Assessment of cognitive function in young children with type 1 diabetes mellitus using electrophysiological tests.

BACKGROUND/OBJECTIVES: Diabetes mellitus is a chronic disease that affects many body systems, including the nervous and auditory systems. It is noted that there is a scarcity of research on the effect of diabetes on cognitive functions in particular and auditory functions in general in children with type 1 diabetes. Therefore, this study was designed to assess cognitive and auditory functions in children with type 1 diabetes mellitus and to correlate the reflection of diabetes control on cognitive functions. METHODS: This study is a case-control study that included 100 children divided into two groups, the patient group, which includes 50 children with type 1 diabetes, and the control group, which consists of 50 healthy children. Subjects in the current study were submitted to pure tone audiometry, speech recognition threshold test, immittancemetry study, and measurement of cortical auditory evoked and P300 potentials (CAEPs and P300). These audiometric measures were statistically analyzed and correlated with the clinical characteristics of the study group. RESULTS: The latency of P300 and CAEPs was significantly increased while the amplitude of P300 and CAEPs was significantly decreased in the patient group compared to the control group (p < 0.001). P300 and CAEPs latency has a positive correlation with HbA1c levels (r = 0.460). In addition, there was significant differences between the two groups regarding the hearing threshold at 8000 Hz, and 28% of patients had bilateral sensorineural hearing loss (SNHL) at 8 kHz. CONCLUSION: The prolonged P300 and CAEPs latency and decreased amplitude in patients indicate a cognitive decline in individuals with type 1 diabetes compared to healthy individuals. HbA1c levels may increase the risk of cognitive impairment in children. In addition, the risk of bilateral SNHL increased at 8 kHz in children with type 1 diabetes mellitus.

Children with Down syndrome: association of Bcl-I polymorphism of nuclear receptor subfamily 3 group C member 1 gene with obesity.

BACKROUND: This study aimed to assess the possible association between rs41423247 (Bcl-I) polymorphism in the gene for the human glucocorticoid receptor (GR) called Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) with obesity in Egyptian children with and without Down syndrome. METHODS: The Bcl-I polymorphism was assessed, using real-time PCR, in 300 children divided into four groups: Down-obese, Down-non obese, normal-obese, and normal non-obese. RESULTS: There was no significant difference between normal-obese and normal-non obese children regarding the Bcl-I genotypes and allele frequencies, while there was a significant difference between Down-obese and Down-non obese children regarding the Bcl-I GC genotype frequency. Again, there was a highly significant difference between Down-obese and normal-non obese children and between children with Down-syndrome (obese and non-obese) and normal children (obese and non-obese) regarding the Bcl-I genotypes and alleles frequencies. CONCLUSIONS: Our study found a weak association of the G allele of Bcl-I rs41423247 with the presence of obesity among normal Egyptian children, while there was a significant association of the mutant C allele of the Bcl-I rs41423247 with Down syndrome, suggesting a possible association with Down syndrome pathophysiology. IMPACT: Bcl-I polymorphism is not strikingly associated with obesity in normal children. The GG genotype is higher in obese normal children but without significant difference. The significant increase of the mutant C allele in Down-children than normal children. This may be relevant to Down syndrome's pathophysiology which disturbs the whole genome's balance.

A Compound Heterozygous Mutation in the Ciliary Gene TTC21B Causes Nephronophthisis Type 12.

Nephronophthisis (NPHP) is one of the renal ciliopathies and is also a cystic renal disorder with an autosomal recessive inheritance, which usually progresses to end-stage renal disease (ESRD). It affects children, adolescents, and young adults. In approximately 15% of cases, the features of a ciliopathy syndrome, which include liver fibrosis, skeletal anomalies, retinal abnormalities, and neurodevelopmental delay, will be present. We describe a case of a 2-year-old male child with ESRD on hemodialysis and a family record of a similar condition (his brother). The clinical features of this child are succinctly summarized. The genetic study was conducted using whole exome sequencing. TTC21B mutational variants were detected in our patient who exhibited nephrotic-range proteinuria, focal segmental glomerulosclerosis, and tubulointerstitial lesions that evolved to ESRD. Compound heterozygous mutations, c.626c > t (p.P209L) in exon 6 and c.450 g > a (p.W150Ter) in exon 5, were uncovered. These findings are in line with the description of autosomal recessive NPHP type 12. Both clinical and pathological diagnoses of NPHP are critical, bearing in mind ESRD as well as its related extrarenal defining features. Identification of the pathogenic variants in the TTC21B gene assisted in the successful proof of the clinical diagnosis NPHP12 as well as providing information for formal suitable prenatal counseling.

