scholarly journals SCN2A Pathogenic Variants and Epilepsy: Heterogeneous Clinical, Genetic and Diagnostic Features

2021 ◽  
Vol 12 (1) ◽  
pp. 18
Author(s):  
Roberta Epifanio ◽  
Roberto Giorda ◽  
Maria Carolina Merlano ◽  
Nicoletta Zanotta ◽  
Romina Romaniello ◽  
...  
Keyword(s):  
De Novo ◽  
Late Onset ◽  
Somatic Mosaicism ◽  
Clinical Manifestations ◽  
Epileptic Encephalopathy ◽  
Variable Degree ◽  
Biological Father ◽  
Diagnostic Features ◽  
Pathogenic Variants ◽  
Epileptic Syndromes

Pathogenic variants of the SCN2A gene (MIM 182390) are associated with several epileptic syndromes ranging from benign familial neonatal-infantile seizures (BFNIS) to early infantile epileptic encephalopathy. The aim of this work was to describe clinical features among five patients with concomitant SCN2A gene variants and cryptogenic epileptic syndromes, thus expanding the SCN2A spectrum of phenotypic heterogeneity. De novo variants were identified in four patients, while one inherited variant was identified in a patient with an unaffected carrier biological father with somatic mosaicism. Two of five patients were diagnosed with a neonatal epileptic encephalopathy. The remaining three patients manifested a focal epileptic syndrome associated with autistic spectrum disorders (ASD) or with a variable degree of intellectual disability (ID), one of them displaying a hitherto unreported atypical late onset epilepsy. Overall, the pattern of clinical manifestations among these patients suggest that any observed neurological impairment may not be directly related to the severity of the electroclinical pattern, but instead likely associated with the mutation itself. Moreover, our results highlight the importance of SCN2A mutational screening in cases of ID/ASD with or without epilepsy.

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome

2021 ◽  
pp. jmedgenet-2020-107604
Author(s):  
Paula Fernández-Álvarez ◽  
Marta Codina-Sola ◽  
Irene Valenzuela ◽  
Gisela Teixidó-Turá ◽  
Anna Cueto-González ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
De Novo ◽  
Normal Population ◽  
Genetic Disorders ◽  
Somatic Mosaicism ◽  
Clinical Signs ◽  
Systematic Analysis ◽  
Pathogenic Variants ◽  
Fibrillin 1 ◽  
Minor Criteria

BackgroundA proportion of de novo variants in patients affected by genetic disorders, particularly those with autosomal dominant (AD) inheritance, could be the consequence of somatic mosaicism in one of the progenitors. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. In Marfan syndrome (MFS), caused by pathogenic variants in the fibrillin-1 gene (FBN1) gene, approximately 25% of the disease-causing variants are reported as de novo. Only a few cases of parental mosaicism have been reported in MFS.MethodsEmploying an amplicon-based deep sequencing (ADS) method, we carried out a systematic analysis of 60 parents of 30 FBN1 positive, consecutive patients with MFS with an apparently de novo pathogenic variant.ResultsOut of the 60 parents studied (30 families), the majority (n=51, 85%) had a systemic score of 0, seven had a score of 1 and two a score of 2, all due to minor criteria common in the normal population. We detected two families with somatic mosaicism in one of the progenitors, with a rate of 6.6% (2/30) of apparently de novo cases.ConclusionsThe search for parental somatic mosaicism should be routinely implemented in de novo cases of MFS, to offer appropriate genetic and reproductive counselling as well as to reveal masked, isolated clinical signs of MFS in progenitors that may require specific follow-up.

Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

2010 ◽  
Vol 13 (2) ◽  
pp. 168-178 ◽  
Author(s):  
Rose White ◽  
Gladys Ho ◽  
Swetlana Schmidt ◽  
Ingrid E. Scheffer ◽  
Alexandra Fischer ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Early Onset ◽  
De Novo ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Mutation Screening ◽  
Clinical Manifestations ◽  
Epileptic Encephalopathy ◽  
Cyclin Dependent Kinase ◽  
Aicardi Syndrome

AbstractRett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

scholarly journals De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

2018 ◽  
Vol 103 (5) ◽  
pp. 666-678 ◽  
Author(s):  
Katherine L. Helbig ◽  
Robert J. Lauerer ◽  
Jacqueline C. Bahr ◽  
Ivana A. Souza ◽  
Candace T. Myers ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Pathogenic Variants

