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Background A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. Objective The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. Methods Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. Results DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. Conclusion Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.

BACKGROUND: Paediatric Neurology (PN) is a discipline focused on diagnosis, comprehensive management and research into diseases of the central and peripheral nervous system from fetal life to transition into adulthood. The European Paediatric Neurology Society first designed and published the European PN training programme in the European Paediatric Neurology Syllabus in 2002. This was important in gaining recognition for the sub-specialty from the European Academy of Paediatrics and the European Academy of Neurology and in 2003 PN was recognized as a sub-specialty of paediatrics and neurology by the Board of the European Union of Medical Specialties. In 2004, the EPNS founded the Committee of National Advisors (CNA) that comprised representatives from national Paediatric Neurology societies, in order to further enhance Europe wide standards in training and practice., The EPNS Training Advisory Board (TAB) offers nation specific advice/support to PN societies on developing training and care systems. In 2019, the 2nd revision of the Paediatric Neurology Syllabus was approved by the EPNS Board and CNA. We aim to give an overview of the training of Paediatric Neurology (PN) specialists (i.e. Paediatric Neurologists), the relevant professional bodies and the current practice of Paediatric Neurology in Europe, as defined geographically by the World Health Organization. METHODS: A structured online data collection form was completed by CNA representatives from European countries. The data included training routes and structure of training, epidemiological data, nature of professional societies, organization of Paediatric Neurology care, research, academic life and recognition of the specialty. RESULTS: Data was collected from 43 European countries of which 38 have a national PN Society. In 10 (6 European Union (EU) and 4 non-EU countries) PN is recognized as a core specialty. In 26 countries PN is recognized as a sub-specialty of Paediatrics, Neurology or both (15 EU-11 non-EU). PN is not recognized as a core or sub-specialty in 7 countries (4 EU and 3 non-EU). In 35 countries paediatric neurologists begin their training from Paediatrics, but in 19 countries PN training from Neurology is also possible or the preferred route. Training in PN differs, but in over 50% of countries the three main training modules named in the 2019 2nd revision of the European PN Syllabus (PN, Paediatrics and adult Neurology) are included. Many countries have already adapted their curriculum to the suggestions in the European PN syllabus. CONCLUSIONS: There is diversity among European countries in terms of professional organization and PN training. The European PN syllabus has had impact on the development of PN training throughout Europe, independent of duration of training or route from paediatrics or neurology. The syllabus provides a basis for the future development of PN training, the recognition of PN as a (sub) specialty in individual countries and for improving the care of children with neurological disorders in Europe. ispartof: EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY vol:28 pages:6-15 ispartof: location:England status: published

Background Most patients present with seizures to pediatric emergency department (PED) are observed for extended periods for the risk of possible acute recurrence. Objective The aim of this study is to determine the risk factors of acute recurrence within first 24 h. Methods Patients who presented to PED with seizure during past 24 h were enrolled. Demographic features, number and duration of seizures, diagnostic studies, physical examination findings, presence and time of seizure recurrence in PED were noted. Results 187 patients were eligible for the study. 46% had recurrence of seizures in 24 h, 90,8% of recurrence within the first 6 h. Univariate analysis showed that younger patients, epileptic patients who were on multiple antiepileptic drugs (AEDs), who had multiple seizures during the past 24 h, who had abnormal neurological examination or neuroimaging findings had increased risk of seizure recurrence. Multivariate analysis showed that number of seizures during the past 24 h and previous use of AEDs was significantly associated with increased risk of recurrence. Conclusion Risk factors for acute recurrence should be evaluated for each patient. Patients without risk factors and no seizures during the first 6 h should not be observed for extended periods in PED.

Yüksek oranda yağ, yeterli miktarda protein ve düşük karbonhidrat içeren ve açlıkta olduğu gibi vücudu glukoz yerine başlıca yağlardan enerji sağlayacak şekilde yönlendiren ketojenik diyet, geçmişten günümüze ilaca dirençli epilepsi hastalarının tedavisinde ilk akla gelen tedavi seçeneğidir. İlk olarak 1920’li yılların başında ‘klasik ketojenik diyet’ ile başlayan geleneksel KD tedavisini, diyetin yeni etki mekanizmalarının keşfedilmesi ile birlikte 2000’li yılların başından itibaren ortaya çıkan ve daha az kısıtlama yapılan alternatif KD’ler izlemiştir. Alternatif diyetler çoğunlukla diyete uyumun azaldığı adölesan (12-18 yaş) dönemde tercih edilse de, ciddi davranış sorunları olan ve diyetten fayda görmesine rağmen diyete uyumun azalması nedeniyle nöbet kontrolü sağlanamayan daha küçük yaştaki çocuklarda da göz önünde bulundurulması gerekebilir. Bu alternatif KD’lerden birisi olan düşük glisemik indeks tedavisi (LGIT) kan glukoz düzeylerini minimal ve stabil düzeyde tutmayı amaçlar ve bu şekilde epileptik nöbetler kontrol altına alınır. LGIT, klasik KD’e oranla daha fazla karbonhidrat (enerjinin yaklaşık %10’u, günde 40-60 g/gün düşük glisemik indeksli karbonhidratlar) ve protein (enerjinin %25’i) alımına, dolayısı ile daha fazla besin tüketimine olanak sağlar. Bu olgu sunumunda, preadölesan dönemde olan ve hafif nöbet bulguları, şiddetli elektroansefalogram (EEG) bozukluğu ve davranış bozuklukları ile izlenen bir vakada, klasik KD uygulamasındaki zorluklar ve LGIT diyetine geçişin tedavinin etkinliği üzerindeki etkileri tartışılmıştır.

