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A 24-month-old boy was referred to our pediatric intensive care unit because of difficulty in weaning from artificial ventilation. He had 2 bronchopneumonia attacks in 2 months; the diagnosis of Pompe's disease was confirmed by low glucosidase activity in lymphocytes and cultured uibroblasts without abnormality in the serum creatine kinase level. Our patient's creatine kinase levels were permanently normal. To the best of our knowledge, our Pompe's case is the first in the literature who has normal creatinine kirtase levels despite earlier onset and rapidly progressive disease. [ABSTRACT FROM AUTHOR]

Cystathionine beta-synthase deficiency (CBSD) is the most prevalent inherited disorder of homocysteine metabolism in the transsulphuration pathway. Research have suggested oxidative stress and inflammation as candidate pathogenic mechanisms in CBSD. This study aims to evaluate mitochondrial dysfunction and oxidative stress biomarkers in cystathionine beta-synthase deficiency (CBSD) patients, which may aid in understanding the pathogenesis of CBSD and improving treatment. The study group comprised 23 patients with a diagnosis of CBSD and healthy controls. We analysed serum levels of NAD + and NADH by fluorometric assay, FGF-21 and GDF-15 by ELISA, mitochondrial DAMPs by real time qRT-PCR, total homocysteine levels in plasma by enzymatic test and compared the results in CBSD group with healthy controls. In patient group, a positive correlation was found between the total homocysteine level and both GDF-15 and NAD + /NADH levels. Furthermore, there was a negative correlation between total homocysteine levels and both total NAD + +NADH and NADH levels. The alterations in NAD + , FGF-21, GDF-15 levels, and NAD + /NADH ratio in patients suggest that oxidative damage coexists with mitochondrial dysfunction in CBSD. Assessment of oxidative damage and addition of anti-oxidant therapy together with mitochondrial support may have additional benefits in reducing long-term morbidity in CBSD patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: An ethical approval (file number; 2023/1637) was obtained from Istanbul Faculty of Medicine Ethics Committee before the study and written informed consent was obtained from each patient or guardian., (© 2024. The Author(s).)

Background/objectives: Phenylketonuria is a hereditary metabolic disorder characterized by a deficiency of phenylalanine hydroxylase. The main treatment for PKU is a phenylalanine-restricted diet. The exclusion of protein rich natural foods and inclusion of low-Phe substitutes may give rise to an imbalanced diet, and the increased risk of overweight and obesity in PKU is a cause for concern. We aimed to evaluate the body composition and nutritional biochemical biomarkers in adult PKU patients who are on Phe-restricted and essential amino acid-supplemented nutrition therapy and to investigate the relationships between these parameters and patient gender, adherence to dietary therapy, and disease type, defined as mild or classic PKU., Methods: The study group comprised 37 PKU patients and 26 healthy siblings as controls. The participants were assessed based on an analysis of anthropometric parameters, body composition, and biochemical test results., Results: PKU patients do not have a higher incidence of overweight and obesity than healthy controls, the proportion of energy derived from carbohydrates in their diets was below the recommended level, and their total energy intake was below the recommended daily allowance. It was remarkable that patients with a treatment adherence ratio of <50% displayed a higher prevalence of overweight and abdominal obesity in comparison to those with a more favorable treatment adherence ratio., Conclusions: In view of the growing prevalence of overweight in the general population, PKU patients should be kept under close long-term follow-up. Particularly in the group with low treatment compliance, more caution should be taken in terms of adverse outcomes.

Classic galactosemia (OMIM#230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of the galactose-1-phosphate-uridyl-transferase enzyme encoded by the GALT gene. Even though a galactose-restricted diet efficiently resolves the acute complications, it is insufficient to prevent long-term complications regarding speech defects, intellectual functioning, premature ovarian failure, cataract, hepatomegaly, dysarthria, ataxia, and tremor. Seventy-seven patients who were genetically diagnosed with classic galactosemia were included in this cohort. Identified novel variants were classified based on their predicted effect on the GALT function. Further, potential genotype-phenotype correlations were investigated via statistical analysis. In total, 18 different sequence variants were identified, including four novels (c.200delG/p.(Arg67Profs * 19), c.533T>G/ p.(Met178Arg), c.708&#95;709delGT/p.(Ser236Argfs * 30), c.467C>A/p.(Ser156 * )). Jaundice was the most common short-term finding with 80% (61/77). Even with early diagnosis, intellectual disability is encountered with 36% (27/74) of the long-term complications. Patients with biallelic missense variants have a significantly higher prevalence of cataracts (OR: 17.9). Longitudinal observations showed attenuation of cataracts and hepatomegaly. This study has shown the GALT variation spectrum of the Turkish population with a 30-year retrospective cohort, submitting a significant contribution to the genotype/phenotype correlation in galactosemia. This study also highlights the cost-effective importance of Sanger sequencing in the diagnosis of single-gene metabolic diseases., (© 2023 University College London (UCL) and John Wiley & Sons Ltd.)

