Evaluation of the Physical Growth in Egyptian Children with Phenylketonuria Under Diet Therapy
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1 Med. J. Cairo Univ., Vol. 81, No. 2, June: , Evaluation of the Physical Growth in Egyptian Children with Phenylketonuria Under Diet Therapy SHERIF M. ZAKI, M.D.* and LAILA K. EFFAT, M.D.** The Departments of Anatomy*, Faculty of Medicine, Cairo University and Molecular Genetic**, National Research Centre, Cairo, Egypt Abstract A phenylalanine-restricted diet is the mainstay of phenylketonuria (PKU) treatment. However, this regime would not normally provide enough protein for growth requirements. The aim of the study was to evaluate the effect of phenylalanine restricted diet on the physical growth in the PKU Egyptian children. Twenty eight PKU children were evaluated for different growth parameters. The study was subdivided into two parts. The cross-sectional part of the study compared between the PKU and the controls. The longitudinal part of the study compared between the PKU at baseline (PKUI) and after 2 years (PKUF). Regarding the weight percentile of PKUI, 85.7% were normal. On the other hand 10.7% and 3.6% of them were under the 3rd and above the 97th percentiles respectively. 75% of them were in the normal height percentile, while 25% were under the 3rd percentile. Regarding their BMI percentile, 67.8% were normal, 21.4% were overweight and 10.8% were obese. All PKUF were in the normal weight percentile. Regarding their height percentile, 78.6% were in the normal centile while 21.4% were under the 3 rd height centile. Finally, regarding their BMI percentile, 46.4% were normal, 35.7% were overweight and 17.9% were obese. In conclusion, most of the PKU children lie within the normal percentiles for weight and height. Retardation in the weight and height growth was observed in a small percentage of these patients. The PKU children who were below the 3 r d percentile for weight caught up the normal growth curve while most of the children who were below the 3 rd percentile for height failed to catch up the normal growth curve and persisted below the 3 rd percentile Finally, with time many PKU children gain more weight and became overweight and obese. Key Words: Physical growth Egyptian Phenylketonuria. Correspondence to: Dr. Sherif Mohamed Zaki, zaky.sherif@yahoo.com Introduction PHENYLKETONURIA (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH) 111. A phenylalanine-restricted diet is the mainstay of PKU treatment [2]. Protein intake is calculated each day, whereby a child is allocated a certain number of units of daily protein, depending upon longitudinal plasma Phe concentrations. Foods such as eggs, milk, cheese, meat, poultry, fish, dried beans and legumes which are high in protein are excluded from the diet [3]. However, the previous regime would not normally provide enough protein for growth requirements [3]. There is a risk of imbalances in essential dietary nutrients [4]. In addition, these patients can also have low concentrations of trace elements and cholesterol, and some disturbance in folate metabolism as well as distortion of their fatty acid profile [5-7]. Several reports have suggested that growth in early childhood in PKU is sub-optimal, relative to non-pku control groups or reference populations [8]. In one study, the PKU children had almost identical height for age but they were heavier than reference children while in another study the growth of the PKU children were close to the expected value [9]. The incidence of PKU in Arabic Populations is approximately up to 1 in 6,000 births which is relatively high compared with other regions and countries [10]. In spite of this high incidence, there is an obvious lack of longitudinal studies concen- 107
