PURPOSE Electroencephalography (EEG) findings related to the eye-closing motion can be defined in... more PURPOSE Electroencephalography (EEG) findings related to the eye-closing motion can be defined in two ways: 'sensitivity to eyes closed' (SEC) and 'eye closure sensitivity (ECS).' Fixation-off sensitivity (FOS) is a different phenomenon induced by the elimination of central vision/fixation. The purpose of our study was to determine the frequencies of SEC, ESC, and FOS, and to analyze the relationship between eyes closure and the fixation-off phenomenon and clinical importance in an unselected population. METHODS We prospectively evaluated 200 routine interictal EEGs by adding a standardized FOS examination protocol between June and September 2015. Goggles covered with semitransparent tape were used to evaluate FOS. We determined SEC when the epileptiform discharges appeared during eye closure and continued during the eye closed state, whereas ECS was defined as transient epileptic abnormalities following the closure of the eyes lasting for 1-4 sec. The patients were evaluated in terms of demographic characteristics, clinical features, and the relationship between SEC, ECS, and FOS. RESULTS We detected SEC in 9 (4.4 %) and ECS in 11 (5.4 %) patients. FOS was detected in four (44.4 %) of the patients who showed SEC, all of whom had occipital epileptiform discharges. A statistically significant correlation was found between FOS and treatment resistance in the SEC group (p < 0.001). In logistic regression analysis, occipital lobe epilepsy (p < 0.001) and age under 20 years (p = 0.004) were found as risk factors for SEC. Another interesting finding was the suppression of epileptic discharges with fixation-off in three of 11 patients with ECS. CONCLUSIONS According to the results of our study, FOS is related to treatment resistance. Therefore, FOS should be evaluated in patients with SEC.
Supplementary Table 1: CCDS transcripts of C19orf12 present in the Ensembl database (GRCh38.p13).... more Supplementary Table 1: CCDS transcripts of C19orf12 present in the Ensembl database (GRCh38.p13). Transcripts with the same CCDS number are designated using the same color.
Noropsikiyatri Arsivi-archives of Neuropsychiatry, Dec 15, 2011
Page 1. Zeynep AYDIN ÖZEMİR, Ege TERZİBAŞIOĞLU*, Serra SENCER, Betül BAYKAN ... İdyopatik Jeneral... more Page 1. Zeynep AYDIN ÖZEMİR, Ege TERZİBAŞIOĞLU*, Serra SENCER, Betül BAYKAN ... İdyopatik Jeneralize Epilepsili Olgularda Talamometri Volumetry of the Thalamus in Idiopathic Generalized Epilepsy Araş tır ma Ma ka le si /Re se arch Ar tic le 243 ...
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service... more This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights Incidental MRI lesions consistent with demyelination occur, but are rare in children. A high rate of later clinical events may occur in children with RIS. Risk of clinical events is higher in children classified with RIS who have spinal cord lesions or oligoclonal bands in the CSF. The role of disease modifying therapy in RIS remains to be studied.
Abstract Objective The purpose of this paper is to describe a child with auditory neuropathy spec... more Abstract Objective The purpose of this paper is to describe a child with auditory neuropathy spectrum disorder (ANSD) associated with Brown-Vialetto-Van Laere (BVVL) syndrome, which is a rare, inherited, neurodegenerative disorder that is caused by defects in riboflavin transporter genes. Design We report the audiological and clinical profile of a child who presented with a complaint of sudden loss of speech understanding associated with an atypical form of ANSD. He was later diagnosed with BVVL. Study Sample An 11-year-old boy with ANSD associated with BVVL. Results The patient’s severe neurological symptoms improved within a year of supplementation with high doses of riboflavin. His fluctuating hearing loss and 0% WDS remained unchanged. The patient was able to use hearing aids without any discomfort after treatment initiation, but he stopped using them again due to a lack of benefit in speech understanding. Although cochlear implantation was recommended, the patient and his family decided not to consider it for another year since they still had hope for complete recovery. Conclusions Sudden-onset ANSD can be the earliest sign of undetected BVVL syndrome. Early detection of BVVL is crucial since all symptoms can be reversible with an early intervention of high doses of riboflavin supplementation.
Background: Everolimus demonstrated efficacy in reducing seizure frequency (SF) with tolerable sa... more Background: Everolimus demonstrated efficacy in reducing seizure frequency (SF) with tolerable safety in patients with TSC-associated treatment-refractory seizures. Objective: This exploratory analysis of EXIST-3 assessed efficacy and safety outcomes in patients who transitioned from placebo in the core phase to everolimus in the extension phase.
Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation ... more Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy
Disease causing novel mutation c.1422_1423del:p.P474fs was identified in ATP13A2. • ATP13A2 mRNA ... more Disease causing novel mutation c.1422_1423del:p.P474fs was identified in ATP13A2. • ATP13A2 mRNA was targeted by nonsense-mediated decay due to the novel mutation. • Absence of ATP13A2 caused iron deposition in patients' fibroblasts indicating KRS. • Hypo-intense regions in patients' brain MRIs indicated possible iron accumulation. • Iron accumulation suggested KRS to be classified in the group of NBIA
Journal of Neurology, Neurosurgery & Psychiatry, 2017
Solute carrier family 12 member 6 ( SLC12A6 ) mutations have been found to be responsible for the... more Solute carrier family 12 member 6 ( SLC12A6 ) mutations have been found to be responsible for the phenotype that causes agenesis of the corpus callosum (CC) with peripheral neuropathy, a condition which is also known as Andermann syndrome (AS). AS is an autosomal-recessive disease with syndromic features that has rarely been reported anywhere in the world other than Quebec, Canada.1 Hereditary neuropathies (HN) and complicated hereditary spastic paraparesis (HSP) call for differential diagnosis, since AS has both neurodevelopmental and neurodegenerative aspects affecting both sensory and motor fibres.1 2 This study presents an AS family who has motor neuropathy without sensory involvement due to a new SLC12A6 mutation. Patient 1 is a 17-year-old man of a first degree cousin marriage. He had hypotonia at birth. At the age of 2 years, he could walk independently, but after 3, he had difficulty in walking, which worsened in years to follow. He suffered from mild mental retardation, had phenotypic long face, hypoplastic maxilla, minimal bilateral ptosis (figure 1) and high-arched palate. Long tapered fingers were remarkable (figure 1). He had thoracic scoliosis and flexion contracture in both ankles. Symmetrical reduced muscle strength and atrophy existed in the proximal and distal muscles, which were more prominent in the lower extremities. Plantar reflex was noted to be extensor, and deep tendon reflexes could be detected. Electromyography (EMG) examination showed that sensory transmissions were normal, but …
The 8p23.1 deletion syndrome is a rare multisystem disorder with high penetrance and a variable p... more The 8p23.1 deletion syndrome is a rare multisystem disorder with high penetrance and a variable phenotypic spectrum that includes congenital heart disease (CHD), intellectual disability, behavioural problems, microcephalia, and sometimes epilepsy. Genomic copy number variations (CNVs) constitute an important genetic risk factor for common genetic generalised epilepsy syndromes (GGEs) and absence seizures. These variations, resulting either from copy loss (microdeletion) or copy gain (duplications), disrupt genes associated with neuronal development. Herein, we report an epilepsy patient who was affected by developmental delay, microcephalia, behavioural problems, CHD, and childhood‐onset absence seizures. The patient had a 4‐Mb de novo microdeletion at 8p23.1. Some of the genes in this region, particularly XKR6 and MIR597, may be involved in the pathogenesis of absence seizures, suggesting that epilepsy may possibly be part of the phenotypic spectrum of the syndrome rather than a co...
PURPOSE Electroencephalography (EEG) findings related to the eye-closing motion can be defined in... more PURPOSE Electroencephalography (EEG) findings related to the eye-closing motion can be defined in two ways: 'sensitivity to eyes closed' (SEC) and 'eye closure sensitivity (ECS).' Fixation-off sensitivity (FOS) is a different phenomenon induced by the elimination of central vision/fixation. The purpose of our study was to determine the frequencies of SEC, ESC, and FOS, and to analyze the relationship between eyes closure and the fixation-off phenomenon and clinical importance in an unselected population. METHODS We prospectively evaluated 200 routine interictal EEGs by adding a standardized FOS examination protocol between June and September 2015. Goggles covered with semitransparent tape were used to evaluate FOS. We determined SEC when the epileptiform discharges appeared during eye closure and continued during the eye closed state, whereas ECS was defined as transient epileptic abnormalities following the closure of the eyes lasting for 1-4 sec. The patients were evaluated in terms of demographic characteristics, clinical features, and the relationship between SEC, ECS, and FOS. RESULTS We detected SEC in 9 (4.4 %) and ECS in 11 (5.4 %) patients. FOS was detected in four (44.4 %) of the patients who showed SEC, all of whom had occipital epileptiform discharges. A statistically significant correlation was found between FOS and treatment resistance in the SEC group (p < 0.001). In logistic regression analysis, occipital lobe epilepsy (p < 0.001) and age under 20 years (p = 0.004) were found as risk factors for SEC. Another interesting finding was the suppression of epileptic discharges with fixation-off in three of 11 patients with ECS. CONCLUSIONS According to the results of our study, FOS is related to treatment resistance. Therefore, FOS should be evaluated in patients with SEC.
Supplementary Table 1: CCDS transcripts of C19orf12 present in the Ensembl database (GRCh38.p13).... more Supplementary Table 1: CCDS transcripts of C19orf12 present in the Ensembl database (GRCh38.p13). Transcripts with the same CCDS number are designated using the same color.
Noropsikiyatri Arsivi-archives of Neuropsychiatry, Dec 15, 2011
Page 1. Zeynep AYDIN ÖZEMİR, Ege TERZİBAŞIOĞLU*, Serra SENCER, Betül BAYKAN ... İdyopatik Jeneral... more Page 1. Zeynep AYDIN ÖZEMİR, Ege TERZİBAŞIOĞLU*, Serra SENCER, Betül BAYKAN ... İdyopatik Jeneralize Epilepsili Olgularda Talamometri Volumetry of the Thalamus in Idiopathic Generalized Epilepsy Araş tır ma Ma ka le si /Re se arch Ar tic le 243 ...
