Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia

BACKGROUND—Associations between genotype and intellectual outcome in patients with phenylketonuria are complicated because intelligence is influenced by many variables, including environmental factors and other genetic determinants. Intellectual changes with age, both on and after relaxation of diet, vary within the patient population. This study aims to determine whether a significant association exists between genotype and change in intelligence after relaxation of diet.METHODS—125 patients with hyperphenylalaninaemia and phenylketonuria whose diet was relaxed after 8 years of age. Verbal, performance, and full scale intelligence quotients at 8, 14, and 18 years were expressed as standard deviation scores (IQ-SDS), and genotype as predicted residual enzyme activity (PRA) of phenylalanine hydroxylase.RESULTS—IQ-SDS at 8, 14, and 18 years were significantly below normal; no association was found between PRA and IQ-SDS. Significant reductions in verbal and full scale IQ-SDS occurred between 8and 14 years and 8 and 18 years. There was a significant association between PRA and the reduction in verbal, performance, and full scale IQ between these years. Multiple regression analysis of 18 year results, using 8 year results as covariates, supported the association between PRA and IQ-SDS; after adjustment for phenylalanine control, both up to and after the age of 8 years, the full scale IQ-SDS at 14 and 18 years was 0.15 higher for each 10% increase in PRA.CONCLUSIONS—Genotype might be useful in predicting the likelihood of intellectual change in patients with hyperphenylalaninaemia and phenylketonuria whose diet is relaxed after the age of 8years.     

Intellectual development after relaxing the diet at the age of 5 years in typical phenylketonuria]

BACKGROUND. No satisfactory controlled trial has yet been completed on typical phenylketonuria (PKU) patients whose treatment was relaxed at the age of 5 years. METHODS. 27 children having typical PKU were treated before the age of 3 months. The intake of phenylalanine and protein was carefully regulated during the first 5 years of life, after which the treatment was relaxed. All children were evaluated after at least 6 years on the relaxed diet. Their IQ scores and school performance were related to the degree of dietary control and plasma phenylalanine values. RESULTS. The IQ scores at 5 years of age were 100 +/- 10.8. Continued evaluation showed that IQ scores remained unchanged. Poor school performance was twice as frequent as in general population; the deficit in the IQ score of this group was 8 points below that of normal sibs. There was no correlation between plasma phenylalanine and the IQ score after the age of 5 years. The positive control decreased with aged. CONCLUSIONS. Children with typical PKU have an IQ deficit relative to their normal sibs just before relaxing treatment. Good dietary control until 5 years of age, maternal intelligence and continuing evaluation during relaxing diet are the best conditions for optimal intellectual progress. There is no evidence that continued treatment during adolescence is beneficial.     

Wechsler subscale IQ and subtest profile in early treated phenylketonuria.

AIM: Mildly depressed IQ is common in treated phenylketonuria. This study explored whether a particular intellectual ability profile typifies early and continuously treated phenylketonuria and whether component skills comprising the IQ relate to socioeconomic and treatment factors. METHODS: IQ scores were collected retrospectively from variants of the "Wechsler intelligence scale for children" performed at age 8 on 57 children with early treated, classic phenylketonuria. The mental ability pattern underlying IQ was investigated by analysing subscale and subtest scores and dietary factors, such as historical phenylalanine blood concentrations. RESULTS: The children's mean full scale IQ of 91.11 was significantly below the healthy population norm. There was a significant discrepancy between their mean verbal IQ (94.65) and mean performance IQ (89.42), suggestive of a spatial deficit, but the data did not support a biochemical or sociological explanation. Individual Wechsler subtests had no distinctive pattern. Phenylalanine control at age 2 was predictive of overall IQ. At this age, children with annual median phenylalanine < 360 micromol/litre (recommended UK upper limit) had a mean IQ 10 points higher than those above. CONCLUSIONS: Early and continuous treatment of phenylketonuria does not necessarily lead to normalisation of overall IQ. Verbal intelligence in the primary school years appears to normalise if blood phenylalanine is maintained below 360 micromol/litre in infancy, but spatial intelligence may remain poor. However, the discrepancy in skill development is not the result of social status or treatment variables. Perhaps weak spatial intelligence is an ancillary effect of a protective rearing style occasioned by the dietary treatment regimen.     

Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria.

A total of 599 children with phenylketonuria, who had been treated early, were followed up prospectively in order to examine the association between intellectual progress from 4 to 14 years of age and control of phenylalanine concentrations. The phenylalanine rose from around 400 mumol/l during the first four years to above 900 mumol/l by 12 years. The children were divided into two cohorts: cohort I comprised 224 children born in the United Kingdom between 1964 and 1971 and cohort II 375 children born between 1972 and 1978. In a previous study it was shown that by 4 years of age these children already had a mean intelligence quotient (IQ) over half a standard deviation below general population norms, and that IQ fell linearly as average phenylalanine concentrations rose. Multiple regression was used to estimate the size of the associations between IQ at later ages and average phenylalanine concentrations in the periods between assessments, after controlling for previous IQ and phenylalanine control, social class, type of phenylketonuria, and factors relating to diagnosis and early management. For each 300 mumol/l rise in average phenylalanine concentrations for those aged 5 to 8 years IQ at 8 years fell by 4-6 points. This compared with a 7-10 point fall in IQ at 4 years for a similar rise in phenylalanine. After 8 years of age the association between IQ and phenylalanine control disappeared in cohort I but persisted in cohort II and was significant up to 10 years of age, although the association was smaller than at 8 years.     

Wechsler subscale IQ and subtest profile in early treated phenylketonuria

AIM—Mildly depressed IQ is common in treated phenylketonuria. This study explored whether a particular intellectual ability profile typifies early and continuously treated phenylketonuria and whether component skills comprising the IQ relate to socioeconomic and treatment factors.
METHODS—IQ scores were collected retrospectively from variants of the "Wechsler intelligence scale for children" performed at age 8 on 57 children with early treated, classic phenylketonuria. The mental ability pattern underlying IQ was investigated by analysing subscale and subtest scores and dietary factors, such as historical phenylalanine blood concentrations.
RESULTS—The children''s mean full scale IQ of 91.11 was significantly below the healthy population norm. There was a significant discrepancy between their mean verbal IQ (94.65) and mean performance IQ (89.42), suggestive of a spatial deficit, but the data did not support a biochemical or sociological explanation. Individual Wechsler subtests had no distinctive pattern. Phenylalanine control at age 2 was predictive of overall IQ. At this age, children with annual median phenylalanine < 360 µmol/litre (recommended UK upper limit) had a mean IQ 10 points higher than those above.
CONCLUSIONS—Early and continuous treatment of phenylketonuria does not necessarily lead to normalisation of overall IQ. Verbal intelligence in the primary school years appears to normalise if blood phenylalanine is maintained below 360 µmol/litre in infancy, but spatial intelligence may remain poor. However, the discrepancy in skill development is not the result of social status or treatment variables. Perhaps weak spatial intelligence is an ancillary effect of a protective rearing style occasioned by the dietary treatment regimen.
     

Loss of intellectual function in children with phenylketonuria after relaxation of dietary phenylalanine restriction