Amac: Medikal tedaviye direncli epilepsi hastalarinda nobet semiyolojisi, skalp-video elektroensefalografi, manyetik rezonans goruntulume (MRG) ve 18-floro-2-deoksi-glukoz pozitron emisyon tomografi (FDG-PET) bulgularinin degerlendirilmesi, epileptojenik odagi lokalize etmede klinik- elektroensefalografi bulgulari ile norogoruntuleme yontemleri arasindaki uyumun degerlendirilmesi amaclandi. Gerec ve Yontemler: Retrospektif olan calismamiz hastane etik kuru onayi alinarak yapildi. Calismaya, Ocak 2011 ile Ocak 2017 tarihleri arasinda, klinik- elektroensefalografi bulgularina gore temporal (30 erkek, 26 kiz, ortalama yas 30,1±8,9 yil) ve ekstra-temporal lob epilepsi (29 erkek, 23 kiz, ortalama yas 22,8±10,9 yil) gruplarina ayrilan ardisik 108 hasta (59 erkek, 49 kiz, ortalama yas 26,6±10,5 yil) dahil edildi. Kategorik-sayisal degiskenler t, Mann-Whitney U, McNemar veya Ki-kare testi ile analiz edildi. Bulgular: Calismaya dahil edilen 108 hastanin 12’si (6 erkek, 6 kiz, ortalama yas 28,7±10,2 yil) epilepsi cerrahisi gecirdi ve bu hastalarin operasyon sonrasi ortalama takip suresi 32 aydi. Klinik- elektroensefalografi bulgulari ile norogoruntuleme yontemleri arasinda en yuksek uyum (%76) hippokampal skleroz disi anormallikler sahip temporal lob epilepsili hastalarda saptandi. MRG’de kortikal gelisimsel anormalliklere sahip hastalardaki, klinik- elektroensefalografi bulgulari ile MRG arasindaki uyum (%84,2), klinik- elektroensefalografi bulgulari ile FDG-PET arasindaki uyumdan (%52,6) yuksekti (p=0,010). T emporal lob epilepsilerindeki k linik- elektroensefalografi bulgulari ile norogoruntuleme yontemleri arasindaki uyum (%48,2), ekstra-temporal lob epilepsilerine (%9,6) gore daha yuksekti (p

Objectives Childhood emotional/behavioral problems in children with epilepsy have been reported to be higher compared with those with typical development or with other nonneurologic health conditions. Increasing interest towards understanding these behavioral comorbidities is reflected in literature. However, longitudinal investigations regarding the course of behavioral problems in children with newly diagnosed epilepsy and normal development are rare, and majority of them involve school-aged children. We aimed to study the behavioral comorbidities of preschool children with newly diagnosed epilepsy and to explore the changes of behavioral problems after one year from the diagnosis in comparison with the healthy group and subsequently, to elucidate the potential developmental, neurologic, and social risk factors associated with these difficulties. Methods Participants were 83 patients, aged between 18 and 59 months, 43 of them were children with new-onset epilepsy, and 40 of them were healthy children as the comparison group. The Child Behavior Check List-1 1/2-5 (CBCL) was used to evaluate emotional/behavioral problems of the children. Maternal anxiety was analyzed by The State–Trait Anxiety Inventory (STAI). The general development of children was evaluated by the Denver-II-Developmental Screening Test (D-II-DST). Sociodemographic characteristics were also collected for all participants. Each evaluation was repeated after one year from the diagnosis. Results Internalizing, externalizing, and total problem scores were higher in children with epilepsy than the control group at baseline, and despite some reduction in several scales, the differences continued across groups after one year. The analysis for the course revealed that behavior problem scores reduced in children with new-onset epilepsy over a year, but it did not change in healthy children. Among the possible factors related to behavior problem scores, in correlation analysis, the duration of screen viewing, socioeconomic status, and maternal education were associated with behavior problem scores. There was no significant association between epilepsy-related variables and the behavior problem scores and the course. Among all possible risk factors in the regression analyses, maternal trait anxiety level was found to be significantly related to the total problems, internalizing, and externalizing scores in the group with epilepsy. Conclusion Behavioral comorbidities of epilepsy are present very early and can be seen at the time of the diagnosis, however, they do not worsen over time in preschool children. Maternal anxiety should be considered as a risk factor for behavioral problems in preschool children with epilepsy. Assisting children and parents and ensuring necessary guidance and support should be a crucial part of epilepsy treatment initiated as soon as the time of diagnosis.

Syncope is a common presenting symptom in the pediatric emergency department (PED). The etiology of pediatric syncope is generally benign. However, differentiating cardiac and other serious causes from benign causes of syncope are crucial. The aim of this study was to evaluate the change of physicians' behavior after introduction of an institutional protocol designed to act as a guide in the assessment and management of syncope patients in the PED.This was a retrospective study, conducted at the PED of our University Children's Hospital. A "pediatric syncope approach protocol" was introduced on March 1, 2019 for quality improvement purposes. Documented information in the medical records, laboratory investigations and the patients' final diagnoses during the six-month periods before and after the protocol introduction were compared.268 patients were included in the study (131 pre-protocol, 137 post-protocol patients). When compared with the pre-protocol group, there was a significant improvement in the documentation of syncope characteristics (prodromal findings, predisposing factors, association with exercise), cardiac, neurological and electrocardiographic (ECG) warning signs and ordering of cardiac markers in the post-protocol group.The introduction of the syncope approach protocol in PED has enabled an evidence-based and systematic evaluation and management of syncope patients, and reduced the rates of low-yield investigations. Sustained implementation of this protocol can have long-term benefits in the care of children with syncope at the emergency department.