STXBP1 encephalopathy

Neurology ◽  
2019 ◽  
Vol 93 (3) ◽  
pp. 114-123 ◽  
Author(s):  
Vanessa Lanoue ◽  
Ye Jin Chai ◽  
Julie Z. Brouillet ◽  
Sarah Weckhuysen ◽  
Elizabeth E. Palmer ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neural Development ◽  
Early Onset ◽  
De Novo ◽  
Basic Research ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Severe Form ◽  
Pathogenic Variants ◽  
Extrapyramidal Features

De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.

scholarly journals Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

2020 ◽  
Vol 51 (04) ◽  
pp. 245-250
Author(s):  
Chloé Angelini ◽  
Marie Thibaud ◽  
Nathalie Aladjidi ◽  
Pierre Bessou ◽  
Sébastien Cabasson ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
De Novo ◽  
Cutis Laxa ◽  
Variable Degree ◽  
Severe Phenotype ◽  
Pathogenic Variants ◽  
Type Iiia ◽  
Recessive Type ◽  
Neurological Phenotype

AbstractCutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.

scholarly journals Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations

2017 ◽  
Vol 3 (6) ◽  
pp. e206 ◽  
Author(s):  
Carla Marini ◽  
Michele Romoli ◽  
Elena Parrini ◽  
Cinzia Costa ◽  
Davide Mei ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Focal Epilepsy ◽  
Brain Mri ◽  
Somatic Mosaicism ◽  
Epileptic Encephalopathy ◽  
Seizure Onset ◽  
Severe Intellectual Disability ◽  
The Mean

Objective:To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations.Methods:Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel.Results:The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism.Conclusions:KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

scholarly journals Mouse Models Characterize GNAO1 Encephalopathy as a Neurodevelopmental Disorder Leading to Motor Anomalies: from a Severe G203R to a Milder C215Y Mutation

2021 ◽  
Author(s):  
Denis Silachev ◽  
Alexey Koval ◽  
Mikhail Savitsky ◽  
Guru Padmasola ◽  
Charles Quairiaux ◽  
...  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Late Onset ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Epileptic Seizures ◽  
Motor Dysfunction ◽  
Neuronal Precursor Cells

Abstract GNAO1 encephalopathy characterized by a wide spectrum of neurological deficiencies in pediatric patients originates from de novo heterozygous mutations in the gene encoding Gαo, the major neuronal G protein. Efficient treatments and even the proper understanding of the underlying etiology are currently lacking for this dominant disease. Adequate animal models of GNAO1 encephalopathy are urgently needed. Here we describe establishment and characterization of mouse models of the disease based on two point mutations in GNAO1 with different clinical manifestations. One of them is G203R leading to the early-onset epileptic seizures, motor dysfunction, developmental delay and intellectual disability. The other is C215Y producing much milder clinical outcomes, mostly – late-onset motor hyperactivity. The resultant mouse models show distinct phenotypes: severe neonatal lethality in GNAO1[G203R]/+ mice vs. normal vitality in GNAO1[C215Y]/+. The latter model further revealed strong hyperactivity and hyperlocomotion in a panel of behavioral assays, without signs of epilepsy, recapitulating the patients’ manifestations. Importantly, despite these differences the two models similarly revealed prenatal brain developmental anomalies, such as enlarged lateral ventricles and decreased numbers of neuronal precursor cells in the cortex. Thus, our work unveils GNAO1 encephalopathy as to a large extent neurodevelopmental malady. We expect that this understanding and the tools we established will be instrumental for future therapeutic developments.

scholarly journals OMIC-08. COMPOUND HETEROZYGOSITY OF POLE AND PMS2 LEADS TO CMMRD-LIKE PHENOTYPE- “POLYNCH” SYNDROME

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i38-i39
Author(s):  
Orli Michaeli ◽  
Hagay Ladany ◽  
Yosef E Maruvka ◽  
Ayelet Erez ◽  
Shay Ben Shachar ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
De Novo ◽  
Clinical Manifestations ◽  
Dna Polymerase Epsilon ◽  
Pathogenic Variants ◽  
Repair Deficiency ◽  
Mutation Burden ◽  
Desmoplastic Medulloblastoma

