Barış Ekici

Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

Preliminary Anatomical and Neurodevelopmental Outcomes of Intravitreal Bevacizumab As Adjunctive Treatment for Retinopathy of Prematurity

Abstract Purpose: To evaluate the two-year follow-up of patients with type 1 retinopathy of prematurity (ROP) who received intravitreal bevacizumab (IVB) as adjunctive treatment. Materials and methods: We conducted a longitudinal follow-up study of premature infants who received 0.625 mg IVB therapy in addition to standard laser photocoagulation therapy. For comparison of the ophthalmological and neurological assessment outcomes of these infants, a control group was formed with 13 birth weight- and gestational age-matched infants who were treated with laser therapy alone for type 1 ROP. The neurological status of the study group and the control group was examined systematically, and neurodevelopmental evaluation was assessed by the Bayley Scales of Infant Development (BSID-III). Results: A total of 18 eyes of 13 infants were included in the study. Anatomical success was obtained in 14 eyes (78%) and retinal detachment was observed in 4 eyes (22%). At two years of age, no significant difference was found in terms of spherical or cylindrical refractive errors compared to the control group. In control group, 2/13 patients’ and in study group, 3/13 patients’ neurological examinations were abnormal. No significant difference was found in the mean cognitive, language or motor BSID-III test scores of the groups. Conclusions: IVB appears to be useful for advanced ROP when laser treatment is precluded or not sufficient for preventing the progression of ROP. This pilot study indicates that IVB seems to contribute no further complications to the complications already present due to prematurity.

Evaluation of etiologic and prognostic factors in neonatal convulsions.

This study evaluated etiologic and risk factors affecting long-term prognoses of neurologic outcomes in newborns with neonatal seizures. We enrolled patients at chronologic ages of 23-44 months, referred to the Department of Pediatric Neurology, Istanbul Medical Faculty, from January 1, 2007-December 31, 2009, after manifesting seizures in their first postnatal 28 days. Of 112 newborns, 41 were female, 71 were male, 33 were preterm, and 79 were full-term. Perinatal asphyxia (28.6%) and intracranial hemorrhage (17%) were the most common causes of neonatal seizures. Cerebral palsy developed in 27.6% of patients during follow-up. The incidence of epilepsy was 35.7%. Almost 50% of patients manifested developmental delay in one or more areas. Global developmental delay was the most common (50.8%) neurologic disorder. The correlation between gestational age or birth weight and adverse outcomes was nonsignificant. Etiology, Apgar score, need for resuscitation at birth, background electroencephalogram, neonatal status epilepticus, cranial imaging findings, type/duration of antiepileptic treatment, and response to acute treatment were all strong prognostic factors in neurologic outcomes. Neonatal seizures pose a threat of neurologic sequelae for preterm and full-term infants. Although the number of recognized etiologic factors in neonatal seizures has increased because of improvements in neonatology and diagnostic methods, perinatal asphyxia remains the most common factor.

The Role of Parental, School, and Peer Factors in Adolescent Bullying Involvement: Results From the Turkish HBSC 2005/2006 Study

The aim of this study was to explore the relationships between involvement in bullying behaviors and school, family, and peer factors. Health Behavior in School Age Children survey questionnaire was used. Of the students surveyed, 20% were both bully and victim, 11% were bully, and 21% were victim. Being male, poor parental support, and poor monitoring by the father were found to be risk factors for being both bully and victim. Poor academic achievement, having peers at different ages, poor quality of friendship, poor communication with parents, and not being isolated by peers were found to be risk factors for being bully. Not liking school, feeling pressured by school work, poor quality of friendship, poor monitoring by the father, close bonding with mother, and poor status of the peer group were found to be risk factors for being victim. These findings highlight the importance that bullying intervention programs should include country-specific and culture-specific influences for success.

Thyroid Hormones in Children on Antiepileptic Therapy

ABSTRACT The aim of this study was to evaluate the thyroid function alterations in a group of epileptic children taking antiepileptic drugs (AEDs). Patients demographic data and the free throxine (fT4) and thyroid-stimulating hormone (TSH) levels at the beginning of the treatment and at the third, sixth and ninth months of AED treatment were recorded retrospectively. A total of 106 children, 59 males and 47 females, were enrolled in the study. Mean patient age was 3.7 years, ranging between 3 months and 14 years. In total, 54% of patients were on valproic acid (VPA), 16% phenobarbital (PB), 14% were on carbamazepine (CBZ), 6% were on oxcarbazepine (OXC), 5% were on levetiracetam, and 5% were on topiramate therapy. There were no significant differences in average fT4 values between the drug groups. But the mean fT4 levels of the patients on VPA therapy showed a clear decrease within the observation period. No significant difference in average TSH values between the groups was detected in the beginning and in the third and sixth month. However, in the ninth month, a significant increase in TSH values was found in the VPA group (p = 0.007). In the patients taking VPA, average TSH values rose progressively while staying within normal limits. During follow-up, thyroid dysfunction were found in 21 patients (19.6%). A statistically significant relationship was found between severe electroencephalography (EEG) findings and thyroid dysfunction (p = 0.041). It was concluded that epileptic children with severe EEG findings and using VPA could have thyroid dysfunction. These patients should be followed up closely by thyroid function tests during treatment.

