Biomedical subjects

C Azen

Publications and source records attributed to C Azen.

At least 19 recordsLinked to original sources

PubMed2004

Neuropsychological outcome of subjects participating in the PKU adult collaborative study: a preliminary review.

Adult subjects with classical phenylketonuria (PKU) who were diagnosed and treated neonatally participated in this long-term follow-up study. Twenty-four subjects received neuropsychological (NP) assessment and a subset received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to identify: (1) pattern of cognitive dysfunction; (2) effect of high blood phenylalanine (Phe) level at time of cognitive testing; and (3) treatment variables that may be associated with cognitive difficulties in adulthood. All subjects had average IQ except one subject in the borderline range. Diet was initiated by the 15th day of life. All subjects except one were on diet until age 6 years (mean years of treatment = 15). Blood Phe levels at cognitive testing ranged from 157 to 1713 micromol/L (mean = 1038); 11 subjects had levels < 1000 micromol/L and 13 subjects had levels >1000 micromol/L. Results suggest that adults with early-treated PKU demonstrate specific cognitive deficits, a number of which are associated with the frontal and temporal area of the brain. Deficits were noted in several domains including executive functioning, attention, verbal memory, expressive naming and verbal fluency. Self-report measures of depression and anxiety were generally in the normal/mild range. The group with a Phe level > 1000 micromol/L scored lower than the group with Phe level < 1000 micromol/L on measures of focused attention, verbal fluency, reaction time, verbal recognition memory, visual memory and naming. Tests of cognitive functioning were often correlated with measures of treatment during childhood rather than with Phe level at the time of cognitive testing. Subjects with abnormal MRI scored significantly lower on two cognitive tests (Trails A and CVLT Recognition Memory). We found no significant correlation between current brain Phe level obtained through MRS (n = 10) and neuropsychological functioning. Future longitudinal investigation with a larger sample size will assist in clarifying the aetiology of neuropsychological deficits and association with treatment history.

Adult↗

PubMed2004

Maternal Phenylketonuria Collaborative Study (MPKUCS)--the 'outliers'.

Analysis of outcome data from 305 of the 414 offspring from the Maternal Phenylketonuria Collaborative Study (MPKUCS), plus 70 control offspring, revealed significant deficits in the IQ (intelligence quotient), as measured by the Wechsler Intelligence Scale for Children--Revised (WISC-R), when maternal metabolic control during pregnancy was delayed and/or inadequate. There were, however, 23 'outliers' (7.5% of the 305) in which the offspring's intellectual IQ was worse (n =10) or better (n =13) than expected. The aim of this study was to determine whether collection parameters were incomplete or whether these subjects were true biological variants influenced by other undetected factors or, perhaps, by modifier genes. Among the 10 offspring whose intellectual functioning was worse than expected, additional complications were uncovered that could explain the poor outcome. Four of the 13 offspring with higher than expected IQ had mothers with mild variants of PKU in which the insult to the fetus would not be expected to be as profound. For the other nine offspring whose intellectual performance was better than expected, there was no explanation, based on the parameters studied. We hypothesize that modifier genes will, at times, protect the fetus despite high maternal concentrations of phenylalanine. Not all offspring from the same (untreated) PKU mother may be similarly affected. Finding the source of these modifiers might effect the treatment of MPKU.

Adolescent↗

PubMed2002

Phenylketonuria in adulthood: a collaborative study.

During 1967-1983, the Maternal and Child Health Division of the Public Health Services funded a collaborative study of 211 newborn infants identified on newborn screening as having phenylketonuria (PKU). Subsequently, financial support was provided by the National Institute of Child Health and Human Development (NICHD). The infants were treated with a phenylalanine (Phe)-restricted diet to age 6 years and then randomized either to continue the diet or to discontinue dietary treatment altogether. One hundred and twenty-five of the 211 children were then followed until 10 years of age. In 1998, NICHD scheduled a Consensus Development Conference on Phenylketonuria and initiated a study to follow up the participants from the original Collaborative Study to evaluate their present medical, nutritional, psychological, and socioeconomic status. Fourteen of the original clinics (1967-1983) participated in the Follow-up Study effort. Each clinic director was provided with a list of PKU subjects who had completed the original study (1967-1983), and was asked to evaluate as many as possible using a uniform protocol and data collection forms. In a subset of cases, magnetic resonance imaging and spectroscopy (MRI/MRS) were performed to study brain Phe concentrations. The medical evaluations revealed that the subjects who maintained a phenylalanine-restricted diet reported fewer problems than the diet discontinuers, who had an increased rate of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity. Psychological data showed that lower intellectual and achievement test scores were associated with dietary discontinuation and with higher childhood and adult blood Phe concentrations. Abnormal MRI results were associated with higher brain Phe concentrations. Early dietary discontinuation for subjects with PKU is associated with poorer outcomes not only in intellectual ability, but also in achievement test scores and increased rates of medical and behavioural problems.

