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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., Medical Research Council [MR/S019111/1]; National Institute of Health Research Senior Investigator Award [NIHR202370]; Medical Research Council Clinician Scientist Fellowship [MR/T008024/1]; NIHR Great Ormond Street Hospital Biomedical Research Centre, This work was supported by the Medical Research Council grant, reference: MR/S019111/1. PG is supported by a National Institute of Health Research Senior Investigator Award (Reference NIHR202370). J.B. is supported by Medical Research Council Clinician Scientist Fellowship MR/T008024/1 and NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Fabry disease is a rare, progressive, X-linked inherited storage disorder due to absent or deficient of lysosomal alfa galactosidase A activity. Deficient activity of alfa-galactosidase A results in progressive accumulation of globotriaosylceramide in a variety of tissues and organs including myocardium, kidney and nerve system. This disorder predominantly affects males; however, female heterozygotes may also be affected with a less severe clinical picture. Classic Fabry disease is usually diagnosed in early age of childhood because of multiorgan involvement whereas cardiac and renal variants of Fabry are manifested in 30-50 years of age because of late onset of clinical picture in which other organs involvement are uncommon. Although Fabry is known as a very rare disease, its prevalence is reported to be higher in patients with ventricular hypertrophy, chronic kidney disease and cryptogenic stroke. From the cardiology point of view, the most important key finding of the disease is unexplained ventricular hypertrophy. However, in clinical practice, ventricular hypertrophy is usually thought to be due to hypertrophic cardiomyopathy in the absence of hypertension or aortic stenosis and Fabry disease is often undiagnosed or overlooked. Early diagnosis and enzyme replacement therapy have been shown to significantly improve prognosis. The aim of this paper is to provide a comprehensive review including epidemiology, prognosis, clinical presentation, diagnosis and therapeutic approaches of cardiac variant of Fabry based on the available data in the literature.

Background Low back pain (LBP) is one of the most common disorders, with many possible causes including intervertebral disc degeneration (IVDD) and Modic changes. In this study we aimed to analyze whether the distribution pattern of Modic changes in the vertebral end-plates was associated with the severity of IVDD. Methods We conducted a cross-sectional analysis of a retrospective database. Patients with constant LBP were evaluated in terms of IVDD and Modic changes on lumbar spine magnetic resonance imaging. Statistical analyses were specifically performed for the lower lumbar levels. Results We evaluated 527 patients. Modic changes were detected in 25% of the patients. Severe IVDD was detected in 90% and 88% of patients with Modic changes through the whole end-plates at L4-L5 and L5-S1 levels, respectively. Patients with Modic changes at L5-S1 level had significantly lower lumbar lordosis. Presence of severe IVDD at L4-L5 and L5-S1 levels was associated with 2.7- and 2.9-times higher risk of more widely distributed Modic changes in those vertebral end-plates, respectively. Conclusions Severe IVDD was significantly more common in patients with Modic changes through the whole end-plate and in those with Modic type I changes.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 +/- 51.4) than in the adult patients (450.0 +/- 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.

Ochronotic arthropathy (OcA) refers to excessive homogentisic acid (HGA) deposition in the musculoskeletal system. Our current understanding of OcA is limited, as there are less than a thousand alkaptonuria (AKU) cases reported in the literature. Herein, we investigated the rheumatological manifestations of OcA in a group of adult AKU patients.Adult AKU patients with symptoms suggestive of OcA were included. Patients underwent a detailed rheumatological assessment. Laboratory testing, including autoantibodies and radiological investigations such as conventional X-rays, andEight out of 12 (66%) patients had symptoms consistent with OcA. The median age at OcA symptoms was 36 (27-48) years, and the presenting symptom was back pain in 87.5% of the patients. All patients had chronic back pain, and three (37.5%) had an inflammatory type of pain character. Radiographic sacroiliitis based on X-rays was present in 2 (25%) cases. MRI of the sacroiliac joints documented bone marrow edema in five (62.5%), and spinal MRI identified corner inflammatory lesions in three patients (37.5%). One patient (12.5%) had rheumatoid arthritis. Extra-articular involvement, including enthesitis (The frequent occurrence of OcA-related inflammatory manifestations in our patients contradicts the conventional concept of OcA as a non-inflammatory disorder. The activation of inflammatory pathways, possibly by the HGA products, may responsible for this condition.Significance and innovationsAbout three-fourths of adult ochronotic arthropathy (OcA) patients in our group had associated inflammatory disease.OcA associated inflammatory diseases were showing a severe phenotypeNearly half of the OcA patients required early prosthesis operations compared to their healthy counterparts.

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.

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families, recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two% of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families, and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialised bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity. The project is supported by TUBITAK (The Scientific and Technological Research Council of Turkey) Project No. 216S771. YO is supported by the Turkish Academy of Sciences’ Young Investigator award, TÜBA-GEBİP (2017). PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer's Society Project Grant (AS-PG-18b-022). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. the Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust. HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Data was analysed using the RD-Connect Genome-Phenome Analysis platform developed under FP7/2007-2013 funded project (grant agreement nº 305444) and funding from EJP-RD and INB/ELIXIR-ES. The study was further supported by the Horizon 2020 research and innovation program via grant 779257 “Solve-RD” (RH, SB, AT and HL). RH, PFC and YO were supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1

Introduction: Nitisinone used in alkaptonuria (AKU) can result in keratopathy due to strongly increased tyrosine levels. Methods: This study aimed to investigate nutritional status and changes in plasma tyrosine and phenylalanine and urinary homogentisic acid (u-HGA) levels in 8 adult AKU patients (mean age, 56.3 ± 4.7 years) who were on tyrosine/phenylalanine-restricted diet together with 2 mg/day nitisinone. Results: The treatment period was 23.4 ± 6.9 months. Daily dietary protein intake was restricted to 0.8–1.0 g/kg/day. Daily tyrosine intake was restricted to 260–450 mg/day for females and 330–550 mg/day for males. Tyrosine/phenylalanine-free amino acid supplements accounted for an average of 56.1% of daily protein intake. The following assessments were performed: anthropometric and plasma tyrosine level measurements every 2 months; ophthalmological examination every 6 months, and nutritional laboratory analyses and measurements of plasma amino acids and u-HGA once in a year. It was targeted to keep the plasma tyrosine level 700 μmol/L was detected. The u-HGA level before and after the 1st year of treatment was 1,429.3 ± 1,073.4 mmol/mol creatinine and 33.6 ± 9.5 mmol/mol creatinine, respectively. None of the patients developed keratopathy or experienced weight loss and protein or micronutrient deficiency. Conclusion: AKU patients should receive tyrosine/phenylalanine-restricted diet for reducing plasma tyrosine level to the safe range. Tyrosine/phenylalanine-free amino acid supplements can be safely used to enhance dietary compliance. Keratopathy and nutrient deficiency should be frequently monitored.

BACKGROUND Functional constipation is an important clinical problem among chidren all over the world. Its main cause is not completely understood. Motilin is a gastrointestinal hormone that increases intestinal motility. In this study, we aimed to investigate the serum motilin levels and its relationship with stool consistency and motilin gene polymorphisms in constipated children. METHODS In this study we investigated 91 constipated patients (mean age 6.84±3.55 years) and 100 healthy controls (mean age 7.78±4.25 years). Serum motilin levels were assessed by sandwich enzyme-linked immunosorbent assay. rs2281820 (c.44 C>T) and rs2281818 (c.66 C>T) mutations were evaluated for motilin gene polymorphisms. RESULTS Serum motilin levels were significantly lower in constipated children than healthy controls (6.20±7.86 vs. 11.54±17.89 pg/mL, respectively, P=0.008). Serum motilin levels were significantly correlated with Bristol stool scale rate (r=0.193, P=0.011) in whole study group, but in the constipation group there was no significant correlation (r=-0.072, P=0.528). There were no differences in terms of presence or distribution of the polymorphisms of rs2281820 (c.44 C>T) and rs2281818 (c.66 C>T) in both groups. There was not a significant difference between different polymorphism groups regarding serum motilin concentrations in whole study group and also in both of the study groups. CONCLUSIONS This study indicated for the first time that serum motilin levels decreased in constipated children. Further studies are needed to clarify whether motilin or motilin gene polymorphisms has a role in pathogenesis of functional constipation.

