scholarly journals PURA-Related Developmental and Epileptic Encephalopathy

2021 ◽  
Vol 7 (6) ◽  
pp. e613
Author(s):  
Katrine M. Johannesen ◽  
Elena Gardella ◽  
Cathrine E. Gjerulfsen ◽  
Allan Bayat ◽  
Rob P.W. Rouhl ◽  
...  
Keyword(s):  
Protein A ◽  
Epileptic Encephalopathy ◽  
Epilepsy Syndrome ◽  
Seizure Freedom ◽  
Clinical Genetic ◽  
Feeding Difficulties ◽  
Pathogenic Variants ◽  
Generalized Seizures ◽  
Element Binding Protein ◽  
Drug Resistant Epilepsy

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

scholarly journals Epileptic Spasms-West syndrome secondary to Dravet syndrome due to SCN gene mutation from India

2021 ◽  
Vol 36 ◽  
pp. 49-53
Author(s):  
Vykuntaraju K. Gowda ◽  
Hemadri Vegda ◽  
Raghavendraswami Amoghimath ◽  
Manojna Battina ◽  
Sanjay K. Shivappa ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Retrospective Chart Review ◽  
Epileptic Encephalopathy ◽  
West Syndrome ◽  
Dravet Syndrome ◽  
Epilepsy Syndrome ◽  
Routine Testing ◽  
Pathogenic Variants ◽  
Epileptic Spasms ◽  
The Mean

Objectives: West syndrome (WS) is a triad of epileptic spasms, developmental delay/regression, and hypsarrhythmia. SCN related epileptic encephalopathy is a rare epilepsy syndrome characterized by an early-onset, severe, and epileptic encephalopathy. The causes of WS are multiple and diverse ranging from genetic to structural, metabolic, and unknown causes. The objectives of the study were to report SCN related epileptic encephalopathies with epileptic spasms. Materials and Methods: This is retrospective chart review of children presenting with epileptic spasms secondary to SCN gene variants from January 2015 to March 2020 in a tertiary care referral center. Results: Out of 15 children, ten were boys. The mean age of presentation was 5 months. Thirteen children had preceded seizures before epileptic spasms in the 1st year of life, two children presented initially with epileptic spasms. No neuro-deficits were noted in all the children. In all the cases electroencephalogram was suggestive of hypsarrhythmia. Routine testing, neuroimaging, and metabolic tests were normal in all the cases. Various pathogenic variants seen in next-generation sequencing were SCN1A in 11, SCN1B and SCN2A in two children each. Three children responded for vigabatrin and five children responded for steroids but all of them had relapse and were refractory to other antiepileptic drugs. Conclusion: SCN related epileptic encephalopathy should be considered in the differential diagnosis of epileptic spasms. These infants present earlier compare to classical Dravet syndrome children.

scholarly journals Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 2824
Author(s):  
Jan H. Döring ◽  
Julian Schröter ◽  
Jerome Jüngling ◽  
Saskia Biskup ◽  
Kerstin A. Klotz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Transmembrane Domain ◽  
Potassium Conductance ◽  
Epileptic Encephalopathy ◽  
Clinical Spectrum ◽  
The Novel ◽  
Developmental Abnormalities ◽  
Pathogenic Variants ◽  
Infantile Seizures ◽  
Early Developmental

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

scholarly journals MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 663
Author(s):  
Stijn van de Plassche ◽  
Arjan PM de Brouwer
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Expression Patterns ◽  
Mediator Complex ◽  
Gene Expression Patterns ◽  
Facial Dysmorphism ◽  
Regulation Of Transcription ◽  
Feeding Difficulties ◽  
Missense Variants ◽  
Pathogenic Variants

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

Surgical management of hypothalamic hamartomas in patients with gelastic epilepsy

