Rapid genome sequencing for critically ill infants: an inaugural pilot study from Turkey.

Introduction: Rare and ultra-rare genetic conditions significantly contribute to infant morbidity and mortality, often presenting with atypical features and genetic heterogeneity that complicate management. Rapid genome sequencing (RGS) offers a timely and cost-effective approach to diagnosis, aiding in early clinical management and reducing unnecessary interventions. This pilot study represents the inaugural use of next-generation sequencing (NGS) as a diagnostic instrument for critically ill neonatal and pediatric ICU patients in a Turkish hospital setting. Methods: Ten infants were enrolled based on predefined inclusion criteria, and trio RGS was performed. The mean age of the participants was 124 days, with congenital abnormalities being the most common indication for testing. Three patients had consanguineous parents. The mean turnaround time from enrollment to delivery of results was 169 h, with a diagnostic yield of 50%. Results: Three patients received a definitive molecular diagnosis, impacting their clinical management. Two patients benefited from the exclusion of Mendelian conditions, leading to alternative diagnoses. Discussion: This study demonstrates the feasibility and results of RGS in Turkish hospital settings, emphasizing the importance of timely genetic diagnosis in reducing the diagnostic odyssey for families and improving patient care. Further research is needed to evaluate the cost-effectiveness and applicability of RGS in the Turkish healthcare system for children with diseases of uncertain etiology.

Synthesis and characterization of a novel ionic liquid for preconcentration of Brilliant Blue FCF (E 133) from some foods by ultrasound assisted temperature controlled ionic liquid dispersive liquid liquid microextraction method prior to spectrophotometric analysis; A comparative study.

In this study, a novel ionic liquid (3-(3-chloro-2-hydroxypropyl)-1-butyl-1H-imidazol-3-ium hexafluorophosphate, (IL-2) was synthesized and characterized by FT-IR, NMR (1H,13C,31P) spectroscopy, and TGA. Two microextraction methods, ultrasonic assisted ionic liquid dispersive liquid liquid microextraction (USA-IL-DLLME) and ultrasonic assisted-temperature controlled ionic liquid DLLME, have been developed for preconcentration of Brilliant Blue FCF (E133) from some food products by the sythesized IL-2. For optimization of the both methods, several parameters such as volume of IL-2, pH, temperature, ultrasonication time, extraction time, centrifugation time, and salt effect were investigated. The obtained results for both methods under optimum conditions were compared. According to these results, the best limit of detection (4.55 µg L -1), enrichment factor (58), preconcentration factor (50), linear range (15-80 µg L -1), relative standard deviation % (1.15 %) were obtained by use of USA-TC-IL-DLLME method. Furthermore, the developed USA-TC-IL-DLLME method was succesfully applied to real samples for the preconcentration of Brilliant Blue FCF.

Re-analysis of whole-exome sequencing data reveals a novel splicing variant in the SLC2A1 in a patient with GLUT1 Deficiency Syndrome 1 accompanied by hemangioma: a case report.

BACKGROUND: GLUT1 Deficiency Syndrome 1 (GLUT1DS1) is a neurological disorder caused by either heterozygous or homozygous mutations in the Solute Carrier Family 2, Member 1 (SLC2A1) gene. SLC2A1 encodes Glucose transporter type 1 (GLUT1) protein, which is the primary glucose transporter at the blood-brain barrier. A ketogenic diet (KD) provides an alternative fuel for brain metabolism to treat impaired glucose transport. By reanalyzing exome data, we identified a de novo heterozygous SLC2A1 variant in a girl with epilepsy. After reversed phenotyping with neurometabolic tests, she was diagnosed with GLUT1DS1 and started on a KD. The patient's symptoms responded to the diet. Here, we report a patient with GLUT1DS1 with a novel SLC2A1 mutation. She also has a hemangioma which has not been reported in association with this syndrome before. CASE PRESENTATION: A 5-year 8-month girl with global developmental delay, spasticity, intellectual disability, dysarthric speech, abnormal eye movements, and hemangioma. The electroencephalography (EEG) result revealed that she had epilepsy. Magnetic resonance imaging (MRI) showed that non-specific white matter abnormalities. Whole Exome Sequencing (WES) was previously performed, but the case remained unsolved. The re-analysis of WES data revealed a heterozygous splicing variant in the SLC2A1 gene. Segregation analysis with parental DNA samples indicated that the variant occurred de novo. Lumbar puncture (LP) confirmed the diagnosis, and the patient started on a KD. Her seizures responded to the KD. She has been seizure-free since shortly after the initiation of the diet. She also had decreased involuntary movements, her speech became more understandable, and her vocabulary increased after the diet. CONCLUSIONS: We identified a novel de novo variant in the SLC2A1 gene in a patient who previously had a negative WES result. The patient has been diagnosed with GLUT1DS1. The syndrome is a treatable condition, but the differential diagnosis is not an easy process due to showing a wide range of phenotypic spectrum and the overlapping symptoms with other neurological diseases. The diagnosis necessitates a genomic testing approach. Our findings also highlight the importance of re-analysis to undiagnosed cases after initial WES to reveal disease-causing variants.