Introduction: The distribution of hippocampal sclerosis (HS) subtypes, according to the classification of the International League Against Epilepsy (ILAE), has been reported mainly in adult patients. We aimed to review the pathological findings in children who had anterior temporal lobectomy accompanied with amygdalohippocampectomy, in view of the current classification, and evaluate postsurgical outcome with respect to HS subtypes in childhood.Methods: Seventy children who underwent temporal resections for treatment of medically refractory epilepsy, with a minimum follow-up of 2 years, were included: the surgical hippocampus specimens were re-evaluated under the HS ILAE classification.Results: Neuropathological evaluations revealed HS type 1 in 38 patients (54.3%), HS type 2 in 2 (2,8%), HS type 3 in 21 patients (30%), and no HS in 9 patients (12.9%). 0170 patients, 23 (32.9%) had dual pathology, and the most common pattern was HS type 3 with low-grade epilepsy-associated brain tumors (LEAT). The distribution of HS types with respect to age revealed that HS type 3 and no HS subgroups had significantly more patients younger than 12 years, compared with those of HS type 1 (90.5%, 77.8% vs 47.4%, respectively). History of febrile seizures was higher in HS type 1. Prolonged/recurrent febrile seizures were most common in patients 12 years and older, whereas LEAT was the most common etiology in patients under 12 years of age (p < 0.001). Patients with HS type 1 had longer duration of epilepsy and an older age at the time of surgery compared with patients with HS type 3 and no HS (p: 0.031, p: 0.007). At final visit, 74.3% of the patients were seizure-free. Seizure outcome showed no significant difference between pathological subtypes.Conclusions: Our study presents the distribution of HS ILAE subtypes in an exclusively pediatric series along with long-term seizure outcome. The study reveals that the leading pathological HS subgroup in children is HS type 1, similar with adult series. Hippocampal sclerosis type 2 is significantly less in children compared with adults; however, HS type 3 emerges as the second most predominant group because of dual pathology, particularly LEAT. Further studies are required regarding clinicopathological features of isolated HS in pediatric cohort. Seizure-free outcome was favorable and similar in all HS types in children. The proportion of HS types may be better defined in pediatric patients with temporal resections, as the current HS ILAE classification becomes more widely used, and may help reveal the surgical and cognitive outcome with respect to HS types.

Acute cerebellitis is a rare condition often considered within the group of acute postinfectious cerebellar ataxia despite its distinctive clinical and imaging features. We retrieved clinical, laboratory, and follow-up data of 15 children diagnosed with acute cerebellitis in our department between 2011 and 2019. There were 10 boys and 5 girls aged 3-15 years, median 9.5 years. The most common first symptoms were ataxia, vomiting, and headache. Magnetic resonance imaging (MRI) generally showed bilateral symmetrical T2 hyperintense changes with moderate swelling in the cerebellar cortex. Tonsillar herniation was present in 73.3% and obstructive hydrocephalus in 26.6%. Etiologic workup for infectious pathogens revealed Mycoplasma pneumoniae, influenza A virus, cytomegalovirus, and varicella zoster virus in 1 case each. Fourteen of 15 patients were treated with intravenous and/or oral steroids and 8 cases with intravenous immunoglobulin. No patient required surgical decompression. Neurologic examination median 12 months later revealed ataxia and dysmetria in 4 cases (27%), accompanied by memory difficulties, dysarthria or tremor. Follow-up magnetic resonance imaging (MRI; n = 12) showed diffuse cerebellar cortical T2-hyperintense signal changes in 11 cases and cerebellar atrophy in 9. The diagnosis of acute cerebellitis rather than acute postinfectious cerebellar ataxia should be considered when headache and vomiting accompany ataxia in a child. Acute cerebellitis heals with sequelae in about one-third of cases. The absence of fatalities in our series suggests early diagnosis, and steroid treatment can increase the chance of recovery. MRI results were not found to be predictive of outcome.

Ozcakar, Zeynep/0000-0002-6376-9189; DUZOVA, ALI/0000-0002-4365-2995; Gocmen, Rahsan/0000-0002-0223-9336 WOS: 000455971500011 PubMed: 30337132 BACKGROUND: COQ2 mutations cause a rare infantile multisystemic disease with heterogeneous clinical features. Promising results have been reported in response to Coenzyme Q10 treatment, especially for kidney involvement, but little is known about the long-term outcomes. METHODS: We report four new patients from two families with the c.437G -> A (p.Ser146Asn) mutation in COQ2 and the outcomes of two patients after long-term coenzyme Q10 treatment. RESULTS: Index cases from two families presented with vomiting, nephrotic range proteinuria, and diabetes in early infancy. These patients were diagnosed with coenzyme Q10 deficiency and died shortly after diagnosis. Siblings of the index cases later presented with neonatal diabetes and proteinuria and were diagnosed at the first day of life. Coenzyme Q10 treatment was started immediately. The siblings responded dramatically to coenzyme Q10 treatment with normalized glucose and proteinuria levels, but they developed refractory focal clonic seizures beginning at three months of life that progressed to encephalopathy. CONCLUSIONS: In our cohort with CoQ10 deficiency, neurological involvement did not improve with oral coenzyme Q10 treatment despite the initial recovery from the diabetes and nephrotic syndrome. (C) 2018 Elsevier Inc. All rights reserved.

To identify physical fitness and activity levels, and health-related quality of life of children with epilepsy in Turkey and compare the results with their healthy peers.The study included 21 children with epilepsy (with no seizures and not taking anti-epileptic drugs for at least a year) and 20 healthy peers. The FitnessGram Physical Fitness Test Battery was used to assess physical fitness, the 6-Minute Walk Test to assess physical performance, the Pediatric Quality of Life Inventory 4.0 (PedsQL) to assess the quality of life, and a pedometer was used to assess the physical activity of the children.The physical fitness assessments including the trunk-lift test and flamingo balance test results were significantly lower in the children with epilepsy (p 0.05). There was no significant difference between the groups in terms of BMI, the cadence-based curl-up test, the push-up test and the back saver sit/reach test (p 0.05). Physical activity, physical performance, and quality of life results were significantly lower in children with epilepsy (p 0.05).The presence of epilepsy may negatively affect many aspects of physical fitness, physical activity, and quality of life in childhood. The children with epilepsy adopted a more sedentary lifestyle than their healthy peers. Quality of life outcomes reveal that epilepsy has negative physical and psychosocial effects on children. These results support the necessity of raising awareness in both health professionals and families to encourage their children to be more active.

ELFN1, a transmembrane leucine rich repeat protein, is involved in signal transduction in both neural cells and ROD ON-bipolar synaptogenesis. We present three siblings with developmental and epileptic encephalopathy and co-morbidities due to ELFN1 gene mutation; this is the first report in literature defining the human phenotype of ELFN1 gene mutation. Clinical, electrophysiological, and radiological findings along with comprehensive genetic studies of the patients and their family members are presented. Developmental and epileptic encephalopathy, autistic features, pyramidal signs, joint laxity, and dysmorphic features are the characteristic findings of this new clinical entity, involving mainly nervous system and possibly connective tissue. Whole exome sequence analysis followed by Sanger sequencing in all family members revealed disease-causing 8 bp frameshift mutation depicted as NM_001128636.2: c.42_49delGGCCGCCA; p. (Ala15Profs*241) in ELFN1. The variant, located in the signal peptide domain in the ELFN1 gene, was found to be homozygous in three patients, and heterozygous in the parents and three healthy siblings. Segregation analysis in family members together with pathogenicity assessment tools strongly supported the damaging effect of the frameshift variant on the function of the ELFN1 protein. Mutations in ELFN1 gene may be considered in patients with neonatal and infantile-onset epileptic encephalopathy before the full clinical picture is apparent.

