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.     

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.     

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.     

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.     

Effect of father's death or departure on growth of poor children in Peru

Between 1966 and 1976, heights and weights were determined yearly on all available children from 163 families who had had at least one child successfully treated for malnutrition between 1961 and 1971 and from eight families who had adopted such a child. Between 1959 and 1976, a total of 72 fathers departed from these families: 12 died, 47 deserted, six were jailed, and seven left to look for work elsewhere. Heights and weights as Z scores and the weight age/height age ratios were analyzed, when available, during four periods around the date of the event: 6 to 18 months before (period 1B), 0 to 6 months before (period 2B), 0 to 6 months after (period 3A), and 6 to 18 months after (period 4A). Mean Z scores for all children measured in the period were already low (-0.26 +/- 0.93 and -0.25 +/- 0.95) during period 1B, were higher during period 2B, (-0.15 and 0.04), lower during period 3A (-0.39 and -0.46), and similar to original levels during period 4A (-0.37 and -0.27). Mean weight age/height age was low (0.93 +/- 0.17) only during period 3A for children 2 to 18 years of age. In paired comparisons for children measured during any two periods there were significant increases in Z height and Z weight from periods 1B to 2B and from periods 1B to 4A in children less than 2 years of age and a significant decrease in the weight age/height age ratio from periods 1B to 3A in those 2 to 18 years of age. Loss of father had little or no further impact on the already poor growth of these children.     

Childhood adherence to a potentially healthy and sustainable Nordic diet and later overweight: The Norwegian Mother,Father and Child Cohort Study (MoBa)

The New Nordic Diet (NND) is a potentially healthy and sustainable dietary pattern represented by locally available and traditionally consumed foods in the Northern countries. The diet has been commonly examined in adult populations, but less is known regarding its potential associations with overweight/obesity in children. We have previously developed child diet scores measuring compliance to the NND at child age 6 and 18 months and 3 and 7 years. In this study, we aimed to describe child and maternal characteristics and assess potential associations between the age‐specific diet scores and child overweight at 8 years. This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), including 14,989 mother–child pairs and uses data from the Medical Birth Registry of Norway (MBRN). The scores measured NND compliance as a total score and categorized into low, medium and high NND compliance at each age point. Using logistic regression models, we investigated the association between each age‐specific score and the odds of overweight at 8 years. In crude analyses, adherence to the NND at 6 months was inversely associated with odds of overweight at 8 years in the continuous score (odds ratio = 0.95, 95% CI [0.91, 0.98]) and when comparing high versus low NND adherence (odds ratio = 0.81, 95% CI [0.70, 0.94]). The association was almost entirely attenuated in the adjusted models. In conclusion, child NND adherence up to 7 years of age was not associated with odds of overweight at 8 years in adjusted analyses.     

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.     

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.     

Predictors of intelligence quotient and intelligence quotient change in persons treated for phenylketonuria early in life

Ninety-one individuals with phenylketonuria who were treated early in life were followed for as many as 22 years. Regression analyses were used to determine the best predictors of IQ and IQ change. Among treatment-related variables, good dietary control of the blood phenylalanine level stood out as the best predictor of IQ. Diet discontinuation and the natural (off diet) blood phenylalanine level best predicted IQ loss, suggesting that diet continuation may be important for children with natural blood phenylalanine levels greater than 18 mg/dL.     

Cows' milk sensitive enteropathy in cystic fibrosis.

Proximal small intestinal mucosal biopsies were carried out in children with cystic fibrosis who had diarrhoea and failed to thrive in spite of adequate treatment, including pancreatic supplements. Histological examination of eight of the 17 biopsies taken over a period of 12 years showed evidence of enteropathy, and accounted for one in 13 (8%) children with cystic fibrosis under 3 years of age attending our clinic. Seven responded to a cows'' milk free diet; the diarrhoea stopped and weight gain increased. One of these responded only when gluten was also excluded from his diet. The eighth child remained on a normal diet and his symptoms did not improve. The enteropathy had resolved in all five patients who had further biopsies taken while receiving treatment, and from 15 months to 3 years of age all the children tolerated a normal diet and continued to thrive. Cows'' milk sensitive enteropathy is an important cause of failure to thrive in children with cystic fibrosis. Small intestinal biopsy is an important investigation in younger children who fail to thrive and have diarrhoea despite adequate treatment.     

