Search

We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate-dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease-causing by meta-SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole-exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified.

Despite major advances in intensive care, sepsis continues to be a major cause of morbidity and mortality. Vitamin D is involved in various physiologic functions, including cellular responses during infection and inflammation. The aim of this study was to evaluate diagnostic value of 25-hydroxyvitamin D in childhood sepsis because it can be fatal if diagnosis delayed. The study included 40 children with sepsis and 20 children without sepsis (control group). We included only the patients with high probable sepsis, judged by clinical and laboratory findings, including positive blood culture. Blood samples were collected from patients with sepsis before treatment (pre-treatment group) and 48-72 hours later (post-treatment group). Treatment varied from ampicillin-sulbactam to cephalosporin. Blood samples were collected from control group once on admission. Serum 25-hydroxyvitamin D levels were significantly higher in sepsis (pre-treatment group) than control group (74 +/- 8 ng/ml vs. 28 +/- 12 ng/ml, p = 0.01) and the serum 25-hydroxyvitamin D levels were decreased to 44 +/- 5 ng/ml (p = 0.01) after treatment. Moreover, we found significant positive correlation between 25-hydroxyvitamin D and each of well-know sepsis markers, C-reactive protein, tumor necrosis factor-a and interleukin-6. A cut-off point of 20 ng/mL for serum 25-hydroxyvitamin D showed 84% sensitivity and 76% specificity for sepsis diagnosis. This is the first study evaluating the diagnostic role of vitamin D in pediatric sepsis, thereby suggesting that serum 25-hydroxyvitamin D level can be used as a diagnostic marker for sepsis with high sensitivity and specificity.

Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures. publisher: Elsevier articletitle: De Novo Loss-of-Function Mutations in CHD2 Cause a Fever-Sensitive Myoclonic Epileptic Encephalopathy Sharing Features with Dravet Syndrome journaltitle: The American Journal of Human Genetics articlelink: http://dx.doi.org/10.1016/j.ajhg.2013.09.017 content_type: article copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. ispartof: American Journal Of Human Genetics vol:93 issue:5 pages:967-975 ispartof: location:United States status: published

The daily supplementation of vitamin D is mandatory for infants. However, there are still conflicting opinions about the exact daily dose. Thus, we aimed to evaluate a daily supplementation dose of 200 IU is sufficient and compared the supplementation doses of 200 and 400 IU per day. One hundred and sixty-nine infants were randomly assigned to two groups (group1, 200 IU/day; group 2, 400 IU/day) and there were 75 infants in group 1 and 64 were in group 2 with a total number of 139. The median levels of 25-hydroxyvitamin D3 were significantly increased in group 2 at the age of 4 months (group 1, 39.60 mcg/L; group 2, 56.55 mcg/L; p

13q deletion syndrome is caused by the absence of a portion of the long arm of chromosome 13. This syndrome is a rare condition characterized by a wide range of clinical findings. Phenotype varies with the location and size of the deletion. We report a female dizygotic twin with a proximal deletion of 13q and failure to thrive, hypotonia, and multiple anomalies included pytosis and total ophthalmology at right side, strabismus at left, bilateral iris heterochromia and telecantus. She had a broad nasal bridge with flat philtrum, micrognathia and antevert ear lobes. Her umbilicus had vanished. Her left coxa was dislocated and left toes were overlapped. She was also found to have hypertriglyceridemia, hypercholesterolemia, and hypothyroidism. Chromosome analysis showed a proximal deletion of chromosome 13 [karyotype 46,XX,del(13) (q14.2q31.3)] which was confirmed by high-resolution microarray based comparative genomic hybridization. The described patient is unique among similar rare cases with different deletion breakpoints. It is the first case of 13q14.2q31.3 deletion where the breakpoints are clearly defined, indicating the importance of detailed clinical description and high-resolution genomic analysis for characterization of rare genetic syndromes.

