RESUMEN
UNLABELLED: Tyrosine supplementation has not consistently been found to improve neuropsychologic function in phenylketonuria (PKU), possibly because of failure to achieve adequate levels of tyrosine in the brain. OBJECTIVES: To evaluate blood levels achieved after tyrosine supplementation in treated PKU and calculate brain influxes of tyrosine and other large neutral amino acids before and with tyrosine supplementation. STUDY DESIGN: Ten subjects with PKU receiving a phenylalanine-restricted diet were studied over 48 hours; each received tyrosine supplementation (300 mg/kg) on day 2. Plasma phenylalanine and tyrosine were measured every 2 hours, and all free amino acids were measured every 6 hours. Brain influxes of tyrosine and other large neutral amino acids were calculated. RESULTS: Plasma tyrosine levels were low normal at baseline. With supplementation there was a substantial but unsustained rise in plasma tyrosine. Calculated brain influx of tyrosine was 27% +/- 19% of normal before supplementation, increasing to 90% +/- 58% of normal with supplementation. Nevertheless, calculated influx remained less than 70% of normal at 50% of the time points. The calculated brain influxes of all other large neutral amino acids except tryptophan were 20% to 40% of normal before and with tyrosine supplementation. CONCLUSIONS: Tyrosine supplementation in the diet for PKU produces marked but nonsustained increases in plasma tyrosine levels, with calculated brain influx that often remains suboptimal. This could explain the lack of consistent neuropsychologic benefit with tyrosine supplementation.
Asunto(s)
Fenilcetonurias/tratamiento farmacológico , Tirosina/uso terapéutico , Adulto , Aminoácidos/metabolismo , Encéfalo/metabolismo , Niño , Femenino , Humanos , Masculino , Tirosina/sangreRESUMEN
BACKGROUND: Women with untreated phenylketonuria (PKU) often have poor reproductive outcomes. OBJECTIVE: We assessed the effects of intakes of major nutrients on plasma phenylalanine concentrations and we measured phenylalanine hydroxylase activity and phenylalanine intakes in pregnant women with PKU. DESIGN: Dietary intakes and plasma phenylalanine concentrations were compared in 4 subject groups defined on the basis of plasma phenylalanine concentrations: group 1 (n = 23), <360 micromol/L by 10 wk gestation and 120-360 micromol/L throughout the remainder of pregnancy; group 2 (n = 46), <600 micromol/L but not <360 micromol/L by 10 wk gestation and 120-600 micromol/L throughout the remainder of pregnancy; group 3 (n = 24), <600 micromol/L by 10 wk gestation but >600 micromol/L at least once thereafter; group 4 (n = 147), never <600 micromol/L. RESULTS: Except in the first trimester, mean intakes of phenylalanine, energy, and fat tended to be greater in group 1 than in the other groups. The mean protein intake of group 1 tended to be greater than that of the other groups. Intakes of protein (P < 0.0001), fat (P < 0.0001), and energy (P < 0.007) were negatively correlated with maternal plasma phenylalanine concentrations. It appeared that genotype did not affect phenylalanine tolerance. CONCLUSIONS: Maternal genotype appeared to have little influence on phenylalanine requirements during the first trimester. Early decline and maintenance of maternal plasma phenylalanine concentrations at <360 micromol/L and mean protein intake greater than the recommended dietary allowance (RDA) with mean energy intake near the RDA resulted in the best reproductive outcomes. Inadequate intakes of protein, fat, and energy may result in elevated plasma phenylalanine concentrations and may contribute to poor reproductive outcomes.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Fenilalanina Hidroxilasa/metabolismo , Fenilalanina/sangre , Fenilcetonuria Materna/sangre , Registros de Dieta , Ingestión de Energía , Femenino , Genotipo , Humanos , Fenilalanina/administración & dosificación , Fenilcetonuria Materna/enzimología , Fenilcetonuria Materna/genética , Embarazo , Resultado del Embarazo , Aumento de PesoRESUMEN