Peripheral blood eosinophils and IL-4 in infancy in relation to the appearance of allergic disease during the first 6 years of life

Eosinophils in peripheral blood and serum levels of interleukin (IL)-4 were analysed at 3 and 18 months and at 6 years in a prospective study comprising 67 children, of whom the majority had atopic heredity. The children were monitored from birth up to 6 years of age and the findings were related to family history of allergy and development of allergic disease. Twenty-nine children (43%) of the original group of 67 children were diagnosed as allergic at the age of six. Fifteen of 23 children with eosinophilia (>4 x 10(8) eosinophils/l) at 3 months of age were regarded as allergic at 6 years, when compared with 12 out of 38 children with normal eosinophil counts at 3 months (chi2 = 6.7, p < 0.01). Children with detectable IL-4 in serum at 18 months were more often allergic at 6 years, when compared with those children with no detectable IL-4 (chi2 = 8.6, p < 0.01). Furthermore, the allergic children had a mean IL-4 value of 0.35 microg/l (95% CI: 0.10-1.48) at 18 months, when compared with 0.17 microg/l (95% CI: 0.10-0.72, p < 0.001) in the non-allergic children. At 6 years of age, only nine children had detectable levels of IL-4 and five of them were classified as allergic. Eosinophilia at this age was also associated with allergic disease. We conclude that eosinophilia during infancy and increased levels of IL-4 at 18 month of age are associated with allergic disease during the first 6 years of life. This might indicate that the first 2 years of life are particularly important for the development of allergy.     

BLOOD PRESSURE IN CHILDREN AND ADOLESCENTS

Abstract. Blood pressure (BP) levels were recorded in 2 223 male and 2 205 female children and adolescents ranging in age from 7 to 18 years. In addition, 521 male adults (soldiers) ranging in age from 21 to 25 years were included in the study. Children and adolescents who participated in the survey were selected at random from the Elementary and High Schools. The results of the study showed that a gradual increase occurred in the systolic, as well as in the diastolic component of blood pressure from 7 to 18 years of age. By contrast, there was no increase with age in the systolic and diastolic blood pressure in the young male adult subjects, who had BP measurements comparable to those observed in children. A child was characterized as hypertensive according to the criteria outlined by Master et al. Children with BP between the 90th and the 95th percentile were considered as suspect hypertensive, whereas those with BP exceeding the 95th percentile were considered definitely hypertensive. The overall incidence of hypertension in children in this survey was 3.1%.     

Pancreatic exocrine and endocrine function after pancreatectomy for persistent hyperinsulinaemic hypoglycaemia of infancy.

AIM: To evaluate long term detailed pancreatic endocrine and exocrine function in children with persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) after 85-95% pancreatectomy. METHODS: Six children with PHHI between 0.9 and 12.7 years after pancreatic resection underwent clinical and investigative follow up at 1.0 to 14.9 years of age. One child with PHHI who had not had pancreatectomy was also assessed. Standard endocrine assessment, pancreatic magnetic resonance imaging (MRI), and detailed direct and indirect tests of exocrine pancreatic function were performed. RESULTS: Pancreozymin-secretin stimulation test results were normal in only one child, borderline in two, and deficient in four, one of whom requires daily pancreatic enzyme supplements. Pancreolauryl tests performed in three children were borderline in two and abnormal in the other. Only one child had low faecal chymotrypsin values. One child developed insulin dependent diabetes at 9 years and two children at 1.0 and 13.3 years require diazoxide to maintain normoglycaemia. MRI showed no major regrowth of the pancreatic remnant after resection (n = 5). CONCLUSIONS: Clinical evidence of endocrine or exocrine dysfunction has developed in only two patients to date, but detailed pancreatic function testing suggests subclinical deficiency in all but one of our patients with PHHI. Although 95% pancreatectomy results in postoperative control of blood glucose, subclinical pancreatic insufficiency is present on long term follow up and development of diabetes mellitus and exocrine failure remain ongoing risks.     

The Natural History of Childhood Asthma Through Adolescence

A follow-up of the natural history of childhood asthma at 17-18 years in a randomly selected population of asthmatic and control children who had been studied clinically and physiologically at 7, 10 and 14 years of age, has been conducted by questionnaire. Of the sample still in the study at 14 years of age, 77% of the asthma population replied, representing 65% of the original sample. There had been significant amelioration of asthma in those children who still had asthma at 14 years of age. Of those children with episodic asthma, approximately half had ceased wheezing while the remainder had relatively infrequent episodes. Those children with chronic asthma continued to wheeze but in just over half, asthma appeared to be episodic. Of the children who had ceased wheezing before 14 years of age, 17% had recurrence in the 12 months prior to review. However, in only 1 subject were the episodes of asthma frequent.     

Single-dose pharmacokinetics of daptomycin in children with suspected or proved gram-positive infections

BACKGROUND: New antimicrobials such as daptomycin fill a void in the growing need for antibiotics effective against resistant Gram-positive pathogens. Although the pharmacokinetics of daptomycin have been well characterized in adults, no studies have evaluated the pharmacokinetics and tolerability in a pediatric population. METHODS: Twenty-five children (12-17 years, n = 8; 7-11 years, n = 8; 2-6 years, n = 9) were enrolled in this multicenter, open-label study. Daptomycin was administered as a single 4-mg/kg intravenous dose followed by repeated blood sampling for 24 hours. Daptomycin was quantitated from plasma using a validated high performance liquid chromatography method and pharmacokinetic variables determined using a model-dependent approach. RESULTS: Daptomycin systemic exposure decreased with decreasing age, reflecting more rapid rates of clearance in younger children. Total body exposure estimates in adolescents were approximately 1.7x those observed in children <6 years of age (374.4 versus 215.3 microg*h/L), they were comparable to those observed in adult historic controls. Estimates of apparent elimination half-life averaged 6.7 hours in adolescents, 5.6 hours in children 7-11 years of age, and 5.3 hours in children <6 years of age. One child had an adverse event (infusion site reaction) considered to be related to study drug. CONCLUSIONS: Systemic drug exposure after a single weight-adjusted daptomycin dose is reduced in younger children compared with adolescents and adults consequent to an apparent age-associated change in total plasma clearance.     