Neurodevelopmental disorders (NDDs) have broad heterogeneity both clinically and genetically. Inborn errors of metabolism can be one of the reasons of neurodevelopmental disruption causing specific NDDs. Although there is tremendous advance in molecular identification via next-generation sequencing (NGS), there are still many unsolved patients with NDD. Reanalysis of NGS data with different pipelines can at least partially accomplish this challenge. Herein, we report clinic and genetic components of an adult sib-pair with an undiagnosed NDD condition, which has been solved through reanalysis of whole-exome sequencing (WES). Parallel analysis of SNP-based genotyping and WES was performed to focus on variants only in loci with positive logarithm of the odds scores. WES data was analyzed through three different pipelines with two distinct bed files. Reanalysis of WES data led us to detect a homozygous FOLR1 variant (ENST00000393676.5:c.610C > T, p.(Arg204Ter), rs952165627) in the affected sib-pair. Surprisingly, the variant could not be detected in the first analysis as the variant region is not included in the first bed file which may frequently be used. Biochemical tests of CSF have confirmed the genetic analysis, CSF folic acid levels were detected low in sib-pair, and intravenous folinic acid treatment improved the disease course for the first 6 months of follow-up even at late diagnosis age. Although combined analysis of SNP-based genotyping and WES is a powerful tool to reveal the genetic components of heterogeneous diseases, reanalysis of genome data still should be considered in unsolved patients. Also, biochemical screening helps us to decipher undiagnosed NDD that may be a treatable neurometabolic condition., (© 2023. Fondazione Società Italiana di Neurologia.)

This expert-opinion-based document was prepared by a group of specialists in pediatric inherited metabolic diseases and infectious diseases including administrative board members of Turkish Society for Pediatric Nutrition and Metabolism to provide guidance for the care of children with lysosomal storage disorders (LSDs) during the COVID-19 pandemic in Turkey. The experts reached consensus on key areas of focus regarding COVID-19-based risk status in relation to intersecting immune-inflammatory mechanisms and disease patterns in children with LSDs, diagnostic virus testing, particularly preventive measures and priorities during the pandemic, routine screening and diagnostic interventions for LSDs, psychological and socioeconomic impact of confinement measures and quarantines and optimal practice patterns in managing LSDs and/or COVID-19. The participating experts agreed on the intersecting characteristics of immune-inflammatory mechanisms, end-organ damage and prognostic biomarkers in LSD and COVID-19 populations, emphasizing the likelihood of enhanced clinical care when their interaction is clarified via further studies addressing certain aspects related to immunity, lysosomal dysfunction and disease pathogenesis. In the context of the current global COVID-19 pandemic, this expert-opinion-based document provides guidance for the care of children with LSDs during the COVID-19 pandemic based on the recent experience in Turkey., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Akgun, Gokcay, Mungan, Sivri, Tezer, Zeybek and Ezgu.)