Adult↗

PubMed2001

Intake of major nutrients by women in the Maternal Phenylketonuria (MPKU) Study and effects on plasma phenylalanine concentrations.

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.

Diet Records↗

PubMed2001

Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study.

The frequency and types of congenital heart disease in offspring from pregnancies in women with hyperphenylalaninemia were examined in the international prospective Maternal Phenylketonuria Collaborative Study. Relationships of congenital heart disease in offspring to the basal blood phenylalanine level in the mother, metabolic control through diet during pregnancy, and phenylalanine hydroxylase mutations in mother and offspring were determined. The 416 offspring from 412 maternal phenylketonuria pregnancies that produced live births and 100 offspring from the 99 control pregnancies were included in this examination. Thirty-four of the 235 offspring (14%; 95% CI, 10.2 to 19.6%) from pregnancies in phenylketonuric women with a basal phenylalanine level > or = 900 microM (15 mg/dL) [normal blood phenylalanine < 120 microM (2 mg/dL)] and not in metabolic control [phenylalanine level < or = 600 microM (10 mg/dL)] by the eighth gestational week had congenital heart disease compared with one control offspring (1%) with congenital heart disease. One offspring among the 50 (2%) from mothers with non-phenylketonuria mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented compared with expected percentages among those with congenital heart disease in the general population. A basal maternal phenylalanine level > 1800 microM (30 mg/dL) significantly increased the risk for bearing a child with congenital heart disease (p = 0.003). Phenylalanine hydroxylase mutations in the mothers and offspring did not have an independent relationship to congenital heart disease but were related through the basal maternal phenylalanine levels. The data in this study indicate that a basal maternal phenylalanine level of 900 microM may be a threshold for congenital heart disease, that women with the most severe degree of phenylketonuria are at highest risk for bearing such a child, and that prevention of the congenital heart disease requires initiation of the low phenylalanine diet before conception or early in pregnancy with metabolic control no later than the eighth gestational week.

Female↗

PubMed2000

Outcome at age 4 years in offspring of women with maternal phenylketonuria: the Maternal PKU Collaborative Study.

CONTEXT: Untreated maternal phenylketonuria (PKU) increases risk for developmental problems in offspring. The extent to which this risk is reduced by maternal dietary therapy at various stages of pregnancy is not known. OBJECTIVE: To determine whether dietary treatment during pregnancy of women with PKU affects developmental outcomes of offspring. DESIGN: The Maternal PKU Collaborative Study, an ongoing, longitudinal prospective study begun in 1984. SETTING: A total of 78 metabolic clinics and obstetrical offices in the United States, Canada, and Germany. PARTICIPANTS: A total of 253 children of women with PKU (n = 149), with untreated mild hyperphenylalaninemia (n = 33), or without known metabolic problems (comparison group; n = 71) were followed up to age 4 years. INTERVENTION: Women with PKU were offered a low-phenylalanine diet prior to or during pregnancy with the aim of maintaining metabolic control (plasma phenylalanine < or =10 mg/dL [< or =605 micromol/L]). Women with mild hyperphenylalaninemia, who had plasma phenylalanine levels of no more than 10 mg/dL (605 micromol/L) on a normal diet, were not treated. MAIN OUTCOME MEASURES: Children's scores on cognitive and behavioral assessments (McCarthy Scales of Children's Abilities, Test of Language Development, Achenbach Child Behavior Checklist, Vineland Adaptive Behavior Scales, and Home Observation for Measurement of the Environment), compared by maternal metabolic status at 0 to 10 weeks', 10 to 20 weeks', and after 20 weeks' gestation. RESULTS: Scores on the McCarthy General Cognitive Index decreased as weeks to metabolic control increased (r = -0.58; P<.001). Offspring of women who had metabolic control prior to pregnancy had a mean (SD) score of 99 (13). Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks' gestation had a General Cognitive Index score 2 SDs below the norm. Overall, 30% of children born to mothers with PKU had social and behavioral problems. CONCLUSIONS: Our data suggest that delayed development in offspring of women with PKU is associated with lack of maternal metabolic control prior to or early in pregnancy. Treatment at any time during pregnancy may reduce the severity of delay.