Introduction Intradiscal vacuum phenomenon (IVP) is the collection of gas within the intervertebral discs. It has been reported with various spinal disorders. The exact role of IVP in spinal degeneration leading to low back pain (LBP) is unclear. We aimed to obtain the prevalence of IVP in patients with LBP. Our second aim was to understand whether IVP was associated with intervertebral disc degeneration (IVDD), Modic changes, and subchondral sclerosis (SS). Methods A total of 12.450 consecutive patients with chronic LBP were evaluated in terms of having abdominal computed tomography (CT) scan concomitant with lumbar spine magnetic resonance imaging (MRI) using radiological database of three spine centers. We excluded the patients with a history of malignancy, metabolic disease, spinal infection, traumatic or osteoporotic spine fracture, and spine surgery. All lumbar levels were evaluated in terms of IVDD and Modic changes on MRI, while they were evaluated in terms of IVP and SS on CT scans. Results We included 219 patients. Severe IVDD, Modic changes, IVP, and SS were seen in 53.9% (n: 118), 38.8% (n: 85), 26.5% (n: 58), and 16% (n: 35) of the patients, respectively. Intradiscal vacuum phenomenon was closely associated with severe IVDD (OR: 8.204), Modic changes (OR: 3.547) and SS (OR: 4.231). Discussion Intradiscal vacuum phenomenon was closely associated with severe IVDD, Modic changes, and SS. Further prospective clinical and laboratory studies are necessary to better delineate the pathogenesis of IVP.

Objectives This study aimed to investigate the frequency and status of depression and anxiety among mothers of children with inborn errors of metabolism (IEM) who were on a restricted diet and previously experienced metabolic crises. Methods This cross-sectional multicenter descriptive study included 93 children with IEM who were on restricted diet. The patients were divided into two groups: those who had experienced metabolic crises (n=44, urea cycle defect, organic acidemia, maple syrup urine disease, hereditary fructose intolerance) and those who had not experienced previous metabolic crises (n=49; phenylketonuria, galactosemia, and non-ketotic hyperglycinemia). The control group comprised 37 healthy children. The mothers of the patients and control participants answered a questionnaire about their and their children's demographic and clinical characteristics and completed the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-S and STAI-T). Results The maternal BDI, STAI-S, and STAI-T scores were 6.3±5.2, 36.1±11.2, and 39.9±8.8, respectively, in the control group. The maternal BDI, STAI-S, and STAI-T scores of the children who had experienced (19.2±9.7; 44.0±12.4; 47.9±10.6) and those who had not experienced (13.9±9.1; 40.7 ±8.6; 45.3±8.3) a crisis were significantly higher than for the controls. The BDI score was significantly higher for the mothers of children who had experienced a crisis (p=0.011), whereas no significant difference was determined between the two patient groups regarding STAI-S and STAI-T scores. The mothers of four children who had experienced metabolic crises were on antidepressant therapy. Conclusion Although their children were on a similar restricted diet, the mothers of children who previously experienced or who had the risk of experiencing metabolic crises had higher depression scores as compared with the mothers of children who did not experience a previous crisis. Early supportive therapy may be required for the families of these patients to lower the burden of stress.

EgeUn###, Classical galactosemia is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in the GALT gene. With the benefit of early diagnosis by newborn screening, the acute presentation of galactosemia can be prevented. In this study, we describe the clinical phenotypes, time of diagnosis and GALT genotypes of 76 galactosemia patients from Turkey, where the disease is not yet included in the newborn screening program. The median age at first symptom was 10 days (range 5-20), while the median age at diagnosis was 30 days (range 17-53). Nearly half of the patients (36 patients, 47.4%) were diagnosed later than age 1 month. Fifty-eight individuals were found to have 18 different pathogenic variants in their 116 mutant alleles. In our sample, Q188R variant has the highest frequency with 53%, the other half of the allele frequency of the patients showed 17 different genotypes. Despite presenting with typical clinical manifestations, classical galactosemia patients are diagnosed late in Turkey. Due to the geographical location of our country, different pathogenic GALT variants may be seen in Turkish patients. In the present study, a clear genotype-phenotype correlation could not be established in patients.

Strict low-phenylalanine diet is associated with an increased risk of developing micronutrient deficiencies in patients with phenylketonuria (PKU). The primary objective of this single-center, case-control study was to assess the nutritional parameters of patients with PKU on strict low-phenylalanine diet without vitamin and mineral supplementation compared to a healthy control group. Secondary objective was to identify the adequacy of vitamin/mineral supplementation in phenylalanine-free (Phe-free) amino acid formulas.A total of 112 age- and sex-matched patients with PKU and 36 controls who did not take vitamin or mineral supplementation at least for the last 6 months were enrolled in the study. Biochemical and hematological markers including hemoglobin, serum vitamin B12, folic acid, iron, ferritin, transferrin saturation, copper, prealbumin, albumin, total protein, phosphorus, calcium, 25-hydroxy vitamin D, zinc, vitamin A and vitamin E levels were screened from fasting morning blood samples.One hundred and twelve patients with classical PKU (53 females, 47.3%) and 36 healthy controls (18 females, 50.0%) were enrolled in the study. The mean age of patients with PKU was 136.8 ± 82.1 months (18-377). Median serum vitamin B12 level of patients with PKU was found to be higher than the control group (p = 0.002). Vitamin B12 deficiency was 15.2% and 30.6% in patients with PKU and healthy controls, respectively (p = 0.040). Mean serum folic acid level was higher in patients with PKU than the control group (p 0.0001). In 55.4% of patients with PKU, and 2.8% of the control group, serum folic acid level was above the reference range (p 0.0001). The frequency of ferritin and prealbumin values above the reference range was found to be higher in patients with PKU compared to the control group (44.4% vs 16.9%, p = 0.001; 38.8% vs 22.1%, p = 0.020, respectively). 25-Hydroxy vitamin D deficiency was detected in 53.6% and 47.2% of patients with PKU and the control group, respectively. Mean serum copper level was higher in the well-controlled (114.3 ± 26.7 μg/dL) group than the poorly controlled group (101.0 ± 29.1 μg/dL) (p = 0.022).Phe-free amino acid formulas provide adequate vitamin A and zinc levels in patients with PKU, and result in excess folic acid, vitamin B12, copper and vitamin E values that are higher than required levels. Our results demonstrate a high percentage of vitamin D deficiency in patients with classical PKU and also in healthy controls in Turkey.