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Objective: Premature adrenarche (PA) has been suggested as a risk factor for future health problems, such as metabolic syndrome and early menarche. However, not all girls with PA have these features and it is not certain who will develop them. We propose that these abnormalities might be identified earlier, even before they are visible., Design: Case-control study., Setting: Tertiary care hospital., Participants: Forty-eight girls with premature pubarche due to PA and age (mean age 7.6 ± 1.0 years), weight, body mass index (BMI), birth weight and gestational age-matched 49 girls with no palpable breast tissue., Measurements: Early pubertal pelvic and breast ultrasonographic changes and their associations with obesity and metabolic parameters were evaluated. Blood samples were collected, breast and pelvic ultrasound examinations were performed and bone ages were assessed., Results: Girls with PA were taller and their bone ages were higher (p = .049 and p = .005). Fasting blood glucose, insulin, triglycerides, high-density lipoprotein and low-density lipoprotein cholesterol were not different between the groups. Luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol were not different either. Ultrasonography revealed breast gland tissue in 30% of girls with PA and 5% of controls (p = .006). Uterine volume and endometrial thickness were higher in girls with PA (p = .03 and p = .04). Endometrial thickness was positively associated with serum insulin levels in the whole study group and after adjusting for age, diagnosis, BMI, mean ovarian volume and LH, FSH, estradiol levels, this association remained with a borderline p-value (R 2  = 0.486, p = .050)., Conclusions: We found early changes in uterus and breast glands of girls with PA and endometrial thickness was positively associated with insulin levels., (© 2021 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: The prevalence of allergic disorders is on the rise, affecting about 10% of the population. In this retrospective cohort, we investigated prevalence of allergic disorders, associated risk factors, and the outcome of food allergies., Material and Methods: We analyzed data from birth cohorts of two university hospitals' well-child outpatient clinics. Factors related to onset and type of allergic diseases were assessed from demographic, socioeconomic, and clinical data., Results: Analyses were performed on 949 (431F/518M) infants at a mean current age of 28±6 months. Any allergic disease was established among 177 cases (22%); atopic dermatitis in 123 (12.8%), respiratory allergies in 55 (5.7%), and food allergy in 41 (4.3%). The risk for allergic disorders was found to be significantly increased for male gender (OR: 2.31, 95% CI; 1.54-3.46), and positive parental atopy (OR: 1.94, 95% CI; 1.31-2.86). The risk of food allergies was significantly higher in the male gender (OR: 2.47, 95% CI; 1.21-5.02), who consumed egg-white between 6 and 12 months (OR: 2.34, 95% CI; 1.22-4.48), and who were formula-fed before 6 months (OR: 2.16, 95% CI; 1.14-4.10). We found no significant association between the rate of food allergy outgrowth or food induced-anaphylaxis with regards to the timing of introducing egg-white into the diet., Conclusions: Although the introduction of egg-white into infant diet at 6-12 months of life appeared as an independent risk for any food allergy, none of the patients developed anaphylaxis. Age at symptom onset and outgrowing food allergy were similar compared to those introduced egg-white after 12 months. We recommend promoting exclusive breastfeeding during the first 6 months of life, and avoidance of prolonged restrictive diets for children with food allergy.

Background: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson's disease (PD)., Objective: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA) mutations, which pose a significant risk for developing PD., Methods: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBAmc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach., Results: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBAmc and HC groups, respectively (p = 0.012). Significant increased connectivityConclusion:Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD.

Objectives: To evaluate the impact of dyspnea and chronic self-care management outcomes of an Education-Based Intervention Program (EBIP) compared to routine care. Methods: The population of the study consisted of self-care management scale of 61 patients diagnosed with chronic obstructive pulmonary disease (COPD) stage 2 and within one month after discharge. A total of 51 conforming patients were divided into experimental and control groups for a single-blind randomized trial. Data were collected using an introductory information form, the baseline dyspnea index (BDI), pulmonary function test (PFT), the self-care management process in chronic illness (SCMP-G) scale and body mass index (BMI). There were no addition interventions to the control group. The intervention group underwent a 3-month EBIP intervention that included education, house visits and follow-ups through phone calls between March 2019 and June 2019. The data were analyzed using Kolmogorov-Smirnov and Shapiro-Wilk tests, χ2, Mann Whitney U and Wilcoxon signed-rank tests. p less than 0.05 was statistically significant. Results: The study was completed with a total of 40 COPD patients. The effect of the EBIP training program on BDI, PFT, and SCMP-G scores in the intervention group was statistically proven (p less than 0.05). However, the differences between the groups in the BDI sub-dimension of functional impairment and PFT were not statistically significant (p greater than 0.05).  Conclusion: Providing patients with illness-related education through EBIP provided a partial improvement in dyspnea and a significant improvement in chronic care management among COPD patients.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants., (© 2020 Wiley Periodicals LLC.)

