Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.

Determinants of Circulating Soluble Leptin Receptor and Free Leptin Index in Indonesian Pre-Pubertal Obese Male Children: A Preliminary Cross-Sectional Study.

PURPOSE: This study aimed to investigate the clinical and metabolic determinants of circulating soluble leptin receptor (CSLR) and free leptin index (FLI) in pre-pubertal obese male children. METHODS: We conducted a preliminary cross-sectional study at three tertiary hospitals and one public primary school. Eighty obese male children without growth and developmental abnormalities aged 5-9 years were recruited. In these children, obesity was solely caused by excessive food intake, and not by acute illness, medications, endocrine abnormalities, or any syndrome. Body mass index (BMI), body fat mass, carbohydrate intake, fat intake, high density lipoprotein cholesterol level, low density lipoprotein cholesterol level, triglyceride level, and Homeostatic Model Assessment for Insulin Resistance are the potential determinants for leptin regulation, which is represented by CSLR level and FLI. RESULTS: Carbohydrate was the main source of energy. BMI and body fat mass had negative weak correlation with CSLR and positive weak correlation with FLI. Furthermore, carbohydrate intake was found to be independently associated with CSLR based on the results of the multiple linear regression analysis. Following an increase in carbohydrate intake, CSLR level decreased progressively without any negative peak. CONCLUSION: Leptin regulation in prepubertal obese male children is associated with body composition and dietary intake. Carbohydrate intake is useful for predicting CSLR. Lipid profiles and insulin resistance are not related to both CSLR and FLI. Treatment and prevention of leptin resistance in obese children should focus on reducing BMI, fat mass, and carbohydrate intake.

The Effect of Vitamin E Supplementation on Lipid Profiles and Adiponectin Levels in Obese Adolescents: A Randomized Controlled Trial.

BACKGROUND: low-grade chronic inflammation in obese individuals contributes to the development of lipid abnormality and insulin resistance. Vitamin E has antioxidant and insulin-sensitizing properties, mediated by adiponectin. In this study, we aimed to evaluate the effect of vitamin E supplementation on lipid profiles and adiponectin levels in obese adolescents. METHODS: this was a randomized, double-blind, controlled study. Obese adolescents aged 14-18 years, with no history of taking anti-obesity or antioxidant drugs, were recruited and randomized into two groups: vitamin E and placebo. The dose of vitamin E was 400 IU/day. Intervention was administered for two months. Lipid profiles and adiponectin levels were measured at baseline and after intervention. Primary outcomes were analyzed using the per-protocol analysis principle. Statistical analysis was performed using the independent t-test or the Mann-Whitney U test. RESULTS: a total of 66 subjects completed the intervention study, 34 in the vitamin E group and 32 in the placebo group. Lipid profiles and adiponectin levels at 2 months after intervention did not differ significantly between the two groups. Changes from the baseline level were also not significantly different between the two groups and were inconsistent from one subject to another. CONCLUSION: in obese adolescents, vitamin E supplementation of 400 IU/day for 2 months does not significantly affect lipid profiles and adiponectin levels.

Genetics and genomic medicine in Indonesia.

Genetics and genomic medicine in Indonesia.

The role of apolipoprotein E polymorphism in improving dyslipidemia in obese adolescents following physical exercise and National Cholesterol Education Program Step II intervention.

BACKGROUND: Lifestyle changes are important factors for managing dyslipidemia before considering blood lipid-lowering drugs. However, genetic factors can influence the response outcome. OBJECTIVE: We aimed to determine a dyslipidemia management strategy in obese adolescents. PATIENTS AND METHODS: A total of 60 dyslipidemic obese adolescents received physical exercise and the NCEP step II diet for 28 days. Apolipoprotein E (apo E) genotypes and blood lipid levels were compared before and after interventions. RESULTS: The apo E3/E3 genotype was found to be common in all subjects. Mean levels of total cholesterol, triglyceride, and low-density lipoprotein-cholesterol (LDL-C) improved in subjects with the E3 allele after the intervention, but not the E2 allele. Total cholesterol and LDL-C, but not triglyceride levels, improved in subjects with the E4 allele. DISCUSSION: Apo E alleles might influence improvement in lipid profiles after diet and exercise interventions. These results could inform personalized dyslipidemia management in obese adolescents, to determine which subjects would benefit from blood lipid-lowering drugs.

The role of uncoupling protein 2 and 3 genes polymorphism and energy expenditure in obese Indonesian children.