Fourteen patients with classic phenylketonuria (PKU) were treated with a phenylalanine restricted diet from early infancy. All had satisfactory dietary control, with serum phenylalanine concentrations ranging between 2 to 5 mg/dL. Dietary restriction was discontinued in all these children between ages 5 and 6 years, and a free diet allowed. Developmental testing was performed using the Cattell Infant Intelligence Scales (1 to 2 years), Stanford-Binet Intelligence Scale (2 to 4 years), Wechsler Intelligence Scale for Children (WISC) and the revised version (WISC-R) (less than 5 years). Mean IQ for the group (Stanford-Binet and WISC) at termination of dietary therapy was 104 +/- 13. Four to 7 years after discontinuation of dietary therapy, mean IQ for the group was 90 +/- 13. The severity correlated, to some degree, with duration of unrestricted diet, but not with initial serum phenylalanine concentrations, age at initiation of therapy, or IQ at time diet was discontinued. Several children are experiencing difficulties, both attentional and academic, in school. Two children have had a change in the EEG from normal to abnormal. Neurologic testing performed after 4 to 7 years off diet demonstrated deficits in visual-motor integration or cognitive problem-solving in most children. The mean developmental age for the group for perceptual-motor integration was 1.2 years below the mean chronologic age of the group. This deterioration in intellectual function suggests that discontinuation of the phenylalanine-restricted diet is hazardous for some children with classic phenylketonuria.     

Intellectual and school performances in early-treated classical PKU patients

Conclusion We did not observe any loss of mean IQ scores measured at 11 when PKU diet was stopped as early as 5 years of age compared to 8 years. Nevertheless, 44% of these children presented learning disabilities and repeated one or more school years. These difficulties appear before or at early elementary school level and are independent of the age of diet discontinuation between 5 and 8 years. They seem to be related to perceptual motor dysfunction, suggesting the possibility of a specific deficit that could seriously interfere with academic progress but which is not accompanied by obvious impairment of overall intellectual functioning [1, 4–7, 9]. Among the children who repeated at least 1 year, there was a much higher percentage of pupils who repeated 2 or more school years than in the scholar national average population. The most important factor related to these difficulties seems to be the parents' socioeconomic status, which is also correlated with the children's IQ scores. This influence is not due to the quality of the diet, which is roughly similar for all the patients whatever their school performance. PKU seems to amplify learning difficulties already present in unaffected siblings. Whether the difficulties would be avoided by continuing the diet throughout elementary school remains undemonstrated.Abbreviations NEMI new metric scale of intelligence - WISC Wechsler intelligence scale of children - PKU phenylketonuria     

Dietary patterns in infancy and cognitive and neuropsychological function in childhood

Background: Trials in developing countries suggest that improving young children’s diet may benefit cognitive development. Whether dietary composition influences young children’s cognition in developed countries is unclear. Although many studies have examined the relation between type of milk received in infancy and subsequent cognition, there has been no investigation of the possible effect of variations in the weaning diet. Methods: We studied 241 children aged 4 years, whose diet had been assessed at age 6 and 12 months. We measured IQ with the Wechsler Pre‐School and Primary Scale of Intelligence, visual attention, visuomotor precision, sentence repetition and verbal fluency with the Developmental Neuropsychological Assessment (NEPSY), and visual form‐constancy with the Test of Visual Perceptual Skills. Results: In sex‐adjusted analyses, children whose diet in infancy was characterised by high consumption of fruit, vegetables and home‐prepared foods (‘infant guidelines’ dietary pattern) had higher full‐scale and verbal IQ and better memory performance at age 4 years. Further adjustment for maternal education, intelligence, social class, quality of the home environment and other potential confounding factors attenuated these associations but the relations between higher ‘infant guidelines’ diet score and full‐scale and verbal IQ remained significant. For a standard deviation increase in ‘infant guidelines’ diet score at 6 or 12 months full‐scale IQ rose by .18 (95% CI .04 to .31) of a standard deviation. For a standard deviation increase in ‘infant guidelines’ diet score at 6 months verbal IQ rose by .14 (.01 to .27) of a standard deviation. There were no associations between dietary patterns in infancy and 4‐year performance on the other tests. Conclusions: These findings suggest that dietary patterns in early life may have some effect on cognitive development. It is also possible that they reflect the influence of unmeasured confounding factors.     

