Phenotypic spectrum of patients with GABRB2 variants: from mild febrile seizures to severe epileptic encephalopathy

2020 ◽  
Vol 62 (10) ◽  
pp. 1213-1220 ◽  
Author(s):  
Ying Yang ◽  
Wenshu Xiangwei ◽  
Xiaoli Zhang ◽  
Jiangxi Xiao ◽  
Jiaoyang Chen ◽  
...  
Keyword(s):  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Phenotypic Spectrum ◽  
Spectrum Of Patients

Mutation and Phenotypic Spectrum of Patients With RASopathies

2020 ◽  
Vol 58 (1) ◽  
pp. 30-33
Author(s):  
Meenakshi Lallar ◽  
Sunita Bijarnia-Mahay ◽  
I. C. Verma ◽  
Kaushik Mandal ◽  
Ratna Dua Puri
Keyword(s):  
Phenotypic Spectrum ◽  
Spectrum Of Patients

scholarly journals Improving early diagnosis of rare diseases using Natural Language Processing in unstructured medical records: an illustration from Dravet syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tommaso Lo Barco ◽  
Mathieu Kuchenbuch ◽  
Nicolas Garcelon ◽  
Antoine Neuraz ◽  
Rima Nabbout
Keyword(s):  
Natural Language Processing ◽  
Early Diagnosis ◽  
Natural Language ◽  
Language Processing ◽  
Rare Diseases ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Written Information ◽  
Medical Reports

Abstract Background The growing use of Electronic Health Records (EHRs) is promoting the application of data mining in health-care. A promising use of big data in this field is to develop models to support early diagnosis and to establish natural history. Dravet Syndrome (DS) is a rare developmental and epileptic encephalopathy that commonly initiates in the first year of life with febrile seizures (FS). Age at diagnosis is often delayed after 2 years, as it is difficult to differentiate DS at onset from FS. We aimed to explore if some clinical terms (concepts) are significantly more used in the electronic narrative medical reports of individuals with DS before the age of 2 years compared to those of individuals with FS. These concepts would allow an earlier detection of patients with DS resulting in an earlier orientation toward expert centers that can provide early diagnosis and care. Methods Data were collected from the Necker Enfants Malades Hospital using a document-based data warehouse, Dr Warehouse, which employs Natural Language Processing, a computer technology consisting in processing written information. Using Unified Medical Language System Meta-thesaurus, phenotype concepts can be recognized in medical reports. We selected individuals with DS (DS Cohort) and individuals with FS (FS Cohort) with confirmed diagnosis after the age of 4 years. A phenome-wide analysis was performed evaluating the statistical associations between the phenotypes of DS and FS, based on concepts found in the reports produced before 2 years and using a series of logistic regressions. Results We found significative higher representation of concepts related to seizures’ phenotypes distinguishing DS from FS in the first phases, namely the major recurrence of complex febrile convulsions (long-lasting and/or with focal signs) and other seizure-types. Some typical early onset non-seizure concepts also emerged, in relation to neurodevelopment and gait disorders. Conclusions Narrative medical reports of individuals younger than 2 years with FS contain specific concepts linked to DS diagnosis, which can be automatically detected by software exploiting NLP. This approach could represent an innovative and sustainable methodology to decrease time of diagnosis of DS and could be transposed to other rare diseases.

Genetic epilepsy with febrile seizures plus

Neurology ◽  
2017 ◽  
Vol 89 (12) ◽  
pp. 1210-1219 ◽  
Author(s):  
Yue-Hua Zhang ◽  
Rosemary Burgess ◽  
Jodie P. Malone ◽  
Georgie C. Glubb ◽  
Katherine L. Helbig ◽  
...  
Keyword(s):  
Genetic Data ◽  
Febrile Seizures ◽  
Original Description ◽  
Molecular Data ◽  
Genetic Determinants ◽  
Genetic Epilepsy ◽  
Phenotypic Spectrum ◽  
Clonic Seizures ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

Objective:Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum.Methods:We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years.Results:We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene.Conclusion:As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.

A Case of Neonatal Epileptic Encephalopathy due to SCN2A Mutation Responsive to a Ketogenic Diet

2018 ◽  
Vol 07 (04) ◽  
pp. 148-151 ◽  
Author(s):  
Fahad A. Bashiri ◽  
Abrar Hudairi ◽  
Malak Al Ghamdi ◽  
Adel A. Mahmoud
Keyword(s):  
Ketogenic Diet ◽  
Treatment Modality ◽  
Genetic Diagnosis ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Intractable Seizures ◽  
Ohtahara Syndrome ◽  
Newborn Girl ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

AbstractNeonatal seizures may have multiple causes including metabolic and genetic etiologies. If a genetic diagnosis is known, it can guide the physician to choose the most appropriate treatment modality. SCN2A mutation is a rare cause of epileptic encephalopathy in the neonatal age group. It has a wide phenotypic variation, ranging from benign familial epilepsy to a malignant form of epilepsy. This mutation has been associated with Ohtahara syndrome, migrating focal seizures of infancy, West syndrome, Lennox–Gastaut syndrome, and generalized epilepsy with febrile seizures plus. We present the case of a newborn girl who presented with multiple types of seizures, starting at the age of 3 days. Our initial investigations were not able to identify the etiology of her intractable seizures. Whole exome sequencing confirmed an SCN2A mutation. Various antiepileptic drugs (AEDs), including phenobarbitone, phenytoin, levetiracetam, topiramate, vigabatrin, carbamazepine, clonazepam, and mexiletine, were tried. However, none provided an optimal response. She ultimately showed a dramatic response to the ketogenic diet (KD). This report highlights the effectiveness of the KD as a treatment modality for SCN2A mutation-related epileptic encephalopathy, particularly when seizures are intractable and unresponsive to conventional AEDs.