Anti-GM2 antibody positive Guillain-Barré syndrome presenting with ataxia in a pediatric patient: An atypical manifestation.

Guillain-Barré syndrome (GBS) is the most prevalent cause of acquired paralytic neuropathy in children, however, ataxia as the initial presenting sign in children is very rare. Antiganglioside antibodies are presumed to have an important role in the pathophysiology and some phenotypic correlations have been reported. Anti-GM2 antibody, unlike other antibodies, is far less detected in GBS. Here, we report a 7.5-year-old female, initially presenting with ataxia, an atypical presenting symptom in a child, is promptly diagnosed and treated successfully as GBS. Atypical history of urinary infection in our patient is an interesting aspect. The presence of isolated anti-GM2 IgM antibody and ataxia in a pediatric patient is rare. In this case report, we aim to describe an atypical initial presentation, with positive anti-GM2 antibodies, as well as review literature on isolated anti-GM2 positive pediatric GBS patients.

Acute flaccid myelitis outbreak through 2016-2018: A multicenter experience from Turkey.

AIM: We aim to describe the demographic characteristics, etiology, neurophysiology, imaging findings, treatment, prognosis, and prognostic factors of acute flaccid myelitis. METHODS: The clinical data, laboratory test and, magnetic resonance imaging (MRI) results of pediatric patients diagnosed with acute flaccid myelitis according to the Centers for Disease Control criteria between August 1, 2016, and December 31, 2018, from 13 centers in Turkey were reviewed. RESULTS: Of the 34 cases identified, 31 were confirmed (91.2%). Eighteen patients (55.9%) were boys. The median patient age was 4 years (interquartile range 2.5-6.9 years). Most of the patients were admitted in 2018 (n = 27). A preceding history of a febrile illness was reported in all patients, with a median of 4 days (interquartile range 3-7 days) before symptom onset. Thirty-one patients had T2 hyperintensity on spinal MRI, and 18 patients had cerebrospinal fluid pleocytosis. The most common infectious agents were entero/rhinoviruses (n = 5) in respiratory specimens. All patients except one received immunotherapy either alone or in combination. Among 27 patients with follow-up data 24 had persistent weakness. Involvement of four limbs together with an abnormal brain MRI at onset were associated with a poor prognosis. CONCLUSION: The number of patients with acute flaccid myelitis increased since 2012, spiking with every 2-year interval, largely in the pediatric population. The median age decreases with every outbreak. Clinicians should be aware of the clinical picture for early collection of specimens and early start of rehabilitation programs. Further studies are needed to better characterize the etiology, pathogenesis, risk factors, and treatment of this rare condition.

Hypothalamic hamartoma presenting with infantile spasms.

BACKGROUND: Hypothalamic hamartomas (HH) generally present with gelastic seizures. It is very unusual for a pediatric patient with HH to present with infantile spasms (IS). CASE PRESENTATION: Here we present a 6-month-old boy diagnosed with IS whose brain magnetic resonance imaging (MRI) showed an 18 × 18 × 16 mm mass in the hypothalamus. His seizures did not respond to antiepileptic treatment with vigabatrin and valproic acid. He had disconnective surgery for HH. Immediately postoperatively, his seizures subsided and he has now been seizure-free for 2 years. CONCLUSION: Although hypothalamic hamartomas generally present with gelastic seizures, they should also be considered in the differential diagnosis of infantile spasms.