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Cow's milk is one of the most common of the foods that cause food allergies in children. Here, we present a 10-month-old male who was diagnosed with having an allergy to cow's milk and who developed an anaphylactic reaction after being recently vaccinated with a measles vaccine. Case: The patient had been diagnosed with atopic dermatitis and cow's milk allergy at 40 days old after a rash appeared on his face and arms while exclusively breastfeeding. At 9 months, on his routine welfare outpatient appointment, he developed a facial rash and swelling, wheezing, difficulty breathing, and cyanosis within 10 min of having his first measles vaccination (M-VAC ® ; Serum Institute of India, Hadapsar, Pune, India). After an allergy evaluation and a physical examination that showed that he was otherwise healthy, he was diagnosed with an allergy to cow's milk, which was then eliminated from his diet. Laboratory evaluations were as follows: serum immunoglobulin E (IgE) to cow's milk: 36.2 kU/L, α-lactalbumin: 9.39 kU/L, β-lactoglobulin: 8.74 kU/L, casein: 34.2 kU/L, latex-specific (sp)IgE: 0.10 kU/L, gelatin spIgE: <0.35 kU/L (normal levels <0.35 kU/L; Pharmacia, Uppsala, Sweden). Results revealed lactalbumin hydrolysate as one of the M-VAC ingredients according to the manufacturer's package insert. Conclusion: In most cases with a cow's milk allergy, vaccines are administered without any problems because the amount of milk proteins contained in the vaccines is not sufficient to represent a risk factor for anaphylaxis; however, the vaccine content should be examined for possible allergens, particularly for children with food allergies, before vaccinating. We should keep in mind when determining the agent responsible for an allergic reaction that the risk from a residual component of milk protein in vaccines can differ according to the nutritional habits of the population., Competing Interests: No competing financial interests exist., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.

Background: Baby-led weaning (BLW) is an approach to introducing solid foods to infants that gives control of the feeding process to the infant. Anecdotal evidence suggests that BLW is becoming popular with parents, but scientific research is limited to a few publications. This study assessed growth, hematological parameters and iron intake in 6-12-month-old infants fed by traditional or baby-led complementary feeding., Methods: We recruited 280 healthy 5-6-month-old infants allocated to a control (traditional spoon feeding; TSF) group or an intervention (BLW) group in a randomized controlled trial. Infant growth, hematologic parameters and iron intake were evaluated at age 12 months., Results: Infants in the TSF were significantly heavier than those in the BLW group. Mean weight in the BLW group was 10.4 ± 0.9 kg compared with 11.1 ± 0.5 kg in the TSF group. There was no statistically significant difference in the iron intake from complementary foods between the BLW (7.97 ± 1.37 mg/day) and TSF (7.90 ± 1.68 mg/day) participants who completed the diet records. Hematologic parameters were similar at 12 months. The incidence of choking reported in the weekly interviews was not different between the groups., Conclusions: To the best of our knowledge, this is the first randomized -controlled study to have examined the impact of weaning method on iron intake, hematological parameters and growth in breast-fed infants. BLW can be an alternative complementary feeding type without increasing the risk of iron deficiency, choking or growth impairment., (© 2018 Japan Pediatric Society.)

BackgroundIn this study, we examined the hypothesis that weight gain and linear growth during the first years of life influence the onset of puberty both in girls and in boys.MethodsA cohort of 157 healthy children, aged 6-9 years, was evaluated and their growth patterns were analyzed retrospectively. Repeated measures mixed model was used to examine the longitudinal anthropometric data.ResultsGirls with pubertal signs were heavier than their peers starting at 9 months of age (P=0.02), and the difference became more evident over time (P<0.001). Accelerated weight gain between 6 and 15 months of age was found to increase the odds of having a pubertal sign at the study visit (odds ratio (OR)=34.5) after adjusting for birth weight, gestational age and current age, height, weight, and BMI (P=0.004). Anthropometric indices of boys with or without pubertal signs were not significantly different at the study visit, but boys with accelerated height gain between 9 and 15 months of age were more likely to have pubertal signs (OR=15.8) after adjusting for birth weight, gestational age and current age, height, weight, and BMI (P=0.016).ConclusionEarly growth acceleration might be important for the timing of puberty in both genders.

Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic, and multisystem lysosomal storage disease. Enzyme replacement therapy (ERT) with the recombinant human arylsulfatase B enzyme (galsulfase [Naglazyme]) is recommended as first-line therapy. It is generally reported as safe and well tolerated. Frequently observed mild to moderate infusion-related reactions which can be easily handled by reducing or interrupting the infusion and/or administering additional antihistamines, antipyretics, and corticosteroids are mostly mediated by non-IgE mechanisms. Here we report two children with MPS VI who experienced IgE-mediated reactions with galsulfase at the second year of the therapy. One child had anaphylaxis and the other had urticarial eruptions. They could receive ERT after successful rapid desensitization. To our knowledge, this is the second report on galsulfase allergy with IgE-mediated reaction. It is important to recognize IgE-mediated reactions since they can be life-threatening and do not respond to the standard therapies. We recommend allergy skin tests in the evaluation of infusion-related reactions unresponsive to standard therapies, so that continuation of ERT will be feasible after successful desensitization.