scholarly journals Phenotypic spectrum of patients with cystic fibrosis and cystic fibrosis-related disease carrying p.Arg117His

2019 ◽  
Vol 18 (2) ◽  
pp. 265-270 ◽  
Author(s):  
Katherine Keenan ◽  
Annie Dupuis ◽  
Katherine Griffin ◽  
Carlo Castellani ◽  
Elizabeth Tullis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Related Disease ◽  
Phenotypic Spectrum ◽  
Spectrum Of Patients

scholarly journals YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xing-Guang Ye ◽  
Zhi-Gang Liu ◽  
Jie Wang ◽  
Jie-Min Dai ◽  
Pei-Xiu Qiao ◽  
...  
Keyword(s):  
Missense Mutation ◽  
De Novo ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Myoclonic Epilepsy ◽  
Missense Mutations ◽  
Regional Effect ◽  
Diverse Range ◽  
Mild Phenotype ◽  
Truncating Mutation

YWHAG, which encodes an adapter protein 14-3-3γ, is highly expressed in the brain and regulates a diverse range of cell signaling pathways. Previously, eight YWHAG mutations have been identified in patients with epileptic encephalopathy (EE). In this study, using trios-based whole exome sequencing, we identified two novel YWHAG mutations in two unrelated families with childhood myoclonic epilepsy and/or febrile seizures (FS). The identified mutations included a heterozygous truncating mutation (c.124C>T/p.Arg42Ter) and a de novo missense mutation (c.373A>G/p.Lys125Glu). The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment. The other affected individuals presented FS. The truncating mutation was identified in the family with six individuals of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency are relatively less pathogenic. Analysis on all missense mutations showed that nine mutations were located within 14-3-3γ binding groove and another mutation was located at residues critical for dimerization, indicating a molecular sub-regional effect. Mutation Arg132Cys, which was identified recurrently in five patients with EE, would have the strongest influence on binding affinity. 14-3-3γ dimers supports target proteins activity. Thus, a heterozygous missense mutation would lead to majority dimers being mutants; whereas a heterozygous truncating mutation would lead to only decreasing the number of wild-type dimer, being one of the explanations for phenotypical variation. This study suggests that YWHAG is potentially a candidate pathogenic gene of childhood myoclonic epilepsy and FS. The spectrum of epilepsy caused by YWHAG mutations potentially range from mild myoclonic epilepsy and FS to severe EE.

scholarly journals Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder

2021 ◽  
Vol 7 (2) ◽  
pp. e579
Author(s):  
Kenneth A. Myers ◽  
Carla Marini ◽  
Gemma L. Carvill ◽  
Amy McTague ◽  
Julie Panetta ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Sleep Disturbance ◽  
Behavioral Problems ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Epileptic Encephalopathy ◽  
Seizure Type ◽  
Convulsive Status Epilepticus ◽  
Phenotypic Spectrum ◽  
Hot Weather

ObjectiveTo describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia.MethodsWe performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures.ResultsTwenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days–13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance.ConclusionsMBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.

Novel mutations in TUBB8 expand the mutational and phenotypic spectrum of patients with zygotes containing multiple pronuclei

Gene ◽  
2021 ◽  
Vol 769 ◽  
pp. 145227
Author(s):  
Qianqian Sha ◽  
Wei Zheng ◽  
Xie Feng ◽  
Ruiying Yuan ◽  
Huiling Hu ◽  
...  
Keyword(s):  
Novel Mutations ◽  
Phenotypic Spectrum ◽  
Spectrum Of Patients

Dravet Syndrome: Early Diagnosis and Emerging Therapies

2019 ◽  
Vol 08 (02) ◽  
pp. 031-037
Author(s):  
Tyler J. Burr ◽  
Karen L. Skjei
Keyword(s):  
Status Epilepticus ◽  
Early Diagnosis ◽  
Seizure Control ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Long Term Outcomes ◽  
Treatment Algorithms ◽  
Emerging Therapies

AbstractDravet's syndrome (DS) or severe myoclonic epilepsy of infancy is a rare, genetic, and infantile-onset epileptic encephalopathy. DS presents with recurrent febrile seizures and/or febrile status epilepticus in developmentally normal infants, and subsequently evolves into a drug-resistant mixed-seizure disorder with developmental arrest or regression. As many defining clinical features of DS do not become evident until 3 to 4 years of age, diagnosis is often delayed. Early seizure control, particularly the prevention of status epilepticus in infancy, has been shown to correlate with better long-term outcomes. Thus, early diagnosis and seizure control is crucial. Several treatment algorithms have been published in recent years to guide antiepileptic drug selection and escalation. Last year, two agents, stiripentol and cannabidiol, were approved by the U.S. Food and Drug Administration specifically for use in DS, and a third has been submitted (fenfluramine). Additional therapies, including serotonin modulators lorcaserin and trazodone, verapamil, and several first-in-class medications, are currently in various phases of investigation.

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