AIM: Uncoupling protein (UCP) genes, which may contribute to energy metabolism in mitochondria, may be involved in the pathogenesis of obesity. We analyzed the differences in energy expenditure between single nucleotide polymorphisms (SNPs) UCP3-55C/T, UCP3 Y210Y, and UCP2 A55V among Indonesian children. METHODS: The study included 76 schoolchildren (36 obese and 40 healthy; mean age, 12.8 years) in Semarang, Indonesia. Body composition was measured by bioelectrical impedance analysis; resting energy expenditure (REE) by indirect calorimetry; physical activity by uniaxial accelerometer; and total energy expenditure (TEE) by the equations extrapolated from REE and physical activity. UCP3-55C/T, UCP3 Y210Y, and UCP2 A55V were examined by restriction length fragment polymorphism analysis. RESULTS: The TEE of the subjects with the T/T genotype at UCP3-55C/T after adjusting for fat-free mass (63.2±7.2 kcal/kg/day) and T/T at UCP2 A55V (62.8±5.6 kcal/kg/day) was lower than that of the subjects with the C/C and C/T genotypes (p<0.05). The REE of the subjects with these T/T genotypes tended to be lower than that of the subjects with C/C and C/T (p≥0.05). No significant differences in REE or TEE were found between the UCP3 Y210Y genotypes. CONCLUSIONS: The subjects with the T/T genotypes of UCP3-55C/T or UCP2 A55V had lower TEE than those with other genotypes.

Regurgitation and gastroesophageal reflux disease in six to nine months old indonesian infants.

PURPOSE: Regurgitation is known to peak at the age of 3-4 months, with a sharp decrease around the age of 6 months. Little is known about the natural evolution of infants who still regurgitate after the age of 6 months. METHODS: Hundred thirty-one infants older than 6 months regurgitating more than once a day were followed for a period of 3 months. RESULTS: According to our data, gastroesophageal reflux disease (GERD) is seldom at this age. Most of the infants regurgitated 3 or more times/day and spit up an estimated volume of more than 15 mL. Eighty-five parents were educated regarding frequency of feeding. There were only 6 infants that still had frequent regurgitation (>3 times/day) despite an appropriate feeding schedule. The Infant GER Questionnaire score reached a score of 0 in 50% of the infants after one month of follow-up and in 81.9% at the third month of follow-up. There was an increase of the "weight for age z-score" trends in infants that still regurgitated at the end of follow-up and a declining z-score in infants that no longer regurgitated. An explanation may be that infants that regurgitate drink larger volumes than infants who do not regurgitate. Conservative treatment (reassurance, dietary treatment, behavioral advice) resulted in a significant better outcome than natural evolution. CONCLUSION: Regurgitation that persisted after the age of 6 months, strongly decreased during a 3-month follow-up with conservative treatment. GERD is rare in this age group; therefore, anti-reflux medication is only seldom needed.

Glycerol kinase deficiency: residual activity explained by reduced transcription and enzyme conformation.

Four unrelated patients with glyceroluria ranging from 7 to 170 mmol/l were studied. The activity of glycerol kinase (GK) in cultured fibroblasts was determined with a specific enzyme assay and with two indirect methods, that is, incorporation into macromolecules of [(14)C] from [(14)C]glycerol and its oxidation to [(14)C]CO(2). Exon amplification and RT-PCR were used to identify mutations. In patient 1, with low activity in all three assays, we identified a c.1194A>C (E398D) missense mutation. In patient 2 with a considerable activity of the GK enzyme (22% of reference), oxidation to [(14)C]CO(2) (37%) and a high incorporation of [(14)C] into macromolecules (92%), we identified a c.182T>C (L61P) mutation that causes the enzyme to have a higher K(m) for glycerol ( approximately 300 microM) than normals (2-8 microM). In patient 3, the GK activity estimated by the three different methods ranged from 16 to 22% of reference. Analysis of mRNA from the GK gene revealed three alternatively spliced transcripts. A mutation in intron 3 (g.16835G>A) resulted in an insertion of a cryptic exon between exon 2 or 3 and exon 4. Patient 4 with minor glyceroluria (7 mmol/l) and normal plasma glycerol concentration had normal activity with all three assay methods, thus excluding GK deficiency (GKD) as a cause of slight glyceroluria. To evaluate fully patients with glyceroluria, one needs to measure the GK activity and relate this and the clinical data to genetic findings. Residual enzyme activities in cultured fibroblasts can be found in GKD patients with severe clinical symptoms.