The major source of protein in the dietary treatment of phenylketonuria(PKU) is a phenylalanine-free amino acid mixture. Traditionally, these medical products have also contained other nutrients and have been in powder form. However, their disagreeable taste and odour, the large volume required to provide sufficient protein and the inconvenience of their preparation and storage have hindered compliance with consumption among adolescents and adults. We studied the acceptability of a new medical product for the treatment of PKU. This product, Phlexy-10 (SHS North America, Gaithersburg, MD, USA), is available in three forms: sachets of premeasured powder to be constituted as a drink, fruit-flavoured bars and prefilled capsules. A vitamin-mineral mixture is separately provided. The forms are interchangeable because each component (one sachet, one bar or 20 capsules) provides 10g of amino acids. Since the product is primarily a source of amino acids, protein requirements can be met using a smaller volume than with traditional medical products. Eleven subjects enrolled in a 24-week trial that included clinical and laboratory evaluations. Nine subjects completed the study and 8 remained on the Phlexy-10 after the study. The powder drink was the favourite module used. One-third of the subjects included the bars and another third included the capsules in their regimens. The vitamin-mineral mixture was the least acceptable component. Mean weekly blood phenylalanine decreased by 40% from mean baseline levels. Blood concentrations of vitamins and minerals were normal except for a low zinc concentration in two subjects and a low vitamin B12 concentration in another. The lower caloric content and the separate vitamin-mineral mixture require careful monitoring of these nutrients. Phlexy-10 appears to be an adequate medical product for the treatment of PKU. Its convenience, flexibility of form and improved taste are appealing to many individuals on diet for PKU.
Asunto(s)
Proteínas en la Dieta/uso terapéutico , Aceptación de la Atención de Salud , Fenilcetonurias/dietoterapia , Adolescente , Adulto , Aminoácidos/sangre , Niño , Dieta , Proteínas en la Dieta/administración & dosificación , Proteínas en la Dieta/efectos adversos , Femenino , Humanos , Masculino , Fenilalanina/sangre , Vitaminas/administración & dosificación , Vitaminas/uso terapéuticoRESUMEN
The importance of complete or almost complete intake of the recommended amount of phenylalanine-free amino acid mixture (AAM) for control of blood phenylalanine level in patients being treated for phenylketonuria (PKU) has not been universally appreciated. We observed the effect of complete intake of AAM on plasma phenylalanine levels during hospitalization in 6 patients with PKU (5 pregnant women with PKU and 1 child) who had poor metabolic control because of less than full compliance with prescribed AAM intake. Before hospitalization, all but 1 of the patients had blood phenylalanine levels above 1,000 mumol/L; in 1 patient the blood phenylalanine level was 703 mumol/L. During 9 periods of observation in the 6 patients, the levels of plasma phenylalanine decreased to the recommended range of below 360 mumol/L within 2 to 6 days of hospitalization. These experiences indicate a close relationship between compliance with prescribed AAM intake and control of blood phenylalanine level. We propose that hospitalization be considered when patients with PKU who are consuming a phenylalanine-restricted diet fail to maintain blood phenylalanine levels in the targeted range despite reported compliance with the prescribed intake of dietary phenylalanine and AAM.
Asunto(s)
Aminoácidos/administración & dosificación , Dieta con Restricción de Proteínas , Fenilalanina/sangre , Fenilcetonuria Materna/dietoterapia , Adulto , Aminoácidos/metabolismo , Preescolar , Ingestión de Alimentos , Femenino , Humanos , Cooperación del Paciente , Fenilalanina/efectos adversos , Fenilalanina Hidroxilasa/genética , Fenilcetonuria Materna/prevención & control , Embarazo , Resultado del EmbarazoRESUMEN
Lower than average concentrations of tyrosine could be a factor in the fetal damage produced by maternal phenylketonuria (PKU). Dietary supplementation with L-tyrosine has been inconsistent in these reported pregnancies. Consequently, we studied the response to supplementation with L-tyrosine in five maternal PKU pregnancies. Before supplementation the mean plasma tyrosine concentration during midpregnancy was only 34 micromol/L compared with the expected value of 45 micromol/L in the normal population. A single dose of 1.3 g L-tyrosine was sufficient to raise plasma tyrosine concentrations well above the recommended minimum concentration of 45 micromol/L. The response was rapid and sustained over a 3-h study period in each subject and was associated with a markedly increased ratio of tyrosine to large neutral amino acids. These results indicate that the plasma tyrosine concentration can be increased to normal or above-normal values in maternal PKU pregnancies for a period of > or = 3 h by supplementation of the diet with L-tyrosine. The high ratio of tyrosine to large neutral amino acids indicates that tyrosine might readily cross the placenta and provide sufficient tyrosine to the fetus to support normal protein and catecholamine synthesis in what otherwise might be a tyrosine-poor environment.