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service... more This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights Incidental MRI lesions consistent with demyelination occur, but are rare in children. A high rate of later clinical events may occur in children with RIS. Risk of clinical events is higher in children classified with RIS who have spinal cord lesions or oligoclonal bands in the CSF. The role of disease modifying therapy in RIS remains to be studied.
Abstract Objective The purpose of this paper is to describe a child with auditory neuropathy spec... more Abstract Objective The purpose of this paper is to describe a child with auditory neuropathy spectrum disorder (ANSD) associated with Brown-Vialetto-Van Laere (BVVL) syndrome, which is a rare, inherited, neurodegenerative disorder that is caused by defects in riboflavin transporter genes. Design We report the audiological and clinical profile of a child who presented with a complaint of sudden loss of speech understanding associated with an atypical form of ANSD. He was later diagnosed with BVVL. Study Sample An 11-year-old boy with ANSD associated with BVVL. Results The patient’s severe neurological symptoms improved within a year of supplementation with high doses of riboflavin. His fluctuating hearing loss and 0% WDS remained unchanged. The patient was able to use hearing aids without any discomfort after treatment initiation, but he stopped using them again due to a lack of benefit in speech understanding. Although cochlear implantation was recommended, the patient and his family decided not to consider it for another year since they still had hope for complete recovery. Conclusions Sudden-onset ANSD can be the earliest sign of undetected BVVL syndrome. Early detection of BVVL is crucial since all symptoms can be reversible with an early intervention of high doses of riboflavin supplementation.
Background: Everolimus demonstrated efficacy in reducing seizure frequency (SF) with tolerable sa... more Background: Everolimus demonstrated efficacy in reducing seizure frequency (SF) with tolerable safety in patients with TSC-associated treatment-refractory seizures. Objective: This exploratory analysis of EXIST-3 assessed efficacy and safety outcomes in patients who transitioned from placebo in the core phase to everolimus in the extension phase.
Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation ... more Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy
Disease causing novel mutation c.1422_1423del:p.P474fs was identified in ATP13A2. • ATP13A2 mRNA ... more Disease causing novel mutation c.1422_1423del:p.P474fs was identified in ATP13A2. • ATP13A2 mRNA was targeted by nonsense-mediated decay due to the novel mutation. • Absence of ATP13A2 caused iron deposition in patients' fibroblasts indicating KRS. • Hypo-intense regions in patients' brain MRIs indicated possible iron accumulation. • Iron accumulation suggested KRS to be classified in the group of NBIA
Journal of Neurology, Neurosurgery & Psychiatry, 2017
Solute carrier family 12 member 6 ( SLC12A6 ) mutations have been found to be responsible for the... more Solute carrier family 12 member 6 ( SLC12A6 ) mutations have been found to be responsible for the phenotype that causes agenesis of the corpus callosum (CC) with peripheral neuropathy, a condition which is also known as Andermann syndrome (AS). AS is an autosomal-recessive disease with syndromic features that has rarely been reported anywhere in the world other than Quebec, Canada.1 Hereditary neuropathies (HN) and complicated hereditary spastic paraparesis (HSP) call for differential diagnosis, since AS has both neurodevelopmental and neurodegenerative aspects affecting both sensory and motor fibres.1 2 This study presents an AS family who has motor neuropathy without sensory involvement due to a new SLC12A6 mutation. Patient 1 is a 17-year-old man of a first degree cousin marriage. He had hypotonia at birth. At the age of 2 years, he could walk independently, but after 3, he had difficulty in walking, which worsened in years to follow. He suffered from mild mental retardation, had phenotypic long face, hypoplastic maxilla, minimal bilateral ptosis (figure 1) and high-arched palate. Long tapered fingers were remarkable (figure 1). He had thoracic scoliosis and flexion contracture in both ankles. Symmetrical reduced muscle strength and atrophy existed in the proximal and distal muscles, which were more prominent in the lower extremities. Plantar reflex was noted to be extensor, and deep tendon reflexes could be detected. Electromyography (EMG) examination showed that sensory transmissions were normal, but …
The 8p23.1 deletion syndrome is a rare multisystem disorder with high penetrance and a variable p... more The 8p23.1 deletion syndrome is a rare multisystem disorder with high penetrance and a variable phenotypic spectrum that includes congenital heart disease (CHD), intellectual disability, behavioural problems, microcephalia, and sometimes epilepsy. Genomic copy number variations (CNVs) constitute an important genetic risk factor for common genetic generalised epilepsy syndromes (GGEs) and absence seizures. These variations, resulting either from copy loss (microdeletion) or copy gain (duplications), disrupt genes associated with neuronal development. Herein, we report an epilepsy patient who was affected by developmental delay, microcephalia, behavioural problems, CHD, and childhood‐onset absence seizures. The patient had a 4‐Mb de novo microdeletion at 8p23.1. Some of the genes in this region, particularly XKR6 and MIR597, may be involved in the pathogenesis of absence seizures, suggesting that epilepsy may possibly be part of the phenotypic spectrum of the syndrome rather than a co...
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