Abstract Mono-allelic germline pathogenic variants (PV) in one of the mismatch repair (MMR) system genes cause Lynch syndrome, associated mainly with colon and endometrial cancer in adults. Germline PVs in DNA polymerase epsilon (POLE) are associated with a dominantly inherited syndrome which confers risk for polyposis and colon cancer. Brain tumors have been described as part of Lynch syndrome and POLE associated syndrome, mostly in adults. Constitutional mismatch repair deficiency (CMMRd) is caused by bi-allelic mutations in the MMR genes, associated with multiple café au lait macules (CAMs) and high incidence of pediatric cancer, including brain tumors. Both MMRD and POLE associated tumors have high tumor mutation burden (TMB), however, microsatellite status is usually unstable in MMR tumors, and stable in POLE. Germline POLE and CMMRd tumors have different mutational signatures, as is signature of MMR tumors with secondary somatic POLE. We describe a 4.5 y/o male who presented with a grossly metastatic SHH-activated, TP53-wildtype desmoplastic medulloblastoma. Physical examination was noted for CAMs. Family history was positive for a heterozygous POLE variant with variable clinical manifestations. Immunohistochemistry of the tumor showed loss of nuclear expression of the MMR gene PMS2, specifically in tumor cells. Analysis showed exceptionally high TMB (up to 276 Mut/Mb) and both the MMR and the POLE signatures. Germline analysis detected the familial POLE variant as well as a de novo heterozygous PMS2 PV. The phenotype of the patient together with the tumor’s features, led us to classify this case as a CMMRd-like. The patient had a partial response to intensive chemotherapy and is currently on immunotherapy without radiation. Collectively, our data suggest that heterozygous simultaneous germline mutations in MMR and polymerase genes can lead to novel “POLYNCH syndrome” that manifests with an ultra-hypermutant aggressive tumor and requires appropriate treatment and surveillance.

scholarly journals Analysis of clinical manifestations and diagnosis of late-onset myasthenia gravis

2020 ◽  
Vol 10 (1) ◽  
pp. 53-63
Author(s):  
A. N. Khalmurzina ◽  
T. M. Alekseeva ◽  
S. V. Lobzin ◽  
D. I. Rudenko ◽  
V. V. Kryuchkova
Keyword(s):  
Elderly Patients ◽  
Myasthenia Gravis ◽  
Late Onset ◽  
Age Groups ◽  
Clinical Manifestations ◽  
Neuromuscular Diseases ◽  
The Elderly ◽  
Vascular Pathology ◽  
Common Symptom ◽  
Diagnostic Features

Introduction. Myasthenia gravis is one of the most common autoimmune neuromuscular diseases, the peak incidence is in the age of 20–40 years. However, studies show that throughout the world in recent decades there has been an increase in the prevalence and incidence of myasthenia gravis among older people.Purpose of the study – to evaluate the clinical manifestations and diagnostic features of myasthenia gravis in patients with an onset of diseases in the elderly.Materials and methods. The retrospective, non-interventional study included 315 patients over 18 years old with a reliable (3 out of 4 criteria) and an undoubted (4 out of 4 criteria) diagnosis of myasthenia gravis, the duration of the disease for up to 5 years, undergoing inpatient treatment from 2001 to 2017 years. The severity of the clinical manifestations of myasthenia gravis was assessed using the Myasthenia Gravis Foundation of America scale. We were taken into account the information about the first symptoms, duration of the period from the onset of the disease to the verification of the diagnosis, results of the examinations, the presence of concomitant diseases and treatment methods.Results. The most common symptom of myasthenia gravis in the group of patients with debut disease aged 60 years and older was ptosis (p <0.001). The crises and pathology of the thymus were less common in elderly patients (p <0.0001). The concentration of antibodies to acetylcholine receptors was the same (p = 0.05) among all patients. The level of antibodies to titin was increased in patients with lateonset (p = 0.0014). The presence of bronchopulmonary pathology made worse the course of myasthenia gravis in elderly people (p = 0.01), while cardiovascular and cerebrovascular diseases, as well as diabetes mellitus, did not occur (p >0.005). At the first examination in the group of elderly patients among the incorrectly diagnoses prevailed: stroke or decompensation of chronic cerebral ischemia (p = 0.0002). With a comparable duration and severity of myasthenia gravis in different age groups, the combination of anticholinesterase drugs, glucocorticosteroids and azathioprine (p = 0.01) at a lower daily dose (100 mg) was more often used for the treatment of elderly patients compared with young and middle-aged groups (150 mg) (p = 0.03).Conclusion. Diagnosis of myasthenia gravis in elderly patients presents the greatest difficulties, and symptoms of manifestation during initial treatment are often regarded as a manifestation of vascular pathology. Despite the presence of concomitant diseases characteristic of this age group, myasthenia gravis does not differ in the severity of the course. To achieve remission and compensation of symptoms, elderly patients do not need large doses of symptomatic and pathogenetic drugs.

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