Background: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data., Methods: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications., Results: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 μM) and NTBC-levels in the therapeutic range (20-40 μM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood)., Conclusion: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

Background: Cup feeding has been used as an alternative feeding method for preterm infants., Objective: The purpose of this study was to determine the effect of bottle and cup feeding on exclusive breastfeeding rates at hospital discharge and 3 and 6 months post-discharge in late preterm infants., Methods: Included in the study were preterm infants of 32 to 35 weeks' gestation fed only by intermittent gastric tube at the time of recruitment; 522 infants were randomly assigned to 2 groups: the cup-fed group (n = 254) and bottle-fed group (n = 268). Main outcomes were prevalence of exclusive breastfeeding at discharge and 3 and 6 months after discharge, and length of hospital stay., Results: Infants randomized to cup versus bottle feeding were more likely to be exclusively breastfed at discharge home (relative risk [RR], 1.58; 95% confidence interval [CI], 1.36-1.83), 3 months after discharge (RR, 1.64; 95% CI, 1.42-1.89), and 6 months after discharge (RR, 1.36; 95% CI, 1.14-1.63). There was no significant difference between groups for length of hospital stay. The mean hospital stay was 25.96 ± 2.20 days in the bottle-fed group and 25.68 ± 2.22 days in the cup-fed group. There was no significant difference between groups for time spent feeding, feeding problems, or weight gain in hospital., Conclusion: Cup feeding significantly increased the likelihood of late preterm infants being exclusively breastfed at discharge and 3 and 6 months after discharge, and cup feeding did not increase the length of hospital stay. Overall, we recommend cup feeding as a transitional method prior to breastfeeding for late preterm infants during hospitalization.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by deficiency in the glycogen debranching enzyme (gene symbol: AGL) with two enzyme activities: transferase and glucosidase. A missense mutation causing isolated glucosidase deficiency has never been reported. In this study, we examined 23 patients of Turkish ancestry and identified a novel missense mutation p.R1147G with isolated glucosidase deficiency, along with nine AGL mutations: six nonsense mutations (p.W373X, p.R595X, p.Q667X, p.Q1205X, p.W1327X and p.Q1376X), one deletion (c.1019delA) and two splicing mutation (c.293+2T>G and c.958+1G>A). As p.R1147G impaired glucosidase activity, but maintained transferase activity in vitro, a 12-year-old girl homozygous for p.R1147G was diagnosed with having isolated glucosidase deficiency. Of nine other mutations, p.W1327X and c.1019delA were recurrent, whereas seven mutations were novel. Six patients with p.W1327X were all from two nearby cities on the East Black Sea and shared the same AGL haplotype, indicating a founder effect in Turkish patients. Patients with the same mutations had identical haplotypes. Our results provide the first comprehensive overview of clinical and molecular features of Turkish GSD III patients and the first description of the missense mutation associated with isolated glucosidase deficiency.

Background: Ghrelin is the natural ligand of GH secretagogue receptor. It has several metabolic functions including regulation of food intake, energy homeostasis, and body weight. An inverse relationship between fasting plasma ghrelin and insulin concentrations has been shown. Being born large for gestational age (LGA) has an increased risk of developing insulin resistance., Objective: The aim of this study was to evaluate ghrelin levels in LGA born children who have no obesity at prepubertal ages and the effect of intrauterine and postnatal growth on ghrelin levels. Patients and methods Thirty-two (17F, 15M) LGA born non-obese children (mean (+/-s.e.m.) age 4.4+/-0.3 years) were evaluated with respect to glucose, insulin, and ghrelin levels. Their data were compared with that of non-obese 45 (19F, 26M) appropriate for gestational age (AGA) children (mean (+/-s.e.m.) age 4.0+/-0.1 years)., Results: LGA children, who had similar age and body mass index (BMI) standard deviation score (SDS) as AGA children, had significantly higher insulin (P=0.044) and at a borderline significance higher homeostasis model assessment-insulin resistance levels (P=0.054) than AGA children. Ghrelin level was significantly lower in LGA born than AGA born children (P=0.001) even after controlling for age, sex, and BMI (P=0.006). There were no differences between genders in insulin and ghrelin levels. Multivariate analysis revealed that birth weight was the only significant parameter influencing ghrelin levels (R(2)=0.13, B=-0.007, P=0.002)., Conclusions: LGA born non-obese prepubertal children have lower ghrelin levels when compared with age and BMI matched AGA children. Birth weight seems to have the only significant effect on the reduced ghrelin levels.