Positron emission tomography findings in children with infantile spasms and autism

The purpose of this study was to evaluate positron emission tomography (PET) findings in patients diagnosed with infantile spasms and autism. This study includes 90 patients who were diagnosed with infantile spasms at the Department of Pediatric Neurology in the Istanbul University Medical Faculty between 1995 and 2007. Of the 90 patients, 15 patients who were diagnosed with autism using the Autism Behaviour Checklist and Childhood Autism Rating Scale and a control group of nine patients without autism but with infantile spasms underwent PET examination. Mean patient age (± standard error, SE) varied between 3 years and 16 years (7.8 ± 4 years), while the mean follow-up time (±SE) varied between 2 years and 16 years (average: 7.1 ± 4 years). Autism was present in 11 patients with symptomatic spasms and in four patients with cryptogenic spasms (p=0.009). On the PET scans of the 15 patients with autism, 13 (86.7%) had significantly decreased metabolic activity in the temporal lobe (p<0.001), nine (60%) had significantly decreased activity in the frontal lobe (p=0.004), and seven (46.7%) had significantly decreased activity in the parietal lobe (p=0.022). In our opinion, hypometabolism in the frontal and parietal lobes, in addition to that previously reported in the temporal lobe, plays a role in the development of autism in patients with infantile spasms.

Neonatal hypoxic ischemic encephalopathy: an update on disease pathogenesis and treatment

ABSTRACT Introduction: Hypoxic ischemic encephalopathy (HIE) is the most important reason for morbidity and mortality in term-born infants. Understanding pathophysiology of the brain damage is essential for the early detection of patients with high risk for HIE and development of strategies for their treatments. Areas covered: This review discusses pathophysiology of the neonatal HIE and its treatment options, including hypothermia, melatonin, allopurinol, topiramate, erythropoietin, N-acetylcyctein, magnesium sulphate and xenon. Expert commentary: Several clinical studies have been performed in order to decrease the risk of brain injury due to difficulties in the early diagnosis and treatment, and to develop strategies for better long-term outcomes. Although currently standard treatment methods include therapeutic hypothermia for neonates with moderate to severe HIE, new supportive options are needed to enhance neuroprotective effects of the hypothermia, which should aim to reduce production of the free radicals and to have anti-inflammatory and anti-apoptotic actions.

Neurodevelopmental outcome of 31 patients with borderline fetal ventriculomegaly.

AIM We present the neurodevelopmental outcome of patients with isolated borderline fetal ventriculomegaly. METHODS The present study was carried out at the Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University in July-December 2010. Prenatal second trimester detailed ultrasound examinations were performed by obstetricians at the Prenatal Diagnosis Department of Istanbul Medical School, and 31 consecutive patients aged 8-33 months have been included in the study. Four patients with atrial diameters of over 15 mm and three patients with central nervous system development anomalies were excluded from the study. In order to assess the neuromotor development of patients, neurologic examinations and the Bayley Scales of Infant Development (BSID-III) were used. RESULTS Nine patients were female (29%) and 22 were male (71%). In the postnatal period, tuberous sclerosis was found in one patient, Down syndrome in one, and equinovarus foot deformity in one. Atrial diameter was <12 mm in 18 patients and >12 mm in 13. Cranial ultrasounds done in the first postnatal month revealed persisting ventriculomegaly in nine patients. The two patients who scored significantly low in all areas on the Bayley Scales of Infant Development were the patients with Down syndrome and tuberous sclerosis. The one scoring low in the motor area was the patient with the equinovarus foot deformity. The BSID-III scores of the patients whose prenatal ventricle diameter was <12 mm were within normal limits. The four patients showing slight developmental delay were the ones whose cranial ultrasound in the first postnatal month showed persisting ventriculomegaly. CONCLUSION In patients with borderline fetal ventriculomegaly, atrial diameter being more than 12 mm, the condition persisting in the first postnatal month and the presence of accompanying syndromes and malformations all constitute clear risk factors for neurodevelopmental outcome.

Brain Malformations Associated With Knobloch Syndrome—Review of Literature, Expanding Clinical Spectrum, and Identification of Novel Mutations

BACKGROUND Knobloch syndrome is a rare, autosomal recessive, developmental disorder characterized by stereotyped ocular abnormalities with or without occipital skull deformities (encephalocele, bone defects, and cutis aplasia). Although there is clear heterogeneity in clinical presentation, central nervous system malformations, aside from the characteristic encephalocele, have not typically been considered a component of the disease phenotype. METHODS Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, we investigated the protein expression pattern of COL18A1 in the mid-fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database. RESULTS We identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. On further investigation of these patients and their families, we found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. Our data strongly support an important role for COL18A1 in brain development, and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII. CONCLUSIONS This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology-allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. We suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1 mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of an encephalocele.

Epilepsy treatment by sacrificing vitamin D

Epilepsy is one of the most common neurologic disorders in childhood that often requires long term treatment with antiepileptic drugs. Both antiepileptic treatment and the comorbidities associated with epilepsy have a negative impact on bone health in growing children. Given the fact that vitamin D deficiency is a major public health problem worldwide, clinicians caring for children with chronic diseases should be aware of effects of the medication on the bone metabolism. Yet, vitamin D deficiency due to antiepileptic treatment is an overlooked issue among neurologists. In this review, we briefly describe vitamin D metabolism and the effect of vitamin D in the brain. We also discuss the literature in terms of vitamin D deficiency and antiepileptic treatment in the pediatric population.