Behavior disturbance in 8-year-old children with early treated phenylketonuria. Report from the MRC/DHSS Phenylketonuria Register.

Using the Rutter Behavior Questionnaire, schoolteachers assessed the frequency of common abnormal behavior in 544 8-year-old children with phenylketonuria who were born in the United Kingdom and in whom the diagnosis was made by routine testing in infancy, either during the early years of screening (cohort 1, births 1964 to 1971) or after a national reorganization of the program (cohort 2, births 1972 to 1977). All children received treatment before 4 months of age. Two matched control subjects were assessed for each patient. Compared with the controls, patients in cohorts 1 and 2 receiving a strict low-phenylalanine (phe) diet (average phe concentration less than 600 mumol/L) were 1.5 and 1.7 times, respectively, more likely to have deviant behavior; those receiving a less well controlled diet were 2.5 and 1.9 times, respectively, more likely to show such behavior. Patients more often had mannerisms, hyperactivity, and signs of anxiety and were less responsive and more solitary than were controls. On the other hand, they were not more aggressive, untruthful, or disobedient, nor absent from school more frequently. The increased frequency of deviant behavior may be the result of both psychologic stress and neurologic impairment.

The investigation of atypical psychosomatic illness. A team approach to diagnosis.

The experience of 12 children with atypical psychosomatic illness who presented considerable diagnostic difficulties is described. All patients were admitted to the hospital, and using a team approach, it was possible to make a confident diagnosis. No organic disease was identified, and a psychosomatic diagnosis was made. In general, atypical symptoms and signs, false-positive investigations, and differing medical opinion had compounded the diagnostic difficulties. The value of the observations made by ward staff of the childrens' symptoms and behavior is stressed.

Amino acid and protein requirements in a preterm infant with classic phenylketonuria.

A preterm infant with classic phenylketonuria required rather less than 90 mg/kg of phenylalanine and between 270 and 290 mg/kg tyrosine daily to achieve a rate of weight gain of around 20 g/kg per day. Using Lofenalac as the low phenylalanine food, the intake of tyrosine, an essential amino acid for patients with phenylketonuria seemed to be limiting in respect of growth.

The role of vitamin E in the treatment of the neurological features of abetalipoproteinaemia and other disorders of fat absorption.

Studies in patients with abetalipoproteinaemia and other chronic and severe fat malabsorptive states, and neuropathological studies in the vitamin E-deficient human, monkey and rat indicate that vitamin E is important for normal neurological function. Appropriate vitamin E supplementation is, therefore, advisable for all patients with chronic fat malabsorption who have low serum vitamin E concentrations.

Prevalence of obesity in British children born in 1946 and 1958.

The prevalence of overweight at ages 7 and 11 years and in late adolescence was compared in two nationally representative cohorts of British children born in 1946 and 1958. Overweight was defined as weight that exceeded the standard weight for height, age, and sex by more than 20% (relative weight greater than 120%). The prevalence of overweight among 7 year olds born in 1958 was nearly twice that among those born in 1946. Changes in infant feeding practices, food supply, and level of physical activity might be responsible for this difference. By adolescence the prevalence of obesity in both cohorts had increased but the difference between cohorts had almost disappeared. Around 9% of adolescent girls and 7% of adolescent boys were overweight. If infant feeding practices have an influence on prevalence of overweight at 7 years the data from the two cohorts suggest that such an effect does not persist. In neither cohort was there a significant relation between the prevalence of obesity and social class in boys, but in girls the prevalence was higher among those from the lower socioeconomic groups. Correlation coefficients showing the strength of the relation between relative weights at different ages were remarkably similar for both cohorts. The risk of being obese later in childhood for those who had not been obese at the age of 7 was less than one in 10, whereas for those with a relative weight greater than 130% the risk exceeded six in 10.

Vitamin E and neurological function: abetalipoproteinaemia and other disorders of fat absorption.

Evidence that vitamin E is important for normal neurological function in humans is presented. First, in abetalipoproteinaemia early therapy with vitamin E delays and may prevent the development of the neurological complications, and in patients with established lesions treatment can arrest or reverse the neuropathy. Second, in other chronic disorders of fat absorption with severe vitamin E deficiency, neurological manifestations which are very similar to those described in untreated abetalipoproteinaemia can be improved by vitamin E. Vitamin E supplementation is therefore advisable for all patients with chronic fat malabsorption who have low serum vitamin E concentration. Serum vitamin E concentrations should also be measured in patients with spinocerebellar disorders, whatever the aetiology.

Vitamin E and neurological function.

Three lines of evidence indicate that vitamin E is important for normal neurological function in man. First, in abetalipoproteinaemia early therapy with vitamin E delays, and may prevent, the development of neurological complications, and in patients with established lesions treatment can arrest or reverse the neuropathy. Secondly, in other chronic disorders of fat absorption with severe vitamin E deficiency, neurological manifestations can be improved by vitamin E. Thirdly, the neuropathological changes observed in vitamin-E-deficient states in man (such as abetalipoproteinaemia, chronic liver disease, and cystic fibrosis) are similar to those reported in vitamin-E-deficient rats and monkeys.

Longitudinal study of obesity in the National Survey of Health and Development.

In a nationally representative cohort of 5362 children born in one week in March 1946 weights and heights were recorded at 6, 7, 11, 14, 20, and 26 years. Overweight was defined as a weight that exceeded the standard weight for height, age, and sex by more than 20% (relative weight greater than 120%). The prevalence of overweight was 1.7% and 2.9% in boys and girls respectively at 6 years; 2.0% and 3.8% at 7 years; 6.4% and 9.6% at 11 years; 6.5% and 9.6% at 14 years; 5.4% and 6.5% at 20 years; and 12.3% and 11.2% at 26 years. The risk of being overweight in adulthood was related to the degree of overweight in childhood and was about four in 10 for overweight 7-year-olds. Analysis of the data in the reverse direction showed that 7% and 13% respectively of 26-year-old overweight men and women had been overweight at the age of 7. These results suggest that there is no optimal age during childhood for the prediction of overweight in adult life and that excessive weight gain may begin at any time. Overweight children are more likely to remain overweight than their contemporaries of normal weight are to become overweight.