Final intelligence in late treated patients with phenylketonuria

Despite neonatal screening programmes, there is still a number of patients with phenylketonuria who are not diagnosed and start treatment late. The question in this study was to evaluate which factors will contribute, other than the quality and duration of dietary treatment, to final outcome in late treated patients with phenylketonuria. We retrospectively analysed the data of 40 patients with phenylketonuria, of whom 2 patients at 35 and 24 years of age had a normal IQ despite never being treated. In 38 patients starting dietary treatment between 0.7 and 7 years of age, mean IQ/DQ at diagnosis was 52.7 (SD=16) (mean age 2.5 years), final IQ (mean age 33.5 years) was 79.0 (SD=16), the difference was highly significant (P < 0.0001). Important factors for the final intelligence in adult late treated patients with phenylketonuria were onset (r=т.46, P < 0.009) and DQ/IQ (r=0.51, P < 0.002) when dietary treatment was started. Thus, in late treated patients with phenylketonuria, in addition to the quality and duration of treatment, the outcome is mainly influenced by the age of starting treatment and also by the intellectual status of the patient. In one of the two patients with normal intelligence, nuclear magnetic resonance spectroscopy showed that brain phenylalanine was undetectable even though blood phenylalanine was 30 mg/dl. A second metabolic disorder may protect these patients from severe brain damage. Conclusion These data indicate that brain damage in untreated or late treated patients with phenylketonuria is influenced by various genetic factors.     

Phenylalanine control and family functioning in early-treated phenylketonuria

The association between effective metabolic control and patients' intelligence test performance and behavior in phenylketonuria (PKU) has been demonstrated frequently. The present study reexamined this relationship in a population of 41 young children with early-treated PKU, and added a dimension of family investigation to determine relationships between dietary phenylalanine control and patient functioning, family functioning and phenylalanine control, and family functioning and patient functioning. Significant correlations were found between concurrent phenylalanine control and patients' intelligence test scores, and lifetime phenylalanine control and patients' social competence. Parent-report measures of family psychological adjustment, stress, interaction, and socioeconomic status showed no significant association with children's dietary phenylalanine control. Family cohesion and adaptability correlated positively with patients' cognitive performance. Results support a policy of diet continuation in PKU, and suggest that family interaction patterns influence patient functioning. Longitudinal study of family factors in PKU is indicated.     

Novel PKU treatment methods

Identification of a disease causing gene rarely leads to the invention of a novel therapy. Even in the case of genetic disorders or diseases greatly influenced by a hereditary component, knowledge about the genotype does not necessarily result in the invention of a novel therapy. In many cases effective treatment was introduced earlier without any existing knowledge of the molecular basis of the disease, or even without a full recognition of the pathomechanisms. Phenylketonuria is the best known example. Great expectation are connected with experimental therapy of phenylketonuria: enzymatic therapy, blocking the brain-blood barrier for phenylalanine and novel forms of low phenylalanine diet. Molecular diagnostics could be helpful in identifying patients responsive to non-standard therapy, such as tetrahydrobipterin supplementation. Novel research and development strategies will contribute to a reduction of the negative aspects of present treatment and they will facilitate normal physical a intellectual development of children with phenylketonuria, as well as to help patients in their everyday life.     

Intellectual development in 12-year-old children treated for phenylketonuria

Intelligence and achievement test scores were evaluated for 95 12-year-old children with phenylketonuria who had begun dietary therapy during the neonatal period. Dietary control of blood phenylalanine below 900 mumol/L was maintained beyond age 10 years in 23 children; 72 others had blood phenylalanine persistently above that level at ages ranging from 18 months to 10 years. Test scores at age 12 years were negatively correlated with the age at initiation of diet and with blood phenylalanine levels from ages 4 to 10 years, and positively correlated with parent IQ scores and the age at loss of dietary control. Children who maintained phenylalanine levels below 900 mumol/L beyond age 10 years showed no deficits in test scores, except for arithmetic, the scores of which declined between ages 6 and 12 years in 90% of the children in this study. These data strongly support a recommendation that dietary restriction of phenylalanine should be maintained through adolescence.     