Genetic Variants and Haplotypes of Tryptophan Hydroxylase 2 and Reelin Genes May Be Linked with Attention Deficit Hyperactivity Disorder in Egyptian Children.

Attention-deficit hyperactivity disorder (ADHD) has been proposed to stem from multiple etiologies, perhaps genetic in nature with biological and psychosocial motivates. Tryptophan hydroxylase 2 (TPH2) and Reelin (RELN) genes may play a key role in triggering ADHD. The purpose of this case-controlled study was to explore the linkage of the genetic variants of TPH2 and RELN genes with ADHD. One hundred Egyptian children with ADHD and 105 age and sex matched controls constituted the study samples. Genotyping was performed for TPH2 (rs11179027; rs1843809) and RELN (rs736707; rs362691) gene polymorphisms using real time PCR assay. The alleles and genotype frequencies of TPH2 and RELN gene polymorphisms were assessed in all study participants. The frequencies of the alleles of TPH2 rs11179027 (OR = 1.75, 95% CI = 1.08-2.85, p = 0.022), TPH2 rs1843809 (OR = 3.67, 95% CI = 1.82-7.43, p = <0.001), and RELN rs736707 (OR = 1.61, 95% CI = 1.03-2.51, p = 0.035) were significantly associated with ADHD, while there was no significant difference between ADHD patients and controls regarding the frequency of RELN rs362691 (OR = 1.34, 95% CI = 0.73-2.48, p = 0.34). The frequencies of CTAG, CTGG, CTAC, CTGC, and GTAC haplotypes were significantly higher in ADHD patients than in controls (p = 0.011, 0.005, 0.015, 0.001, and 0.027, respectively). In conclusion, TPH2 rs11179027, TPH2 rs1843809, and RELN rs736707 gene alleles and haplotypes might be significantly correlated with the genetic susceptibility to ADHD in Egyptian children.

The Genetic Variants of IKZF1 Gene Linked with the Growing Risk of Childhood Acute Lymphoblastic Leukaemia.

BACKGROUND: The zinc finger protein IKAROS (IKZF1) is an essential transcription factor in haematopoiesis that is involved primarily in lymphoid tissue differentiation. Many studies have indicated that IKZF1 alterations may be associated with acute lymphoblastic leukaemia, but the results remain controversial. OBJECTIVE: We aimed to investigate the association of the rs4132601 T/G and rs10272724 T/C IKZF1 gene polymorphisms with the risk of childhood acute lymphoblastic leukaemia and to determine whether these genetic variants affect the clinical parameters and the iron profiles of these children cohort. METHODS: This case control study was conducted on 170 Egyptian children comprising of two groups: group (I) included 90 children diagnosed with acute lymphoblastic leukaemia and group (II) comprised of 80 ages and sex-matched healthy control children. The studied polymorphisms were genotyped using PCR restriction fragment length polymorphism (PCR-RFLP). RESULTS: A higher frequency of the mutant GG genotype and G allele of rs4132601 was found in the patient group than in the control group. The results also showed a significant difference among the rs10272724 genotypes, with a higher frequency of the mutant CC genotype and C allele in the patients than in controls. The mutant GG genotype of rs4132601 and the mutant CC genotype of rs10272724 were associated with a higher serum ferritin level and transferrin saturation and an older age at diagnosis of acute lymphoblastic leukaemia than the other genotypes. CONCLUSION: IKZF1 rs4132601 and rs10272724 could be considered significant risk contributors to childhood acute lymphoblastic leukaemia and may impact the iron profiles in these children.

Establishment of blood pressure nomograms representative for Egyptian children and adolescents: a cross-sectional study.