Effects of delipidated serum and lipoprotein-deficient serum on sterol biosynthesis and efflux in cultured skin fibroblasts - a comparison of the behaviour of cells from a control with those from a heterozygote and homozygote for familial hypercholesterolaemia.

The biosynthesis and efflux of sterols from cells into the medium were investigated in skin fibroblasts from a control, a patient with obligate heterozygous familial hypercholesterolaemia and a patient with the homozygous condition. The behaviour of the cells was studied in two lipid free media (lipoprotein deficient and delipidated serum), with and without the addition of low density lipoproteins (LDL) in order to find experimental conditions which showed maximum differences between the three cell lines. Incorporation of [14C]acetate into sterols in the presence (repression) and absence (induction) of LDL was similar in the normal and heterozygous cells, whereas the homozygous cells showed reduced repression and increased induction. In all three cell lines induction of sterol synthesis was greater with delipidated than lipoprotein deficient serum. The efflux of sterols in both the presence and absence of LDL did not differ between the three cell lines, but it was greater when LDL was added to the medium and when delipidated serum was used. Sterol biosynthesis and efflux from the cells of the heterozygote did not differ significantly from those of the control.

A polymorph bactericidal defect and a lupus-like syndrome.

We describe a child with primary defect of polymorph bacterial killing associated with systemic lungs erythematosus. We suggest that her autoimmune disease results from chronic bacterial antigen stimulation and propose a hypothetical model linking immunodeficiency with autoimmunity.

Effect of naloxone in a previously undescribed hypothalamic syndrome. A disorder of the endogenous opioid peptide system?

A syndrome of disordered hypothalamic function with abnormal control of temperature, appetite, and thirst, hyperprolactinaemia, and inappropriate vasopressin release is described in a 13-year-old boy who, in addition, had insensitivity to pain and a more general disorder affecting mood, sleep, and control of respiration. A disturbance of the opioid peptide system is postulated. Naloxone reversed central analgesia, altered urine fluid and electrolyte excretion, modified the hormonal response to gonadotrophin-releasing and thyrotrophin-releasing hormones, and improved the auditory and visual reaction times. Specific opioid antagonists may have a therapeutic role.

Studies in primary hypomagnesaemia: evidence for defective carrier-mediated small intestinal transport of magnesium.

A 4 year old male with primary hypomagnesaemia was studied using balance and steady-state perfusion techniques. Magnesium balance was negative and could be accounted for by increased faecal losses, renal conservation being normal; calcium balance was normal. After oral magnesium therapy magnesium balance became positive. The perfusion studies demonstrated net loss of magnesium into the intestinal lumen when low concentrations (1 and 2 mmol/l) of magnesium were perfused in contrast with control subjects; whereas at high concentrations (10 mmol/l a net absorption of a magnitude similar to control values was observed. In the control subjects sequential perfusion of increasing concentrations of magnesium demonstrated a curvilinear relationship between rates of absorption and the lower concentrations (1, 2, and 4 mmol/l) with an apparent Km and Vmax of 4.5 mmol/l and 91 nmol/min/cm respectively. At the higher concentrations (6 and 10 mmol/l) the relationship was linear. These data suggest that two separate transport systems participate in the absorption of magnesium from the proximal small intestine; a carrier-mediated system which saturates at low intraluminal concentrations, and a simple diffusional process. The possibility of the second transport system being a carrier-mediated process with a very much higher Km cannot be excluded. In primary hypomagnaesaemia the results suggest that the primary abnormality is a defect in carrier-mediated transport of magnesium from low intraluminal concentrations of magnesium.

Fetal damage despite low-phenylalanine diet after conception in a phenylketonuric woman.

A woman with phenylketonuria gave birth to an infant with a cardiac defect and microcephaly despite introduction of a low-phenylalanine diet 5 weeks after conception (3 weeks after the first missed period). In maternal phenylketonuria fetal damage leading to reduced brain growth and cardiac malformations probably occurs within a few weeks of conception.

Behavioural deviance in children with early treated phenylketonuria.

A sample of 99 early treated phenylketonuric children showed higher levels of behavioural deviance than 197 matched controls. For boys this excess of behavioural deviance persisted when IQ was taken into account. For phenylketonuric girls however it was restricted to those with IQs less than 70. The type of behavioural deviance shown by the boys over the whole IQ range was predominantly neurotic. The levels of behavioural deviance found in phenylketonuric children were among the highest that have been reported for children with various handicapping conditions.

Effect of stopping low-phenylalanine diet on intellectual progress of children with phenylketonuria.

Forty-seven patients at the Hospital for Sick Children, London, who had phenylketonuria and were on a low-phenylalanine diet (21 early-treated--that is, treatment started before the age of 4 months--and 26 late-treated) were placed on a normal diet between the ages of 5 and 15 years. They showed significant falls in mean IQ of about six points after the diet was withdrawn. Twenty-two similar patients (five early-treated and 17 late-treated) at the Universitäts-Kinderklinik, Heidelberg, who were placed on a relaxed low-phenylalanine rather than a normal diet, showed smaller and non-significant falls in mean IQ. During the period of strict diet none of the patients in London or Heidelberg showed any consistent falls in IQ. These results suggest that complete withdrawal of the low-phenylalanine diet during childhood leads to a fall in intellectual progress in many patients.