Child Behavior↗

PubMed2000

The International Collaborative Study of Maternal Phenylketonuria: status report 1998.

UNLABELLED: The Maternal Phenylketonuria Study began in 1984 and during the intervening years, 572 pregnancies in hyperphenylalaninemic women and 99 controls and their outcomes have been evaluated. Among hyperphenylalaninemic women who delivered a live infant, only 15.9% were treated and in metabolic control preconceptually, however, another 18.4% were in control by 10 weeks. Compared to the results reported by Lenke and Levy in 1980, there is a marked improvement in outcome with treatment. Microcephaly was unusual in preconceptually treated pregnancies with well controlled phenylalanine restricted diets. Even in pregnancies that established control after conception but before the 8th week, congenital heart disease did not occur in the offspring, however, it did occur in 12% of pregnancies not achieving control until after 10 weeks of pregnancy. CONCLUSION: The recommended level of blood phenylalanine during pregnancy is 120-360 mumol/l. Best results were obtained by close cooperation between the attending obstetrician and a metabolic team experienced in the care of persons with phenylketonuria.

Adult↗

PubMed2000

The international study of pregnancy outcome in women with maternal phenylketonuria: report of a 12-year study.

OBJECTIVE: The purpose of this report was to update the results of the Maternal Phenylketonuria Collaborative Study, which was established to assess the efficacy of a phenylalanine-restricted diet in preventing morbidity among the offspring of women with hyperphenylalaninemia. STUDY DESIGN: During a 12-year period 576 women with hyperphenylalaninemia were enrolled in this study. Outcome measures were stratified according to classification of maternal hyperphenylalaninemia and the time at which dietary control of phenylalanine level was achieved. RESULTS: Optimal physical and cognitive fetal outcomes occurred when maternal blood phenylalanine level <600 micromol/L was achieved by 8 to 10 weeks' gestation and maintained throughout pregnancy (trimester average, </=600 micromol/L). CONCLUSIONS: The achievement of blood phenylalanine level control through a phenylalanine-restricted diet significantly diminished the occurrence of congenital abnormalities among offspring of women with hyperphenylalaninemia and improved early intellectual progress of these offspring.

Adult↗

PubMed2000

Maternal phenylketonuria syndrome: congenital heart defects, microcephaly, and developmental outcomes.

OBJECTIVE: A cohort of women with phenylketonuria (PKU) were selected to explore the impact of phenylalanine (Phe) levels and other factors on congenital heart defects (CHDs), microcephaly, and development of their offspring. STUDY DESIGN: Three hundred fifty-four women with PKU were followed up weekly with diet records, blood Phe levels, and sonograms obtained at 18 to 20 and 32 weeks' gestation. At birth, 413 offspring were examined and followed up at 6 months and annually by means of Bayley Mental Developmental Index and Psychomotor Developmental Index tests at 1 and 2 years. The women had Wechsler Adult Intelligence Scales and DNA testing. RESULTS: Thirty-one offspring had CHDs; of these, 17 also had microcephaly. Mean Phe levels at 4 to 8 weeks' gestation predicted CHDs (P <.0001). An infant with a CHD had a 3-fold risk of having microcephaly when the mother had higher Phe levels (P =.02). The Bayley Mental Developmental Index and Psychomotor Developmental Index scores correlated with both CHDs (P =.037 and.0015, respectively) and microcephaly (P =.0001 for both). No direct relationship to the PKU mutation was found. CONCLUSION: None of the women whose offspring had CHDs had blood Phe levels in control during the first 8 weeks of gestation. Women with PKU need to be well controlled on a low-phenylalanine diet before conception and throughout pregnancy.

Adult↗

PubMed1999

Serum cobalamin, homocysteine, and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities.