定量超声技术在评价儿童青少年骨骼发育中的价值

目的探讨定量超声（QUS）技术在评价儿童青少年骨骼发育中的价值。方法以0~18岁儿童为研究对象,用QUS测量其胫、桡骨骨强度,其中2岁以下只测量胫骨,2岁以上胫桡骨同时测量,并用原子吸收法测量部分儿童末梢血钙。结果1.QUS测量结果反映健康儿童胫、桡骨骨强度非线性增长趋势;2.不同部位骨强度存在明显差异,胫、桡骨骨强度评价不一致率为30.1%;3.骨代谢异常高危儿骨强度水平明显低于正常儿,高危儿骨强度下降人数占71.1%;疑似缺钙儿童47.9%骨强度下降;4.末梢血钙正常组44.2%骨强度下降,而血钙下降组59.7%骨强度正常,2种检测方法无明显相关性。结论QUS适用于监测不同年龄儿童骨强度情况,特别是青少年;对骨代谢异常高危儿童具有较高检出率;同时测量儿童胫、桡骨,可准确、全面地反映儿童骨营养状况;结合末梢血钙可更好评价体内钙水平。     

Peripheral blood lymphocyte subsets in healthy Turkish children

Immunophenotyping of peripheral blood lymphocyte subpopulations is essential for the diagnosis and follow-up of children with immunodeficiencies and other immune disorders. The relative size and absolute number distributions (median and 5-95%) of lymphocyte subsets, including cord blood (Coulter, EPICS-XL) were examined by flow cytometry in 190 healthy subjects from birth to 18 years of age with a view to obtaining normal reference values for Turkish children of the following age groups: cord blood (n:29), birth to 1 year (n:41), 1 to 2 years (n:30), 2 to 6 years (n:30), 6 to 10 years (n:30), and 10 to 18 years (n:30). The relative size of CD2+, CD3+CD16-56-, CD3+CD8+ T lymphocytes increased while the relative size and absolute counts of those together with CD3+CD4+ and CD19+, CD20+ B lymphocytes decreased with age. The percentage of CD3-CD16+56+ NK cells increased from 0-1 year to 10-18 years; however, absolute count of CD3-CD16+56+ NK cells remained stable and unchanged in all age groups. The relative size and absolute count of activation markers (CD3+CD25+ and HLADR+) decreased from 0-1 year through 10-18 years age group. This study has once more demonstrated that both the percentage and the absolute number of lymphocyte subsets in cord blood and peripheral blood of healthy infants and children changed with age. Therefore, comparison of results to those of age-matched healthy controls is of utmost importance in the reliable and accurate evaluation of lymphocyte subsets reflecting cellular immunity in children.     

Clinical and Laboratory Study of Children Exposed in utero to Maternal Rubella

Clinical and serological findings are described in 218 children aged 1 to 4 years who were exposed in utero to maternal rubella infection, and who were apparently normal at birth. 84 children were reassessed at 6 to 8 years of age. At the first examination, 23% of children had rubella-like defects, the most common of which was deafness associated in some cases with retinopathy. There was a close correlation between the incidence of rubella defects and both the time of exposure to maternal rubella and the presence or absence of rubella antibodies in the blood at the first examination (1 to 4 years). Children who were seropositive and who were exposed to maternal rubella before the 20th week of pregnancy were at highest risk. Of the 84 children who were reassessed at 6 to 8 years of age, further defects were detected in 9 out of the 49 seropositive children. No further defects were encountered in the seronegative group. 17% of initially seropositive children showed loss of antibody by the second examination, but this, with one exception, was confined to normal children with low antibody titres. These findings stress the importance of long-term follow-up in children at greatest risk.     

Serum carotene concentrations in normal infants and children

The blood of 444 healthy Canadian children (246 males and 198 females) aged 6 days to 18 years was analyzed to determine the concentration of serum carotene. The serum carotene concentration was very low in the first six months of life. In the first three months of life, breast fed infants had significantly higher serum carotene concentration than infants who were formula fed. Infants 7 to 12 months of age had the highest serum carotene concentration. The serum carotene concentration dropped off after the age of one year and remained low until two years of age. After two years of age, the serum carotene concentration showed a progressive and small rise until the age of six to seven years and then fell until the age of 14 to 18 years. The serum carotene concentration did not appear to vary according to the sex of the child except for infants 7 to 12 months of age. In infants 7 to 12 months of age, girls had a higher serum carotene concentration. The measurement of the serum carotene concentration is a simple screening test for fat malabsorption. Our study provides the normal range of serum carotene concentration for children of various age groups.     

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.