2008 ◽  
Vol 25 (3) ◽  
pp. E8 ◽  
Author(s):  
Bassam Addas ◽  
Elisabeth M. S. Sherman ◽  
Walter J. Hader
Keyword(s):  
Quality Of Life ◽  
Epileptic Encephalopathy ◽  
Clinical Syndrome ◽  
Seizure Freedom ◽  
Interstitial Radiotherapy ◽  
Hypothalamic Hamartomas ◽  
Surgical Options ◽  
Gelastic Epilepsy ◽  
Refractory Seizures

Gelastic epilepsy (GE) associated with hypothalamic hamartomas (HHs) is now a well-characterized clinical syndrome consisting of gelastic seizures starting in infancy, medically refractory seizures with or without the development of multiple seizure types, and behavioral and cognitive decline. It has been postulated that the development of the HH-GE syndrome is a result of a progressive epileptic encephalopathy or secondary epileptogenesis, which is potentially reversible with treatment of the HH. A variety of surgical options for the treatment of HHs exist, including open and endoscopic procedures, radiosurgery, interstitial radiotherapy, and stereotactic radiofrequency thermocoagulation. Surgical treatment can result in seizure freedom in up to 50% of patients and can be accompanied by significant improvements in behavior, cognition, and quality of life. Partial treatment of HHs may be sufficient to reduce seizure frequency and improve behavior and quality of life with less risk. A component of reversible cognitive dysfunction may be present in some patients with an HH-GE syndrome.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

scholarly journals Yield of peripheral sodium channels gene screening in pure small fibre neuropathy

2018 ◽  
Vol 90 (3) ◽  
pp. 342-352 ◽  
Author(s):  
Ivo Eijkenboom ◽  
Maurice Sopacua ◽  
Janneke G J Hoeijmakers ◽  
Bianca T A de Greef ◽  
Patrick Lindsey ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Clinical Features ◽  
Genetic Screening ◽  
Clinical Genetic ◽  
Genetic Studies ◽  
Small Fibre Neuropathy ◽  
Reference Centre ◽  
Pathogenic Variants ◽  
Small Fibre ◽  
Genetic Science

BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

Surgical outcomes in children with bottom-of-sulcus dysplasia and drug-resistant epilepsy: a retrospective cohort study

2021 ◽  
pp. 1-11
Author(s):  
Puneet Jain ◽  
Ayako Ochi ◽  
Carter McInnis ◽  
Hiroshi Otsubo ◽  
O. Carter Snead ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Medical Records ◽  
Focal Cortical Dysplasia ◽  
Seizure Freedom ◽  
Language Mapping ◽  
Resective Surgery ◽  
Histological Data ◽  
Drug Resistant Epilepsy ◽  
Video Eeg

OBJECTIVE Bottom-of-sulcus dysplasia (BOSD) is challenging to identify radiologically. The aim of this study was to explore seizure outcomes after resective surgery or MR-guided laser interstitial thermal therapy (MRgLITT) in children with BOSD. METHODS Children with radiologically defined BOSD who underwent resective surgery or MRgLITT, with at least 1 year of follow-up were included. Clinical, radiological, neurophysiological, and histological data were extracted from medical records. Invasive video EEG (IVEEG) was used to evaluate the ictal onset zone or motor/language mapping, wherever appropriate. Histology of MRI-visible BOSD, including the overlying and adjacent cortex, was also evaluated. RESULTS Forty-one children with BOSD underwent surgical treatment. The lesion was initially overlooked on MRI in 20 patients (48.8%). Of 34 patients who underwent IVEEG and who had available ictal data, the ictal onset zone extended beyond the MRI-visible BOSD in 23 patients (67.6%). Surgical treatment included lesionectomy (24 patients), extended lesionectomy (12 patients), lobectomy (1 patient), and ablation of BOSD (4 patients). The pathology in 37 patients who underwent resection showed focal cortical dysplasia type IIB and type IIA in 21 (53.8%) and 16 patients (41%), respectively. Seizure freedom was achieved in 32 patients (78.1%) after a mean follow-up of 4.3 years. CONCLUSIONS Seizure outcomes after resective surgery or MRgLITT in children with BOSD were generally favorable. The authors found that the neurophysiological abnormality and pathology often extended beyond the MRI-visible BOSD.