To evaluate the usefulness of renal zinc clearance/glomerular filtration rate ratio (R(ClZn)/GFR) as an indicator of marginal zinc deficiency that is generally associated with iron deficiency in childhood.Zinc status was evaluated in 36 iron-deficient children (22 boys and 14 girls) who ranged in age from 1 to 10 years using serum zinc concentration and U(Zn/Cr) and R(ClZn)/GFR ratios. The results were compared with the zinc status of 36 similar-aged healthy children (24 boys and 12 girls).Serum zinc concentrations were 96.72 +/- 2.13 microg/dL and 93.93 +/- 1.95 microg/dL in iron-deficient and healthy subjects, respectively (p0.05). U(Zn/Cr) ratios were 0.54 +/- 0.04 microg/mg and 0.88 +/- 0.04 microg/mg (p0.0001); R(ClZn)/GFR ratios were 2.27 x 10(-3) +/- 0.20 and 3.32 x 10(-3) +/- 0.20 (p0.001) in iron-deficient and healthy subjects, respectively. Individual values of R(ClZn)/GFR and U(Zn/Cr) ratios correlated with hemoglobin (Hb) concentrations (r = 0.34, p0.01 and r = 0.26, p0.05). Data grouped according to the ranges of Hb concentrations and R(ClZn)/GFR and U(Zn/Cr) ratios fit the following equations: The statistically significant difference in U(Zn/Cr) and R(ClZn)/GFR ratios between groups indicates decreased urinary estimation of marginal zinc deficiency, whereas no change was observed in serum zinc concentrations. According to the regression equation, it can be postulated that the R(ClZn)/GFR ratio is a linear function of Hb concentration and the U(Zn/Cr) ratio.R(ClZn)/GFR ratio was a reliable indicator for reduction in urinary zinc excretion; it estimated the marginal zinc deficiency associated with iron deficiency. The R(ClZn)/GFR ratio can be calculated using one sample of blood and urine; thus it could serve as an alternative indicator of marginal zinc deficiency, especially in routine health care.

Yalçın Çapan, Özlem (Arel Author), Purpose: The SCN1A gene is one of the most commonly mutated human epilepsy genes associated with a spectrum of phenotypes with variable degrees of severity. Despite over 1200 distinct mutations reported, it is still hard to draw clear genotypephenotype relationships, since genetic and environmental modifiers contribute to the development of a particular disease caused by an SCN1A mutation. We aimed to initiate mutational screening of the SCN1A gene in Turkey and advance further our understanding of the relationship between the SCN1A sequence alterations and disease phenotypes such as GEFS+, DS and related epileptic encephalopathies. Methods: Mutational analysis of the SCN1A gene was carried out in 46 patients with DS, late-onset DS, GEFS+ and unspecified EE using either direct Sanger sequencing of the coding regions and exon/intron boundaries or massively parallel sequencing. Results: Nineteen point mutations, 12 of which were novel were identified, confirming the clinical diagnosis of the patients. Patients with a mutation (either truncating or missense) on linker regions had significantly later disease onset than patients with mutations in homology regions. The presence of SCN1A mutations in two clinically unclassified patients supported the association of SCN1A mutations with a wide range of phenotypes. Conclusion: The conventional Sanger sequencing method was successfully initiated for the detection of SCN1A point mutations in Turkey in epilepsy patients. Furthermore, a modified strategy of massively parallel pyro-sequencing was also established as a rapid and effective mutation detection method for large genes as SCN1A.

Serum vitamin B12 and folate, and their functional markers, plasma homocysteine and urinary methylmalonate (uMMA) were measured in 204 healthy, term infants at birth, and at 2 and 6 months. Compared with infants receiving formula food, those fed mother's milk had lower vitamin B12 and folate at 2 and 6 months. In infants receiving mother's milk, vitamin B12 levels were similar at birth (238 pg/ml) and 2 months (243 pg/ml), whereas with formula milk the level was significantly higher at 2 months (558 pg/ml) than at birth (257 pg/ml). Vitamin B12 was negatively correlated with homocysteine at birth and 6 months. The level of uMMA (mmol/mol creatinine) was higher at 2 (mother's milk, 25.5; formula, 23.97) and 6 months (19.77; 15) than at birth (11.97; 10.88), and was not correlated with vitamin B12 levels. Homocysteine may be a reliable marker of vitamin B12 status in neonates and infants; however, uMMA is not suitable as a marker of vitamin B12 status.