2 108 Evaluation of the Physical Growth in Egyptian Children trating upon the effect of phenylalanine restricted diet on the physical growth in the Arabic Populations. The aim of this study was to evaluate the effect of phenylalanine restricted diet on the physical growth in Egyptian children with PKU. The study was done in two parts; the cross-sectional part, comparing between the PKU and their matched controls and the longitudinal part, comparing between the PKU at baseline of the study (PKUI) and after 2 years (PKUF). Patients and Methods Our study included 28 children with phenylketonuria recruited from the Association of Genetic and Metabolic Disorders and Studied in the Pediatric Clinic National Research Centre (NRC). The patients were diagnosed clinically and the diagnosis was confirmed by measurement of the blood (ph) level. The mentally, socially and the congenital anomalies' affected patients were excluded from the study. The selected patients were receiving a low protein diet consisting of low protein breads and pastas (Wheat starch, Metamucil and Methylcellulose), fresh fruits and vegetables Informed consents were taken from the parents of the children according to guidelines by the ethical committee of NRC, Dokki, Egypt and according to the World Medical Association (WMA) Declaration of Helsinki Sixth revision guidelines [12]. The clinic visit for each patient was monthly, monitoring the growth status and the diet compliance; diet adherence was determined based on the patient's report. Monthly blood phenylalanine levels were done. Anthropometric measurements were taken following standardized techniques [13]. The weight was measured to the nearest 0.1Kg with a digital balance and the patients in light clothes and without shoes. Height was measured to the nearest 0.5cm with a stadiometer. Body mass index (BMI) was calculated according to BMI = Weight/height 2 (Kg/m 2 ). Z scores for weight and height (WAZ and HAZ) were calculated, referring to the CDC (Centre for Disease Control and Prevention) reference growth values. Height, weight, and BMI percentiles were calculated using the 2000 Centers for Disease Control Growth Charts [14]. In the cross-sectional part of the study (at baseline measurement), body weight, height and BMI were compared between the PKUI patients and 42 age and sex matched controls. All the control children were healthy with no known medical illness. In the longitudinal part of the study, the weight, length, WAZ, HAZ and BMI at baseline of the study (PKUI) and after 2 years (PKUF) were compared with each other and compared with data from the CDC reference growth values (BMI-percentile- CDC). According to the CDC, children and youth were classified based on their BMI-percentile-CDC to underweight (BMI <5 percentile), healthy weight (BmI=5th _84th percentile), overweight (BMI = percentile), or obese (BMI >94) [14]. Statistical analysis: The results were computerized and analyzed statistically using SPSS version 20. Results were expressed as means±standard deviation (SD). The independent t-test was used to compare between two groups and paired t-test was used to detect the changes in the quantitative data after diet for 2 years. The quantitative data were examined by Kolmogrov Smirnov test for normality. Level of significance was considered at p-value <0.05. Concerning the Z score, a score, between 2 and +2, was considered within the normal range [15]. Results Seventeen males (60.7%) and eleven females (39.3%) patients were followed-up in the current study. The mean age of the PKUI was (7.2±3.4 yrs), their median age was 6.5 yrs, and their age range was 3-14 yrs. At the end of the study, the mean age of the PKUF was (9.2±3.4 yrs), the median was 8.5 yrs, and the age range was 5-16 yrs. The control group consisted of twenty two males (52.4%) and twenty females (47.6%). Their mean age was 8.5±3.3 yrs, their median age was 8 yrs, and their age range was 2-17 yrs. In the cross-sectional part of the study (at baseline measurement): The weight and height of the PKUI children decreased 25% and 10% respectively compared to their matched control group (p<0.05). Consequently, the Z scores for weight (WAZ) and for height (HAZ) of the PKUI decreased compared to that of the control group (p<0.05). There was no statistical significant difference neither in the BMI nor in the BMI-percentile-CDC (p>0.05) in the PKUI patients compared to their fellow in the control group (Table 1).
