Development of intelligence in early treated phenylketonuria

Designs, analyses and results of longitudinal studies of intelligence of patients treated early for phenylketonuria (PKU) are reviewed. All studies converge on the conclusion that after the age of 10 years, IQ development is stable for different degrees of dietary relaxation. On average, for each 300 wmol/l increase in blood phenylalanine (Phe) levels pre-school, IQ decreases by about half a standard deviation. Children with Phe levels below 400 wmol/l in early and middle childhood had the best outcomes which were near normal. PKU seems to suppress the global level of IQ without impairment of domain-specific competencies. For historical reasons there is no research on IQ development of early treated patients in middle or late adulthood, and it remains unclear whether older age groups might carry new risks. Conclusion It is argued that control group designs, meta-analysis, and interdisciplinary studies combining psychology, neurology and neuropathology could increase the understanding of phenylketonuria as well as the scientific basis of its treatment.     

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 8 and 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 8 years.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Very low birth weight infants: effects of brain growth during infancy on intelligence quotient at 3 years of age

To evaluate the role of postnatal growth on IQ at 3 years of age, 139 appropriate for gestational age, very low birth weight infants (less than 1.5 kg) born in 1977 and 1978 were studied at 40 weeks (term), and at 8, 20, and 33 months (corrected) of age. Weight, height, and head circumference were measured at each age, neurologic status was measured at 20 months, and Stanford Binet IQ at 33 months. Multiple regression analysis revealed that head circumference at 8 months of age is the best growth predictor of IQ at 3 years of age. Path analysis was performed to measure the effects of biologic and social factors measured earlier in life on IQ at 3 years. These factors explained 43% of the variance in IQ at 3 years of age. Head circumference at 8 months had a direct effect on IQ at 3 years, controlling for all other variables in the model. Neonatal risk had an indirect effect via head circumference. Neurologic impairment had direct and indirect (via head circumference) effects; race and socioeconomic status had direct effects on IQ but no effects on growth at 8 months of age. Thus, brain growth at 8 months significantly influenced 3 year IQ at 3 years of age among very low birth weight infants, even when medical and sociodemographic variables were controlled.     

Phenylketonuria: diet for life or not?

In order to evaluate the argument whether or not a restricted phenylalanine diet should be maintained for life in patients with phenylketonuria (PKU), 16 patients with early treated PKU but off diet since their 11th birthday were investigated. The evaluation included a detailed neurological examination, IQ, neurophysiological testing and MRI of the brain. Even if IQ and electrophysiological studies were normal or unchanged if compared to results before diet discontinuation, all patients revealed abnormal neurological signs. We conclude that the diet should be continued during adult life, but somewhat higher phenylalanine levels (<10mg/dl;<600 micromol/l) than at younger ages should be allowed.     

Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997

Treatment of hyperphenylalaninaemias due to phenylalanine hydroxylase deficiency with a low phenylalanine (Phe) diet is highly successful in preventing neurological impairment and mental retardation. There is consensus that, for an optimal outcome, treatment should start as early as possible, and that strict blood Phe level control is of primary importance during the first years of life, but for adolescent and adult patients international treatment recommendations show a great variability. A working party of the German Working Group for Metabolic Diseases has evaluated research results on IQ data, speech development, behavioural problems, educational progress, neuropsychological results, electroencephalography, magnetic resonance imaging, and clinical neurology. Based on the actual knowledge, recommendations were formulated with regard to indication of treatment, differential diagnosis, and Phe level control during different age periods. The development of the early-and-strictly-treated patient in middle and late adulthood still remains to be investigated. Therefore, the recommendations should be regarded as provisional and subject to future research. Efficient treatment of phenylketonuria has to go beyond recommendations for blood Phe level control and must include adequate dietary training, medical as well as psychological counselling of the patient and his family, and a protocol for monitoring outcome. Conclusions Early-and-strictly-treated patients with phenylketonuria show an almost normal development. During the first 10 years treatment should aim at blood Phenyl-alanine levels between 40 and 240 μmol/L. After the age of 10, blood phenylalanine level control can be gradually relaxed. For reasons of possible unknown late sequelae, all patients should be followed up life-long. Received: 11 July 1997 / Accepted in revised form: 25 August 1998     

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.     

Influence of Excess Dietary Phenylalanine on Phenylalanine Levels in Rat Brain

Pregnant and non-pregnant rats were fed the commercial chow with or without 7% L-phenylalanine. Phenylalanine levels in the blood and various organs in these rats were determined by the fluorometric method. 1) The liver and kidney levels were little influenced with 7% phenylalanine diet, whereas the brain level was elevated to approximately twice the normal value, when the blood levels was also increased to the same extent. The elevated levels of both brain and blood returned to normal levels after changing to normal diet. 2) Blood phenylalanine levels in the fetus averaged twice as high as the maternal levels. Brain levels of phenylalanine in the fetus were remarkably elevated in proportion to the elevation of blood levels. On the other hand, the elevation of maternal brain levels were not proportional to that of blood levels.     