Central tegmentum tract hyperintensities in pediatric neurological patients: Incidence or coincidence.

AIM: The central tegmental tract hyperintensities (CTTH) have been found in many different pediatric neurological conditions. There is only scarce data about the value of this radiological phenomenon. In this study we aimed to show the neurological conditions associated with this radiological finding. MATERIALS AND METHODS: We performed a retrospective analysis of all pediatric brain MRI's between 2013 and 2015. After finding those patients with CTTH, we evaluated them in the pediatric neurology clinic. RESULTS: There were 41 out of 1464 brain MRI's with CTTH with 2.8% prevalence. Thirty four patients (23 male, age range 3months-98months) were available for evaluation. CTTH were present in mainly younger age group. There were many different neurological conditions associated with CTTH. These included brain tumors, epilepsy, developmental delay, metabolic disorders and genetic syndromes. CONCLUSION: CTTH is found in many different pediatric neurological conditions. Further neuropathological and prospective MRI and clinical studies are needed to better understand this interesting radiological finding.

Understanding sleep problems in children with epilepsy: Associations with quality of life, Attention-Deficit Hyperactivity Disorder and maternal emotional symptoms.

PURPOSE: This study aimed to (1) compare sleep problems between children and adolescents with epilepsy and non-epileptic controls, and (2) examine whether there is an association between sleep problems and quality of life, Attention-Deficit Hyperactivity Disorder (ADHD) and mothers' emotional symptoms. METHOD: Fifty-three patients from a cohort of epilepsy (aged 7-18 years) and 28 controls with minor medical problems (aged 7-18 years) were included. Parents completed Children's Sleep Habits Questionnaire (CSHQ) and Kinder Lebensqualitätsfragebogen: Children's Quality of Life Questionnaire-revised (KINDL-R) for patients and controls. Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S) parent and teacher forms were used to assess ADHD symptoms for patients. Mothers of the patients completed Beck Depression Inventory and State-Trait Anxiety Inventory (STAI). Neurology clinic charts were reviewed for the epilepsy-related variables. RESULTS: Children with epilepsy had a higher CSHQ Total score than the control group. Those with a CSHQ score >56 (which indicates moderate to severe sleep problems) had lower scores on KINDL-R. Parent-rated T-DSM-IV-S Total and Hyperactivity-Impulsivity scores, STAI trait and Beck scores were found to be higher in those with a CSHQ score >56. Significant positive correlations were found between CSHQ Total score and T-DSM-IV-S, STAI trait and Beck scores. Binary logistic regression analysis revealed that T-DSM-IV-S Total, Inattention and Hyperactivity-Impulsivity scores were significantly associated with a higher CSHQ Total score. None of the epilepsy-related variables were found to be related with the CSHQ Total score. CONCLUSION: Among children with epilepsy, sleep problems lead to a poor quality of life. The link between sleep problems and psychiatric symptoms must be conceptualized as a bilateral relationship. ADHD appears to be the strongest predictor of sleep problems.

Self-concept in children and adolescents with epilepsy: The role of family functioning, mothers' emotional symptoms and ADHD.

PURPOSE: This study aimed to identify the associated factors of poor self-concept in children and adolescents with epilepsy. METHODS: Fifty-three patients with uncomplicated epilepsy (aged 7-18years) and 28 healthy controls were included. Study measures included the Piers-Harris 2 Self-Concept Scale, Family Assessment Device (FAD), Turgay DSM-IV based ADHD rating Scale (T-DSM-IV-S), Conners' Teacher Rating Scale (CTRS-R), Beck Depression Inventory and State-Trait Anxiety Inventory (STAI). Neurology clinic charts were reviewed for the epilepsy-related variables. RESULTS: While the Piers-Harris 2 total score was not significantly different between the groups, patients with epilepsy had lower (poorer) scores on freedom from anxiety and popularity subscales. Linear regression analysis revealed that the problem solving, affective responsiveness, general functioning and communication scores of FAD; total and inattentiveness scores of T-DSM-IV-S and mothers' Beck scores were associated with the total score of Piers-Harris 2. Epilepsy-related factors were not found to be associated with self-concept scores. CONCLUSION: Poor self-concept in children with epilepsy is associated with negative family functioning, mothers' emotional symptoms and ADHD, especially the symptoms of inattentiveness.

