Dilşad Türkdoğan

PRRT2 Mutations are the major cause of benign familial infantile seizures

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late‐onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone. Hum Mutat 33:1439–1443, 2012.

Lipid Peroxidation and Antioxidative Enzyme Activities in Childhood Epilepsy

This study aimed to investigate the relationship among lipid peroxidation, subsequent activation of scavenger enzymes (superoxide dismutase and glutathione peroxidase), and the presence of structural abnormality in 52 epileptic children receiving monotherapy (medically responsive) or polytherapy (medically intractable). Plasma lipid peroxidation in epileptic patients with abnormal magnetic resonance imaging (MRI) findings significantly increased as compared with that of 16 healthy children (P < .05), whereas antioxidant enzymes were not significantly affected. Both medically controlled and intractable children with normal MRI had higher activities of superoxide dismutase than those of controls (P < .05). The activity of superoxide dismutase in epileptic patients with structural abnormality did not significantly change as compared with controls. Activity of glutathione peroxidase in all of the epileptic children was not significantly different from controls. The activity of antioxidant enzymes or plasma malonyldialdehyde levels did not correlate with duration of epilepsy, frequency of seizures (> one seizure per month or not), and the presence or localization (focal, multifocal, or generalized) of electroencephalographic or MRI abnormalities. Increased plasma lipid peroxidation may be causally related to the presence of structural abnormality rather than ongoing epileptic activity or therapy status. (J Child Neurol 2002;17:673-676).

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Purpose:  Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome‐wide linkage meta‐analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type–related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively.

Visual and auditory event related potentials in epileptic children : a comparison with normal and abnormal MRI findings

Visual and auditory event related potentials (VERPs and AERPs) in 32 epileptic children with magnetic resonance imaging (MRI) abnormalities and 18 with normal MRI were recorded and compared to the data of 21 healthy children. Of all 50 epileptic children (34 male, 16 female) aged 14.42+/-4.27 (7-20) years, 21 were medically intractable and receiving polytherapy. The mean latencies of N2 and P3 components of VERPs and AERPs in all epileptic children were significantly higher than those of the controls (P<0.05). Epileptic children with structural abnormalities had more prolonged latencies of N2 and P3 components of AERPs and VERPs than those of the healthy children (P<0.05). The epileptic children with normal MRI had significantly more prolonged latency of N2 and P3 of VERPs and P3 of AERPs than those of the controls (P<0.05). The difference of the mean latency of N2 and P3 components or the mean amplitude of P3 components of ERPs between the two epileptic groups was insignificant. The type of medication (mono- versus polytherapy) did not affect the wave components of ERPs. We suggest that epileptic activity, itself, leads to prolonged N2 and P3 components of AERPs and VERPs. The presence of structural abnormality indicated by imaging is not a predictor of ERPs abnormalities.

When Is EEG Indicated in Attention-Deficit/Hyperactivity Disorder?

The authors investigated the parameters for predicting epileptiform abnormalities in a group of children diagnosed with attention-deficit/hyperactivity disorder (ADHD). The sample consisted of 148 subjects aged between 6 and 13 (8.76 ± 1.26; 25.7% female) years. Subtypes of ADHD and comorbid psychiatric disorders were defined according to DSM-IV criteria. The Wechsler Intelligence Scale for Children–Revised was applied to all patients. Most of the subjects (89.2%) had wakefulness and sleep electroencephalography examinations lasting about one hour. The authors found out that the coexistence of speech sound disorder (odds ratio [OR] 3.90, 95% confidence interval [CI]: 1.61-9.48) and higher Digit Span test performance (OR 1.24, 95% CI: 1.06-1.44) predicted the presence of accompanying epileptiform abnormalities. The prevalence of epileptiform abnormalities was 26.4%, and they were frequently localized in the frontal (41%) and centrotemporal (28.2%) regions. Higher percentage of speech sound disorder co-occurrence (64%) in subjects with rolandic spikes suggests that epileptiform abnormalities associated with ADHD can be determined genetically at least in some cases. Pathophysiology of epileptiform abnormalities in ADHD might have complex genetic and maturational background.

An association analysis at 2q36 reveals a new candidate susceptibility gene for juvenile absence epilepsy and/or absence seizures associated with generalized tonic–clonic seizures

Purpose:  To further evaluate the previously shown linkage of absence epilepsy (AE) to 2q36, both in human and WAG/Rij absence rat models, a 160‐kb region at 2q36 containing eight genes with expressions in the brain was targeted in a case–control association study involving 205 Turkish patients with AE and 219 controls.

