Maternal phenylketonuria syndrome: studies in mice suggest a potential approach to a continuing problem.

BackgroundUntreated phenylketonuria (PKU), one of the most common human genetic disorders, usually results in mental retardation. Although a protein-restricted artificial diet can prevent retardation, dietary compliance in adults is often poor. In pregnant PKU women, noncompliance can result in maternal PKU syndrome, where high phenylalanine (Phe) levels cause severe fetal complications. Enzyme substitution therapy using Phe ammonia lyase (PAL) corrects PKU in BTBR Phe hydroxylase (Pahenu2) mutant mice, suggesting a potential for maternal PKU syndrome treatment in humans.MethodsWe reviewed clinical data to assess maternal PKU syndrome incidence in pregnant PKU women. We treated female PKU mice (on normal diet) with PAL, stabilizing Phe at physiological levels, and mated them to assess pregnancy outcomes.ResultsPatient records show that, unfortunately, the efficacy of diet to prevent maternal PKU syndrome has not significantly improved since the problem was first noted 40 years ago. PAL treatment of pregnant PKU mice shows that offspring of PAL-treated dams survive to adulthood, in contrast to the complete lethality seen in untreated mice, or limited survival seen in mice on a PKU diet.ConclusionPAL treatment reduced maternal PKU syndrome severity in mice and may have potential for human PKU therapy.

Maternal Phenylketonuria International Collaborative Study revisited: evaluation of maternal nutritional risk factors besides phenylalanine for fetal congenital heart defects.

Maternal phenylketonuria (MPKU) is known to affect fetal outcome, often being associated with microcephaly and congenital heart defects (CHD) if the maternal diet is not appropriately managed. We hypothesized that other nutrients aside from phenylalanine (Phe) may have significant effects on fetal outcome in MPKU pregnancies. The 416 pregnancies that resulted in live births reported in the Maternal PKU Collaborative Study (MPKUCS) were grouped according to whether or not the offspring were diagnosed with CHD. The groups were compared on first-trimester values of maternal data, including weight gain, plasma amino acids, protein and Phe intake, and red blood cell (RBC) folate. Patients were also grouped by first-trimester average blood Phe (≤910 µmol/L and >910 µmol/L) and then divided by total natural protein and medical food intake. The CHD group of 28 offspring had significantly higher blood Phe and lower proline, valine, methionine, isoleucine, leucine, lysine, arginine, and RBC folate. A significantly higher risk for CHD was found in the groups with lower natural protein and medical food intake, regardless of blood Phe levels. Insufficient natural protein and medical food product intake appears to be a risk factor for CHD independent of first-trimester plasma Phe levels. Low RBC folate and plasma methionine levels in the CHD group may suggest involvement of global DNA hypomethylation.

Síndrome de fenilquetonuria materna, un nuevo desafío para Chile / Maternal phenylketonuria syndrome, a new challenge for Chile

Phenylquetonuria (PKU) is a hereditary disease, caused by the deficiency or absence of the enzyme phenylalanine hydroxylase, which produces an abnormal conversion of phenylalanine (Phe) to tyrosine. If PKU is not diagnosed and treated during the neonatal period, blood accumulation of Phe causes neurological damage. Chile has a neonatal screening program for PKU and congenital hypothyroidism since 1992; this program has diagnosed 162 PKU patients in Chile, which are being followed-up in INTA, Universidad de Chile. Nowadays, there are 20 PKU patients in adolescence, so we face a new challenge such as maternal PKU syndrome. This syndrome refers to the teratogenic effect of Phe in a pregnant PKU female. The most frequent anomalies are intrauterine growth retardation, microcephaly, global development retardation and congenital heart defects. Their occurrence is directly related to maternal Phe during pregnancy. In order to assure a normal pregnancy and to prevent this syndrome, levels of Phe in blood should be kept between 2 and 6 mgldl prior to conception and throughout pregnancy. Considering this challenge, INTA has proposed a strict protocol of follow-up to improve the compliance to nutritional therapy and prevent maternal PKU syndrome.