Objective Anti-N-methyl- d -aspartate receptor encephalitis (a-NMDARe) is an acute or subacute encephalopathy where electroencephalogram (EEG) is frequently obtained as part of the workup. Although no diagnostic EEG finding has been described so far, the definition of specific or typical patterns might help to distinguish this group among various encephalopathies of childhood. We examined EEG recordings of our patients with a-NMDARe in order to describe the most frequent findings. Methods Clinical and laboratory data and digital EEG recordings of 12 pediatric patients diagnosed with a-NMDARe in two major child neurology centers are evaluated. Results We reviewed 43 EEG recordings from 12 children with a-NMDARe and followed their evolution for a median of 6 (range: 1–60) months. Initial EEG was abnormal in 11/12 patients. The most frequent finding was focal or diffuse slowing of the background rhythm. Generalized rhythmic delta activity, brief rhythmic discharges (BRDs), and occipital intermittent rhythmic delta activity (OIRDA) were seen in two patients each. Diffuse excess beta frequency activity was seen in three patients. Extreme delta brushes were observed in 5/12 (41.7%) patients, disappeared in 4–6 months (two patients), or persisted at 10–17 months (two patients). Epileptic activity was seen in seven patients (58%) and lateralized periodic discharges in one. On follow-up EEGs, most epileptic activity disappeared in a median of 8 months. Conclusions A normal EEG is rare in a-NMDARe. Focal or diffuse slowing, epileptic activity, and extreme delta brush are common findings. Epileptic activity in early EEGs do not persists in most patients. Severe diffuse slowing may predict neurological impairment if confirmed in larger series.

Introduction Neurofibromatosis type 1 (NF1) is accompanied by epileptic seizures in 4–7% of patients. We examined clinical, electrophysiological, and radiological features associated with epilepsy in our NF1 series in order to identify risk factors. Methods We reviewed data of 641 pediatric patients with NF1 diagnosis according to National Institutes of Health (NIH) criteria in Hacettepe University records from January 2008–August 2018. Demographic features, NF1-related clinical and imaging characteristics, age at onset of epilepsy, seizure semiology, and frequency, electroencephalogram (EEG) findings, and response to treatment were noted. Results Twenty-six patients with NF1, 15 male, 11 female, had epilepsy. Age at seizure onset was 6 months to 13 years. Seizure semiology was focal with impaired awareness (n = 9, 34%), focal aware motor (n = 2, 8%), focal to bilateral tonic–clonic (n = 3, 12%), generalized tonic–clonic (n = 7, 28%), absence (n = 3, 12%), infantile spasms (n = 1), and unclassified type (n = 1). None had a history of status epilepticus. The EEG findings were normal for age in ten patients (38%). Others had focal (n = 8, 30%), generalized (n = 7, 27%), or multifocal (n = 1, 4%) discharges. On brain magnetic resonance imaging (MRI) signal intensity changes typical for NF1 (neurofibromatosis bright objects, NBOs) were the most common finding (80%), followed by normal MRI (20%). There was no relation between the localization of NBOs and discharges on EEG. Seventeen patients (65%) were seizure-free at the time of the study; 11 of them still under medication including four on multiple antiepileptic drugs. The rate of learning problems and NBO were significantly higher in patients with NF1 with epilepsy compared to those without. Discussion Epilepsy in NF1 is associated with relatively infrequent seizures and good response to treatment. Learning disorders are markedly frequent in this group, irrespective of the severity of epilepsy. The absence of correlation between the localizations of epileptiform discharges and lesions on MRI support the role of cellular or synaptic mechanisms rather than structural causes in the pathogenesis of epilepsy.

We present a novel multisystem disease in two siblings with clinical features resembling a lysosomal storage disease. These included coarse face, dysostosis multiplex, respiratory difficulty, proteinuria with glomerular foamy cells, neurological involvement with developmental delays, pyramidal signs, and severe chronic anemia. Detailed enzymatic analysis for lysosomal diseases and whole-exome sequencing studies excluded known lysosomal storage diseases in the proband. Subsequently, genome-wide genotyping and exome sequencing analysis of the family indicated two large homozygous regions on chromosomes 5 and 12, and strongly suggested that a homozygous p. R498W missense mutation in the VPS33A gene might be responsible for this novel disease. Segregation analysis in family members and mutation prediction tools' results also supported the damaging effect of the missense mutation on the function of the Vps33a protein, which plays a role in the vesicular transport system. Electron microscopic studies of the cornea of the proband showed findings supportive of dysfunction in vesicular transport. The clinical phenotype and genetic studies support the suggestion that the siblings most probably have a novel disease very likely caused by a VPS33A gene defect.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare complication of cranial radiotherapy characterized by migraine-like headache and transient neurological deficits with typical gyriform enhancement on magnetic resonance imaging (MRI). Potential underlying mechanisms are endothelial damage or dysfunction, vascular instability, vasospasm and, neuronal dysfunction.We report an 11-year-old girl with a primary diagnosis of medulloblastoma presented with acute-onset severe headache and left-sided weakness, 20 months after completing cranial radiotherapy. MRI demonstrated unilateral cortical swelling and concomitant leptomeningeal, gyral contrast enhancement, and MR perfusion imaging showed increased cortical perfusion in the right temporo-parieto-occipital region. Her symptoms resolved spontaneously over several days.SMART syndrome appears to be a reversible, long-term complication of cranial radiotherapy. So far, a limited number of pediatric patients with SMART syndrome have been reported. Prompt recognition of clinical signs and radiological imaging of SMART syndrome may help prevent unnecessary interventions and initiate appropriate diagnostic workup and management.