Effect of dietary non-compliance on development in phenylketonuria--studies of 14-year-old patients

25 children with early treated PKU were studied at the age of 14 years. The IQ was higher at the age of 6-8, 10 and 14 years if the dietary control was good (75% of the control values up to 10 mg/dl) compared to children with poor control. The IQ however decreased up to the age of 14 years in both groups. Discontinuation of the diet in children with a good dietary control at the age of 6 years because of a normal EEG after phenylalanine loading causes a decrease of the IQ from 100 at 6 years to 90 at 10 years. The IQ remains stable thereafter up to 14 years. The IQ ist lower at the age of 7 or 8 years in those children in whom the discontinuation of diet is delayed because of abnormal EEG after phenylalanine loading at the age of 6 years, but remains stable up to the age of 14. According to these results a discontinuation of the diet at the age of 6 years can not be recommended even if the EEG is normal after phenylalanine load.     

Early breastfeeding is linked to higher intelligence quotient scores in dietary treated phenylketonuric children

Strict control of phenylalanine intake is the main dietary intervention for phenylketonuric children. Whether other dietary-related factors improve the clinical outcome for treated phenylketonuric children in neurodevelopmental terms, however, remains unexplored. We retrospectively compared the intelligence quotient (IQ) score of 26 school-age phenylketonuric children who were either breastfed or formula fed for 20-40 days prior to dietary intervention. Children who had been breastfed as infants scored significantly better (IQ advantage of 14.0 points, p = 0.01) than children who had been formula fed. A 12.9 point advantage persisted also after adjusting for social and maternal education status ( p = 0.02). In this sample of early treated term infants with phenylketonuria there was no association between 1Q scores and the age at treatment onset and plasma phenylalanine levels during treatment. We conclude that breastfeeding in the prediagnostic stage may help treated infants and children with phenylketonuria to improve neurodevelopmental performance.     

Factors affecting cognitive, motor, behavioral and executive functioning in children with phenylketonuria

We administered measures of cognitive, frontal lobe (executive), behavioral and motor functioning to 18 children with classical phenylketonuria, aged 12–101 months, in order to determine the relationship of age, current and lifetime average phenylalanine levels, and individual variation (standard deviation of lifetime average levels) to these functions. On measures of cognitive function, in children ≥ 3 y of age lower current phenylalanine levels were associated with higher cognitive functioning. On a behavioral temperament scale designed for normal children, we found that higher current and average phenylalanine levels correlated with more difficult temperament. Motor function was also poorer in children with phenylketonuria, and was most impaired in children with current phenylalanine levels >360μmol/l. We also identified a previously unreported correlation between increased individual variation and poorer executive function performance, a finding that may raise new management concerns about level fluctuations. Maintenance of phenylalanine levels μ 360 μml/l may be necessary for optimal performance in children with phenylketonuria.     

Embryofetopathy caused by postnatally detected maternal phenylketonuria

A case of a now 10-month-old female infant is reported, who presented at birth with microcephalus, growth retardation, dystrophia, facial dysplasia and cardiac defect. Etiologically a classical phenylketonuria of the mother with very high levels of serum phenylalanine (51 and 41 mg/dl, respectively), which was not known until then, was diagnosed already after her confinement. The mother, aged 26, originates from Roumania. She had never been treated by any phenylalanine-limited diet. Psychological testing revealed a severely reduced intelligence (IQ = 63). The child, having normal levels of serum phenylalanine, presented with mild statomotor retardation at the age of ten months. Even in countries with a general neonatal screening program, a hitherto undiagnosed maternal phenylketonuria has to be considered within the differential diagnosis of a dystrophic microcephalic newborn, beside more common causes like the fetal alcohol syndrome.     

