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.

Generation n + 1: Projected numbers of babies born to women with PKU compared to babies with PKU in the United States in 2009.

Newborn PKU screening has been available since the mid-1960s, and the first group of screened babies is now a complete reproductive cohort (age 15-44). Untreated maternal PKU (MPKU) often results in significant developmental and physical disabilities in exposed fetuses, and could potentially offset some or all of the benefits produced by newborn PKU screening and dietary treatment. Based on the age distribution of the United States population in 2009, and using different estimates of PKU frequency (1/10,000; 1/15,000; 1/20,000), the projected number of babies born to women with PKU was compared to the projected number of babies born with PKU. In 2009, there were about 62,000,000 women age 15-44, with a fertility rate of 66.7 births/1,000 women. Of these women, depending on the incidence of PKU, 3,097-6,195 were estimated to have PKU, and they would have delivered 207-413 babies. In that same year, the number of births was 4,118,055, which would have resulted in 206-412 babies with PKU. Thus, in the United States, at all estimates of PKU frequency, the number of babies exposed to MPKU is equal to the number of babies born with PKU. This ratio varies with the fertility rate but is not dependent on the incidence of PKU. The benefits of newborn PKU screening and treatment could be significantly curtailed if adequate resources, education, and funding are not available to follow and monitor women with MPKU and their babies.

[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.

Maternal phenylketonuria syndrome and case management implications.

Well-established dietary protocols have prevented mental retardation for infants born with phenylketonuria (PKU). Dietary protocols for managing females with PKU in their reproductive years exist but are not followed by most of them. Infants who are born to mothers with PKU who are not on dietary treatment usually have serious medical problems, such as mental retardation, heart defects, and other serious congenital anomalies (e.g., orofacial clefting and bladder exstrophy)--a condition known as maternal PKU syndrome. The focus of this article is to review the pathophysiology, associated developmental issues, and existing management protocols used to manage these two separate but highly connected disorders.

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."

Aproximación al tratamiento nutricional de los errores innatos del metabolismo (II) / Approaches to the dietary treatment of inborn errors of metabolism (II)

El tratamiento nutricional de los errores innatos del metabolismo (EIM) constituye en la actualidad el pilar más importante en el manejo global de estas enfermedades. Nuestra intervención dietética no sólo debe intentar asegurar un adecuado crecimiento y desarrollo del niño sino que, al mismo tiempo, tenemos que programar un enfoque nutricional específico según el defecto metabólico del que se trate. En este artículo (segundo de cinco partes) y el siguiente abordamos los aspectos diatéticos y nutricionales de algunos de los trastornos más frecuentes que afectan el metabolismo de los aminoácidos (AU)

Maternal phenylketonuria: a continuing problem.

OBJECTIVES: To estimate the number of women of childbearing age in New South Wales whose children are at risk of the maternal phenylketonuria (PKU) syndrome (intellectual disability, microcephaly, congenital malformations). SETTING: New South Wales, 1996. DESIGN: Comparison of number of women with PKU aged 15-44 years on the NSW PKU database (observed number) with expected number derived from population data. MAIN OUTCOME MEASURES: Observed and expected numbers of women with PKU (defined as blood phenylalanine levels > or = 400 mumol/L, and phenylalanine-restricted diet recommended) by age; number with no clinical contact with the PKU service in previous year; outcomes of pregnancies in women with PKU (January 1994 to July 1996). RESULTS: 110 women aged 15-44 years with PKU were listed on the database. The expected number was 145 (95% confidence interval, 122-171). The difference was greatest in the 30-44 years age group (born before comprehensive newborn screening), with only 55% of the expected number listed. Sixteen women who had been diagnosed with PKU at birth were not having regular follow-up, while 18 women had been diagnosed only after investigation of abnormalities in their children. Of 28 pregnancies managed by the NSW PKU service, 19 were considered unaffected by the maternal PKU syndrome and five affected (another three did not reach term; one outcome was unknown). Of 46 unmanaged pregnancies, all were affected. CONCLUSION: There is an urgent need for better follow-up of women with PKU and for education of health professionals about the MPKU syndrome, its recognition, the risks of untreated pregnancy and the benefits of dietary treatment.

[Maternal hyperphenylalaninemia in a population of healty Czech women. 18 years' experience with mass screening, diet therapy and metabolic monitoring]. / Materské hyperfenylalaninémie v ceské populaci zdravých tehotných zen. 18leté zkusenosti s fakultativním screeningem, dietní lécbou a metabolickým sledováním.

BACKGROUND: Elevated phenylalanine levels in maternal blood (hyperphenylalaninaemia) during pregnancy damages the developing foetal tissues. Early detection of pregnant women with hyperphenylalaninaemia and adherence to a low phenylalanine diet already before conception and throughout pregnancy can prevent this damage. The objective of the investigation are results achieved screening and strict monitoring of low phenylalanine dietetic treatment in detected pregnant women of the Prague population. METHODS AND RESULTS: 186 350 healthy women of the Prague population were examined by the chromatographic screening test in a venous blood sample during their first visit in a maternity welfare centre and 22 positive cases were detected (incidence 1:8470). In 86% mild, persistent or benign forms of phenylketonuria were involved. Nineteen patients were treated by a low phenylalanine diet and the phenylalanine tolerance was monitored as well as the nitrogen balance, amino acids in serum and urine, protein markers, trace elements, vitamins, lipids, the body mass index-BMI, changes of body weight after introduction of the dietetic treatment and treatment during pregnancy. A significant increase of the phenylalanine tolerance by 20 to 200% was found, mostly in the second half of pregnancy and reduced values of serum and urinary selenium. The decrease of body weight when the diet was introduced and the increment during pregnancy correlated with the BMI value. In the other investigated parameters no significant deviations were found. CONCLUSION: Fifteen healthy children with normal psychomotor development delivered by 12 mothers with hyperphenylalaninaemia provide evidence of the effectiveness of prenatal screening for hyperphenylalaninaemia during pregnancy.

The North American Collaborative Study of Maternal Phenylketonuria. Status report 1993.

Neonatal screening for phenylketonuria (PKU) has created an unexpected problem as females with PKU are reaching childbearing age. Surveys have revealed that maternal phenylalanine blood concentrations above 1200 mumol/L are associated with microcephaly, mental retardation, congenital heart defects, and intrauterine growth retardation among their offspring. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk for producing these fetal abnormalities. To examine this problem, the North American Maternal PKU Collaborative Study has been developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings indicate 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 mumol/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.