BACKGROUND: Low cobalamin concentrations and mild hyperhomocysteinemia are common in the elderly but ethnic differences have not been defined. OBJECTIVE: Our objective was to determine the demographic characteristics of cobalamin deficiency in the elderly and its role in their hyperhomocysteinemia. DESIGN: We measured serum cobalamin, total homocysteine (Hcys), and methylmalonic acid (MMA) concentrations in 725 subjects >60 y old, and folate concentrations in 520 subjects. RESULTS: After exclusion of subjects taking cobalamin supplements or with renal insufficiency, high prevalences of low cobalamin (11.8%), high MMA (16.6%), and high Hcys (26.1%) concentrations were seen. Most cobalamin concentrations <140 pmol/L appeared to reflect deficiency because 78. 3% of them were accompanied by abnormal metabolites. Subjects with cobalamin concentrations of 140-258 pmol/L had significantly fewer metabolic abnormalities. A low cobalamin concentration and renal insufficiency were the strongest predictors of abnormal Hcys concentrations. Elderly men had higher Hcys concentrations than did women (P = 0.0001). Whites and Latin Americans had lower cobalamin concentrations than did blacks and Asian Americans (P < 0.005). Whites also had higher Hcys concentrations than all the other groups (P < 0.05). When included in the analysis, renal insufficiency in subjects was associated with 23.8% of all high Hcys and 25.5% of all high MMA concentrations; most with renal insufficiency were Asian American and black men. CONCLUSIONS: Mild cobalamin deficiency is most common in elderly white men and least common in black and Asian American women. Hyperhomocysteinemia, which is most strongly associated with low cobalamin concentrations, is also most common in elderly whites, whereas that associated with renal insufficiency is more common in blacks and Asian Americans. Ethnic differences in cobalamin deficiency and the Hcys patterns associated with it or with renal insufficiency warrant consideration in supplementation strategies. Extending suspicion of deficiency to persons with cobalamin concentrations of 140-258 pmol/L appears to provide more disadvantages than advantages.

Aged↗

PubMed1999

Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.

OBJECTIVE: To examine the relationship of phenylalanine hydroxylase (PAH) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria (PKU). METHODOLOGY: PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study (MPKUCS). A total of 84 different mutations were detected, and complete genotype was obtained in 199 individuals. Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to one of four classes of severity (severe PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). Then, 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications. The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity. These patients are considered functionally hemizygous. RESULTS: The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level. Cognitive performance (IQ) was also significantly related to genotype. The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96, respectively, whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84, respectively. Of the patients with PKU, 92% had been treated during childhood. Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations. Females with moderate or mild PKU who were treated early and treated for >6 years showed IQ scores 10 points above average for their group. CONCLUSIONS: The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances. Both factors depend on the intellectual resources of the mother with PKU. The significant relationship among genotype, biochemical phenotype, and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy.

Female↗

PubMed1998

Neonatal neurological assessment of offspring in maternal phenylketonuria.

This study assesses the impact of prenatal and postnatal factors in maternal phenylketonuria (PKU). The Dubowitz Neurological Assessment of the Preterm and Full-term Newborn Infant was administered within the first 8 days of life to 56 offspring of women with PKU and 45 controls. Follow-up testing of the maternal PKU offspring at age 1 year consisted of the Bayley Scales of Infant Development and the Receptive-Expressive Emergent Language Scale (REEL). In addition, the Home Observation for Measurement of the Environment (HOME Scale) was given. Birth weight was lower (z = 2.0, p = 0.045), birth length was lower (z = 2.1, p = 0.03) and birth head circumference was smaller (z = 3.5, p = 0.0005) in the maternal PKU offspring than in the control infants. Examiners rated 29% of the maternal PKU offspring and 9% of the control infants abnormal (Fisher's exact test, p = 0.01). At 1 year of age, 19% of the maternal PKU offspring attained a Bayley Developmental Quotient (DQ) and a score on the Bayley Motor Scale below 85; 19% had receptive language delay; and 26% had expressive language delay. The gestational age at which the mother attained metabolic control was an important factor associated with birth measurements, the Dubowitz Rating and subsequent developmental scores. The Dubowitz Neurological Assessment score did not predict developmental outcome (chi-square = 1.3, p = 0.53), while the HOME score correlated with the DQ (r = 0.36, p = 0.02). In logistic regression analyses, the home environment was a greater determinant of risk for a low DQ than whether or not the mother attained metabolic control prior to pregnancy (OR = 0.85, p = 0.02). These results suggest that treatment strategies addressing both prenatal and postnatal factors will most effectively reduce risks in maternal PKU.