Assessment of sedated pediatric brain with 3D-FLAIR sequence at 3T MRI.

BACKGROUND AND PURPOSE: In sedated pediatric brains, 2D-FLAIR causes increased signal intensity of the cerebrospinal fluid (CSF) leading to false-positive diagnoses. Our aim is to determine whether increased CSF signal intensity is observed on 3D-FLAIR images. METHODS: In this institutional review board-approved study, a 2-year retrospective analysis of our MRI database was conducted which revealed 48 sedated pediatric patients with normal cranial MRI findings and 3D-FLAIR sequence. One adult volunteer was imaged before and after O2 inhalation with 2D and 3D-FLAIR sequences. The hyperintensity in the subarachnoid spaces and basal cisterns were quantified as follows: 0: artifact free; 1: homogeneous minimal CSF signal; 2: abnormal CSF signal. Inter-observer agreement was assessed with kappa agreement analysis. RESULTS: Grade 0 and grade 1 signals were observed at inferior to Liliequist membrane (LLQ) in 48/48 and 0/48 cases; prepontine cistern 47/48 and 1/48; superior to LLQ 26/48 and 22/48; 4th ventricle 16/48 and 32/48; 3rd ventricle 34/48 and 14/48; lateral ventricle 3/48 and 45/48; subarachnoid space 36/48 and 12/48, respectively. No patients showed grade 2 signal. Inter-observer agreement was 0.81-1. In the volunteer, after O2 inhalation, grade 2 signal intensity was evident on 2D-FLAIR however; 3D-FLAIR did not show any signal increase. CONCLUSIONS: In sedated pediatric brains, 3D-FLAIR suppresses CSF signal, and enables reliable assessment free from CSF artifacts.

Identification of fetal precentral gyrus on diffusion weighted MRI.

To investigate the association of the diffusion-weighted MR imaging characteristics of fetal preCG and gestational age. Forty-four fetuses with normal brain MRI findings were included in the study. Gestational ages ranged from 18 to 36 weeks (mean 25.2 weeks). All exams were performed with a 1.5-T scanner using a body array coil during free maternal breathing without sedation. Precentral gyrus was defined as the hyperintense strip anterior to the central sulcus, on the superior section of axial brain images at the level of superior frontal cortex. The presence of preCG hyperintensity was noted as observed/subtle/not observed at different b values (500, 1000 s/mm(2)) and on apparent diffusion coefficient (ADC) maps and compared to the imaging characteristics of the superior frontal cortex. Precentral gyrus was first detected at 25 weeks as a hyperintense strip on DWI and hypointense strip on ADC maps. Display of preCG b 1000 s/mm(2) images were better than b 500 s/mm(2). Between 25 and 27 weeks, in 40% of fetuses preCG was observed on one hemisphere, and it was evident bilaterally in 60% of cases. Starting from the 28th week, preCG was observed on both hemispheres in 100% of cases. Diffusion weighted imaging helps better understanding of the evolution of fetal preCG. The hyperintense preCG strip starts to appear at 25 weeks, and when interpreting fetal DWI after 28 weeks this may be a sign to be sought for in all fetuses and an indicator for normal development.

Ictal electrocardiographic changes in children presenting with seizures.