Background and Objective: Being born as large for gestational age (LGA) has an increased risk of developing insulin resistance. Hypoadiponectinaemia is associated with insulin resistance. The aim of this study was to evaluate adiponectin levels and insulin resistance in association with body composition in LGA born non-obese children at prepubertal ages., Patients and Methods: Thirty-five (17 female and 18 male) LGA born non-obese children (mean age 4.8 +/- 0.3 years) were evaluated with respect to glucose, insulin, IGFBP-1, leptin, adiponectin levels and body composition by DEXA. Their data were compared to that of non-obese 49 (20 female, 29 male) appropriate for gestational age (AGA) children (mean age 3.8 +/- 0.1 year)., Results: LGA children, who had similar body mass index standard deviation scores (BMI SDS) as AGA children, had significantly higher insulin (P = 0.043) and statistically borderline significant homeostasis model assessment-insulin resistance (HOMA-IR) levels (P = 0.054) than those of AGA children. Adiponectin levels were significantly lower in LGA than AGA children (P = 0.004) even after controlling for age, sex and BMI (P = 0.016). IGFBP-1, leptin levels and body composition did not show a difference. When the LGA group was divided into subgroups according to birth weight, the analysis revealed that after controlling for BMI, being an LGA and having a higher birth weight in the upper half were associated with lower adiponectin levels (estimated marginal means of logarithmic adiponectin levels 2.6 +/- 0.2 vs. 2.1 +/- 0.2 microg/ml, P = 0.042)., Conclusion: LGA children have higher insulin and lower adiponectin levels than AGA children in spite of similar BMI. Adiponectin is a better indicator of insulin resistance in LGA children at prepubertal ages and is affected by birth weight.

Background: Ghrelin, the natural ligand of the GH secretagogue receptor, has potent orexigenic effect. Ghrelin levels are negatively associated with insulin secretion, increased in anorexia, and reduced in obesity. Increased ghrelin levels may be associated with early postnatal growth in preterm born children., Objective: Aim of this study was to evaluate ghrelin and insulin levels at prepubertal ages in preterm born children born appropriate for gestational age (AGA) or small for gestational age (SGA) and relationships with catch-up growth (CUG) in a prospective cross-sectional study., Methods: Eighty-four preterm born children grouped as preterm SGA (n=28) and preterm AGA (n=56) were evaluated at age 4.7+/-0.2 and 4.7+/-0.1 years with respect to their ghrelin and insulin levels. Their data were compared with that of body mass index matched term SGA (n=35) and term AGA (n=44) children of age 4.6+/-0.2 and 3.8+/-0.1 years. All children had height appropriate for their target height. CUG was defined as the difference between birth size and recent size and expressed as Delta height and Delta weight SDS., Results: Preterm SGA and preterm AGA children had similar ghrelin levels (1717.0+/-166.9 and 1656.5+/-103.8 pg/ml), although Delta height and Delta weight SDS in preterm SGA were significantly higher than in preterm AGA children (P<0.001). Ghrelin levels in both preterm groups were higher than term SGA (469.2+/-132.5 pg/ml) and term AGA children (659.6+/-143.3 pg/ml; P<0.001 for all). Delta Height and Delta weight SDS of the term SGA children were similar to that of preterm SGA children. Ghrelin did not have correlation with CUG but had inverse correlation with recent anthropometric indices. Insulin was significantly higher in term SGA children than other groups (P<0.001)., Conclusions: Preterm children have higher ghrelin levels at prepubertal ages regardless of the magnitude of their CUG. Term SGA children, on the other hand, behave differently and have lower ghrelin levels than preterm children at prepubertal ages, which may be related to elevated insulin levels in this group.