To investigate the relationship between the newly discovered adipocytokines and increasing body weight (paralleled by increased insulin resistance), and antiepileptic drug therapy with valproic acid (VPA).44 children with idiopathic, generalized epilepsy treated with valproic acid (VPA), and 40 control group children were included in this study.Both the VPA-treated group and the control group showed no significant difference in terms of age, total cholesterol and LDL-cholesterol. Subjects in the VPA group had significantly higher BMI-SDS than control subjects (2.3±0.15 vs -0.04±0.8, p0.001). HOMA-IR, apelin and visfatin levels were significantly increased (4.95±2.07 vs 1.46 vs 0.6, p0.001; 2.21±1.14 vs 0.57±0.15, p0.001; 31±12 vs 18.4±10.4, p0.001; respectively), and adiponectin levels were significantly lower in the VPA group (2.02±1.03 vs 12.4±6.1, p0.001). Triglyceride levels were significantly increased (126±70 vs 80±40 mg/dL, p=0.001), and HDL-cholesterol levels were significantly lower in the VPA group. Vaspin levels were higher in the VPA group than the control group, but the difference was not significant.Based on the findings of this study, apelin, visfatin and adiponectin levels may be considered as potential regulators of glucose and fat metabolism during valproic acid therapy.

To further evaluate the previously shown linkage of absence epilepsy (AE) to 2q36, both in human and WAG/Rij absence rat models, a 160-kb region at 2q36 containing eight genes with expressions in the brain was targeted in a case-control association study involving 205 Turkish patients with AE and 219 controls.Haplotype block and case-control association analysis was carried out using HAPLOVIEW 4.0 and inhibin alpha subunit (INHA) gene analysis by DNA sequencing.An association was found between the G allele of rs7588807 located in the INHA gene and juvenile absence epilepsy (JAE) syndrome and patients having generalized tonic-clonic seizures (GTCS) with p-values of 0.003 and 0.0002, respectively (uncorrected for multiple comparisons). DNA sequence analysis of the INHA gene in 110 JAE/GTCS patients revealed three point mutations with possible damaging effects on inhibin function in three patients and the presence of a common ACTC haplotype (H1) with a possible dominant protective role conferred by the T allele of rs7588807 with respective p-values of 0.0005 and 0.0014.The preceding findings suggest that INHA could be a novel candidate susceptibility gene involved in the pathogenesis of JAE or AE associated with GTCS.

Background Apelin is a novel adipocytokine produced by white adipose tissue that binds the APJ receptor with high affinity. Insulin may have a role in regulation of apelin synthesis and secretion from the adipose tissue. Objective To investigate blood apelin concentrations in children with type 1 diabetes mellitus (T1DM) and display association of apelin with adiponectin, body mass index (BMI), lipids and insulin sensitivity. Methods Thirty patients with T1DM and 45 healthy controls were enrolled. Apelin levels were measured along with BMI, lipids, fasting plasma glucose, HbA1c and adiponectin levels. Results Plasma apelin and adiponectin levels were significantly higher in the diabetic group when compared to controls. No correlation was found between the apelin blood concentrations and adiponectin, BMI, lipids and insulin sensitivity. Conclusions Children with T1DM have significantly increased circulating apelin levels when compared to healthy controls. However, no significant relation was found between the apelin and BMI, glucose, lipids and adiponectin levels, and also insulin sensitivity.

The aim of this study was to assess the adiponectin and visfatin concentrations in small-for-gestational age (SGA), appropriate-for-gestational age (AGA), and large-for-gestational age (LGA) newborns and their mothers. Sixty parturients giving birth to 20 term AGA singleton infants, 20 term singleton SGA infants, and 20 term singleton LGA infants were included into the study.Mean visfatin levels were found significantly higher in the SGA (p0.001) and LGA (p0.001) groups, and adiponectin levels were found significantly lower in the SGA group (p0.001) when compared with the AGA group. The SGA and LGA groups had higher insulin concentrations and HOMA-IR in comparison with the AGA group. The visfatin, glucose levels, and HOMA-IR (p0.001, p0.001, and p: 0.002, respectively) were higher in the LGA group than SGA group.We found significantly higher insulin and visfatin levels in LGA neonates and lower adiponectin levels in SGA neonates. We concluded that the relationship between adiponectin and visfatin and insulin sensitivity (metabolic disturbances) is very complex with little evidence of correlation in SGA and LGA neonates.

