Hüseyin Per

Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Septic arthritis in childhood

Abstract Background: The purpose of the present study was to determine whether there was a difference between septic arthritis (SA) combined with osteomyelitis and SA alone with regard to clinical and laboratory findings, such as symptoms on admission, age, sex, joint involvement and isolated micro‐organisms, and a relationship between age and joint involvement in SA. In addition, we also aimed to determine the prognostic factors in SA.

Reversible posterior leukoencephalopathy syndrome in childhood: report of nine cases and review of the literature

Reversible posterior leukoencephalopathy syndrome (RPLS) is recently described disorder with typical radiological findings in the posterior regions of the cerebral hemisphere and cerebellum. Its clinical symptoms include headache, decreased alertness, mental abnormalities, such as confusion, diminished spontaneity of speech, and changed behavior ranging from drowsiness to stupor, seizures, vomiting and abnormalities of visual perception like cortical blindness. RPLS is caused by various heterogeneous factors, the commonest being hypertension, followed by non-hypertensive causes such as eclampsia, renal diseases and immunosuppressive therapy. We presented nine patients with RPLS who had primary diagnoses such as acute post-streptococcal glomerulonephritis, idiopathic hypertension, the performing of intravenous immunoglobulin for infection with crescentic glomerulonephritis, erythrocyte transfusion for severe iron deficiency, l-asparaginase treatment for acute lymphoblastic leukemia and performing of granulocyte-colony stimulating factor for ulcerative colitis due to neutropenia. Early recognition of RPLS as complication during different diseases and therapy in childhood may facilitate precise diagnosis and appropriate treatment.

Torticollis secondary to posterior fossa and cervical spinal cord tumors: report of five cases and literature review

Torticollis is either congenital or acquired in childhood. Acquired torticollis is not a diagnosis but rather a sign of an underlying disorder. The causes of acquired torticollis include ligamentous, muscular, osseous, ocular, psychiatric, and neurologic disorders and may be a symptom of significant abnormalities of the spinal cord and brain, such as spinal syrinx or central nervous system neoplasia. Torticollis is rarely considered to be an initial clinical presentation of posterior fossa and cervical spinal cord tumors. We report five cases of pediatric tumors with torticollis at the onset: an astrocytoma originating from the medulla oblongata, another presumptive astrocytoma of the spinal cord located between C1 and C6 cervical vertebrae (not operated), an ependymoma located throughout the whole cervical spinal cord extending into the bulbomedullary junction, an astrocytoma originating from the bulbus and extending into the posterior fossa, and another case of a eosinophilic granuloma located extradurally through the anterior and posterior portions of the vertebral bodies from C3 to C7 producing the collapse of the sixth cervical vertebra. All five cases were seen in children, aged between 3 and 12 years. All these cases reflect the misinterpretation of this neurological sign and the lack of association with the possibility of spinal or posterior fossa tumor. This delay in the diagnosis of these diseases led to progressive neurological deterioration and to the increase in the tumor size, which made surgical intervention difficult and the prognosis unfavorable. Although torticollis secondary to tumors is rarely seen, it is necessary to be kept in mind in the differential diagnosis.

Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors

Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.

Amitraz poisoning in children.

There is no information available in the general paediatric literature about amitraz poisoning. In the present study, which is the largest series in the literature, we report 24 children with amitraz poisoning.