Background: Being small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in later life. Adiponectin is a strong determinant of insulin sensitivity., Objective: The aim of this study was to evaluate insulin resistance and adiponectin levels in SGA born children with catch-up growth (CUG) in the absence of obesity in prepubertal ages and relations with body composition and insulin-like growth factor binding protein (IGFBP)-1., Methods: Twenty-four (15F, 9M) SGA born children with CUG but without obesity were evaluated at age 6.3 +/- 0.5 years with respect to glucose, insulin, IGFBP-1, leptin and adiponectin levels, and body composition by dual-energy X-ray absorptiometry (DEXA). Their data were compared to that of 62 (27F, 35M) appropriate for gestational age (AGA) children., Results: SGA and AGA children had similar height standard deviation score (SDS) corrected for parental height and body mass index (BMI) SDS. Homeostasis model for insulin resistance (HOMA-IR) was significantly high in SGA (0.7 +/- 0.6) than in AGA children (0.4 +/- 0.2) (P = 0.029). There were no significant differences in leptin, IGFBP-1, adiponectin, and total and truncal fat between SGA and AGA children. However, being born SGA and having higher BMI in the upper half for the distribution in the sample, although within normal ranges, was associated with lower adiponectin levels (estimated means of log adiponectin levels 3.8 +/- 0.3 vs. 4.4 +/- 0.1 microg/ml, P = 0.040)., Conclusions: SGA children with CUG and with no obesity have higher insulin levels compared to AGA children. Both SGA birth and recent size seem to have an effect on serum adiponectin levels in childhood.

Background: Premature born children may show insulin resistance in childhood which may be due to intrauterine or postnatal adverse environmental factors., Objective: Aim of this study was to evaluate insulin resistance and body composition in preterm born children born appropriate for gestational age (AGA) or small for gestational age (SGA) and relations with IGF-I, IGFBP-3 axis., Methods: Ninety-three preterm born children grouped as premature SGA (n = 30) and premature AGA (n = 63) were evaluated at age 4.6 +/- 0.2 years and 4.7 +/- 0.1 years with respect to their glucose, insulin, IGF-I, IGFBP-3, IGFBP-1, leptin levels and body composition by dual-energy X-ray absorptiometry. Their data were compared to that of body mass index (BMI) matched term SGA (n = 42) and term AGA (n = 44) children of age 4.5 +/- 0.2 and 3.8 +/- 0.1 years. All children had height appropriate for their target height. Insulin resistance was evaluated by basal insulin and homeostasis model assessment for insulin resistance (HOMA-IR)., Results: Basal insulin level was similar in preterm AGA (4.3 +/- 1.4 pmol/l) and term AGA (7.9 +/- 6.4 pmol/l) children at similar and normal BMI levels. Preterm SGA children had insulin levels (5.0 +/- 3.6 pmol/l) similar to preterm AGA children but significantly lower than that in term SGA children (23.7 +/- 20.8 pmol/l) (P = 0.001). Similar results were obtained for HOMA-IR. Term SGA children had also significantly lower IGFBP-1 levels. Body composition, leptin and IGFBP-3 did not differ between the respective groups. IGF-I was lower in preterm AGA (5.0 +/- 0.6 nmol/l) than in term AGA (8.3 +/- 1.2 nmol/l) (P < 0.001) children., Conclusions: Premature born AGA and SGA children do not have insulin resistance when compared to term children if they have made a catch-up growth appropriate for their target height and have normal BMI. The similar insulin levels in preterm SGA and preterm AGA children together with increased insulin levels in term SGA children points to the fact that it is the intrauterine restriction in the third trimester that has an adverse effect on future adverse metabolic outcome.

Objective: A prospective sonographic study of the normal thymus was performed to determine the size changes with age and to compare the results according to some clinical conditions, such as sex, breast versus formula feeding, and term or preterm status., Methods: One hundred fifty-one healthy infants underwent thymic sonography. Maximal transverse and longitudinal dimensions and anteroposterior dimensions of the right and left lobes were measured, and thymic indices were calculated. Mean values of thymic measurements for each group (sex, age, breast or formula feeding, and term or preterm status) were determined. The results were statistically evaluated., Results: Thymic dimensions showed the maximal values at about 4 to 6 months and gradually decreased after 6 to 8 months. No significant differences were found between mean values of thymic dimensions according to the sex and formula- versus breast-fed groups. As expected, the term group had greater thymic size values than the preterm group, probably because of positive correlations between thymus size, birth weight, and height., Conclusions: The thymus is clearly and easily visualized on sonography in the 0- to 2-year age period. This may be useful for evaluating qualitative and quantitative properties of the thymus and determining size changes according to age in various clinical conditions.