BACKGROUND: The aim of this study was to determine electrocardiographic changes in children during seizures. METHODS: We assessed heart rate changes, RR intervals and QT changes during 47 seizures in children. Consecutive QT and RR intervals were measured for 60 s before the seizures, during the seizures and 60 s after the seizures during video electroencephalography monitoring. RESULTS: There were 47 seizures in 18 patients. Five patients had generalized seizures and 13 patients had focal seizures. Twelve patients were male. The mean age during monitoring was 10.1 years (range 4 months-19 years). Ictal tachycardia was seen in every seizure. No ictal bradycardia was noted. There was only one dropped beat in a patient. The mean ictal heart-rate-corrected QT (QTc) interval was significantly higher than the postictal measurements (P= 0.005). Mean ictal QTc variation tended to increase during seizures and then decreased below the pre-ictal measurements in the postictal period. However these changes were statistically insignificant (P > 0.05). RR variance was significantly decreased during seizures compared to the postictal period and the standard deviation of the RR intervals was significantly decreased in the ictal period compared to the pre-ictal period (P= 0.014 and P= 0.001, respectively). CONCLUSION: Tachycardia is the main finding in seizures in children. Ictal bradycardia and cardiac arrhythmias are very rare despite being more frequent in adults with seizures.

Association of sleep duration with socio-economic status and behavioural problems among schoolchildren.

AIM: In this population-based study, we aimed to determine the total sleep duration (TSD), its association with socio-economic status (SES) and behavioural symptoms among schoolchildren. METHODS: A cross-sectional study was performed among schoolchildren in Istanbul. A structured questionnaire evaluating the sleep schedule variables was filled out by their parents. SES was determined according to the Turkish SES scale. RESULTS: The mean age of 2669 children was 8.2 ± 2.4 years, and 51% of the students were girls. The mean TSD was 10.20 ± 1.04, and the mean bedtime was 21.57 ± 0.56 (both in hours, minutes ± SD). Boys tended to go bed later (p = 0.004) and slept less than girls (p = 0.02). The duration of sleep disruptions increased (p < 0.001), whereas TSD decreased with age (p < 0.001). Multiple linear regression revealed that waking time and TSD decreased significantly (p < 0.05) with higher SES among both girls and boys. Sleep fragmentation was associated with habitual snoring, parasomnias, daytime sleepiness and conduct symptoms. CONCLUSION: Decreased total sleep duration is more prominent in boys, older children and children among higher socio-economic status. Insufficient sleep attributed to shortened total sleep duration by age and higher socio-economic status might have a negative effect on both sleep hygiene and psychological well-being in schoolchildren.

Basal ganglia location of subependymal giant cell astrocytomas in two infants.

Subependymal giant cell astrocytomas are benign tumors that constitute one of the primary features of tuberous sclerosis. Two infants with tuberous sclerosis had very unusual subependymal giant cell astrocytomas, confirmed on biopsy in one of the infants. In both cases, contrast-enhanced cranial magnetic resonance imaging suggested a calcified intra-axial mass with diffuse basal ganglia involvement extending into the lateral ventricle. Computed tomography confirmed calcification in both cases. The first patient had right temporal lobectomy for intractable epilepsy. Biopsy of the basal ganglia lesion in that case suggested subependymal giant cell astrocytoma. In infants, subependymal giant cell astrocytomas can present with unusual morphology and may feature diffuse basal ganglia involvement and severe calcification.

EEG abnormalities and epilepsy in autistic spectrum disorders: clinical and familial correlates.

Our aim was to examine the characteristics of EEG findings and epilepsy in autistic spectrum disorders (ASD) and the associated clinical and familial risk factors. Fifty-seven children (86% male) with ASD, mean age 82+/-36.2 months, were included in the study. Thirty-nine (68.4%) children had the diagnosis of autism, 15 (26.3%) had Pervasive Developmental Disorder Not Otherwise Specified, and 3 (5.3%) had high-functioning autism. One hour of sleep and/or awake EEG recordings was obtained for each child. All patients were evaluated with respect to clinical and familial characteristics and with the Childhood Autism Rating Scale, the Autism Behavior Checklist, and the Aberrant Behavior Checklist. The frequency of interictal epileptiform EEG abnormalities (IIEAs) was 24.6% (n=14), and the frequency of epilepsy was 14.2% (n=8). IIEAs were associated with a diagnosis of epilepsy (P=0.0001), Childhood Autism Rating Scale Activity scores (P=0.047), and a history of asthma and allergy (P=0.044). Epilepsy was associated with a family history of epilepsy (P=0.049) and psychiatric problems in the mother during pregnancy (P=0.0026). Future studies with larger samples will help to clarify the possible associations of epilepsy/IIEAs with asthma/allergy, hyperactivity, and familial factors in ASD.