Background Vitamin B12 deficiency frequently appears in phenylketonuria patients having a diet poor in natural protein. The aims of this study were to evaluate vitamin B12 status in phenylketonuria patients by using combined indicator of vitamin B12 status (cB12) as well as methylmalonic acid and homocysteine, more specific and sensitive markers, in comparison with healthy controls. Methods Fifty-three children and adolescents with phenylketonuria under dietary treatment and 30 healthy controls were assessed cross-sectionally. Serum vitamin B12 and folate concentrations were analysed by chemiluminescence immunoassay. Plasma methylmalonic acid and total homocysteine concentrations were measured by liquid chromatography-tandem mass spectrometry and liquid chromatography, respectively. cB12 was calculated by using a formula involving blood parameters. Results Methylmalonic acid and folate concentrations in phenylketonuria group were higher compared with controls. Methylmalonic acid concentrations were high in 56.5% of the patients and 26.7% of the controls with normal vitamin B12 concentrations. Based on cB12, a significant difference within the normal values was detected between the groups. However, although 24.5% of phenylketonuria patients and 13.3% of controls had decreased vitamin B12 status according to cB12, there was no significant difference. Conclusion Children and adolescents with phenylketonuria having a strict diet can be at risk of functional vitamin B12 deficiency. This deficiency can be accurately determined by measuring methylmalonic acid concentrations. Calculation of cB12 as a biochemical index did not provide additional information compared with the measurement of methylmalonic acid alone, but may be helpful for classification of some patients with increased methylmalonic acid as having adequate vitamin B12 status.

Inborn errors of metabolism consist of a heterogeneous group of disorders with various organ systems manifestations, and some metabolic diseases also cause immunological disorders or dysregulation. In this review, metabolic diseases that affect the immunological system and particularly lead to primary immune deficiency will be reviewed. In a patient with frequent infections and immunodeficiency, the presence of symptoms such as growth retardation, abnormal facial appearance, heart, skeletal, lung deformities, skin findings, arthritis, motor developmental retardation, seizure, deafness, hepatomegaly, splenomegaly, impairment of liver function tests, the presence of anemia, thrombocytopenia and eosinophilia in hematological examinations should suggest metabolic diseases for the underlying cause. In some patients, these phenotypic findings may appear before the immunodeficiency picture. Metabolic diseases leading to immunological disorders are likely to be rare but probably underdiagnosed. Therefore, the presence of recurrent infections or autoimmune findings in a patient with a suspected metabolic disease should suggest that immune deficiency may also accompany the picture, and diagnostic examinations in this regard should be deepened.

Purpose Ketogenic diet (KD) is an effective non-pharmacological treatment for drug-resistant epilepsy. The aim of this study was to investigate the efficacy, tolerability and complications of olive oil-based KD in epileptic children. Method In this single-center, prospective study, patients were followed up at 1, 3, 6 and 12 months after KD initiation. Initially, blood ketone levels were measured daily, and as needed thereafter to maintain the levels between 4 and 5 mmol/L. Patient demographics, seizure frequency, serum biochemistry, abdominal ultrasonography and adverse effects were recorded. Efficacy of KD was defined as ≥50% seizure reduction. Results A total of 389 patients with drug-resistant epilepsy receiving KD from 2012 to 2016 were included. One hundred patients (25.7%) stopped the diet for different reasons in the first year, and 369, 314, 225 and 160 patients have been receiving KD treatment for 1, 3, 6 and 12 months, respectively. At 1, 3, 6 and 12th months, 65.8% (243/369), 74.7% (235/314), 70.6% (159/225) and 83.1% (133/160) of the patients were responders, respectively. None of the children had an increased seizure-frequency. Hyperlipidemia (50.8%), selenium deficiency (26.9%), constipation (26.2%), sleep disturbances (20.0%), nephrolithiasis (3.0%), hyperuricemia (3.0) and hepatic side effects (2.6%) were the most common complications of KD. Previous adrenocorticotropic hormone (ACTH) use due to epileptic encephalopathy and presence of constipation at baseline or during KD treatment were found the predictors of treatment efficacy. Conclusion KD is an effective and well-tolerated treatment option for patients with drug-resistant epilepsy. Previous history of ACTH use and constipation during KD treatment are important factors that affect the efficacy of KD treatment.

Aim:Precocious puberty (PP) is defined as the appearance of secondary sexual characteristics before the age of nine in boys or eight in girls. Due to changing socio-economic conditions, nutritional habits and environmental factors, the onset of normal puberty is being seen at younger ages these days. The purpose of this study was to evaluate the dietary habits and environmental factors in cases that presented to or were being followed up by the Child Endocrinology Clinic with symptoms of PP.Materials and Methods:The study group included 50 girls aged 2-8 years who presented with symptoms of PP and whose diagnosis was being monitored. A survey noting food consumption was made recording the girls’ dietary habits, fast food consumption and frequency, information about their health, physical activity (PA) and environmental factors using a 24-hour-recall technique.Results:The mean age of the girls was 7.1±0.9 years. According to body mass index z-scores, 62.0% of the girls were overweight [(≥+1 standard deviation (SD)], 34.0% were normal (≥+1 SD

Herein, a rhodamine based nanosensor platform (RHD–NPs) was designed and prepared for the sensing of Hg2+ in the near–perfect aqueous medium (v/v, 0.01/99.99, acetone/water). The structure, aqueous stability, surface charge and particle size of RHD–NPs were analyzed by using zeta particle sizer, scanning electron microscopy (SEM) and UV–Vis spectrophotometry. The spherical shaped morphology of RHD–NPs has 61.4 nm particule size. The interaction ability of RHD–NPs towards various heavy metal ions was evaluated with UV–Vis and fluorescence spectroscopies. After the transferring of Hg2+ to RHD–NPs, a new absorption band at 562 nm was observed due to the ring–opening mechanism of rhodamine structure. The remarkable emission enhancement at 582 nm was observed through the adding of Hg2+ because of chelation–enhanced fluorescence (CHEF) and aggregation–induced enhanced emission (AIEE) phenomena. RHD–NPs nanosensor system showed good selectivity for Hg2+ monitoring with a nanomolar–level detection limit of 6.56 nM. The binding constant of RHD–NPs with Hg2+ was determined to be 10.06 × 103 M−1 based on the Benesi–Hildebrand graph and a maximum value of Job’s graph was about 0.5 ratio (1:1) between RHD–NPs and Hg2+.The smartphone–based technique revealed an outstanding potential of the RHD–NPs platform for the sensing of Hg2+ without further device. A visual colorimetric strip based on papers with excellent selectivity towards Hg2+ without interfering competition ions, was produced with the white–to–pink color signal change. The RHD–NPs was also employed for the quantitative determination and real–time monitoring of Hg2+ in real samples.

Acid Ceramidase Deficiency (Farber disease, FD) is an ultra-rare Lysosomal Storage Disorder that is poorly understood and often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). Hallmarks of FD are accumulation of ceramides, widespread macrophage infiltration, splenomegaly, and lymphocytosis. The cytokines involved in this abnormal hematopoietic state are unknown. There are dozens of ceramide species and derivatives, but the specific ones that accumulate in FD have not been investigated. We used a multiplex assay to analyze cytokines and mass spectrometry to analyze ceramides in plasma from patients and mice with FD, controls, Farber patients treated by hematopoietic stem cell transplantation (HSCT), JIA patients, and patients with Gaucher disease. KC, MIP-1 alpha, and MCP-1 were sequentially upregulated in plasma from FD mice. MCP-1, IL-10, IL-6, IL-12, and VEGF levels were elevated in plasma from Farber patients but not in control or JIA patients. C16-Ceramide (C16-Cer) and dhC16-Cer were upregulated in plasma from FD mice. a-OH-C18-Cer, dhC12-Cer, dhC24:1-Cer, and C22:1-Cer-1P accumulated in plasma from patients with FD. Most cytokines and only a-OH-C18-Cer returned to baseline levels in HSCT-treated Farber patients. Sphingosines were not altered. Chitotriosidase activity was also relatively low. A unique cytokine and ceramide profile was seen in the plasma of Farber patients that was not observed in plasma from HSCT-treated Farber patients, JIA patients, or Gaucher patients. The cytokine profile can potentially be used to prevent misdiagnosis of Farber as JIA and to monitor the response to treatment. Further understanding of why these signaling molecules and lipids are elevated can lead to better understanding of the etiology and pathophysiology of FD and inform development of future treatments. (C) 2016 Elsevier B.V. All rights reserved.