OBJECTIVE: To define nomograms for blood pressure in Egyptian children and adolescents. METHODS AND STUDY DESIGN: A total of 60 025 Egyptian children from birth to 19 years were enrolled in this cross-sectional randomised study from December 2015 to March 2017. They were selected from diverse geographical districts in Egypt. Healthy children who fulfilled the inclusion criteria, which included good nutritional history, absence of fever or documented underlying disease at the time of examination, no evidence of haemodynamically significant illness, and no antihypertensive drugs or other chronic drug administration, were included in the study. Body weight, recumbent length (for less than 24 months) and height (from 2 years to 19 years), and blood pressure were measured using standard mercury sphygmomanometers. RESULTS: Blood pressure increases with age in both boys and girls. The 90th percentile of systolic and diastolic blood pressure among Egyptian children was different from other ethnic populations (American and Turkish children) in both sexes. Systolic and diastolic blood pressure showed a positive correlation with weight and height in both sexes (p<0.001). CONCLUSION: We assumed that normal blood pressure curves should be used cautiously during childhood, and it is recommended that every population have its own normal standard curve to define measured blood pressure levels in children. These centiles increased our knowledge and awareness of normal blood pressure among Egyptian children and adolescents. The percentiles will distinguish children and young adolescents with increased blood pressure and will be of value to both medical practice and scientific research.

The genetic variant "C588T" of GABARG2 is linked to childhood idiopathic generalized epilepsy and resistance to antiepileptic drugs.

PURPOSE: Previous studies have suggested that GABARG2 (Gamma-Aminobutyric acid type A Receptor Gamma 2 subunit) could be a gene of interest in genetic epilepsy; through possible associations with increased epilepsy susceptibility or resistance to antiepileptic drugs. The present study was designed to explore whether the GABARG2 C588 T (rs211037) genetic variant predicts susceptibility to epilepsy and pharmacoresistance among Egyptian children with Idiopathic Generalized Epilepsy (IGE). METHODS: A cohort of 210 Egyptian children was divided into two groups for this case-control study: group (I) included 100 children with IGE, group (II) comprised of 110 paediatric healthy controls. PCR-RFLP was used to amplify the C588 T polymorphism of the GABARG2 gene, which was digested with APOI restriction enzymes. RESULTS: There was a higher frequency of the TT genotype (P = 0.004) and T allele (P = 0.002) of the C588 T polymorphism of the GABARG2 gene in patients than controls. Besides, there was a substantial increase of the T allele among drug-resistant patients compared with those responding to antiepileptic drugs (P = 0.00015). Children with the C allele were four times more likely to be responsive to antiepileptic drugs than non-C-allele-carriers. CONCLUSION: The C588 T polymorphism of GABARG2 is associated with an increased risk of developing childhood IGE and may modulate patients' response to antiepileptic drugs.

Low serum zinc level: The relationship with severe pneumonia and survival in critically ill children.

BACKGROUND: Zinc deficiency is common among children in developing countries; but, there is still conflicting evidence on whether the alteration in zinc metabolism is the predictive of disease severity in the setting of critical illness. OBJECTIVES: To assess serum zinc levels in children admitted with pneumonia, and also to study the relationship between zinc levels and severity and mortality from pneumonia. METHODS: In a prospective cohort study, we enrolled 320 critically ill children admitted to the paediatric intensive care unit (PICU) with severe pneumonia (group 1) in addition to 160 children admitted into wards with pneumonia (group 2). Serum zinc measured in all patients on admission. RESULTS: Serum zinc level was significantly lower among patients admitted to PICU (group 1) compared with patients admitted to wards (group 2) (P < .001). There was a highly statistically significant decrease in zinc level in critically ill children complicated by sepsis, mechanically ventilated cases and those who died. Regarding the diagnosis of sepsis, zinc had an area under the curve (AUC) of 0.81 while C-reactive protein (CRP) had an AUC of 0.83. Regarding the prognosis, zinc had an AUC of 0.649 for prediction of mortality, whereas the AUC for Pediatric risk of mortality (PRISM), Pediatric index of mortality2 (PIM2) and CRP were 0.83, 0.82 and 0.78, respectively. The combined zinc with PRISM and PIM2 has increased the sensitivity of zinc for mortality from 86.5% to 94.9%. CONCLUSION: Zinc has both a diagnostic and a prognostic value for children with pneumonia.