3 Sherif M. Zaki & Laila K. Effat 109 In the longitudinal part of the study: 30% and 10% increase in the weight and height was observed at the end of the study (PKUF) compared to their weight and height at the beginning of the study (PKUI) (p<0.05). Their mean weight and height percentiles at the end of the study (PKUF) were higher (39% and 11% respectively) compared to their weight and height at the beginning of the study (PKUI) (p<0.05 and 0.7 respectively). 50% increase of the BMI and 19% increase the BMI-percentile-CDC of PKUF in comparison to their fellows in the PKUI, but all these increases were statistically insignificant (p>0.05) (Table 2). Percentiles of the different growth parameters: Regarding the weight percentile of PKUI, 24 (85.7%) were normal, Three (10.7%) were below the 3rd percentile and only one child (3.6%) was above the 97th percentile. Regarding the height percentile for this group, 21 (75%) were in the normal percentile and 7 (25%) were below the 3rd percentile. Finally, regarding BMI percentile in this group, 19 (67.8%) were normal, 6 (21.4%) were overweight and 3 (10.8%) were obese. The weight percentiles of the all the PKUF were normal. Regarding their height percentile, 22 (78.6%) were in the normal percentile and 6 (21.4%) were below the 3rd percentile. Finally, regarding their BMI percentile, 13 (46.4%) were normal, 10 (35.7%) were overweight and 5 (17.9%) were obese. Regarding the weight percentile of the control group, 37 (88 %) were normal, 5 (12 %) was above the 97th. Regarding their height percentile, 37 (88%) were also normal, like the weight, 4 (9.5%) were below the 3rd percentile and only one (2.5%) was above the 97th percentile. Finally, regarding their BMI percentiles, 30 (71.5%) were normal, 2 (4.7%) were overweight and 10 (23.8%) were obese (Table 3). Table (1): Comparison between the growth parameters of the PKUI and the control in the baseline. Type N Mean SD t test p value Weight: Weight (Kg) PKUI * Control Weight percentile PKUI * Control WAZ PKUI * Control Height: Height (cm) PKUI * Control Height percentile PKUI * Control HAZ PKUI * Control BMI (Kg/m 2 ) PKUI Control BMI percentile PKUI CDC Control * p-value <0.05 is statistically significant. Table (2): Comparison between the growth parameters of the PKUI and the PKUF. Type N Mean SD t test p value Weight: Weight (Kg) PKUI * PKUF Weight percentile PKUI * PKUF WAZ PKUI PKUF Height: Height (cm) PKUI * PKUF Height percentile PKUI PKUF HAZ PKUI PKUF BMI (Kg/m 2 ) PKUI PKUF BMI percentile PKUI CDC PKUF * p-value <0.05 is statistically significant.
4 110 Evaluation of the Physical Growth in Egyptian Children Table (3): Percentiles of BMI, weight and height in the control and the PKU patients. Type N % Mean SD Median Range Control Underweight Normal Overweight Obesity 0 0 PKUI Underweight 0 0 Normal Overweight Obesity PKUF Underweight 0 0 Normal Overweight Obesity Weight percentile: Control <3 r d percentile Normal >97th percentile PKUI <3rd percentile Normal >97th percentile PKUF <3 r d percentile 0 0 Normal >97th percentile Height percentile: Control <3rd percentile Normal >97th percentile PKUI <3rd percentile Normal >97th percentile 0 0 PKUF <3rd percentile Normal >97th percentile 0 0 Discussion In recent years, there has been much focus on research on non-dietary treatments in PKU. However, diet is likely to remain the major treatment for many years to come The outcome of growth in the PKU depends on therapeutic approach, genetic background and novel alimentary substitutes. An international study comparing and evaluating these differences between centers would be extremely interesting [17]. At the baseline of our study, all weight growth parameters were decreased in the PKUI compared to the control group. WAZ for PKUI was -0.2±1.2 compared to of the controls (0.6±1.2). So, the PKUI group still lies within the normal range of the growth weight as the Z-scores between -2 and +2 are within the normal range [15]. Only 3 (10.7%) of the KUI children were below the 3rd percentile for weight. Following-up the weight parameters for the PKU patients, improvement of the weight was observed in the PKUF. WAZ for the PKUF was 0.1±0.9 compared to that of the PKUI (-0.2±1.2). In addition, all PKUF were within the normal growth weight percentile which means that even the three PKUI children who were under the 3rd percentile for weight caught up the normal growth. Beyond the second year, when diet is less restricted, restoration of the normal growth curve for PKU children occurs [18]. Similar to the weight parameters, all the height growth parameters of the PKUI decreased compared to that of the control group. HAZ for PKUI was - 0.9±1.1 compared to that of the control (-0.16±1.1).