Introduction Vagus nerve stimulation (VNS) has been used as an adjunctive therapy for both children and adults with refractory epilepsy, over the last two decades. In this study, we aimed to evaluate the long-term effects and tolerability of VNS in the pediatric drug-resistant epilepsy (DRE) and to identify the predictive factors for responsiveness to VNS. Methods We retrospectively reviewed the medical records of pediatric patients who underwent VNS implantation between 1997 and 2018. Patients with ≥ 50% reduction of seizure frequency compared with the baseline were defined as “responders”. The clinical characteristics of responders and nonresponders were compared. Results A total of 58 children (male/female: 40/18) with a mean follow-up duration of 5.7 years (3 months to 20 years) were included. The mean age at implantation was 12.4 years (4.5 to 18.5 years). Approximately half (45%) of our patients were responders, including 3 patients (5.8%) who achieved seizure freedom during follow-up. The age of seizure-onset, duration of epilepsy, age at implantation, and etiologies of epilepsy showed no significant difference between responders and nonresponders. Responders were more likely to have focal or multifocal epileptiform discharges (63%) on interictal electroencephalogram (EEG), when compared to nonresponders (36%) (p = .07). Vocal disturbances and paresthesias were the most common side effects, and in two patients, VNS was removed because of local reaction. Conclusion Our series had a diverse etiological profile and patients with transition to adult care. Long-term follow-up showed that VNS is an effective and well-tolerated treatment modality for refractory childhood onset epilepsy. Age at implantation, duration of epilepsy and underlying etiology are not found to be predictors of responsiveness to VNS. Higher response rates were observed for a subset of patients with focal epileptiform discharges.

Hereditary spastic paraplegias (HSPs) are a group of genetic disorders resulting in pyramidal tract impairment, predominantly in lower limbs. KIF1C gene has recently been identified as one of the genetic causes of HSP and associated with pure or complicated HSP. We present three patients with complicated HSP from two unrelated families, who had early onset progressive cerebellar signs and developed pyramidal tract signs during follow-up. Whole exome sequencing in these patients followed by segregation analysis identified novel truncating KIFIC mutations (c.463C> T; p.R155* and c.2478delA; p.A1a828Argfs*13). Neuroimaging findings showed cerebral and upper cervical spinal atrophy, bilateral symmetrical pyramidal tract involvement, and focal cerebral white matter lesions. Patients with KIFIC mutations may present with cerebellar signs and pyramidal findings may emerge later, therefore complicated HSP should be considered in the differential diagnosis of unidentified cases with cerebellar dysfunction. (C) 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

ObjectiveAntiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery. MethodsWe collected IQ scores of children from the TTS cohort with both pre- and postoperative neuropsychological assessments (NPAs; n=301) and analyzed whether reduction of AEDs prior to the latest NPA was related to postoperative IQ and delta IQ, using linear regression analyses. Factors previously identified as independently relating to (delta) IQ, and currently identified predictors of (delta) IQ, were considered possible confounders and used for adjustment. Additionally, we adjusted for a compound propensity score that contained previously identified determinants of timing of AED withdrawal. ResultsMean interval to the latest NPA was 19.818.9 months. Reduction of AEDs at the latest NPA significantly improved postoperative IQ and delta IQ (adjusted regression coefficient [RC]=3.4, 95% confidence interval [CI]=0.6-6.2, p=0.018 and RC=4.5, 95% CI=1.7-7.4, p=0.002), as did complete withdrawal (RC=4.8, 95% CI=1.4-8.3, p=0.006 and RC=5.1, 95% CI=1.5-8.7, p=0.006). AED reduction also predicted 10-point IQ increase (p=0.019). The higher the number of AEDs reduced, the higher was the IQ (gain) after surgery (RC=2.2, 95% CI=0.6-3.7, p=0.007 and RC=2.6, 95% CI=1.0-4.2, p=0.001, IQ points per AED reduced). InterpretationStart of AED withdrawal, number of AEDs reduced, and complete AED withdrawal were associated with improved postoperative IQ scores and gain in IQ, independent of other determinants of cognitive outcome. Ann Neurol 2015;78:104-114

Objective: The aim of this study was to evaluate the clinical and imaging characteristics, treatment results, and prognosis of patients with electrical status epilepticus during sleep (ESES). Method: A total of 22 patients with ESES pattern on EEG were retrospectively studied. Results: The first neurological symptoms were seen at a mean age of 4.4 years. The first symptoms in 77% of the patients were seizures. Other symptoms were hyperactivity, restlessness, insomnia, disinhibition, autistic behavior, speech retardation and deterioration in school performance. Diagnosis of ESES was made at a mean age of 7.45 years, approximately 3 years after the first symptom. Magnetic resonance imaging (MRI) was abnormal in 36% of the patients. Single photon emission computed tomography (SPECT) showed focal hypoperfusion after resolution of ESES involving left temporoparietal and right posterior temporal areas in four patients including three with normal MRI, and one with periventricular leukomalacia without focal cortical lesion. First line treatment with valproic acid monotherapy was not effective. Electrical status epilepticus during sleep disappeared in 82% of the patients on clobazam and 70% of the patients on clonazepam in combination with valproic acid within a few months. Topiramate was not found to be effective. A significant decrease in intelligence quotient (IQ) scores was found in 66% of the patients compared to the baseline. Conclusions: ESES should be considered in children with new onset behavioral, cognitive, and speech problems with or without seizures. The high frequency of focal seizures and focal findings on SPECT suggest a focal origin. Clonazepam and clobazam were most effective in our cohort.

Cocukluk cagi epilepsilerinde erken tedavi ile nobet kontrolunun saglanmasi, tekrarlayan nobetlere bagli noronal hasarin engellenmesi, normal gelisimin yakalanmasi, ilac yan etkilerinin en aza indirilmesi ve hayat kalitesinin artirilmasi acisindan buyuk onem tasir. Direncli epilepsinin tedavi secenekleri arasinda epilepsi cerrahisi son yillarda giderek artan bir agirlik kazanmistir. Ekstratemporal epilepsilerin oraninin daha fazla olmasi, etyolojide gelisimsel lezyonlarin one cikmasi nedeniyle pediatrik epilepsi populasyonu eriskin yas grubuna oranla daha refrakter bir profil cizer. Bununla birlikte epilepsi cerrahisi sonuclarinin nobet kontrolu acisindan eriskin ve cocuk yas grubunda benzer sonuclar verdigi gosterilmistir; yetiskinlerde oldugu gibi sut cocugu yas grubu dahil cocukluk caginda da basariyla uygulanabilmektedir. Bu yazida cocukluk cagi epilepsilerinde epilepsi cerrahisi uygulamalari tartisilacaktir.