T-Regulatory Cell Subsets in Children with Type 1 Diabetes Mellitus: Relation to Control of the Disease.

BACKGROUND: Type 1 diabetes mellitus is described as a chronic metabolic disorder characterized by aggressive immune &#946;-cell destruction. There are a number of varied immune mechanisms for sustaining self-tolerance in opposition to the autoimmune disorders. A recessive tolerance is accomplished by thymic gland via a negative assortment of different clones, while a dominant tolerance is accomplished by the regulatory T cells (Treg) in the periphery. Treg (CD4+ CD25+FOXP3+) are subsets of T cells which have an essential role in maintaining tolerance. OBJECTIVE: To evaluate peripheral Treg (CD4+; CD25+; FOXP3+) in children cohort with T1DM. METHODS: This study included 64 children diagnosed with T1DM and 35 age- and sex-matched healthy children as controls. All children were clinically evaluated and subjected to assessment of complete blood count (CBC), glycated hemoglobin, surface and cytoplasmic detection of Treg by flow cytometry. RESULTS: This study showed that the frequency of Treg (CD4+; CD25+; FOXP3+) was significantly lower in diabetic children than with normal controls (P<0.001). There was a significant (P <0.001) reduction in the Treg (CD4+; CD25+; FOXP3+) in T1DM children with uncontrolled (Hemoglobin A1c>7%) as compared to those with controlled (Hemoglobin A1c<7%) disease. CONCLUSION: Diminished Treg in T1DM proved that auto-reactivation of T-cell as a result of the breakdown of immune tolerance takes part in the elaboration of autoimmune disorders as T1DM. Treg may be used in immunotherapy, thus preventing T1DM development due to its pivotal role in immune tolerance.

A66G and C524T polymorphisms of methionine synthase reductase gene are linked to the development of acyanotic congenital heart diseases in Egyptian children.

Methionine synthase reductase (MTRR) is one of the main regulatory enzymes in the homocysteine/folate pathway. Genes involved in this pathway may play an important role in the development of congenital heart diseases (CHDs). C524T and A66G polymorphisms of MTRR gene may play an imperative role in the development of acyanotic CHDs. This study carried out on 200 children equally divided into 2 groups: group I: 100 children with acyanotic CHDs; and group II: 100 healthy children served as controls. PCR-RFLP method carried out to amplify the A66G and C524T polymorphisms of MTRR gene digested with Xho1and NdeI enzymes. A significant difference(P=0.015) in genotype frequencies of C524T polymorphism between cases and controls, where CC, CT, and TT were 14.0%, 40.0% and 46.0% in patients compared to 38.0,36.0% and 26.0% in controls. Again, a significant difference (P=0.010) in genotype frequencies of A66G polymorphism between the two groups as AA, AG and GG were 26.0%, 32.0% and42.0% in patients compared to 48.0, 36.0% and 16.0% in controls. Also, MTRR A66G and C524T polymorphisms were associated with a higher CHD risk in the homozygote comparison of wild and mutant genotypes and also in heterozygote and mutant comparison. So A66G and C524T polymorphisms of MTRR gene are associated with increased risk of acyanotic CHDs.

Biochemical alteration in children with idiopathic nephrotic syndrome associated with an increased risk of sensorineural hearing loss; additional insights in cochlear renal relationship.