Objective: The effect of ghrelin on growth of the newborn has long been argued, but not fully clarified. In this study, we aimed to investigate the relationship between ghrelin levels and growth parameters in the first 3 months of life. Methods: The study included 60 babies (27 girls and 33 boys) born at gestational ages between 38-42 weeks. The newborns were divided into three groups according to the Lubchenco curves as: small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA). The relationship between ghrelin levels and growth parameters in the third month was investigated. Results: Ghrelin concentrations were significantly higher in SGA (2.4±2.6 ng/dL) babies than in AGA (1.3±0.9 ng/dL) and LGA (1.0±0.8 ng/dL) babies. The lowest ghrelin levels were in the LGA group. In SGA infants, ghrelin concentrations were inversely correlated with change in weight (r=-0.577; p=0.001), change in length (r=-0.361; p=0.005), and change in head circumference (r=-0.387; p=0.002). Conclusion: The results show that at age 3 months, SGA infants had higher ghrelin levels than AGA and LGA infants. Our findings indicate that ghrelin may be involved in the process of catch-up growth in these infants. Conflict of interest:None declared.

Aim: To examine the effects of human chorionic gonadotropin therapy on left ventricular mass index in boys with cryptorchidism. Cryptorchidism is the most frequent anomaly of male genitalia. Patients and Method: Thirty consecutive cryptorchid boys (mean age 4.8 ± 3.2 years, range 1-8 years) undergoing human chorionic gonadotropin (hCG) therapy and 30 healthy controls were enrolled in the study. The patient group received hCG by intramuscular injection twice weekly for 5 weeks. At the end of the therapy, echocardiographic measures were reevaluated. The results of left ventricular mass were indexed to body surface area before and after therapy. Results: Our results showed that cryptorchid boys undergoing hCG therapy had significantly higher left ventricular mass index than healthy controls at the end of therapy (p

Aim The aim of this study was to assess the vaspin and adiponectin concentrations on markers of insulin sensitivity and obesity in pubertal obese children and adolescents. Material and methods Plasma vaspin and adiponectin level and its relationships with body mass index standard deviation score (BMI-SDS), insulin sensitivity and lipids were analyzed in 33 pubertal obese children (19 girls and 14 boys) and 36 healthy control children (18 girls and 18 boys) aged 11–16 years. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) and fasting glucose-to-insulin ratio (FGIR). Plasma vaspin and adiponectin concentrations were determined with radioimmunoassay. Results Mean vaspin levels were found significantly higher and inversely, adiponectin levels were found significantly lower in obese pubertal group than control subjects. Vaspin levels were positively correlated with BMI-SDS, triglycerides, fasting insulin and HOMA-IR and negatively correlated with adiponectin levels and FGIR. Adiponectin levels were positively correlated with high density lipoprotein-chloesterol, FGIR and negatively correlated with vaspin, BMI-SDS, fasting insulin and HOMA-IR. Conclusion We found higher vaspin and lower adiponectin levels in obese children and these adipokines were significantly correlated with insulin sensitivity indices in this age.

Henoch-Schönlein purpura (HSP) is a small vessel vasculitis that affects the gastrointestinal and central nervous systems and the kidneys. The disease primarily affects children, but may occur in elderly children with allergic purpura and also in adults. Central nervous system involvement may be the first sign; however, it is rarely encountered. Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome of encephalopathy, headache, visual disturbance and seizures. Its radiological signs can be observed in grey and white matter at the posterior region of the cerebral hemispheres. HSP should be considered in children with PRES in the presence of rash, joint and gastrointestinal symptoms. We reported a 5-year-old patient who developed acute renal failure and PRES by reason of HSP.