We aimed to evaluate structure and functions of central nervous system (CNS) in children with glycogen storage disease (GSD) type 1a. Neurological examination, psychometric tests, electroencephalography (EEG), magnetic resonance imaging (MRI), visual evoked potentials (VEP) and brainstem auditory evoked potentials (BAEP) were performed. The results were compared between patients with good and poor metabolic control and healthy children. Twenty-three patients with GSD type 1a were studied. Twelve patients were in poor metabolic control group and 11 patients in good metabolic control group. Five patients had intellectual disability, 10 had EEG abnormalities, seven had abnormal VEP and two had abnormal BAEP results. MRI was abnormal in five patients. There was significant correlation between the number of hypoglycemic attacks and MRI abnormalities. Central nervous system may be affected in GSD type 1a even in patients with normal neurologic examination. Accumulation of abnormal results in patients with poor metabolic control supports the importance of metabolic control in GSD type 1a.

Öz toprak Ü, Yalnızoğlu D, Karlı-Oğuz K, Lay-Ergun E, Söylemezoğlu F, Bilginer B, Akalan N, Topçu M, Turanlı G. The seizure semiology consistent with frontal lobe symptomatogenic zone in children. Turk J Pediatr 2016; 58: 583-591. The aim of this study is to analyze the seizure semiology consistent with frontal lobe symptomatogenic zone in childhood. We analyzed 549 videotaped seizures from 79 patients (mean age 9.9 ± 3.8 years). Magnetic resonance imaging was normal in 30 patients. The seizures in the time interval of 10 p.m. to 6 a.m. were considered as nocturnal. The mean number of seizures per patient was 6.8 ± 7.3. The mean seizure duration was 25.7 ± 26.9 sec; postictal confusion was 27 ± 16.1 sec (7-92 seconds). The seizures were observed in sleep with a rate of 56.8%; 43.1% of them were during wakefulness. Overall 50.4% of the seizures occured during night-time sleep. Tonic seizure (77.2%) was the most frequent simple motor seizure. Versive seizures were the second most frequent type of simple motor seizure (26.7%). Clonic seizures were 17.7%, complex motor seizures were 20.5%, and dialeptic seizures were 3% of all the seizures. Epileptic spasm, myoclonic seizures, aphasia, and akinetic semiologies were not observed. Vocalization was observed in 16% of the seizures.Frontal lobe seizures in childhood have a short duration, occur frequently, especially during night time sleep, and have a brief postictal period. Tonic semiology, versive semiology are the most frequent seizure semiologies; hypermotor and secondary generalized tonic clonic seizures and vocalizations are observed less in children compared to adults Öz toprak Ü, Yalnızoğlu D, Karlı-Oğuz K, Lay-Ergun E, Söylemezoğlu F, Bilginer B, Akalan N, Topçu M, Turanlı G. The seizure semiology consistent with frontal lobe symptomatogenic zone in children. Turk J Pediatr 2016; 58: 583-591. The aim of this study is to analyze the seizure semiology consistent with frontal lobe symptomatogenic zone in childhood. We analyzed 549 videotaped seizures from 79 patients (mean age 9.9 ± 3.8 years). Magnetic resonance imaging was normal in 30 patients. The seizures in the time interval of 10 p.m. to 6 a.m. were considered as nocturnal. The mean number of seizures per patient was 6.8 ± 7.3. The mean seizure duration was 25.7 ± 26.9 sec; postictal confusion was 27 ± 16.1 sec (7-92 seconds). The seizures were observed in sleep with a rate of 56.8%; 43.1% of them were during wakefulness. Overall 50.4% of the seizures occured during night-time sleep. Tonic seizure (77.2%) was the most frequent simple motor seizure. Versive seizures were the second most frequent type of simple motor seizure (26.7%). Clonic seizures were 17.7%, complex motor seizures were 20.5%, and dialeptic seizures were 3% of all the seizures. Epileptic spasm, myoclonic seizures, aphasia, and akinetic semiologies were not observed. Vocalization was observed in 16% of the seizures.Frontal lobe seizures in childhood have a short duration, occur frequently, especially during night time sleep, and have a brief postictal period. Tonic semiology, versive semiology are the most frequent seizure semiologies; hypermotor and secondary generalized tonic clonic seizures and vocalizations are observed less in children compared to adults

Genetic studies grounded on monogenic paradigms have accelerated both gene discovery and molecular diagnosis. At the same time, complex genomic rearrangements are also appreciated as potent drivers of disease pathology. Here, we report two male siblings with a dysmorphic face, ambiguous genitalia, intellectual disability, and speech delay. Through quad-based whole-exome sequencing and concomitant molecular cytogenetic testing, we identified two copy-number variants (CNVs) in both affected individuals likely arising from a balanced translocation: a 13.5-Mb duplication on Chromosome 16 (16q23.1 → 16qter) and a 7.7-Mb deletion on Chromosome 5 (5p15.31 → 5pter), as well as a hemizygous missense variant in CXorf36 (also known as DIA1R). The 5p terminal deletion has been associated previously with speech delay, whereas craniofacial dysmorphia and genital/urinary anomalies have been reported in patients with a terminal duplication of 16q. However, dosage changes in either genomic region alone could not account for the overall clinical presentation in our family; functional testing of CXorf36 in zebrafish did not induce defects in neurogenesis or the craniofacial skeleton. Notably, literature and database analysis revealed a similar dosage disruption in two siblings with extensive phenotypic overlap with our patients. Taken together, our data suggest that dosage perturbation of genes within the two chromosomal regions likely drives the syndromic manifestations of our patients and highlight how multiple genetic lesions can contribute to complex clinical pathologies.