Developmental Disabilities↗

PubMed1998

Dietary intake of cobalamin in elderly people who have abnormal serum cobalamin, methylmalonic acid and homocysteine levels.

OBJECTIVE: To determine if poor dietary intake can explain the cobalamin-related abnormalities often seen in the elderly. DESIGN: Prospective laboratory survey with a follow-up dietary assessment. SETTING: Social centers for the elderly and an outpatient clinic. SUBJECTS: Ninety-five free-living subjects >60y old with abnormal or suspicious findings in cobalamin-related tests and 78 subjects >60y old with normal results. INTERVENTIONS: Serum cobalamin, methylmalonic acid and homocysteine determinations to assess cobalamin status and a one year food-frequency questionnaire to assess cobalamin intake. RESULTS: Only three of the 173 subjects (1.7%), one of whom had normal cobalamin status, ingested <2 microg cobalamin/d, the Recommended Daily Allowance. Sixty-nine subjects (39.9%) ingested <6 microg/d, but they did not have more abnormal serum cobalamin or metabolite values than those ingesting >6 microg. Ordering all subjects by quintiles according to cobalamin intake revealed no significant trends or differences in any of the serum values either. Moreover, arranging subjects by results of tests of cobalamin status showed that the subjects with abnormal cobalamin status did not differ in cobalamin intake from those with normal cobalamin status, although they did differ in use of supplements. Finally, cobalamin intake, with or without supplements, did not correlate with serum cobalamin or metabolite levels. The absence of any association between cobalamin status and intake contrasts sharply with the significant correlation between folate intake and folate status (P = 0.0001). CONCLUSIONS: The high frequency of mildly abnormal cobalamin status in the elderly cannot be attributed to poor intake of cobalamin. Nondietary explanations, such as malabsorption and other phenomena, must always be sought to explain mild cobalamin deficiency in the elderly.

Aged↗

PubMed1997

Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae.

Maternal phenylketonuria (PKU) in untreated women has resulted in offspring with microcephaly, mental retardation, congenital heart disease (CHD), and intrauterine growth retardation. The Maternal Phenylketonuria Collaborative Study (MPKUCS) was designed to determine the effect of dietary control of blood phenylalanine (Phe) during pregnancy in preventing damage to the fetus associated with untreated Maternal PKU. A cohort of offspring from MPKUS pregnancies was ascertained and examined to evaluate malformations, including CHD, craniofacial abnormalities, microcephaly, intrauterine and postnatal growth retardation, other major and minor defects, and early abnormal neurological signs. For analysis, the women were grouped according to their mean Phe levels in mumol/liter, < or = 360, 361-600, 601-900, or > 900, during critical gestational weeks of 0-8 (N = 203) and 8-12 (N = 190), and average for Phe exposure throughout pregnancy (N = 183). Frequencies of congenital abnormalities increased with increasing maternal Phe levels. Significant relationships included average Phe 0-8 weeks and CHD (P = 0.001); average Phe 8-12 weeks and brain, fetal, and postnatal growth retardation (P < 0.0005 for all), wide nasal bridge (P < 0.0005), and anteverted nares (P = 0.001); and average Phe exposure during the entire pregnancy and neurological signs (P < 0.0005). Although 14% of infants had CHD, none of the CHD occurred at 120-360 mumol/liter and only one (3%) at 361-600 mumol/liter. At levels of 120-360 mumol/liter, there were three infants (6%) with microcephaly, two (4%) with postnatal growth, and none with intrauterine growth retardation, in contrast to 85%, 51%, and 26%, respectively, with Phe above 900 mumol/liter. These data support the concept that women with PKU should begin a low-phenylalanine diet to achieve Phe levels of < 360 mumol/liter prior to conception and should maintain this throughout pregnancy.

Cohort Studies↗

PubMed1997

The relationship of genotype to phenotype in phenylalanine hydroxylase deficiency.