Background Alkaptonuria (AKU) is a metabolic disorder that causes accumulation of oxidized homogentisic acid (HGA) in the connective tissues. The excessive deposition of HGA and its metabolites can cause joint destruction and skeletal abnormalities which the entity is clinically referred as ochronotic arthropathy (OA) [1]. Objectives To assess clinical, demographic features and radiographic findings in patients with OA. Methods Adult AKU patients registered in the database were included in the study. All patients investigated for the presence of OA and inflammatory symptoms. Patients with musculoskeletal symptoms (MSK) underwent conventional X-rays and routine laboratory evaluation. In cases suggestive of inflammatory disease additional work-up such as autoantibodies, HLA-B27 and MRI with inflammatory protocol were performed. Results Six out of 15 patients had symptoms compatible with OA (40%; 4 male [M], 2 female [F], median age 56 [51-62] years). The median duration of MSK symptoms were 7 (2-19) years. None of the patients had family history of rheumatologic disease. Baseline CRP were normal in all patients. The HLA-B27 test was negative in all cases. One patient had high titers of rheumatoid factor along with positive anti-CCP that were accompanying erosive arthritis on MCP joints by X-rays. Two patient had positive ANA. All patients had chronic back pain and had changes compatible with OA in their spines (narrowing of the intervertebral spaces, vacuum phenomenon and intervertebral disc calcification). Two patient had inflammatory type of pain character (IBP). Radiographic sacroiliitis according to modified New York criteria was present in 2 cases. Inflammatory spine and SIJ lesions were detected by MRI in 1 patient. Extra-articular involvement including enthesitis (1 patient), interstitial lung disease (1 patient) and scleritis (1 patient) was also noted. The clinical and demographic characteristics of the OA are given in Table 1. Conclusion There was a high prevalence of inflammatory arthritis (2 axSpA; 1 RA) in OA (50%) which contradicts with the common concept that OA is a degenerative disorder. According to our results, inflammatory disease should be carefully screened in OA patients as accumulated metabolic products may trigger inflammatory pathways. References [1] Phornphutkul, C., et al., Natural history of alkaptonuria. New England journal of medicine, 2002. 347(26): p.2111-2121. Disclosure of Interests None declared

Alkaptonuria (AKU) is an inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase (HGD) as a result of a defect in the HGD gene. HGD enzyme deficiency results in accumulation of homogentisic acid (HGA) in the body, which in turn leads to multisystemic clinical symptoms. The present study aimed to investigate the presenting symptoms, age at diagnosis, and clinical and genetic characteristics of AKU patients followed-up in different centers in Turkey. In this cross-sectional, multicenter, descriptive study, medical records of 66 AKU patients were retrospectively evaluated. Patients’ data regarding demographic, clinical and genetic characteristics were recorded. HGD database ( http://hgddatabase.cvtisr.sk/ ) was used to identify HGD gene variants. Of the patients, 37 (56.1%) presented with isolated dark urine and 29 (43.9%) were diagnosed based on the clinical symptoms or family screening. One of these patients was on follow-up for 2 years due to Parkinsonism and was diagnosed with AKU on further analyses. Signs of ochronosis such as joint pain, low back pain and renal stones developed in childhood in 7 patients. Eight patients were diagnosed with depression via psychiatric evaluation. There were 14 (21.2%) patients operated on for ochronosis. The most frequent mutation observed in the patients was c.175delA, which was followed by c.674G > A and c.1007-2A > T mutations. Four novel mutations (c.189G > A, c.549+1G > T, c.1188+1G > A, and c.334 T > G) were identified in the patients included in the study. In addition to the known signs such as dark urine and skin pigmentation, symptoms involving different systems such as neurological findings and depression can also be encountered in AKU patients. The presence of a change in urine color needs to be questioned in patients presenting with different symptoms such as arthralgia/arthritis, renal stones or low-back pain, particularly in childhood, when skin ochronosis is not pronounced, and further examination should be performed.

Purpose Long-term ketogenic diet (KD) treatment has been shown to induce liver steatosis and gallstone formation in some in vivo and clinical studies. The aim of this retrospective study was to evaluate the hepatic side effects of KD in epileptic children. Method A total of 141 patients (mean age: 7.1±4.1years [2–18 years], 45.4% girls), receiving KD at least one year for intractable epilepsy due to different diagnoses (congenital brain defects, GLUT-1 deficiency, West syndrome, tuberous sclerosis, hypoxic brain injury, etc.) were included in the study. Serum triglyceride, cholesterol, aminotransferase, bilirubin, protein and albumin levels and abdominal ultrasonography were recorded before and at 1, 3, 6, and 12 months following after diet initiation. Results The mean duration of KD was 15.9±4.3months. At one month of therapy, three patients had elevated alanine and aspartate aminotransferase levels. These patients were receiving ketogenic diet for Doose syndrome, idiopathic epilepsy and GLUT-1 deficiency. Hepatosteatosis was detected in three patients at 6 months of treatment. Two of these patients were treated with KD for the primary diagnosis of tuberous sclerosis and one for Landau Kleffner syndrome. Cholelithiasis was detected in two patients at 12 months of treatment. They were receiving treatment for West syndrome and hypoxic brain injury sequelae. Conclusion Long-term ketogenic diet treatment stimulates liver parenchymal injury, hepatic steatosis and gallstone formation. Patients should be monitored by screening liver enzymes and abdominal ultrasonography in order to detect these side effects.

The aim of the present study was to evaluate serum selenium levels in children receiving olive oil-based ketogenic diet (KD) for intractable seizures for at least 1 year. Out of 320 patients who were initiated on KD, patients who continued receiving KD for at least 12 months were enrolled. Sixteen patients who had selenium deficiency at the time of starting KD were excluded. Finally, a total of 110 patients (mean age 7.3 +/- 4.2 years) were included. Serum selenium levels were measured at baseline and at 3, 6, and 12 months after treatment initiation by using atomic absorption spectroscopy. Selenium deficiency was defined as a serum selenium level < 48 mu g/L at each visit. Repeated measure ANOVA with post hoc Bonferroni correction was used for data analysis. Mean duration of KD was 15.3 +/- 4.3 months. Mean serum selenium levels were significantly lower at 6 and 12 months of KD treatment (66.2 +/- 23.3 and 57.2 +/- 16.2 mu g/L, respectively) compared to pre-treatment levels (79.3 +/- 25.7 mu g/L) (p = 0.001). On the other hand, selenium levels did not show any significant difference at 3 months of KD treatment (70.0 +/- 21.2 mu g/L) compared to baseline levels (p = 0.076). A total of 54 patients (49.1%) were diagnosed with selenium deficiency, and oral selenium medication was initiated for these patients. No relevant clinical findings were detected, and echocardiographic findings were normal in all patients. The decline of the serum selenium concentrations after 6 and 12 months of ketogenic diet suggests that patients on this highly prescriptive dietary treatment need close monitoring of this trace element.