Children with Inborn Errors of Phenylalanine Metabolism: Prognosis and Phenylalanine Tolerance

ABSTRACT. Twenty-three children, who were detected by neonatal PKU screening, were followed for 8-18 years in one paediatric centre. Dietary treatment was started if the blood phenylalanine level exceeded 0.72 mmolA. All 23 infants were initially given a low phenylalanine diet. The growth and development rates of the children did not differ significantly from those in a reference population, although one child had mild mental retardation and another had a short attention span. Fourteen children were still on a strict phenylalanine-restricted diet on their last follow-up (at 8-18 years of age). In nine children who were initially put on a low phenylalanine diet, it was possible to normalize the diet between 1/2 and 10 years of age, while maintaining the blood phenylalanine levels between 0.25 and 0.72 mmol/1. It seems likely that those of our patients who markedly increased their phenylalanine tolerance during childhood had a regulatory mutation of the phenylalanine hydroxylase system. A continuous reevaluation of each child treated with a low phenylalanine diet reduces the use of unnecessarily restricted diets.     

Children with inborn errors of phenylalanine metabolism: prognosis and phenylalanine tolerance

Twenty-three children, who were detected by neonatal PKU screening, were followed for 8-18 years in one paediatric centre. Dietary treatment was started if the blood phenylalanine level exceeded 0.72 mmol/l. All 23 infants were initially given a low phenylalanine diet. The growth and development rates of the children did not differ significantly from those in a reference population, although one child had mild mental retardation and another had a short attention span. Fourteen children were still on a strict phenylalanine-restricted diet on their last follow-up (at 8-18 years of age). In nine children who were initially put on a low phenylalanine diet, it was possible to normalize the diet between 1/2 and 10 years of age, while maintaining the blood phenylalanine levels between 0.25 and 0.72 mmol/l. It seems likely that those of our patients who markedly increased their phenylalanine tolerance during childhood had a regulatory mutation of the phenylalanine hydroxylase system. A continuous reevaluation of each child treated with a low phenylalanine diet reduces the use of unnecessarily restricted diets.     

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??Objective The intellectual profiles of children with AS were studied in order to better interpret their behavioral characteristics.Methods Totally 114 children of 6.08~14.24 years old with AS were examined by the China-Wechsler Intelligence Scale for Children ??C-WISC?? and all subtests were administrated.Results The level of intelligence of chidren ranged from mildly impaired to very superior??the average verbal intelligence quotient????VIQ????performance intelligence quotient??PIQ??and full intelligence quotient??FIQ?? were respectively 101.52±18.72??88.30±17.40 and 94.90±17.75??There was statistically significant difference between the VIQ and PIQ among children with AS and a tendency of VIQ??PIQ was showed??P??0.01??. The differences between scores on three Kaufman factors was significant??P??0.01??. Children with AS scored the highest on similarity??vocabulary and information subtests and scored the lowest on picture completion??picture arrangement and coding subsets in full scale??score on comprehension subtest was the lowest in the verbal scale and scores on block design and object assembly subtest were the highest in performance scale.Conclusion The intelligence structures of children with AS are not balanced??which is characterized by a combination of assets and deficits.     

URINARY PHENYLALANINE EXCRETION IN HYPERPHENYL-ALANINEMIC CHILDREN

24-hour phenylalanine loading tests were done in 5 children with persistent hyperphenyl-alaninemia off diet. The urinary excretion of phenylalanine were compared to the excretion after loading of phenylketonuric children on diet. Serum phenylalanine of children with persistent hyperphenylalaninemia returned to preloading levels (285 μmol/l) within 24 hours. These children, however, excreted phenylalanine during phenylalanine loading in lesser quantities than patients with phenylketonuria on diet. Serum phenylalanine of phenylketonuric children on diet attained preloading levels (300 μmol/l) approximately 14 days after loading. Thus, the present data do not support the hypothesis that hyperphenylalaninemic patients are phenylketonurics protected by increased urinary excretion of phenylalanine.