The prevalence of headache and its association with socioeconomic status among schoolchildren in istanbul, Turkey.

OBJECTIVE: The etiology and pathogenesis of migraine and other types of headache are still under discussion. An interaction of organic, psychological, and psychosocial factors is operative. In this study, we aimed to determine the prevalence of headache and its association with socioeconomic status among schoolchildren. STUDY DESIGN: A cross-sectional study was performed on 2669 schoolchildren via a parental questionnaire. Socioeconomic status was determined according to the Turkish socioeconomic status scale. RESULTS: The mean age of the students was 8.2 +/- 2.4 years. The headache prevalence was 46.2% (95% CI: 44.3-48.1). The prevalence of migraine was 3.4% (95% CI: 2.8-4.1), the prevalence of probable migraine was 8.7% (95% CI: 7.6-9.8), and that of non-migraine headache was 34.1% (95% CI: 32.3-35.9). Multivariate analysis revealed that older age, being a girl, having a family history of headache, and exposure to passive smoking at home were independently associated with headache. There was an inverse association between socioeconomic status and all 3 types of headaches after adjusting for age, sex, family history of headache, and presence of passive smoking. When the group with the lowest socioeconomic status was taken as the reference category, the odds ratios for the highest socioeconomic group were 0.33 (95% CI: 0.16-0.69, P = .003) for the migraine, 0.30 (95% CI: 0.11-0.89, P = .029) for the probable migraine, and 0.34 (95% CI: 0.16-0.72, P = 0.005) for the non-migraine headache. CONCLUSION: Headache is more common among children with lower socioeconomic groups. Social causation can play a role in the pathogenesis of headache.

Corpus callosum agenesis in trisomy 8p11.23 and monosomy 4q34 because of maternal translocation.

We report on a 3-year-old boy with partial trisomy 8 p11.23-->pter and partial monosomy 4q34-->qter, associated with developmental delay, complete agenesis of the corpus callosum, and mild dysmorphic features. Although agenesis of the corpus callosum is not a rare finding among chromosomal abnormalities, partial trisomy 8p together with partial monosomy 4q, resulting from a maternal translocation, was not previously reported, to the best of our knowledge.

Deep brain stimulation for Holmes' tremor related to a thalamic abscess.

BACKGROUND: Medical treatment is usually ineffective for Holmes' tremor, and surgery is the treatment of choice for many patients. Here we report the case of a 14-year-old girl who developed Holmes' tremor related to a thalamic abscess and was successfully treated with thalamic deep brain stimulation. CASE REPORT: The patient presented with left hemiparesis and headache and was hospitalized. Investigation revealed a thalamic abscess in the left cerebral hemisphere. The abscess was drained via stereotactic surgery and a course of antibiotic treatment was completed. Four months after treatment, the patient developed Holmes' tremor in her left upper extremity. When attempts at medical treatment with levodopa, clonazepam, and trihexyphenidyl all failed, an implant was placed and deep brain stimulation of the ventral intermediate nucleus of the thalamus was initiated. During 2.5 years of follow-up, her tremor diminished by 90%. CONCLUSION: This case demonstrates that medically resistant Holmes' tremor related to a thalamic lesion can be successfully treated with thalamic deep brain stimulation.

Reversible EEG changes during rotavirus gastroenteritis.

Rotavirus can cause seizures and encephalopathy in infants and young children. We report reversible EEG abnormalities in a 2 year and 7 month old boy who had a single seizure during rotavirus gastroenteritis. His EEG showed bilateral independent temporoparietal sharp waves. The EEG was normal 10 days after the first EEG and the patient has been followed with no neurological sequelae. The EEG literature in children developing seizures secondary to rotavirus infection including ours suggest the involvement of mostly posterior cerebral areas. The localization and reversibility of the process can enlighten the pathophysiology underlying this disorder.