (till 2003 it was below 4mg/ dl). The blood had been taken from every newborn on filter paper Standard 903 between third and seventh day of the child's life. The verification of recognition in 1985-1988 was applied by Guthrie test, in 1989-2006 by the fluorymetric McCaman and Robins method, and since 2007 by colorimetric method. RESULTS: in 1985-1998 the group of 137 newborns was distinguished due to the newborn screening (1:4.204), the classic PKU was recognized at 96 (1:5.999), however in next years (after change of method) due to screening 186 (1:4.788) newborns were distinguished, the classic PKU was recognized at 94 (1:5.236) newborn children. The lowering the point of cut-off influenced on frequency recognizing mild HPA, which grew up from 1:25.909 to 1:12.720. In 2001 we verified the recognition at 51 of 93 women (data were have gained over from archive of Outpatient Department), who where identified by the neonatal screening in 1985-1998, and in the face of observed phenylalanine values (<10 mg/dl - mild HPA) did not require dietetic treatment, and they gave up with medical care gradually. With regard on possibility pronouncement the signs of maternal PKU at their offspring, we ask 45 of them to contact with our Outpatient Clinic again, but only 36 with different reasons answered, at 28 of them the phenylalanine concentration was raised: 2-4 mg/dl - in 1 patient; 4-6 mg/ dl - in 6 patients; 6-10 mg/dl - in 11 patients; 10-20 mg/dl - in 12 patients. With this reason at 19 women the low-phenylalanine diet had to be introduce. CONCLUSIONS: 1. Applied Guthrie test limited the individual differentiating diagnostics of HPA, which led to relinquishment of medical observation, especially in girls and young women, the birth the child with maternal PKU could be the result of that. 2. Introduction of colorimetric method improved the detecting of the mild PKU and hyperphenylalaninemia considerably.

ACOG Committee Opinion No. 449: Maternal phenylketonuria.

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) metabolism characterized by a deficiency of the hepatic enzyme, phenylalanine hydroxylase, an enzyme responsible for the conversion of phenylalanine to tyrosine, and elevated levels of Phe and Phe metabolite. All women with PKU or hyperphenylalaninemia should be strongly encouraged to receive family planning and preconception counseling. Women with PKU or hyperphenylalaninemia should begin appropriate, medically directed dietary phenylalanine restriction before conception.

Finding the fertile woman with phenylketonuria.

This review highlights two groups of women with phenylketonuria (PKU) who are at risk of producing offspring with maternal phenylketonuria (MPKU) embryopathy: (I) those not yet diagnosed; (II) those lost to follow-up. The world literature is reviewed, including that published from the International MPKU Collaborative Study (MPKUCS) and evidence is presented to support our hypothesis that at least 10% of subjects with untreated "classical PKU" will have relatively normal intellectual function and that a significantly higher percentage of the less severe "variants" (who make up approximately 50% of the total) will have IQ's measured within the normal range. The offspring of the females with these PKU variants, however, are not as fortunate-most suffering profound damage in-utero if the pregnant woman is not treated. However, the offspring of the mildest variant (untreated) "non-PKU mild hyperphenylalaninemia (MHP)" - blood phenylalanine 200-600 micromol/L - appear to be unaffected. This latter variant makes up 10-15% of the total. Many of these women, born before neonatal screening began in the jurisdiction of their birth, are unaware of their disease. Others, whose diet was discontinued in childhood, may not remember why they were on special diets. Our literature review has revealed reports, since 1990, of 60 women with previously undiagnosed PKU, most with relatively normal intellectual function, who produced 119 offspring, virtually all profoundly damaged. It is pointed out that the recent trend, in industrialized countries, of delayed child-bearing may be a factor. Reports are presented from various jurisdictions showing that up to 10% of known women with PKU in the reproductive age group have been lost to follow-up. "Selective Prenatal Screening or Case-Finding" for fertile women with PKU is recommended and a template is presented.