Objectives The aim of this study is to investigate the effects of earmolds made of silicone and acrylic on outer ear canal resonance characteristics in terms of resonance frequency and amplitude measured in a hearing aid fitting. Materials and methods Outer ear canal resonance frequencies and amplitudes in open ears and those measured with silicone and acrylic ear molds were obtained from 30 participants between the ages of 20 and 25 years (average age, 22.0 years; 18 females and 12 males) with a real ear gain measurement. To observe the changes depending on probe tube placement, test-retest variation was investigated in 10 participants before the study. Results There was no statistically significant difference between open ear canal resonance frequencies and those measured with silicone and acrylic earmolds (p>0.05). the silicone earmold resonance amplitude values were statistically significantly lower than the open ear canal resonance amplitudes when compared to those of the acrylic earmolds (p Conclusion Depending on the changes occurring in outer ear resonance features as a result of earmold materials used in hearing aid fittings, the application of earmolds should be done by experienced specialists.

BACKGROUND Only a small number of studies on computerized cytomorphometry have been performed for thyroid FNAC. The present study aimed to determine the usefulness of computerized cytomorphometry methods to further classify thyroid lesions as benign or malignant and to compare the practicability and value of using Papanicolaou (Pap) and Giemsa stains in thyroid FNAC by evaluating their association to various cytologic nuclear parameters. METHODS Fifty-eight thyroid lesions diagnosed by FNAC and categorized according to the Bethesda system for reporting thyroid cytopathology were evaluated in terms of various cytologic nuclear parameters, including nuclear area (NA), nuclear perimeter (NP), nuclear density (ND), long nuclear diameter (LND), and short nuclear diameter (SND). The Pap- and Giemsa-stained slides were examined separately. RESULTS In the malignant cases, NA, NP, LND, and SND were higher than in the benign cases for both the Pap and Giemsa stains. NA, NP, LND, and SND were higher in Giemsa than Pap for both the benign and malignant groups. Statistically significant differences were detected between the benign and malignant cases in the AUS category. CONCLUSIONS Computerized cytomorphometry is useful in distinguishing between benign and malignant lesions in thyroid FNAC. The measurement of cytologic nuclear parameters in cases suggestive of AUS may be useful for the probable classification of cases as benign or malignant. Although further studies are needed, in nuclear morphometric assessment of thyroid FNAC, Giemsa staining may be more useful and valuable than the Pap stain because of its association with various cytologic nuclear parameters. Diagn. Cytopathol. 2016;44:902-911. © 2016 Wiley Periodicals, Inc.

Amac : Bu calismada meme malign neoplazm tanisi konmus hastalarda risk duzeyi degerlendirildi ve risk faktorlerinin erken tani icin yapilan tarama calismalarina katkisi arastirildi. Hastalar ve yontemler : Turgut Ozal Universitesi Tip Fakultesi Hastanesi Genel Cerrahi poliklinigine Ocak 2005 - Aralik 2012 tarihleri arasinda meme hastaliklari sikayetiyle basvuran, meme formu tam olarak doldurulmus meme malign neoplazmi tanisi konmus 290 kadin hasta (ort. yas 49.2 yil; dagilim 25-75 yil) calismaya dahil edildi. Veri toplama araci olarak hastanenin elektronik veri tabani ve verilerin degerlendirilmesinde sayi ve yuzdelik dagilimlar kullanildi. Bulgular : Arastirma kapsaminda yer alan kadinlarin %90’inin 35 yas ustu, %86.6’sinin evli, %59’unun fazla kilolu oldugu belirlendi. %93.8’inin 15 yas oncesi menars, %61.7’sinin adetlerinin duzensiz, %44.8’inin premenopozal donemde, %38.3’unun postmenopozal donemde ve %54.5’inin 50 yas sonrasi menopoz donemde oldugu belirlendi. %33.8’inin iki cocuga gebe kaldigi, %52.8’inin bir veya iki kez dogum yaptigi ve %60.4’unun ilk dogumlarini 20-30 yas araliginda yaptigi, %39’unun cocuklarini en cok 12 ay emzirdigi, %72.1’inin oral kontraseptif kullanmadigi, kullananlarin %84’unun bes yildan az kullandigi, %92.4’unun hormon replasman tedavisi kullanmadigi, kullananlarin %81.8’inin bes yildan az kullandigi belirlendi. Kadinlarin %90.7’sinin rahim ve yumurtaliklara ait patolojilerinin olmadigi, %69.3’unun memeyle ilgili herhangi bir ameliyat gecirmedigi, %74.4’unun ailesel meme kanseri oykusu olmadigi, %41.2’sinin yakinmasinin olmadigi ve %52.8’inde fizik muayene bulgusu saptandigi belirlendi. Sonuc : Arastirma kapsamina alinan kadinlarin meme kanseri gelismesine neden olan guncel risk faktorlerine anlamli olcude sahip olduklari ve kadinlarin erken tani icin yapilan tarama islemlerinde etkin rol ustlenmeleri gerektigi kanisina varildi. Bu baglamda kadinlarin bilinclendirilmesi icin yapilmasi gereken calismalarin oldukca onemli oldugu dusunuldu.

Background:Fabry disease (FD) is a rare metabolic disorder caused by the mutations in the α-galactosidase A (GLA) gene. FD patients present with heterogeneous clinical manifestations, which may overlap with systemic diseases including familial Mediterranean fever (FMF). Recurrent episodes of fever, abdominal pain, and arthralgias can be observed in both disorders and this may lead to misdiagnosis.Objectives:To investigate FD prevalence in mild and severe FMF patients.Methods:A total of 66 FMF patients, according to the Tel-Hashomer criteria, were included in the study. Patients were grouped into mild (Group 1) and severe (Group 2) subsets according to the severity score. α-GLA enzyme activity and mutations in the GLA gene were performed. Demographic features, clinical findings, MEFV mutations and treatments were recorded.Results:The clinical and demographical characteristics of the patients were given in Table 1. In severe form, 27 patients were using biological drug and 40.7% had amyloidosis. Symptoms related to FD including hypohidrosis, acroparesthesias, and painful neuropathies, were not different between the groups. Only one patient in group 1 had a low GLA enzyme activity (0.1 nmol/h/ml;Normal >2.5) which also had mutations in the GLA gene but MEFV mutation test was negative. (Table 2). This patient was a 39-year-old female with recurrent abdominal pain, distal extremity pain and the presence of fever during the attacks. She was heterozygous for R301Q. In detailed history, she reported mild acroparesthesias, hypohidrosis, and tinnitus.Table 1.Demographic and clinical findingsAll patientsn: 66Group 1n: 32Group 2n: 34p-valueAge, median (min./max.)34 (17/64)27 (17/59)36 (18/64)0.192Male, n (%)36 (54.5)14 (43.8)22 (64.7)0.137Disease duration, median (min./max.)20.5 (1/57)12.5 (2/50)25 (1/57)0.006Family history of FMF, n (%)41 (62.1)22 (68.8)19 (57.6)0.443Alpha-galactosidase A (nmol/h/ml), median (min./max.)5.9 (0.1/16)5.6 (0.1/9.6)6 (3.1/16)0.330Abdominal pain, n (%)58 (87.9)31 (96.9)27 (79.4)0.030Fever, n (%)54 (81.8)25 (78.1)29 (85.3)0.532Arthritis, n (%)34 (51.5)10 (31.3)24 (70.6)0.003Pleuritis, n (%)31 (47)19 (59.4)12 (35.3)0.083Painful neuropathy, n (%)23 (34.8)13 (40.6)10 (29.4)0.440Acroparesthesias, n (%)9 (13.6)6 (18.8)3 (8.8)0.240Angiokeratomas, n (%)0 (0)0 (0)0 (0)-Cardiac abnormalities1 (1.5)1 (3,1)0 (0)0.485Tinnitus, n (%)4 (6.1)3 (9.4)1 (2.9)0.274Hearing loss, n (%)2 (3)2 (6.2)00.086Hypohydrozis, n (%)2 (3)1 (3.1)1 (2.9)0.965Cornea verticillata, n (%)0 (0)0 (0)0 (0)-Proteinüria, n (%)13 (19.7)2 (6.3)11 (32.4)0.012Colchine dosing (mg/day), median (min./max.)2 (1/3)1 (1/2)2 (1/3)Table 2.MEFV mutant alleles and GLA mutationsAll patientsn: 66Group 1n: 32Group 2n: 34Alpha -galactosidase A (GLA) gene mutations, n (%)1 (1.5)1 (3.1)0 (0)M694V mutations, n (%)47 (35.6)17 (26.5)30 (44.1)Non-M694V mutations, n(%)36(27.2)20 (31.2)16 (23.5)Conclusion:In this study, we showed the following: 1) the FD rate in the total FMF group was 1.5% (3.1% in group 1), 2) none of the patients in the severe FMF subset had abnormal enzyme activity or mutations related with FD, 3) symptoms related with FD such as hearing loss, hypohidrosis, acroparesthesias, and painful neuropathies also noted in FMF patients particularly in the milder group. Based on our results, FD should be considered in the differential diagnosis of FMF particularly in patients with atypical symptoms.Disclosure of Interests:None declared