Heterozygous loss-of-function mutations in the GNAL gene encoding the α subunit of the heterotrimeric G protein Golf (Gαolf) are known to cause isolated dystonia.1,2 Gαolf is enriched in the striatum where it couples D1 dopamine (D1R) and A2A adenosine (A2AR) receptors to the activation of adenylyl cyclase type 5 (AC5). Mutations in ADCY5 , the gene encoding AC5, are also known to lead to chorea and dystonia.3,4 Previous functional studies of mutated Gαolf variants have revealed deficiencies in activation after D1R stimulation.1,5 Acknowledgment: The authors thank the patients and their family for their participation; without their support, this work would not have been possible.

Sixth cranial nerve (SCN) palsy is an uncommon but important neurological problem in patients admitted to pediatric emergency department. The underlying etiology of SCN palsy has a wide range from viral infections to intracranial tumors; therefore, a careful and systematic approach is necessary while examining these patients.Fourteen patients who presented with acute SCN paralysis to pediatric emergency department during the last 10 years were examined.The age at the time of admission ranged between 14 months and 16 years (median, 9.5 years). Of the 14 patients, 5 were girls and 9 were boys. A total of 3 of the 14 patients had bilateral cranial nerve VI paralysis, and 9 patients had additional abnormal findings on neurological examination. Neuroimaging studies included cranial tomography (n = 3) and brain magnetic resonance imaging in all patients. The underlying etiology was malignancy (n = 3); glioma, medulloblastoma, acute lymphoblastic leukemia, and dural sinus thrombosis (n = 2); as well as Guillain-Barre syndrome (n = 2), multiple sclerosis (n = 1), pseudotumor cerebri (n = 1), and meningitis (n = 1). The remaining 4 patients had miscellaneous benign etiologies.Other lesions of primary brain tumors causing increased intracranial pressure constitute 50% of the underlying etiology, followed by Guillain-Barre syndrome (14.2%). However, these patients had neurological symptoms signs, in addition to diplopia or SCN paralysis. Patients admitted to pediatric emergency department with acute SCN paralysis should be examined in detail to disclose the underlying etiology especially if they present with additional clinical signs or symptoms.

Epilepsy surgery is a standard of care in the treatment of medically intractable epilepsy. Twenty five percent of patients with intractable epilepsy in childhood can be candidates for epilepsy surgery. Corpus callosotomy is a surgical treatment option for patients with potentially injurious drop attacks and disabling generalized seizures. Postoperative improvement of cognition and speech are important gains after epilepsy surgery particularly during childhood. The aim of this study is to evaluate the outcome of corpus callosotomy for the treatment of childhood onset medically intractable epilepsy in a developing pediatric epilepsy surgery center. We report 16 patients who underwent two thirds anterior corpus callosotomy for treatment of refractory seizures in childhood. All patients had drop attacks or multiple types of seizures, yet some showed focal onset with secondary generalization on electroencephalogram (EEG). One patient was seizure free (class 1 outcome), five had class 2A outcome, five had class 2B outcome, and five had class 3 outcome. Overall 11/16 (69%) of our patients improved significantly after anterior callosotomy. Corpus callosotomy remains to be a fairly good choice of surgical treatment for childhood onset medically intractable epilepsy in selected patients.

Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up. Pediatr Blood Cancer 2014;61:928–930. © 2013 Wiley Periodicals, Inc.

Subacute sclerosing panencephalitis (SSPE) is a serious, often fatal disease that responds poorly to current treatment modalities. Recently, the ability of mesenchymal stem cells (MSCs) to produce neurotrophic factors and inflammatory molecules has placed them among potential treatment agents for neurological conditions. We report the results of four patients treated with MSC for SSPE. The patients were followed up clinically, and by periodical laboratory evaluations, magnetic resonance imaging (MRI), and electroencephalography. One patient deteriorated to stage III of the disease, two patients remained in the same stage, and one died from disease progression and respiratory problems. Neurological findings and electroencephalography scores were consistent with the clinical course of the patient whereas MRI showed new inflammatory lesions in two patients. This is the first report of the application of MSC in SSPE. No benefit is demonstrated.

Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice(1-4). We previously published a study describing humans with inherited ISG15deficiency but without unusually severe viral diseases(5). We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia(6-9). We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18(10,11), a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.

Six patients admitted to the Department of Pediatric Neurology at Hacettepe University Children's Hospital between 1992 and 1997 with a clinical diagnosis of Rasmussen encephalitis received surgical treatment for their intractable epilepsy. MRI, SPECT and WADA tests were performed in patients with an epileptic focus demonstrated on routine or long-term video EEG monitoring. Viral studies using the PCR methodology were performed in cases with histopathological evidence of Rasmussen encephalitis. The ages of these patients ranged between 7 and 16 years, and the mean age at onset of seizures was 7.1+/-2.2 years. In four patients seizures presented as epilepsia partialis continua and were refractory to anticonvulsive drug therapy. In three cases intravenous immunoglobulin therapy yielded temporary and partial improvement in seizure control. The mean presurgical follow-up duration was 2.04+1.74 years, and early surgical intervention for epilepsy was performed in one case. The surgical approach selected for the treatment of epilepsy was resective surgery with electrocorticography. The mean postoperative follow-up duration was 32.3+17.2 months. Seizures were fully controlled in one patient, in whom surgery was performed 3 months after the seizures first started. Early surgical intervention may provide histopathological evidence for diagnosis as well as effective seizure control.

Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain-3 at LGMD2A (15q15), and four members of the sarcoglycan (SG) complex, alpha-SG at LGMD2D (17q21), beta-SG at LGMD2E (4q12), gamma-SG at LGMD2C (13q12), and delta-SG at LGMD2F (5q33-q34). The gene product at LGMD2B (2p13-p16) is still unknown and at least one other gene is still unmapped. We investigated 20 Turkish families (18 consanguineous) diagnosed as having LGMD2. Most of our patients had onset of symptoms before age 10. The phenotypes varied from severe to benign. We analyzed the SG complex by immunofluorescence and/or western blot. Genotyping was performed using markers defining the six known loci and the suspected genes were screened for mutations. Six of 17 index cases showed deficiency of the SG complex, by immunofluorescence and/or western blot. Seven cases involved one of the known genes of the SG complex (alpha, 2; beta, 1; and gamma, 4 cases), and five mutations were documented in the alpha- and gamma-SG genes. After linkage analysis, 10 families were characterized as having LGMD2A (calpain-3 deficiency), and all mutations were eventually identified. One family was classified as having LGMD2B and 1 family that has normal SGs was linked to the chromosome 5q33-q34 locus (LGMD2F). In 1 family there was no linkage to any of the known LGMD2 loci. It appears that in Turkey, there is a broad spectrum of genes and defects involved in LGMD2. It may be possible to correlate genotype to phenotype in LGMD2. All severe cases belonged to the gamma-SG-deficiency group. Nine calpain-3-deficient cases had intermediate and 1 had moderate clinical courses. The LGMD2B patient had a moderate clinical expression, whereas the LGMD2F case was truly benign.