Atypical Presentation of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency with Developmental Epileptic Encephalopathy

2021 ◽  
Author(s):  
Francesca Marchese ◽  
Elena Faedo ◽  
Maria Stella Vari ◽  
Patrizia Bergonzini ◽  
Michele Iacomino ◽  
...  
Keyword(s):  
Amino Acid ◽  
Autosomal Recessive ◽  
Epileptic Encephalopathy ◽  
Dopa Decarboxylase ◽  
Acid Decarboxylase ◽  
Homozygous Mutation ◽  
Amino Acid Decarboxylase ◽  
Pathogenic Variants ◽  
Neurological Features ◽  
Decarboxylase Deficiency

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder resulting from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. The neurological features of AADC deficiency include early-onset hypotonia, oculogyric crises, ptosis, dystonia, hypokinesia, impaired development, and autonomic dysfunction. We report a patient with genetically confirmed AADC deficiency presenting with developmental epileptic encephalopathy (DEE). We report a boy with severe intractable epileptic spasms and DEE. The patient was evaluated for cognitive and neurologic impairment. Exome sequencing revealed a homozygous mutation (NM_000790.4:c.121C > A; p.Leu41Met) in the DDC gene. This case expands the clinical spectrum of AADC deficiency and strengthens the association between dopa decarboxylase deficiency and epilepsy. Additional studies are warranted to clarify the mechanisms linking dopa decarboxylase dysfunction to DEE.

scholarly journals Retention Rate and Efficacy of Perampanel with a Slow Titration Schedule in Adults

2020 ◽  
pp. 1-7
Author(s):  
Mazen Basheikh ◽  
R. Mark Sadler
Keyword(s):  
Seizure Frequency ◽  
Retention Rate ◽  
Responder Rate ◽  
Dose Titration ◽  
Seizure Freedom ◽  
Chart Audit ◽  
Generalized Seizures ◽  
Included Patient ◽  
Generalized Epilepsy

ABSTRACT: Rationale: The manufacturer of perampanel (PER) suggests an initial adult dose of 2–4 mg/day and an upward dose titration of 2 mg at no more frequently than 1- or 2-week intervals when used with enzyme-enhancing antiepileptic drugs (AEDs) or nonenzyme-enhancing AEDs, respectively. The general practice in our clinic is an initial dose of PER 2 mg/day and titrated by 2 mg/4 weeks to an initial target of 6 mg/day. Methods: Retrospective chart audit of patients starting PER in an adult epilepsy clinic between September 2013 and November 2016 with at least one 6-month follow-up visit was reviewed. Data collection included patient demographics, seizure characteristics, past and concurrent therapy, monthly seizure frequency before PER and at 6-month visit, and characteristics of PER discontinuation. Efficacy of treatment was assessed with the Engel classification and 50% responder rate. Results: N = 102 patients; mean age = 40 years and 54% females. Focal onset seizures 85%, generalized 13%, and unknown 2%. Median prior AED exposure = 6 (range 3–20); median concomitant AED use = 2 (range 1–5). Follow-up range was 6–37 months. The median seizure frequency/month prePER treatment was 6 (range 0–30) for focal onset seizures and 1 (range 0–6) for generalized seizures. The retention rate amongst all patients at 6 months was 78.4%. At 6-month follow-up, 36% of all patients achieved Engel class I (seizure freedom) (30.7% of patients with focal onset seizures and 63.6% with generalized epilepsy). The 50% responder rate was 52% and 82% for focal and generalized epilepsy, respectively. Conclusion: PER has a good retention rate when titrated slowly and thus encouraging seizure freedom results in an otherwise medically refractory epilepsy population.

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