OBJECTIVES: Children with Idiopathic Nephrotic Syndrome (INS) are at risk of hearing loss due to the adverse impact of medications and related immunological and genetic factors on both cochlea and kidney. So this work was planned to evaluate hearing status in children with INS and to clarify the possible associated risk factors by interpreting the clinical and laboratory profiles of those children. METHODS: Ninety children with INS aged 5-14 years [30 patients with steroid-sensitive nephrotic syndrome (SSNS), 30 patients with steroid dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS), and 30 patients with steroid-resistant nephrotic syndrome (SRNS)], and 90 age and sex matched normal controls were enrolled into this study. Laboratory measurements of serum calcium, creatinine, cholesterol, blood urea and other relevant investigations were done. Pure tone audiometry was done with the sensory-neural hearing loss (SNHL) diagnosed when the level bone conduction was >20 dB and the difference in air to the bone gap was <15 dB. RESULTS: 40% children with INS had SNHL, mostly of mild degree HL and primarily occurred at the lower frequencies. A highly significant statistical difference between controls and various types of nephrotic syndrome regarding pure tone audiometry measurements at frequencies 250, 500, 1000 Hz, whereas insignificant difference interpreting pure tone audiometry measurements in 2000, 4000 and 8000 Hz. CONCLUSIONS: Children with different phenotypes of nephrotic syndrome are at risk of sensorineural hearing impairment. The hazards associated with this impairment were higher blood pressure, hypercholesterolemia, hypoalbuminemia, and hypocalcemia.

Serum Neutrophil Gelatinase-Associated Lipocalin: A Diagnostic Marker in Pediatric Sepsis.

OBJECTIVES: Sepsis is a life-threatening condition that arises when the response of the body to infection injures its own tissues and organs. The early prediction of sepsis by current clinical and laboratory methods remains inadequate. Serum neutrophil gelatinase-associated lipocalin level is increased in sepsis irrespective of renal dysfunction. Therefore, we aimed to correlate the serum neutrophil gelatinase-associated lipocalin value determined at admission with clinical progression and severity of disease in critically ill children and to declare its role as a potential diagnostic and prognostic marker for sepsis in critically ill children in the emergency department. DESIGN: A prospective cohort study. SETTING: The study carried out at the PICU of Menoufia University Hospital. PATIENTS: We serially enrolled 120 critically ill children admitted to the PICU at 2 fixed days per week in addition to 40 healthy children served as controls. INTERVENTIONS: Clinical examination was performed including calculation of the Pediatric Risk of Mortality and Pediatric Index of Mortality 2. Serum neutrophil gelatinase-associated lipocalin measurement was performed for patients at admission and for the controls. Patients were followed up for 30 days. The discriminatory power of neutrophil gelatinase- associated lipocalin was determined using the receiver-operating characteristic and other predictive likelihood values. MEASUREMENTS AND MAIN RESULTS: Serum neutrophil gelatinase-associated lipocalin level was significantly higher among the total patient cohort and those with sepsis than among the controls (p < 0.001), also in patients with systemic inflammatory response syndrome without sepsis and patients without systemic inflammatory response syndrome (p = 0.04 and <0.001). Furthermore, plasma level of neutrophil gelatinase-associated lipocalin was significantly elevated in nonsurvivors compared with survivors (p < 0. 001). Receiver-operating characteristic curve analysis exhibited an area under the curve of 0.84 for neutrophil gelatinase-associated lipocalin for diagnosis of sepsis, whereas C-reactive protein had an area under the curve of 0.79. Regarding the prognosis, neutrophil gelatinase-associated lipocalin had an area under the curve of 0.74 for prediction of mortality, whereas the area under the curve for Pediatric Risk of Mortality, Pediatric Index of Mortality 2, and C-reactive protein were 0.59, 0.58, and 0.62, respectively. CONCLUSION: Overall, the data support the view that measurement at admission, serum neutrophil gelatinase-associated lipocalin results in substantial added value for early diagnosis and prognostication of sepsis in critically sick children.

Screening for developmental delay in preschool-aged children using parent-completed Ages and Stages Questionnaires: additional insights into child development.