The frequency of late-onset Pompe disease in pediatric patients with limb-girdle muscle weakness and nonspecific hyperCKemia: A multicenter study

The aim of this multicenter study was to screen for late-onset Pompe disease in high-risk children with limb-girdle muscle weakness and nonspecific hyperCKemia using the dried blood spot (DBS) test. Seventy-two children from four pediatric neurology departments in Turkey were enrolled in the study: 37 with limb-girdle muscle weakness and 35 with nonspecific hyperCKemia. Acid α-glucosidase (GAA) activity was measured on DBS by tandem mass spectrometry. Six patients tested positively for Pompe disease. In three patients, one with the limb-girdle muscle weakness and two with nonspecific hyperCKemia, this was confirmed by genetic analysis. The overall frequency of late-onset Pompe disease in the study population was 4.2%. The c.1784C>T mutation found in one patient is a new mutation whereas the c.1655T>C mutation detected in the other two patients is not novel. In conclusion, Pompe disease should be suspected in patients with limb-girdle muscle weakness and nonspecific hyperCKemia. The DBS test is a safe and reliable method of diagnosis but must be confirmed by genetic analysis. In patients with a positive DBS test and negative genetic analysis, tissue assay of GAA should be considered.

Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis: rapid and sustained clinical improvement with steroid therapy starting in the late phase.

Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is an autoimmune/paraneoplastic encephalitis, with neurologic and psychiatric symptoms. Early and aggressive therapy has been shown to improve prognosis although problems with executive functions and memory have continued for several years. A 15-year-old girl had a history of initial symptoms including behavioral difficulties, poor attention, and frequent seizures progressing to a catatonia-like state, 2.5 months after onset of initial symptoms. Anti–NMDA receptor antibodies were detected in serum and cerebrospinal fluid. Subsequent to treatment with methylprednisolone starting 3 months after onset, motor skills, responsiveness, self-care, and speech improved rapidly. Her neuropsychologica profile assessed after 2 months showed global difficulties predominantly in attention, executive functions, memory, and visual perception, which moderately recovered in the 7th and 24th months, respectively. Contrary to current literature supporting the positive impact of early immunomodulatory therapy, a dramatic resolution of major neurologic and psychiatric symptoms was detected with steroid treatment given in the late phase.

SCN1A gene sequencing in 46 Turkish epilepsy patients disclosed 12 novel mutations

PURPOSE The SCN1A gene is one of the most commonly mutated human epilepsy genes associated with a spectrum of phenotypes with variable degrees of severity. Despite over 1200 distinct mutations reported, it is still hard to draw clear genotype-phenotype relationships, since genetic and environmental modifiers contribute to the development of a particular disease caused by an SCN1A mutation. We aimed to initiate mutational screening of the SCN1A gene in Turkey and advance further our understanding of the relationship between the SCN1A sequence alterations and disease phenotypes such as GEFS+, DS and related epileptic encephalopathies. METHODS Mutational analysis of the SCN1A gene was carried out in 46 patients with DS, late-onset DS, GEFS+ and unspecified EE using either direct Sanger sequencing of the coding regions and exon/intron boundaries or massively parallel sequencing. RESULTS Nineteen point mutations, 12 of which were novel were identified, confirming the clinical diagnosis of the patients. Patients with a mutation (either truncating or missense) on linker regions had significantly later disease onset than patients with mutations in homology regions. The presence of SCN1A mutations in two clinically unclassified patients supported the association of SCN1A mutations with a wide range of phenotypes. CONCLUSION The conventional Sanger sequencing method was successfully initiated for the detection of SCN1A point mutations in Turkey in epilepsy patients. Furthermore, a modified strategy of massively parallel pyro-sequencing was also established as a rapid and effective mutation detection method for large genes as SCN1A.

Familial early infantile epileptic encephalopathy and cardiac conduction disorder: A rare cause of SUDEP in infancy

Department of Pediatric Neurology, Marmara University Medical Faculty Istanbul, Turkey Molecular Biology and Genetics, Private Practice, Istanbul, Turkey Department of Pediatric Cardiology, Marmara University Medical Faculty Istanbul, Turkey d Faculty of Biomedical Engineering, Biruni University, Istanbul, Turkey Department of Molecular Biology and Genetics, Biruni University Medical Faculty, Istanbul, Turkey