Clinical spectrum of the pseudotumor cerebri in children: Etiological, clinical features, treatment and prognosis

OBJECTIVE Pseudotumor cerebri (PTC) is a clinical condition characterized by signs and symptoms of increased intracranial pressure, such as headache and papilledema. Our aim was to investigate the etiological and clinical features of pseudotumor cerebri (PTC) in children. MATERIALS AND METHOD We performed a comprehensive analysis of epidemiology, diagnostic work-up, therapy, and clinical follow-up in 42 consecutive patients. RESULTS Totally 42 patients diagnosed with PTC [27 (64.3%) females and 15 (35.7%) males] were included in the study. The average age of the symptoms onset was 10.79±3.43 years (range from 12 months to 17 years). Obesity was found in eleven (26.2%) of them. Two of the patients had familial mediterranean fever, two of them had posttraumatic PTC. The following diseases were one patient, respectively; mycophenolate mofetil-induced PTC, hypervitaminosis A induced PTC, corticosteroid induced withdrawal due to nephritic syndrome, use of oral contraceptives, Guillain-Barre syndrome, urinary tract infection, varicella-zoster virus infection and dural venous sinus thrombosis associated with otitis media. The most common symptom was headache, recorded in 76.2% of the patients. All patients were treated medically. Three patients in our group also required a ventriculoperitoneal shunt. CONCLUSION Pseudotumor cerebri is an avoidable cause of visual loss, both in adults and children. Pre-pubertal obese girls are more common. Medical therapy appeared to be successful in treating pediatric PTC in most patients. Nevertheless, despite adequate treatment, children can rarely experience loss of visual field and acuity; thus, prompt diagnosis and management are important.

The comparison of the effects of dexmedetomidine and midazolam sedation on electroencephalography in pediatric patients with febrile convulsion

Background:  When electroencephalogram (EEG) activity is recorded for diagnostic purposes, the effects of sedative drugs on EEG activity should be minimal. This study compares the sedative efficacy and EEG effects of dexmedetomidine and midazolam.

Iatrogenic Epidermoid Tumor: Late Complication of Lumbar Puncture:

Intraspinal epidermoid tumors can be congenital and acquired. Acquired intraspinal epidermoid tumors are extremely rare. Epidermal elements are implanted into the arachnoid space by trauma, spinal anesthesia, surgery, bullet wounds, myelography, or lumbar puncture. Approximately 40% of acquired epidermoid tumors are considered a late complication of lumbar puncture. The authors report the case of an 8-year-old boy who presented with a 1-year history of back and hip pain and radiating pain to both thighs posterior. Lumbar puncture was performed in the neonatal intensive care unit to rule out meningitis in the patients past medical history. The patient underwent total surgical excision of the epidermoid tumor. Pathologic examination revealed the diagnosis of epidermoid tumor. Keywords: intraspinal epidermoid tumor; lumbar puncture; children

Childhood Stroke: Results of 130 Children From a Reference Center in Central Anatolia, Turkey

BACKGROUND Although stroke among children is rare, it can cause significant morbidity and mortality. We aim to share our experience of children with arterial ischemic stroke. METHODS The initial symptoms, demographical features, risk factors, neurological examination, neuroradiological findings, and clinical follow-up data of 130 Turkish children seen between 2002 and 2013 were retrospectively analyzed. RESULTS Sixty-eight patients were male. Thirty of the children were aged from 1 to 12 months (seven of them died in this period). Focal neurological signs were the most common presentation, and hemiplegia or hemiparesis were the most common focal signs. Underlying risk factors were detected in 103 patients. Infections and congenital heart disease were the most common risk factors. Seven of the nine children with recurrent arterial ischemic strokes had one or more underlying diseases (moyamoya disease in two children along with factor V Leiden mutation, tuberculous meningitis, congenital heart disease, homocystinuria, and hemiconvulsion-hemiplegia-epilepsy syndrome). The arterial ischemic stroke was located in the middle cerebral circulation in 68 (36 left and 32 right) and in the posterior cerebral artery in 41. Eighteen children died. The neurological outcome was assessed in 98 children. Of these children, 66 children have neurological deficits and 52 children have seizures. Stroke in the first year of life is more often fatal. Recurrent stroke is associated with poor prognosis. CONCLUSION Tuberculous meningitis is still a risk factor for arterial ischemic stroke in Turkey. Arterial ischemic stroke in the first year of life and recurrent arterial ischemic stroke represent poor prognostic features.