Intellectual disability formerly called mental retardation (MR) is defined as having an IQ score below 70; the term “developmental delay” (DD) is preferred for young children. A detailed clinical history including a three-generation pedigreee and physical examination are the fundamental steps in achieving an etiological diagnosis in MR. Physical examination should be performed with special emphasis on dysmorphological and neurological exam. Genetic studies have priority in the laboratory investigation of a child with MR. Routine karyotyping is recommended regardless of the degree of MR. Fragile X studies are strongly recommended in both females and males with unexplained MR, especially in patients with a positive family history and typical physical and behavioral features. FISH analysis of subtelomeric regions should be reserved for selected patients. Inborn errors of metabolism are seldom seen as the causes of isolated MR but should be considered in the differential diagnosis of patients with MR/DD in populations where the rate of consanguineous marriages is high. Neuroimaging studies should be performed on an indication basis such as abnormal brain size or neurological findings. It is essential to diagnose the underlying etiology of MR for recognition of treatable disorders, determining prognosis, family counseling, and providing prenatal diagnosis when possible.

Congenital muscular dystrophies (CMD) are heterogenous in clinical and pathologic manifestations. The "pure" classical form includes cases without severe impairment of intellectual development (Type 1), and cases with normal or subnormal IQ which show white matter hypodensity on CT scan examination. This latter group is sometimes called the "occidental type cerebro-muscular dystrophy" (OCMD). In this study we report clinical and pathologic findings in 38 cases with pure CMD. Eighteen of them were classified as Type 1 and 20 as OCMD, following the neuroradiological work-up. Statistical analysis between the two groups were done for: age range, consanguinity, multiple joint contractures, maximal motor capacity, facial involvement, high CK, endomysial fibrosis, adiposis, fiber atrophy and necrosis. CK was significantly higher in the OCMD group. Though not statistically significant, multiple joint contractures and muscle fiber necrosis were seen in more OCMD patients. These parameters denoted severity. The results of electrophysiological tests did not show any statistical differences. In pure CMDs there is evidence for overlap between the two sub-groups. OCMD cases may tend to run a more severe course in the presence of significantly higher CK levels.

Moyamoya disease (MMD) is a cerebrovascular disorder involving stenosis of brain vessels. Brain perfusion SPECT in MMD demonstrates impaired perfusion in ischemic areas. We present a 6-year-old boy with MMD. The patient had numbness on the right arm and simultaneous electroencephalography changes while studying arms up on the table. To differentiate seizure and ischemic symptoms, brain perfusion SPECT studies were obtained when the patient was asymptomatic (SPECT-A) and during the symptoms-EEG changes (SPECT-B). SPECT-A showed perfusion defect on the right frontal cortex, hypoperfusion on the right parieto-occipital region and slightly increased perfusion on the left parietal cortex. SPECT-B displayed significant hyperperfusion on the left parietal cortex; hypoperfusion on the right parietal, right temporal, right parieto-occipital and left frontal cortex. Additionally, brain perfusion SPECT of the child's younger brother diagnosed with MMD showed decreased regional cerebral perfusion. Physiopathological mechanisms of our patient's SPECT findings and indications of brain perfusion SPECT in MMD were also discussed.

WOS: 000281616300034, PubMed ID: 20729831, 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(1,2). 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(3-6). 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., Yale Program on Neurogenetics; Yale Center for Human Genetics and Genomics; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RC2 NS070477, UL1 RR024139NIH, UO1MH081896]; National Institutes of Health Neuroscience Microarray ConsortiumUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U24 NS051869-02S1], We are indebted to the patients and families who have contributed to this study. We thank J. Noonan for expert advice and C. Camputaro for her help with three-dimensional reconstruction of the magnetic resonance images. This study was supported by the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, and National Institutes of Health grants RC2 NS070477 (to M.G.), UL1 RR024139NIH (Yale Clinical and Translational Science Award) and UO1MH081896 (to N.S.). SNP genotyping was supported in part by a National Institutes of Health Neuroscience Microarray Consortium award U24 NS051869-02S1 (to S.M.). R.P.L. is an investigator of the Howard Hughes Medical Institute.

Dysembryoplastic neuroepithelial tumors (DNTs) were first described by Daumas-Duport et al. in 1988 as a typically cortical tumor affecting young patients with long-standing, drug-resistant epilepsy. We reviewed the medical records of 29 patients with DNT between 1994 and 2007 at Hacettepe University Children’s Hospital retrospectively; age at the time of surgery, age at seizure onset, electroencephalography (EEG), MRI, medical treatment, surgical procedure, seizure outcome, and pathological findings were documented. Male to female ratio was 15/14. Age at the time of evaluation ranged 4–24 years. Twenty-seven patients (93.1%) had complex partial seizures, one (3.44%) had simple partial seizures, and one patient had generalized seizures. Preop interictal EEG showed epileptiform discharges in 24 patients, while in five patients interictal EEG before surgery showed no epileptiform discharges. Pathologically, 24 of our patients were classified as complex type and five as simple type. MRI showed temporal lesion in 20 (68.9%) patients and nine patients had extratemporal DNT. We choose the type of surgery according to lesion and the epileptojenic zone. Finally, 27 patients had Engel Class IA and two patients had Engel Class IB outcome. Complete resection of the lesion with epileptojenic zone is important for seizure-free outcome. Timing of surgery, extent of surgery, and stopping antiepileptic drugs are still important factors.