Asunto(s)
Fenilcetonurias/tratamiento farmacológico , Tirosina/uso terapéutico , Femenino , Humanos , Intercambio Materno-Fetal , Embarazo , Complicaciones del Embarazo , Tirosina/administración & dosificación , Tirosina/sangreRESUMEN
OBJECTIVES: To document the clinical and neurodevelopmental profiles of a cohort of patients with neonatal-onset propionic acidemia and to determine the efficacy of current therapy with respect to outcome. METHOD: The clinical, neurologic, and developmental status of six patients was prospectively evaluated during a 15-month period. Previous clinical and biochemical data were ascertained from hospital records to determine longitudinal nutritional status, number of episodes of hyperammonemia with ketoacidosis, and developmental performance with respect to age. RESULTS: No deaths resulted from propionic acidemia since the identification of the oldest patient in the series in 1980. Therapeutic intervention (e.g., gastrostomy tube feeding) resulted in improved nutritional status and possibly contributed to improved survival. All children had hypotonia, resulting in a significant effect on motor development; however, focal neurologic deficits and evidence of movement or seizure disorder were absent. Mild cortical atrophy was evident on cranial magnetic resonance imaging in four patients. All children, including two patients with no significant episodes of hyperammonemia and normal growth since the neonatal period, had a mild to moderate degree of intellectual impairment. CONCLUSIONS: The results of our study suggest that current therapy for neonatal-onset propionic acidemia is associated with improved survival and nutritional status, and an absence of focal neurologic deficits. However, hypotonia and cognitive delay were still present, even in children with "optimal" metabolic control. Additional therapeutic advances are required to improve the developmental and cognitive outcome.
Asunto(s)
Propionatos/sangre , Carboxiliasas/deficiencia , Niño , Preescolar , Trastornos del Conocimiento/etiología , Discapacidades del Desarrollo/etiología , Nutrición Enteral , Femenino , Gastrostomía , Humanos , Lactante , Masculino , Metilmalonil-CoA Descarboxilasa , Tono Muscular , Estado Nutricional , Estudios ProspectivosRESUMEN
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.
Asunto(s)
Fenilcetonurias/diagnóstico , Alimentación con Biberón , Lactancia Materna , Calostro/metabolismo , Humanos , Recién Nacido , Tamizaje Masivo , Alta del Paciente , Fenilalanina/sangre , Fenilalanina/metabolismo , Estudios Prospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Young women with phenylketonuria (PKU) are at risk for bearing children with mental retardation, microcephaly, heart defects, and low birthweight. These effects may be prevented if a low phenylalanine diet is maintained prior to and throughout pregnancy. This report describes the procedures of the New England Regional Maternal PKU Project for identifying and locating this population of at-risk women. Newborn screening records, routine umbilical cord blood screening, and PKU Clinic records provided most of the identifying information. We identified 235 women with hyperphenylalaninemia, ages 12 to 44 years. Of these, 183 had PKU or atypical PKU while 52 had non-PKU mild hyperphenylalaninemia. The 235 women represent 88 per cent of the expected number of women with hyperphenylalaninemia in New England. We identified more than the expected number of those with PKU but only 57 per cent of the expected number with mild hyperphenylalaninemia. Developing a national registry, as well as screening women who utilize birth control clinics or prenatal clinics, may be helpful. Implementing routine umbilical cord blood screening programs may be beneficial in efforts to identify women with hyperphenylalaninemia who have had a child and may want more children in the future.
Asunto(s)
Fenilcetonurias/epidemiología , Complicaciones del Embarazo/epidemiología , Adolescente , Adulto , Niño , Métodos Epidemiológicos , Femenino , Enfermedades Genéticas Congénitas , Salud , Humanos , Centros de Salud Materno-Infantil , Registros Médicos , New England , Fenilalanina/sangre , Fenilcetonurias/sangre , Fenilcetonurias/terapia , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/terapia , Mujeres Embarazadas , Factores de RiesgoRESUMEN
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.