Seventy-two adults with phenylketonuria were evaluated to investigate the genotypic relationship to phenotype. Patient data were collected by chart review and medical follow-up as well as current psychological evaluation. Nineteen diagnosed neonatally had remained on a phenylalanine-restricted diet all their lives, whereas 34 who were also diagnosed on newborn screening had discontinued dietary restriction during childhood. Nineteen others who were born prior to newborn screening were diagnosed later than the newborn period on clinical grounds but have remained on dietary restriction. Comparison between intellectual ability, academic achievement, and mental illness was made with degree of diet control as defined by range of blood phenylalanine levels over time. Diet discontinuation in childhood did not significantly lower IQ per se but appeared to diminish academic achievement. The lowest IQ scores were associated with poor dietary restriction of phenylalanine in the diet during childhood. While there appears to be a strong genotypic relationship to phenotypic metabolic parameters in phenylketonuria, there does not seem to be a similar relationship to intellectual ability in adults. Mutation R408W was not strongly related to the occurrence of mental illness in this sample. We conclude that dietary restriction of phenylalanine neonatally and good control contributed to normal intellectual development. Continuation of dietary treatment into adulthood appeared to improve academic achievement in patients with severe phenylalanine hydroxylase mutations.

Adult↗

PubMed1996

Summary of findings from the United States Collaborative Study of children treated for phenylketonuria.

The Collaborative Study of children treated for phenylketonuria (PKUCS) was conducted to investigate prospectively the effects of dietary restriction of phenylalanine on the growth and development of these children. Patients with classic phenylketonuria were identified by newborn screening and began treatment shortly thereafter. All were given the restricted diet until age 6 years, when half were randomly assigned to continue and half to discontinue dietary therapy. By age 10 years, 35% had deviated from randomization. The effects of diagnostic, treatment, and psychosocial factors on cognitive test scores were evaluated through 12 years of age. After controlling for parent IQ, significant correlations were noted between various measures of control of blood phenylalanine and their scores on intelligence, reading, spelling and behavior tests, but not for arithmetic or language scores. Bender Gestalt test scores were related to phenylalanine level at the time of testing, but not to early treatment history. These findings strongly support the importance of early initiation of dietary treatment and continuation of therapy throughout childhood.

Child↗

PubMed1996

The International Collaborative Study on maternal phenylketonuria: organization, study design and description of the sample.

The International Maternal Phenylketonuria (PKU) Collaborative Study commenced in 1984 to evaluate the efficacy of the low-phenylalanine diet in reducing the morbidity associated with maternal PKU syndrome. Four hundred and sixty eight (468) pregnancies resulted in 331 live births, 3 stillbirths, 61 spontaneous abortions, 2 ectopic pregnancies and 71 elective terminations. Since its inception, the study has steadily progressed toward its goal of diet initiation preconception or early in pregnancy. By 1994, 51% of the sample began the diet preconceptionally, with an additional 41% doing so by 8 weeks gestation. The number of adolescent pregnancies has decreased from 31% to 9%, college attendance has increased from 5% to 16%, number of women in the lowest socioeconomic classes has decreased from 95% to 59% and average IQ has increased from 78 to 88. The organization of the network of 130 referral centers and clinics within the U.S.A., Canada and Germany and the objectives of the scientific research investigation have served to provide a derived benefit of outreach, education, reproductive counseling and early diet intervention in a large cohort of PKU women.

Adolescent↗

PubMed1996

Nutrition and reproductive outcome in maternal phenylketonuria.

Maternal weight gain and intake of selected nutrients were correlated with plasma phenylalanine (Phe) concentrations and reproductive outcomes (in 150 and 142 subjects respectively) in the Maternal PKU Collaborative Study. Daily protein intake was negatively correlated with plasma Phe concentration. Birth length, weight and head circumference of offspring were negatively influenced by the length of time required for the maternal plasma Phe to decline below 600 mumol/l (10 mg/dl) and positively influenced by weight gain of mother as a percentage of recommended weight gain. Birth weight and length were positively correlated with maternal protein and energy intakes. During the first trimester, intakes of fat, calcium, phosphorus, vitamin A and folate were significantly greater in women who had a good reproductive outcome than by women who had a poor outcome. In addition to plasma Phe control in maternal phenylketonuria (PKU), maternal weight gain and dietary intake of protein, energy and fat were correlated with outcome. Therefore, nutrient intake and maternal weight gain should be considered along with plasma Phe concentration when managing the therapy of a pregnant woman with PKU.

Diet, Protein-Restricted↗