Summary Organoid technologies have become a powerful emerging tool to model liver diseases, for drug screening, and for personalized treatments. These applications are, however, limited in their capacity to generate functional hepatocytes in a reproducible and efficient manner. Here, we generated and characterized the hepatic organoid (eHEPO) culture system using human induced pluripotent stem cell (iPSC)-derived EpCAM-positive endodermal cells as an intermediate. eHEPOs can be produced within 2 weeks and expanded long term (>16 months) without any loss of differentiation capacity to mature hepatocytes. Starting from patient-specific iPSCs, we modeled citrullinemia type 1, a urea cycle disorder caused by mutations in the argininosuccinate synthetase (ASS1) enzyme. The disease-related ammonia accumulation phenotype in eHEPOs could be reversed by the overexpression of the wild-type ASS1 gene, which also indicated that this model is amenable to genetic manipulation. Thus, eHEPOs are excellent unlimited cell sources to generate functional hepatic organoids in a fast and efficient manner., Graphical Abstract, Highlights • iPSC-derived EpCAM+ endodermal cells generate functional hepatic organoids (eHEPOs) • eHEPOs can be stably maintained in long-term culture • An organoid-based model for a urea cycle disorder (citrullinemia) is generated • Genetic manipulation of disease-specific eHEPOs rescues disease phenotype, Erdal and colleagues generated a hepatic organoid (eHEPO) culture system using human iPSC-derived EpCAM-positive endodermal cells. eHEPOs can be produced within 2 weeks and expanded long term (>16 months) without any loss of differentiation capacity to mature hepatocytes. Starting from patient-specific iPSCs, a urea cycle disorder, citrullinemia, was modeled and disease phenotype was rescued via overexpression of wild-type ASS1 gene.

Two simplified methods based on manual thermally–assisted hydrolysis and methylation (THM) GC and GC × GC with flame ionization detection (FID) were developed for the detection of mycobacteria and Mycobacterium tuberculosis (MTB) in sputum. A central composite design was employed to optimize the THM derivatization conditions. For the detection of MTB the known mycobacterial markers tuberculostearic acid (TBSA) and hexacosanoic acid (C26), as well as three MTB specific markers, the mycocerosates, were evaluated. We found that the optimum conditions for THM release of TBSA and C26 differ from those for maximum release of the mycocerosates. Higher reagent volumes, higher temperatures and longer incubation increase the mycocerosates yield. Application of these conditions unfortunately resulted in unacceptable safety hazards. A GC × GC–FID method was developed that allowed accurate detection of mycocerosates even at poor conversion yields of the derivatization reaction. Using spiked sputum samples from non–TB patients, the detection limit of the method based on TBSA and C26 was found to be comparable to that of microscopy, i.e. 104–105 bacteria/mL sputum. To validate the new test, we compared the results we found for fifteen sputum samples from patients from South Africa suspected of having tuberculosis with those of culture, the gold standard method. Based on the presence of TBSA and C26, all eight microscopy and culture positive samples, and even two microscopy negative but culture positive samples were positive by THM–GC–FID. All five microscopy and culture negative sputum samples were also negative for THM–GC–FID, giving a specificity of 100%. Using GC × GC–FID we could detect mycocerosates, the specific markers for MTB in seven out of ten MTB culture positive sputum samples. The five culture negative cases were also negative for mycocerosates in manual THM–GC × GC–FID giving again 100% specificity. The results obtained indicate that the new methods hold great potential for the early diagnosis of TB in developing countries.

Objective: Classical phenylketonuria (PKU) is on inherited disorder of amino acid metabolism. Since treatment at an early stage is the most important factor effecting prognosis of the disease, the disease is screened with newborn screening program in our and in many countries as well. The basis of treatment is a life-long phenylalanine-restricted diet. In this study, we aimed to evaluate the effect of phenylalanine-restricted diet on anthropometric parameters of patients with the diagnosis of phenylketonuria

Introduction: Several case reports stress that high-dose biotin causes incorrect laboratory results. However, the extent of this interference in children is not systematically studied. Aim: To assess factors associated with biotin interference on thyroid function tests in subjects with biotinidase deficiency. Method: The study included 44 children who were treated with oral biotin (Group 1, median dose: 10 mg/day [25–75p; 10–10], age: 1.83 years [1.04–2.90]) and 30 healthy subjects (Group 2, age: 1.05 years [0.37–3.37]). Thyroid function tests were performed with two different assays, and streptavidin-coated particles were used in order to remove biotin from serum samples of cases with biotin interference. Results: The measurements were first performed with Beckman Coulter. In Group 1, remarkably high levels of fT3 and fT4 were found in 26 (59.1%) and 25 (56.8%) patients, respectively. Thyroid hormone functions were all normal in Group 2. Significantly higher serum biotin levels were detected in interference-positive children (p < 0.001). The serum biotin levels in Group 1 showed a strong positive correlation with fT3 (r = 0.867, p < 0.001) and fT4 levels (r = 0.905, p < 0.001). A serum biotin level of 80.35 µg/L was found to be the best cut-off value for predicting interference (sensitivity: 96.2% and specificity: 94.4%). When analyzed with Siemens Advia Centaur XP, all thyroid function tests were normal in both groups except in one patient (2.27%) with slightly elevated fT3 level in Group 1. Repeated tests with Beckman Coulter after neutralization of biotin with streptavidin magnetic particles in serum samples of the interference-positive cases revealed normal thyroid hormone levels. Conclusion: Interference is an important problem in thyroid function tests in nearly 60% of all children receiving biotin treatment for biotinidase deficiency. Serum levels of biotin rather than the dosage are the main determinant of interference, which can be eliminated by choosing appropriate laboratory methods.