BACKGROUND: Developmental delay is a delay in areas of speech, language, motor, social and cognitive development. Because of the negative impact of intellectual and learning disabilities, early identification of children with developmental and behavioral problems using appropriate screening tests is crucial. OBJECTIVES: Utilization of parent-completed Ages and Stages Questionnaires (ASQs) for detecting the developmental delay in preschool age children and clarification of possible associated risk factors. MATERIALS AND METHODS: This cross-sectional study was conducted on 1012 children aged 24-60 months enrolled from six centers (n=608) and six villages (n=404) located in Menoufia Governorate, Egypt. All children were screened by nine age-based questionnaires in the first stage of assessment. Children whose scores were ≤ cut-off points in one or more of the screened developmental areas were considered to have suspected developmental delay (SDD) and underwent further evaluation in the second stage assessment. RESULTS: Among the 1012 studied children aged 24-60 months, 978 (96.4%) had normal development. SDD had an overall prevalence of 3.4%, with the highest rates of SDD in problem-solving (3%), followed by communication (2.4%), fine motor skills (2.2%) and social-personal domain (1%), with no SDD in gross motor skills. SDD was more commonly observed in boys, with a significant association with both parental education and consanguinity. Problems with learning (32.3%) was the most commonly observed provisional diagnosis, followed by language disorders (29.4%). Children with SDD in more than one area of ASQ skills also had mild to borderline IQ scores. CONCLUSION: The use of of parent-completed ASQs showed an overall prevalence of developmental delay in children aged 24-60 months of3.4%. Male gender, consanguinity and parental education were identified as risk factors for developmental delay. Family counselling about the child's developmental state is needed.

The potential role of incorporating real-time PCR and DNA sequencing for amplification and detection of 16S rRNA gene signatures in neonatal sepsis.

OBJECTIVES: This study aimed to explore whether 16S rRNA gene amplification by real time PCR and sequencing could serve as genetic-based methods in rapid and accurate diagnosis of neonatal sepsis. PATIENTS AND METHODS: This case control study was conducted on 40 neonates suffering from sepsis like manifestations recruited from the neonatal intensive care unit of Menoufia university hospital over a period of 6 months. Their blood samples were used for paired analysis of bacterial growth using BACTEC 9050 instrument and real time PCR assay with subsequent DNA sequencing for bacterial species identification. RESULTS: The detection rate of culture proven sepsis was 70%. By using real time 16S r RNA PCR amplification method, the detection of bacteria was improved to 80%. Real time PCR revealed sensitivity, specificity, positive predictive value and negative predictive value of [100%, 66.7%, 87.5% and 100%] respectively. Compared to culture, the 16S rRNA real time PCR demonstrated a high negative value for ruling out neonatal sepsis. There was significant statistical difference between the PCR positive and negative cases as regards the hematological sepsis score. The results demonstrated the ability of DNA sequencing to recognize 4 pathogens which were negative by blood culture. The time consumed to detect sepsis using blood culture was up to 5 days while it took up to 16 h only by PCR and sequencing methods. CONCLUSION: 16S rRNA gene amplification by real time PCR and sequence analysis could be served as ideal and reliable genetic-based methods to diagnose and rule out sepsis with provision of additional data that cannot be obtained by routine laboratory tests with a shorter turnaround time than those with culture-based protocols.

The potential implication of SCN1A and CYP3A5 genetic variants on antiepileptic drug resistance among Egyptian epileptic children.

PURPOSE: Despite the advances in the pharmacological treatment of epilepsy, pharmacoresistance still remains challenging. Understanding of the pharmacogenetic causes is critical to predict drug response hence providing a basis for personalized medications. Genetic alteration in activity of drug target and drug metabolizing proteins could explain the development of pharmacoresistant epilepsy. So the aim of this study was to explore whether SCN1A c.3184 A/G (rs2298771) and CYP3A5*3 (rs776746) polymorphisms could serve as genetic based biomarkers to predict pharmacoresistance among Egyptian epileptic children. METHODS: Genotyping of SCN1A c.3184 A/G and CYP3A5*3 polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed in 65 healthy control subjects and 130 patients with epilepsy, of whom 50 were drug resistant and 80 were drug responsive. RESULTS: There was a significant higher frequency of the AG genotype (p=0.001) and G allele (p=0.006) of SCN1A polymorphism in epileptic patients than in controls. Also their frequency was significantly higher in drug resistant patients in comparison with drug responders (p=0.005 and 0.054 respectively). No significant association between CYP3A5*3 polymorphism and drug-resistance was found. CONCLUSIONS: Overall, results confirmed the claimed role of SCN1A c.3184 A/G polymorphism in epilepsy and moreover in development of pharmacoresistance among Egyptian epileptic children. CYP3A5*3 variants have no contributing effect on pharmacoresistance among Egyptian epileptic children.