5 Sherif M. Zaki & Laila K. Effat 111 Again, the PKUI group still lies within the normal range of the growth height. Seven (25%) PKUI children were under the 3rd percentile for height. In supporting to our findings, some other authors also found that PKU patients were shorter and lighter than the reference population in their cross sectional study [17]. Following-up the height parameters for the PKU patients, slight improvement of the height was observed in the PKUF. There was an insignificant increase in height percentiles and HAZ of the PKUF compared to their fellow of the PKUI. Of the seven PKUI who were under the 3rd percentile for height, only one patient caught up the normal growth while the remaining six children (21.4%) still below the 3rd percentile. Concerning the changes in the BMI and BMIpercentile-CDC, there were insignificant changes between the two studied groups. None of the PKU patients were underweight using the BMI percentile. Twenty four (85.7%) of the PKUI and all the PKUF were in the normal weight percentile. In addition, 21 (75%) of the PKUI and 22 (78.6%) of the PKUF were in the normal height percentile. Finally, 19 (67.8%) of the PKUI and 13 (46.4%) of the PKUF were in the normal BMI percentile. Most of our studied PKU children caught the normal growth curves. One child only of the PKUI (3.6%) was above the 97th percentile for weight. At the start of the study, 21.4% and 10.8% of the PKUI were overweight and obese respectively. With time, 35.7% and 17.9% of the PKUF were overweight and obese. The PKU children are not limited in their carbohydrate and fat intakes [15], which means that, as any other child; their nutritional caloric intake may exceed their energetic needs. Other probable risk factors of being overweight were lower socioeconomic status (for both sexes) and overweight parents and large stature (for the girls only) [19]. An obvious difference between the catch up of the weight and height growth of the PKU patients after initial period of growth retardation was observed in the current study. The PKUI children who were below the 3rd percentile for weight succeeded to catch up the normal growth curve for weight while most of the children who were below the 3rd percentile for height failed to catch up the normal growth curve for height. In disagreement with our study, European studies found that growth retardation during the first years of life was followed by restoration of the normal growth curve from the second year or later [9,20-22]. Also many longitudinal studies found that children with PKU had the almost identical height for age [9]. The point of the differences between our results and these studies is that in our country there is an absence of national screening programs for early detection of PKU especially in neonates. The late onset of discovery of the PKU patients and the late onset of starting of the Phe restricted diet makes possible differences between the weight and height in their way of dealing to diet therapy. In conclusion, most of the PKU children lie within the normal percentiles for weight and height. Retardation in the weight and height growth was observed in a small percentage of these patients. The PKU children who were below the 3rd percentile for weight caught up the normal growth curve for weight while most of the children who were below the 3rd percentile for height failed to catch up the normal growth curve for height and persisted below the 3rd percentile. Finally, with time many PKU patients gain more weight and became overweight and obese. So, we recommended the early detection of PKU and the early use of Phe restricted diet to avoid the height growth retardation which is difficult to be corrected. Also, care must be taken to avoid the problem of overweight and obesity that may develop with time. References 1- WILLIAMS R.A., MAMOTTE C.D. and BURNETT J.R.: Phenylketonuria: An inborn error of phenylalanine metabolism. Clin. Biochem. Rev., 29 (1): 31-41, FEILLET F. and AGOSTONI C.: Nutritional issues in treating phenylketonuria. J. Inherit. Metab. Dis., 33 (6): , MICHALS-MATALON K.: Developments in phenylketonuria. Topics Clin. Nutr., 16: 41-50, HANLEY W.B.: Adult Phenylketonuria, Am. J. Med., 117: 590-5, LUCOCK M., YATES Z., HALL K, LEEMING R., RY- LANCE G., et al.: The impact of phenylketonuria on folate metabolism Mol. Genet. Metab., 76: , MOSELEY K., KOCH R. and MOSER A.B.: Lipid status and long chain polyunsaturated fatty acid concentrations in adults and adolescents with phenylketonuria on phenylalanine restricted diet. J. Inherit. Metab. Dis., 25: 56-64, SCHULPIS K.H., KARAKONSTANTAKIS T., BART- ZELIOTOU A., KARIKAS G.A. and PAPASSOTIRIOU I.: The association of serum lipids, lipoproteins and apolipoproteins with selected trace elements and minerals in phenylketonuric patients on diet. Clin. Nutr., 23: 401-7, 2004.
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