Maternal hyperphenylalaninemia syndrome: neuropsychological evaluation of four subjects during childhood and adolescence.

Maternal hyperphenylalanemia during pregnancy may induce a severe embryopathy characterized by microcephaly, mental retardation, facial dysmorphy and congenital heart defects. Four subjects, two pairs of sibs, with maternal hyperphenylalaninemia syndrome were included in this study and their neuropsychological performances were assessed. Maternal levels of hyperphenylalaninemia were similar in both mothers, one of them had not been diagnosed with the condition until her two children were examined at the ages of 10 and 6 years. A severe cognitive deficit was detected in all 4 subjects, with a typical profile of impaired perceptive abilities, behavioural disturbances, motor difficulties and poor familiar integration.

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. CASE PRESENTATION: We report on an affected Albanian woman and her seven children. The mother is affected by phenylketonuria and is a compound heterozygote for two pathogenetic mutations, L48S and P281L. The diagnosis was only made in the context of her children, all of whom have at least one severe organic malformation. The first child, 17 years old, has a double-chambered right ventricle, vertebral malformations and epilepsy. She is also mentally retarded, microcephalic, exhibits facial dysmorphies and small stature. The second child, a girl 15 years of age, has severe mental retardation with microcephaly, small stature and various dysmorphic features. The next sibling, a boy, died of tetralogy of Fallot at the age of three months. He also had multiple vertebral and rib malformations. The subsequent girl, now eleven years old, has mental retardation, microcephaly and epilepsy along with facial dysmorphy, partial deafness and short stature. The eight-year-old child is slightly mentally retarded and microcephalic. A five-year-old boy was a premature, dystrophic baby and exhibits mental retardation, dysmorphic facial features, brachydactyly and clinodactyly of the fifth finger on both hands. Following a miscarriage, our index case, the youngest child at two years of age, is microcephalic and mentally retarded and shows minor facial anomalies. All children exhibit features of phenylalanine embryopathy caused by maternal phenylketonuria because the mother had not been diagnosed earlier and, therefore, never received any diet. CONCLUSION: This is the largest family suffering from maternal phenylketonuria reported in the literature. Maternal phenylketonuria remains a challenge, especially in woman from countries without a neonatal screening program. Therefore, it is mandatory to be alert for the possibility of maternal phenylketonuria syndrome in case of a child with the clinical features described here to prevent foetal damage in subsequent siblings.

HIV in pregnancy.

The Center for Disease Control (CDC) has recommended voluntary Human Immunodeficiency Virus (HIV) screening in all pregnant patients. Is the incidence of HIV in women of child bearing age in South Dakota high enough to warrant aggressive testing? Since HIV reporting began in 1985, there have been five cases of maternal to fetal transmission (vertical transmission) of HIV in the state of South Dakota. The incidence of heterosexual transmission of HIV is increasing in South Dakota and in the year 2000, there have been seven new cases of HIV/AIDS diagnosed in women between the ages of 15-39 years of age, "According to June Snyder of the South Dakota Department of Health in April 2001."

[Maternal phenylketonuria]. / Phénylcétonurie maternelle.

The child of a phenylketonuric woman is exposed during pregnancy to a high risk of growth retardation and malformation. The frequency of these abnormalities is proportional to the maternal phenylalanine blood concentrations. If a strict low protein diet is followed before conception and throughout gestation the risks of abnormalities are not higher than in the normal population. The maternal blood phenylalanine levels must be maintained between 120 and 250 mumol/l and the tyrosine blood levels between 45 and 90 mumol/l. Weekly blood analyses are mandatory. Regular dietary controls are necessary to assure that the adequate energetic intake and the correct amounts of vitamins and minerals recommended for a pregnant woman are sustained. A case report is the opportunity to discuss certain practical aspects concerning the monitoring of the pregnancy of a phenylketonuric woman and to make general recommendations.