Functional constipation is a clinical problem with an incompletely understood etiology. Functional bowel diseases have been shown to be related to inflammation in many studies in adults. In this study, we aimed to evaluate leukocytes, C-reactive protein, proinflammatory and anti-inflammatory cytokines, and neopterin levels in children with functional constipation. Seventy-six children with constipation and 71 healthy controls (mean age 7.12 ± 3.46 years and 7.32 ± 4.33 years, respectively, P = 0.991) were included in the study. Leukocytes, C-reactive protein, interleukin (IL)-1β, IL-6, IL-10, IL-12, tumor necrosis factor-alpha (TNF-α) and neopterin levels were assessed in patients and healthy controls. Parameters were measured in the serum using enzyme-linked immunosorbent assay methods. Mean IL-6 (20.31 ± 12.05 vs. 16.2 ± 10.25 pg/mL, respectively, P = 0.003), IL-12 (181.42 ± 133.45 vs. 135.6 ± 83.67 pg/mL, respectively, P = 0.018) and neopterin levels (2.08 ± 1.12 vs. 1.52 ± 1.02 pg/mL, respectively, P = 0.001) were significantly higher in constipated children than healthy controls. Leukocyte and thrombocyte counts, C-reactive protein, and IL-1β, IL-10 and TNF-α levels did not show any difference between the two groups. In this study, IL-6, IL-12 and neopterin levels of constipated patients were found to be higher than those of controls. These results indicate the presence of subclinical inflammation in children with functional constipation.

Aims: To investigate the effect of ketogenic diet on motor function and daily living activities in children with epilepsy. Methods: A total of 62 children (median age 5.0 years) were enrolled. Motor function was assessed using the Gross Motor Function Measure (GMFM), and daily living activities and cognitive functions were assessed using the Functional Independence Measure (WeeFIM) before treatment and 3, 6, and 12 months after ketogenic diet treatment. Results: Significant improvement in total GMFM and WeeFIM scores ( P < .001) were found during the 12 months of ketogenic diet treatment. There was a positive correlation between total GMFM scores and WeeFIM scores at baseline (r= 0.792, P = .0001), and at 3 (r= 0.780, P = .0001), 6 (r= 0.744, P = .0001), and 12 months (r= 0.692, P = .0001) of treatment. Both the responder (50 patients, 80.7%) and nonresponder (12 patients, 19.3%) patient groups showed significantly higher GMFM and WeeFIM scores at 12 months of treatment compared to baseline values. A ≥50% reduction in seizure frequency was observed in 77.4%, 72.6%, and 80.7% of the patients after 3, 6, and 12 months of treatment, respectively. Conclusion: Ketogenic diet treatment improves motor functions and daily living activities in children with epilepsy during the 12 months of treatment.

Acquired coagulopathy is a rare but challenging diagnosis for pediatric emergency physicians. Although the coagulopathy usually presents with mild skin and mucosal hemorrhages, it also can lead to life-threatening events. Thus, accurate interpretation of hints obtained from a detailed history, physical examination, and laboratory findings is essential for the prompt diagnosis and management. This case demonstrates an uncommon cause of coagulopathy; celiac disease that presented with spontaneous bruises and ecchymosis in an adolescent.

Tay-Sachs disease is an autosomal recessive type of lysosomal storage disorder. The disease is very rare in Turkey, with an incidence of 0.54/100,000. The clinical manifestations of Tay-Sachs disease include progressive developmental delay, seizures, deafness, blindness, spasticity, and dystonia, which are caused by the accumulation of gangliosides in the central nervous system. To date, only one case indicating the association between Tay-Sachs disease and central precocious puberty has been reported. Although the mechanism of this association is not clear, it is thought to be due to ganglioside accumulation in the central nervous system or the inhibition of the hypothalamic inhibiting pathway. Herein, we report two patients with genetically proven Tay-Sachs disease who developed central precocious puberty during follow-up. Pubertal development in patients affected by Tay-Sachs disease should be carefully assessed.

WOS: 000442229500021, PubMed ID: 30101073, Background: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. Methods: We sent a cross sectional, survey monkey (R) questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. Results: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months. 53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, >= 26 weeks in 12% and < 17 weeks in 3%. Discussion: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development., Vitaflo, We thank Vitaflo for supporting the publication cost of this paper.

BackgroundFamilial apo C-II deficiency is a rare hereditary disorder frequently caused by lipoprotein lipase (LPL) andAPOC2gene mutations. To date, less than 30 patients with familial apo C-II deficiency with 24 different mutations have been identified in the literature. Here, we describe two familial chylomicronemia syndrome cases in infants with two novel mutations of theAPOC2gene.Case presentationCase 1, a 46-day-old female, was admitted to our hospital for evaluation due to the lipemic appearance of the blood sample. A clinical examination revealed hepatomegaly and lipemia retinalis. Triglyceride level of 6295 mg/dL was decreased with a strict low-fat diet, medium-chain triglycerides (MCT) oil-rich formula and omega-3 fatty acid supplementation. Due to low adherence to the diet, TG elevation was detected and fresh frozen plasma (10 mL/kg/day) was administered for 2 days. A novel homozygous p.Q25X (c.73C>T) mutation in theAPOC2gene was detected. Case 2, a 10-month-old female patient, referred to our center for the differential diagnosis of hyperlipidemia as her blood sample could not be assessed due to its lipemic appearance. Laboratory examinations showed a TG level of 4520 mg/dL which was reduced with a low-fat diet, MCT oil-rich formula and omega-3 fatty acid supplementation. Hepatosteatosis and splenomegaly were determined using abdominal sonography. A novel homozygous IVS2+6T>G (c.55+6T>G) mutation in theAPOC2gene was identified.ConclusionsWe describe two novel homozygous mutations (p.Q25X [c.73C>T] and IVS2+6T>G [c.55+6T>G]) in theAPOC2gene in infants with hyperchylomicronemia. To the best of our knowledge, Case 1 is the youngest patient with familial apo C-II deficiency in the literature to date.

Objective: The aim of the present study was to evaluate the relationship between adipokines and perilipin (PLIN) polymorphisms with non-alcoholic fatty liver disease (NAFLD).

WOS: 000428609400007, PubMed ID: 29469018, Objectives: Many screening methods, such as the Screening Tool Risk on Nutritional Status and Growth (STRONGkids) and the Pediatric Yorkhill Malnutrition Score (PYMS), have been developed to detect malnutrition in pediatric patients. We aimed to explore the prevalence of malnutrition risk in hospitalized children via symptoms and identification of contributing factors, and to examine the efficacy of malnutrition screening tools for hospitalized children. Methods: STRONGkids and PYMS were applied to 1513 inpatients at 37 hospitals in 26 cities from different regions of Turkey. Physical measurements were collected at hospital admission and at discharge. z-Scores of height-for-age, weight-for-age, weight-for-height, and body mass index-for-age were calculated. Results: Overall, 1513 patients were included in the study. A body mass index standard deviation score of less than -2 was present in 9.5% of the study population at hospital admission, whereas 11.2% of the participants had a weight-for-length/height score of less than -2 at hospital admission. According to STRONGkids results, the proportion of the patients with an underlying chronic disease was higher for the patients at high risk of malnutrition than for the patients at medium or low risk (91% compared with 47% or 45%, respectively). PYMS results indicated that patients at high risk of malnutrition have more chronic diseases (75%) than the patients at medium or low risk of malnutrition (55% and 44%, respectively). Conclusions: Use of anthropometric measurements in addition to screening tools to identify hospital malnutrition (such as PYMS, STRONGkids) will prevent some nutritional risk patients from being overlooked. (C) 2017 The Author(s). Published by Elsevier Inc., Nutricia Advanced Medical Nutrition, This study was supported by Nutricia Advanced Medical Nutrition.