Long-term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early

In 34 children with phenylketonuria (PKU) treated early the prognostic value of the age on institution of the diet (within the first 3 months of life) and of the quality of dietary treatment was determined in two different ways: 1) following intelligence closely (IQ) and (2) evaluating the EEG development up to their 12th (n=34) and 15th (n=18) years of life as appropriate. In general, IQ scores were found to be normal from the 4th–15th years of life. In our group of patients there was no effect on the IQ of the timing of diet onset. Children with strict dietary control showed a significantly higher IQ than those with loose control. One hundred and fifty-four EEGs (10/20 system, awake with eyes closed) were recorded at intervals of 2 years and conventionally evaluated. The development of alpha-activity was found to be normal. Beta-activity was enhanced. Abnormal EEG findings like general slowing and generalized paroxysmal activity (GPA) with or without spikes were more frequent in children with PKU than in controls, with the exception of focal abnormalities. EEG abnormalities increased with advancing age independently of IQ development and showed no relation to either the age at the onset nor the quality of dietary treatment.Abbreviations PKU phenylketonuria - PHE phenylalanine - GPA generalized paroxysmal activity - IDC index of dietary control     

The Influence of Phenylalanine Intake on the Chemistry and Behaviour of a Phenylketonuria Child

Summary
Phenylketonuria is a not uncommon cause of mental deficiency (there are probably 1600 cases in Great Britain alone). On the supposition that the high level of phenylalanine or its breakdown products in the blood and cerebrospinal fluid might be responsible for the mental retardation in this disorder we have treated a two year-old child with a diet low in phenylalanine. The introduction of this diet was associated with an appreciable improvement in the patient's mental status and a fall in the level of phenylalanine in the blood and urine. When phenylalanine was again given in fairly large amounts there was an immediate and dramatic deterioration in the child's mental and biochemical condition. A similar phenylalanine intake produced no clinical reaction in a control child.
The main source of aminoacids in the diet was an acid casein hydrolysate which was specially treated to remove phenylalanine. The aim of the phenylalanine-poor diet was to keep the phenylalanine blood level as near the normal range as possible. The preparation of such a diet presents little difficulty if a phenylalanine-free casein hydrolysate is available. Its value in the treatment of other children is at present being investigated; it seems reasonable to assume that patients in the first two years of life will benefit most.     

The Influence of Phenylalanine Intake on the Chemistry and Behaviour of a Phenylketonuric Child

Phenylketonuria is a not uncommon cause of mental deficiency (there are probably 1600 cases in Great Britain alone). On the supposition that the high level of phenylalanine or its breakdown products in the blood and cerebrospinal fluid might be responsible for the mental retardation in this disorder we have treated a two year-old child with a diet low in phenylalanine. The introduction of this diet was associated with an appreciable improvement in the patient's mental status and a fall in the level of phenylalanine in the blood and urine. When phenylalanine was again given in fairly large amounts there was an immediate and dramatic deterioration in the child's mental and biochemical condition. A similar phenylalanine intake produced no clinical reaction in a control child.
The main source of aminoacids in the diet was an acid casein hydrolysate which was specially treated to remove phenylalanine. The aim of the phenylalanine-poor diet was to keep the pbenylalanine blood level as near the normal range as possible. The preparation of such a diet presents little difficulty if a phenylalanine-free casein hydrolysate is available. Its value in the treatment of other children is at present being investigated; it seems reasonable to assume that patients in the first two years of life will benefit most.     

Intelligence and quality of dietary treatment in phenylketonuria.

The records of the Phenylketonuria Register were examined to determine the factors associated with early intellectual progress in children who had received a diet low in phenylalanine from soon after birth. A total of 1031 children were born between 1964 and 1980 and started treatment before they were 4 months of age, and 808 of them were followed up prospectively. In 263 children born between 1964 and 1971 (cohort 1), the mean intelligence quotient (IQ) at 4 years rose with year of birth from 24 points below revised IQ norms to 10 points below; in 545 born between 1972 and 1980 (cohort 2) there was no further rise in IQ and the mean remained eight points below the norms. IQ fell progressively by roughly four points for each four weeks'' delay in starting treatment, for each 300 mumol/l rise in mean phenylalanine concentrations during treatment, and for each five months during the first two years during which phenylalanine concentrations were below 120 mumol/l. Forty six children in cohort 2 had the most favourable treatment characteristics. Their mean IQ, after standardising for social class, was 112.6, and similar to the mean for the same group estimated by multiple regression, and to revised population IQ norms for the period during which the children were tested. The data suggest that many children who are treated early continue to suffer a mild degree of neurological impairment because of the difficulties in fully controlling the metabolic abnormality.     

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.     

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.