La fenilquetonuria (PKU) es una patología hereditaria, producida por la deficiencia o ausencia de la enzima fenilalanina hidroxilasa, lo que impide la metabolización normal de la fenilalanina (FA) a tirosina. La acumulación de fenilalanina en la sangre ocasiona daño neurológico si no es diagnosticada y tratada desde el periodo neonatal. Desde 1992 Chile tiene un programa de pesquisa neonatal de PKU e hipotiroidismo congénito, lo que ha permitido diagnosticar 162 casos con PKU, los que mantienen un seguimiento integral en el INTA, de la Universidad de Chile. Actualmente hay 20 PKU en etapa de adolescencia, por lo que nos enfrentamos a un nuevo desafío, el síndrome de PKU materna. Este síndrome se refiere al efecto teratogénico de la FA en una embarazada con PKU. Las alteraciones más características son el retraso del crecimiento intrauterino, la microcefalia, el retraso global del desarrollo y los defectos cardiacos congénitos. La presencia de estas alteraciones está directamente relacionada con los niveles de FA de la madre durante el embarazo. Para asegurar un embarazo normal y prevenir este síndrome se recomienda la mantención de niveles de FA entre 2 y 6 mg/dl, desde el período preconcepcional y durante todo el embarazo. El INTA considerando este desafío, ha propuesto un protocolo de seguimiento estricto preconcepcional y durante el embarazo con el objetivo de favorecer la adherencia al tratamiento nutricional y prevenir el síndrome de PKU materna.

Factors influencing outcomes in the offspring of mothers with phenylketonuria during pregnancy: the importance of variation in maternal blood phenylalanine.

BACKGROUND: Developmental delay in the offspring of women with phenylketonuria (PKU) can be prevented by maintaining maternal blood phenylalanine (Phe) within a target range (100-250 micromol/L). OBJECTIVE: We aimed to analyze outcomes in the offspring of women with PKU during pregnancy and to identify prognostic factors. DESIGN: Occipitofrontal circumference at birth (OFC-B); developmental scores [developmental quotient (DQ) and intelligence quotient (IQ)]at 1, 4, 8, and 14 y; and the time of starting a Phe-restricted diet (before or after conception) were collected. The influence of maternal Phe concentrations during pregnancy on offspring outcomes also was assessed. RESULTS: The study included 105 children born to 67 mothers with PKU. Mean (+/-SD) OFC-B z scores did not differ between the preconception and postconception diet groups (0.42 +/- 1.24 and -0.96 +/- 1.19, respectively). DQ at 1 y and IQ at 8 y were higher in offspring from the preconception diet group than in offspring from the postconception diet group [DQ: 107 +/- 13.8 and 99.3 +/- 13.3, respectively (P = 0.014); IQ: 110.6 +/- 14.8 and 91.2 +/- 23.9, respectively (P = 0.005)]. Maternal Phe concentrations correlated negatively with DQ and IQ scores, and variations (SD) in all maternal blood Phe correlated negatively with 4-, 8-, and 14-y IQ scores (r = -0.385, -0.433, and -0.712; P = 0.002, 0.008, and 0.031, respectively), even when concentrations were consistently within the target range. CONCLUSIONS: The study suggests that women with PKU should start a Phe-restricted diet before conception. Maintenance of maternal blood Phe within the target range predicts good offspring outcomes, but variations even within that range should be avoided.

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.

Effect of maternal blood phenylalanine level on mouse maternal phenylketonuria offspring.

The genetic mouse model BTBR-Pah(enu2) was used to more thoroughly investigate the pathogenesis of maternal phenylketonuria (MPKU). More specifically, it was used to examine the effect of maternal blood phenylalanine (PHE) level on the pregnancy outcome of MPKU offspring as determined by certain key measures of development at birth (i.e., head circumference, weight, and crown-rump length of offspring). In this study, we clearly observed that elevated maternal blood PHE levels, whether they were caused by the maternal diet or the maternal genotype, were responsible for fetal abnormalities. As in human MPKU, significant reductions (P < 0.0001) in birth weight, crown-rump length, and head circumference were seen in offspring gestated under the condition of high maternal blood PHE levels. These findings strongly suggest that there are sufficient similarities between human MPKU and MPKU in this mouse model to establish it as a very promising model for future studies designed to characterize human MPKU more thoroughly.

Maternal phenylketonuria collaborative study, obstetric aspects and outcome: the first 6 years.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity associated with maternal hyperphenylalaninemia in women of childbearing age with blood phenylalanine levels greater than 240 mumol/L (greater than 4 mg/dl) on an unrestricted diet. STUDY DESIGN: Two hundred thirteen pregnant women with hyperphenylalaninemia that resulted in 134 live births have been enrolled in the study. Outcome measures were subject to the chi 2 test, Fisher exact test, analysis of variance, t test, or Wilcoxon nonparametric test for analysis. RESULTS: Optimal fetal outcome appeared to occur when blood phenylalanine levels less than 600 mumol/L (less than 10 mg/dl) were achieved by 8 to 10 weeks' gestation and maintained throughout pregnancy (trimester averages of less than or equal to 360 mumol/L (less than or equal to 6 mg/dl). Initiation of dietary therapy during the third trimester of pregnancy appears to have little beneficial effect on the fetus. CONCLUSIONS: Preconceptual counseling and early entrance into a prenatal care program is essential in achieving optimal fetal outcome in women with hyperphenylalaninemia.