SummaryWhat is known and objective Carglumic acid is a structural analogue of human N-acetylglutamate, which has become an alternative therapeutic option for hyperammonaemia in organic acidaemias such as isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia, and it has been suggested in other urea cycle disorders such as ornithine transcarbamylase deficiency and carbamoyl phosphate synthetase 1 deficiency. Case description A male newborn was diagnosed with citrullinemia after serum amino acid analyses revealed markedly elevated citrulline concentration together with homozygous p.Gly390Arg mutation in ASS1 gene. The ammonia concentration decreased and blood gas analysis normalized after peritoneal dialysis was performed for three days. Also, sodium benzoate, L-arginine and parenteral nutrition with glucose and lipid therapy were initiated. Until 1 year of age, low adherence to sodium benzoate therapy due to unpleasant taste caused hyperammonaemic episodes and obligated us to initiate carglumic acid (100 mg/kg/day) therapy. During treatment with carglumic acid, the median ammonia level was 45.6 µmol/L. The patient's treatment was switched from carglumic acid to sodium phenylbutyrate when he was 4.5 years old. Currently, the patient is 6.5 years old and remains under follow-up with sodium phenylbutyrate, L-arginine and protein-restricted diet. Plasma ornithine level was found to be significantly lower during the carglumic acid treatment compared to other treatments (P=.039). Also, glutamic acid was found to be higher during the sodium benzoate treatment period compared to other treatment periods (P=.024). What is new and conclusion To the best of our knowledge, this is the first report describing the long-term use of carglumic acid in a patient with argininosuccinate synthetase deficiency.

15th Annual Research Meeting of the WORLDSymposium(TM) -- FEB 04-07, 2019 -- Orlando, FL WOS: 000457351700338 … WORLDSymposium

Ketogenic diet (KD) is one of the most effective therapies for intractable epilepsy. Olive oil is rich in monounsaturated fatty acids and antioxidant molecules and has some beneficial effects on lipid profile, inflammation and oxidant status. The aim of this study was to evaluate the serum lipid levels of children who were receiving olive oil-based KD for intractable seizures at least 1 year. 121 patients (mean age 7.45 +/- A 4.21 years, 57 girls) were enrolled. At baseline and post-treatment 1, 3, 6, and 12 months body mass index-SDS, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride levels were measured. Repeated measure ANOVA with post hoc Bonferroni correction was used for data analysis. The mean duration of KD was 15.4 +/- A 4.1 months. Mean total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher at 1st, 3rd, 6th and 12th months of the KD treatment, compared to pre-treatment levels (p = 0.001), but showed no difference among during-treatment measurements. Mean body mass index-SDS and HDL-cholesterol levels were not different among the baseline and follow-up time points (p = 0.113 and p = 0.067, respectively). No child in this study discontinued the KD because of dyslipidemia. Even if rich in olive oil, high-fat KD causes significant increase in LDL-cholesterol and triglyceride levels. More studies are needed to determine the effect of KD on serum lipids in children using different fat sources in the diet.

OBJECTIVE Mean platelet volume (MPV) is a marker of platelet activation, which is a determinant of inflammation. The first aim of the present study was to investigate the MPV levels in children with amebiasis and compare the MPV levels with healthy controls. The second aim of this study was to evaluate the relationship between MPV and other acute phase reactants. METHODS Seventy six patients with amebic gastroenteritis (mean age 2.64 ± 0.23 years) and 53 healthy controls (mean age 2.35 ± 0.28 years) were enrolled in the study. Entamoeba histolytica was determined in stool using rapid antigen test. RESULTS Complete blood count and C-reactive protein (CRP) levels were assessed for all children. MPV levels of patients with amebiasis were significantly higher than those of control children (8.79 ± 0.09 vs. 7.87 ± 0.09 fL, p = 0.000). Leukocyte and eosinophil counts, C-reactive protein and creatinine levels of the patients were higher than controls. Leukocyte count was positively correlated with MPV (r = 0.192, p < 0.05), platelet count (r = 0.278, p < 0.01), and CRP level (r = 0.205, p < 0.05). CONCLUSION In this MPV levels were significantly higher in children with amebiasis compared to controls. MPV can be used as an acute phase reactant in children with Entamoeba histolytica gastroenteritis.

BackgroundPrevious studies investigating the known risk factors of atherosclerosis in phenylketonuria patients have shown conflicting results. The primary aim of our study was to investigate the serum atherogenic markers in adolescent classical phenylketonuria patients and compare these parameters with healthy peers. The secondary aim was to compare these atherogenic markers in well-controlled and poorly controlled patients.MethodsA total of 59 patients (median age: 12.6 years, range: 11–17 years) and 44 healthy controls (median age: 12.0 years, range: 11–15 years) were enrolled in our study. Phenylketonuria patients were divided into two groups: well-controlled (serum phenylalanine levels below 360 µmol/L; 24 patients) and poorly controlled patients (serum phenylalanine levels higher than 360 µmol/L).ResultsThe mean high-density lipoprotein cholesterol levels of well-controlled patients (1.0±0.2 mmol/L) were significantly lower compared with poorly controlled patients and controls (1.1±0.2 mmol/L, p=0.011 and 1.4±0.2 mmol/L, pConclusionLower high-density lipoprotein cholesterol and higher homocysteine and mean platelet volume levels were detected in phenylketonuria patients. In particular, these changes were more prominent in well-controlled patients. We conclude that phenylketonuria patients might be at risk for atherosclerosis, and therefore screening for atherosclerotic risk factors should be included in the phenylketonuria therapy and follow-up in addition to other parameters.

Congenital rubella syndrome is a transplacental infection that may cause serious devastating damage in the fetus, including intrauterine growth retardation, cataracts, patent ductus arteriosus, hearing loss, microcephaly, thrombocytopenia, and hepatitis. Rubella vaccine is administered for preventing congenital rubella syndrome. It is suggested that patients must be screened for pregnancy before vaccination and should be informed regarding contraception for 3 months after vaccination. Herein, we presented a 1-month-old boy to whom rubella vaccine was administered. After performing multiple diagnostic studies to exclude other liver disorders, the patient, who had high liver enzymes, was diagnosed with congenital rubella infection by his mother's history and positive anti-rubella IgM. His liver enzymes returned to normal at 2 months of age of the follow-up period. Negative anti-rubella IgM was revealed at 6 months of age. As a result, when rubella vaccine is administered in pregnancy, high liver enzymes might occur without other congenital rubella syndrome signs in newborns. Infants who are borne by pregnant women with rubella vaccination should be monitored.

In the early years of phenylketonuria (PKU) treatment, mothers and healthcare professionals often decide to discontinue breastfeeding after the diagnosis of PKU in infants. It was believed to be the only effective way to monitor the infant's intake and allow for precise titration and measurement of the intake of phenylalanine (Phe). In the early 1980s, with the determination of low concentration of Phe in breast milk, breast milk supplemented with Phe-free formula has become an acceptable dietary treatment for infants with PKU. Today, breastfeeding is encouraged and well established in PKU patients. The aim of the present study is to investigate the prevalence and duration of breastfeeding, the effect of breastfeeding on serum Phe levels, and weight gain in infants with PKU.Data were collected from chart reviews. Medical records of 142 children with PKU diagnosed via the national neonatal screening program were analyzed retrospectively.Of the 41 infants with complete medical records, 40 (97.6%) were breastfed following delivery whereas only one (2.4%) was bottle fed. After the diagnosis, breastfeeding was continued in 25 (61%) infants with phenylalanine-free amino acid based protein substitute. The mean duration of breastfeeding was 7.4±4.0 (1-15) months. Serum Phe concentration of breastfed infants (280±163 μmol/L) was significantly lower than non-breastfed infants (490±199 μmol/L) (p0.001). Mean monthly weight gain in the first year of life was significantly higher in breastfed patients (493±159 g/month) compared to non-breastfed patients (399±116 g/month) (p=0.046).In the first year of life, weight gain and serum Phe levels were more favorable in breastfed infants with PKU compared to non-breastfed infants with PKU.