Colleen Azen

Effect of Age at Loss of Dietary Control on Intellectual Performance and Behavior of Children with Phenylketonuria

We determined the effect on intellectual performance and behavior of the age at which dietary control was lost in 119 10-year-old children with phenylketonuria (PKU) who had started on a diet low in phenylalanine before the age of 65 days. The childrens diets were considered to be out of control when their blood phenylalanine concentration persistently exceeded 15 mg per deciliter. The age at which control was lost was the best, and frequently the only, predictor of the childs IQ at the age of 8 or 10 years and of the deficit in the childs IQ as compared with those of his or her unaffected siblings or parents. The age at which control was lost was also the best predictor of the deficit in scores on the Wide Range Achievement Test of children with PKU at the age of eight, as compared with their unaffected siblings, and of behavior problems (Louisville Behavior Checklist). Variables that were not significant included the maximal phenylalanine concentration before dietary therapy, the age at which treatment was started, and the familys coping abilities. The greatest deficiencies in all of these outcomes were observed among children who were out of dietary control before the age of six years. The highest correlation between the IQs of the children with PKU and their respective parents was observed among the children still on the diet at the age of eight years; the lowest, among those who had poor dietary control before the age of six. These findings suggest that phenylalanine restriction should continue after the age of eight years in children with PKU.

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.

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

Summary: 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 µmol/L (mean = 1038); 11 subjects had levels >1000 µmol/L and 13 subjects had levels >;1000 µmol/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 µmol/L scored lower than the group with Phe level <1000 µmol/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.

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.

Neuroradiographic, Endocrinologic, and Ophthalmic Correlates of Adverse Developmental Outcomes in Children With Optic Nerve Hypoplasia: A Prospective Study

BACKGROUND. Developmental delay has been reported to occur with optic nerve hypoplasia, a leading cause of pediatric blindness, but has not been systematically examined for its prevalence and correlation with associated pathologies of optic nerve hypoplasia. OBJECTIVE. The purpose of this study was to determine the developmental outcomes of children with optic nerve hypoplasia and the correlation of development with neuroradiographic, endocrinologic, and ophthalmic findings. METHODS. We conducted a prospective analysis of 73 subjects diagnosed with optic nerve hypoplasia at <36 months of age for developmental outcomes at 5 years of age. Subjects underwent neuroradiographic imaging, endocrinologic testing and examination, and ophthalmologic examination; developmental outcomes were assessed by using the Battelle Developmental Inventory. RESULTS. At 5 years of age, developmental delay was present in 71% of subjects with optic nerve hypoplasia. Of patients with unilateral (18%) and bilateral optic nerve hypoplasia, 39% and 78%, respectively, experienced developmental delay. Corpus callosum hypoplasia and hypothyroidism were significantly associated with poor outcome in all of the developmental domains and an increased risk of delay. Absence of the septum pellucidum was not associated with adverse development. Six subjects had neither a neuroradiographic nor an endocrinologic abnormality, and of those, 4 were developmentally delayed. CONCLUSIOONS. These prospective data confirm the significant association of developmental delay with optic nerve hypoplasia and identify corpus callosum hypoplasia and hypothyroidism as strong correlates. A diagnosis of optic nerve hypoplasia warrants neuroradiographic and endocrinologic testing for risk factors of delay and developmental assessments for early intervention planning.

The international collaborative study of maternal phenylketonuria: status report 1994

Neonatal screening for phenylketonuria (PKU) has created a problem as females with PKU are reaching child‐bearing age. Surveys have revealed that maternal phenylalanine blood concentrations greater than 1200 μmol/l are associated with fetal microcephaly, congenital heart defects and intrauterine growth retardation. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk of producing these fetal abnormalities. To examine this problem, the international maternal PKU collaborative study was developed to evaluate the efficacy of a phenylalanine‐restricted diet in reducing fetal morbidity. Preliminary findings have indicated 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 μmol/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. The results of 402 pregnancies are reviewed.

Paired Comparisons between Early Treated PKU Children and their Matched Sibling Controls on Intelligence and School Achievement Test Results at Eight Years of Age

Early-treated PKU children were compared to their matched non-PKU sibling controls on Wechsler Intelligence Scale for Children (WISC) and Wide Range Achievement Test (WRAT) results at age 8. Fifty-five PKU children had mean WISC Full Scale IQ score of 100, in comparison to a mean of 107 for their matched sibling controls (p=0.001). Treatment parameters significantly correlated with sibling-PKU IQ score differences included maximum diagnostic phe level (r=0.244,p=0.036) and phe levels at age 6 (r=0.329,p=0.007) and at age 8 (r=0.489,p<0.0005). Fifty PKU subjects scored significantly lower than their matched sibling controls on standard scores of the WRAT Reading (102 vs. 107,p=0.016) and Arithmetic (96 vs, 101,p=0.006) subtests, and lower, but not significantly so, in Spelling (100 vs. 103,p=0.145). When the sample was grouped according to diet status at age 8, on-diet PKUs scored at or above the level achieved by their siblings on all three scales of the WISC and all three WRAT subtests, whereas the off-diet group scored from 7 to 13 points below their siblings on all measures.These results suggest that PKU children should restrict phe intake at least through their school years.

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 >240 μmol/L (>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 χ 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 Conclusions: Preconceptual counseling and early entrance into a prenatal care program is essential in achieving optimal fetal outcome in women with hyperphenylalaninemia.

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 >60 y old with abnormal or suspicious findings in cobalamin-related tests and 78 subjects >60 y 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 μg cobalamin/d, the Recommended Daily Allowance. Sixty-nine subjects (39.9%) ingested <6 μg/d, but they did not have more abnormal serum cobalamin or metabolite values than those ingesting >6 μg. 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.Sponsorship: This study was supported by grants DK 32640 and HL 52234 from the National Institutes of Health and by the NIH National Center for Research Resources of the GCRC grant MO1 RR-43. Computational assistance was provided by the NIH NCRR GCRC MO1 RR-43 CDMAS project.

Preliminary report on the effects of diet discontinuation in PKU

A collaborative study of diet discontinuation in children with PKU was initiated in 1973. Children treated with the phenylalanine-restricted diet since early infancy were randomly assigned to continue or discontinue dietary therapy at age 6 years after parental consent was obtained. The 115 children participating in this study range in age from 8 to 13 years. At 6 years of age, the IQ of continuers and discontinuers was 101 and 97, respectively. At 8 years, WISC Full-Scale IQ scores adjusted for mean differences on the 6-year Stanford-Binet IQ were 101 for continuers and 98 for discontinuers (P = 0.075). School performance measured by the Wide Range Achievement Test showed significant differences on reading (3.9 vs 3.2) and spelling (3.3 vs 2.9) grade placement, although scores were above actual grade placement (2.7 vs 2.6) for both groups. Continuers and discontinuers were not different in arithmetic scores, with performance at grade placement of 2.7 and 2.6 respectively. Although these data are preliminary in nature, they suggest that subtle changes in cerebral function may occur in children with PKU in whom the phenylalanine diet has been discontinued.