Burak Tatlı

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.

Genotype-phenotype correlation in vanishing white matter disease

Objective: Vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy characterized by slowly progressive ataxia and spasticity with additional stress-provoked episodes of rapid and major deterioration. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B, which is pivotal in translation of mRNAs into proteins. The disease onset, clinical severity, and disease course of VWM vary greatly. The influence of genotype and gender on the phenotype is unclear. Methods: From our database of 184 patients with VWM, we selected those with the following mutations in the gene EIF2B5: p.Arg113His in the homozygous state (n = 23), p.Arg113His in the compound-heterozygous state (n = 49), p.Thr91Ala in the homozygous state (n = 8), p.Arg113His/p.Arg339any (n = 9), and p.Thr91Ala/p.Arg339any (n = 7). We performed a cross-sectional observational study. Evaluated clinical characteristics were gender, age at onset, age at loss of walking without support, and age at death. Means, male/female ratios, and Kaplan-Meier curves were compared. Results: Patients homozygous for p.Arg113His had a milder disease than patients compound heterozygous for p.Arg113His and patients homozygous for p.Thr91Ala. Patients with p.Arg113His/p.Arg339any had a milder phenotype than patients with p.Thr91Ala/p.Arg339any. Overall, females tended to have a milder disease than males. Conclusions: The clinical phenotype in VWM is influenced by the combination of both mutations. Females tend to do better than males.

Prenatal diagnosis of diastematomyelia: presentation of eight cases and review of the literature

Diastematomyelia is a rare form of spinal dysraphism. We present eight cases of diastematomyelia diagnosed prenatally in our institution as well as a review of the literature in order to determine the prognosis of isolated cases of this very unusual condition.

Intracranial Ultrasound Abnormalities and Fetal Cytomegalovirus Infection: Report of 8 Cases and Review of the Literature

Objectives: The aim of this study was to evaluate fetal intracranial and other ultrasonographic findings in cytomegalovirus (CMV) infection. Methods: Data on amniotic fluid CMV-DNA-PCR-positive pregnancies detected in our institution between January 2006 and June 2009 were reviewed retrospectively. Fetal biometric measurements, fetal anatomy, amniotic fluid volume, placental thickness and texture were analyzed for abnormalities. Results: Eight fetuses were diagnosed with congenital CMV infection during the study interval. Their mean gestational age at diagnosis was 25.8 weeks (range: 23–29). All fetuses had intracranial abnormalities; increased periventricular echogenicity (n = 7), ventriculomegaly (n = 5), intracranial calcifications (n = 4), intraventricular adhesions (n = 4), thalamic hyperechogenicity (n = 3), mega cisterna magna (n = 3), lissencephaly (n = 2), vermian defect (n = 2) and cerebellar cyst (n = 1). All of them had accompanying extracranial findings, including hyperechogenic bowel (n = 6), cardiomegaly (n = 3), pericardial effusion (n = 2) and hepatosplenomegaly (n = 1). Intrauterine growth retardation was detected in 3 cases. Five pregnancies were terminated, and 1 intrauterine death occurred. The remaining 2 delivered vaginally at term. One of the live-born babies suffers from tetraparesis, mental retardation and autism, and the other has mild hemiplegia. Conclusions: The spectrum of sonographic findings may vary widely in patients with congenital CMV infection in the prenatal period. CMV should be kept in mind in differential diagnosis, particularly in fetuses with intracranial sonographic findings such as ventriculomegaly, calcifications, intraventricular adhesions and increased periventricular echogenicity.

Quantification of neurometabolites in subacute sclerosing panencephalitis by 1H-MRS

The authors studied 20 patients with subacute sclerosing panencephalitis (SSPE) to investigate the correlations between MRI, magnetic resonance spectroscopy (MRS), and clinical status. MRI findings did not correlate with clinical status. By contrast, all patients had reductions in N-acetyl aspartate (NAA) and increase in myoinositol (mI) (p < 0.01), and NAA and mI concentrations correlated with clinical severity (p < 0.05). During follow-up, NAA continued to decline. 1H-MRS may be a useful measure of disease severity and progression in SSPE.

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.

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.

Molecular genetic screening of MBS1 locus on chromosome 13 for microdeletions and exclusion of FGF9, GSH1 and CDX2 as causative genes in patients with Moebius syndrome.

Moebius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies, and occasionally associated with orofacial, limb and musculoskeletal malformations. Abnormal development of cranial nerves V through XII underlines the disease pathogenesis. Although some investigations suggested that a causative gene may lie on 13q12.2-q13, there have been no molecular studies targeting possible microdeletions in this region to date. In the present study, we performed microdeletion analyses on 13q12.11-q13 in nine patients, and sequenced three candidate genes in nineteen patients for functional relevance and further resolution of our screening. We ruled out microdeletions on the critical region as a common cause of Moebius syndrome and excluded FGF9, GSH1 and CDX2 genes.

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.

An Unusual Cause of Fulminant Guillain-Barré Syndrome: Angel's Trumpet

A 5-year-old previously healthy boy presented with typical findings of Guillain-Barré syndrome and unilateral tonic pupil. He was placed on mechanical ventilation for 35 days for respiratory failure. Plasmapheresis and two courses of intravenous immunoglobulin therapy were given to the patient, and he experienced stepwise recovery from his illness. This case of acute motor axonal neuropathy type Guillain-Barré syndrome is novel in that the cause was established as ingestion of a toxic solanaceous plant, angels trumpet (Brugmansia suaveolens; syn. Datura suaveolens). Understanding the signs and symptoms of angels trumpet toxicity can allow for early diagnosis and proper case management.